Modern Flu : British Medical Science and the Viralisation of Influenza, 1890—1950 [1 ed.] 9781137339539, 9781137339546

Table of contents :
Acknowledgements
Contents
Abbreviations
List of Figures
List of Tables
1 Historicising Flu: Viral Identities of Influenza
2 Naming Flu: Classification and Its Conflicts
1 Naming Influenza
2 New Classifications
3 Epidemic Catarrh
4 Hippocratic and ‘Heroic’ Treatments
5 Epidemic Identities
3 Modernising Flu: Re-aligning Medical Knowledge of the ‘Most Protean Disease’
1 Making Influenza Communicable
2 Proteus in the Clinic
3 The Influenza Germ
4 A New Influenza
5 Re-aligning Clinical, Public Health and Laboratory Medicine
4 Fighting Flu: Military Pathology and the 1918–1919 Pandemic
1 The War and the Pandemic
2 War Pathology
3 A New Disease?
4 Disputed Germs
5 Mixed Vaccines
6 Reckoning and Reconstruction
5 Mobilising Flu: The Medical Research Council and the Genesis of British Virus Research
1 Competing Visions
2 New Agents, Old Problems
3 Experimentalising Pathology
4 The Virus Scheme
5 Uses of the Pandemic
6 Modelling Flu: Dog Distemper and the Promise of Virus Research
1 Making Virus Instruments
2 A Proxy Disease
3 Translating Viruses into Vaccines
4 The ‘Flu Problem’
5 Limits of Control
7 Viralising Flu: Towards a New Medical Consensus
1 Virus Neutralization
2 Ferret Flu
3 Putting Mice to Work
4 A Virus Disease?
5 Collaboration and Consensus
8 Globalising Flu: Systems of Surveillance and Vaccination
1 ‘A New Complicating Factor’
2 Experimental Vaccines
3 Harnessing the Chick Egg
4 American Methods
5 World Influenza Programme
6 Test and Tensions
9 Conclusion: ‘The Most Protean Disease’
10 Coda: Influenza and Covid-19
1 Which Influenza?
2 Challenges of Control
3 Zoonotic Connections
4 System Failures
5 Cautionary Lessons
Select Bibliography
Index

Citation preview

MEDICINE AND BIOMEDICAL SCIENCES IN MODERN HISTORY

Modern Flu British Medical Science and the Viralisation of Influenza, 1890–1950 Michael Bresalier

Medicine and Biomedical Sciences in Modern History

Series Editors Carsten Timmermann, University of Manchester, Manchester, UK Michael Worboys, University of Manchester, Manchester, UK

The aim of this series is to illuminate the development and impact of medicine and the biomedical sciences in the modern era.The series was founded by the late Professor John Pickstone, and its ambitions reflect his commitment to the integrated study of medicine, science and technology in their contexts. He repeatedly commented that it was a pity that the foundation discipline of the field, for which he popularized the acronym ‘HSTM’ (History of Science, Technology and Medicine) had been the history of science rather than the history of medicine. His point was that historians of science had too often focused just on scientific ideas and institutions, while historians of medicine always had to consider the understanding, management and meanings of diseases in their socioeconomic, cultural, technological and political contexts. In the event, most of the books in the series dealt with medicine and the biomedical sciences, and the changed series title reflects this. However, as the new editors we share Professor Pickstone’s enthusiasm for the integrated study of medicine, science and technology, encouraging studies on biomedical science, translational medicine, clinical practice, disease histories, medical technologies, medical specialisms and health policies. The books in this series will present medicine and biomedical science as crucial features of modern culture, analysing their economic, social and political aspects, while not neglecting their expert content and context. Our authors investigate the uses and consequences of technical knowledge, and how it shaped, and was shaped by, particular economic, social and political structures. In re-launching the Series, we hope to build on its strengths but extend its geographical range beyond Western Europe and North America. Medicine and Biomedical Sciences in Modern History is intended to supply analysis and stimulate debate. All books are based on searching historical study of topics which are important, not least because they cut across conventional academic boundaries. They should appeal not just to historians, nor just to medical practitioners, scientists and engineers, but to all who are interested in the place of medicine and biomedical sciences in modern history. This series continues the Science, Technology and Medicine in Modern History series.

Michael Bresalier

Modern Flu British Medical Science and the Viralisation of Influenza, 1890–1950

Michael Bresalier Department of History, Heritage, and Classics Swansea University Swansea, UK

ISSN 2947-9142 ISSN 2947-9150 (electronic) Medicine and Biomedical Sciences in Modern History ISBN 978-1-137-33953-9 ISBN 978-1-137-33954-6 (eBook) https://doi.org/10.1057/978-1-137-33954-6 © The Editor(s) (if applicable) and The Author(s), under exclusive licence to Springer Nature Limited 2023 The author(s) has/have asserted their right(s) to be identified as the author(s) of this work in accordance with the Copyright, Designs and Patents Act 1988. This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Cover illustration: World Health Organization/Eric Schwab, 1953 This Palgrave Macmillan imprint is published by the registered company Springer Nature Limited The registered company address is: The Campus, 4 Crinan Street, London, N1 9XW, United Kingdom

Acknowledgements

This book could not have been completed without colleagues, friends, family, and strangers across two continents. My thinking about the history of infections began when I was a master’s student at York University in Toronto. A graduate course on ‘AIDS and Culture’, run by the inimitable Deborah Britzman, opened my eyes to the social and cultural history of epidemics and disease, and to how to ask questions about the historicity and implications of medical and scientific knowledge. York University was a hive of intellectual activism at the time, and it was my good fortune to befriend and start collaborating with Eric Mykhalovskiy on the social dimensions of accessing and taking HIV/AIDS treatments. Eric and I shared an interest in how and why HIV was being framed as an ‘emerging infection’ by international health experts and organisations. Our discussions planted the seed of an idea to develop a long-term historical perspective on this new category of infections and the organisations tackling them as major global health problems. The idea brought me to the Department of History and Philosophy of Science at the University of Cambridge as a doctoral student and into a remarkably vibrant community of historians and philosophers. I was fortunate to be supervised by Nick Hopwood, who not only taught me much about how to be a historian of modern medicine, but also suggested that I could use influenza as a lens through which to explore practical and institutional developments in virology, public health, and disease control

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that had become essential to contemporary approaches to emerging infections. Soraya de Chadarevian and Nick Jardine helped sharpen my focus. Little did I know that this would mark the beginnings of a project that would lead me back to nineteenth-century medicine, science, and public health in Britain and, eventually, to writing this book. Many people have helped me come to grips with the tangled history of influenza and its connections to histories of medicine, public health, bacteriology, epidemiology, and virology. I am grateful for discussions with and path-breaking work done by Mark Honigsbaum, Andrew Mendelshon, Ilana Löwy, Jean-Paul Gaudillière, Anne Hardy, and especially, John Eyler. Jacob Steere-Williams provided invaluable comments on my conceptual framework. Early on, Mark Jackson asked pertinent questions about the changing meanings of influenza and its identity as an ‘epidemic’ disease. A conference I co-organised with Patrick Zylberman in 2010 on the afterlives of the 1918–19 influenza pandemic was a wonderful chance to connect with and share ideas with historians seeking to expand the scope of research beyond the so-called Spanish Influenza. A number became important interlocutors: Kenton Kroker, Virginia Berridge, George Dehner, Donald Avery, and Esyllt Jones. More than anyone, Michael Worboys has helped shape my ideas about and approaches to the modern history of influenza. For over a decade, he has been an inspiring mentor, collaborator, and friend, whose work on the making and reception of bacteriology in Britain has had a profound impact on my own thinking about the viralisation of flu. Joining Mick’s Wellcome Trust project on ‘Medicine and Modernity’ as a research associate at the Centre for History of Science, Technology, and Medicine at the University of Manchester brought me into wonderfully supportive and dynamic research group. Over regular lunches and coffee, Robert Kirk, Neil Pemberton, and Duncan Wilson shared their insights on writing research animals into the history of medicine and biology. Elizabeth Toon and Carsten Timmerman were always ready to offer a critical eye. Ian Burney gave me sage advice on sharing and publishing my research. The late John Pickstone read and commented on an early draft of this book. I still have his scrawled handwritten notes, which I revisited as I was revising the manuscript. I hope he’d be satisfied with the final product. Along the way, I have benefited from the support of other colleagues. I am grateful for having had the chance to work with Abigail Woods as a research fellow on her Wellcome Trust ‘One Health’ project at

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the Centre for the History of Science, Technology, and Medicine at King’s College London. Abigail’s rigour, generosity, and passion for positioning animals at the heart of medical history have informed much of my research and thinking. I’m sure she’d agree that I could have done more to foreground the pigs, ferrets, and mice (not to mention the fowl and other animals) that are so central to the history of influenza. Rachel Mason Dentinger and Angela Cassidy, my ‘One Health’ co-fellows, never hesitated to suggest ways to put influenza into a broader multispecies perspective. David Edgerton was a great support while I was at the Centre, readily offering wise words on finishing a manuscript and incisive historiographical questions. I cannot say enough about the support of my colleagues in the Department of History, Heritage, and Classics at Swansea University. David Turner, Christopher Laucht, Martin Johnes, Adam Mosley, and Sarah Crook have each taken time to query and nudge me about this project. Tomás Irish deserves special mention for his steadfast encouragement. I am especially indebted to him for taking the time, while completing his own book, to offer valuable comments and suggestions on two draft chapters. I also wish the thank the School of Culture and Communication for granting me sabbatical for the winter term of 2022; being freed from teaching and administration gave me the time revise and complete the manuscript. This book would never have come into being without the hidden work of librarians and archivists at the Wellcome Library and Archives, Rockefeller Archives, the National Archives (UK), the WHO archives, and Pasteur Institute Archives. I am particularly grateful to Robert Moore, former librarian and archivist at the now defunct NIMR Library at Mill Hill, who gave me access to personnel papers of those involved in the Institute’s early influenza virus research. A Rockefeller Archives Centre grant allowed me to spend time in Tarrytown, New York sifting through the RIMR and IHD influenza papers. A European Science Foundation grant allowed me to work on influenza documents at the WHO archives in Geneva and on the extensive collections on influenza virology at the Pasteur Institute Archives in Paris. I must also thank the late Dr. David Andrewes, son of C. H. Andrewes, the virologist who is central to the story of influenza virus. Back in 2012, after tracking down his email, I contacted him and his wife about holding an informal interview about his father. He graciously invited me to his home, where I had lunch, and spent an engaging afternoon discussing his

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father’s career and unique personality. While I was unable to incorporate the interview into this book, it helped round out a person with whom I had only engaged with through publications and memoirs. I would like to thank the following publishers for permission to reprint here portions of previously published material: ‘Neutralizing Flu: “Immunological Devices” and the Making of a Virus Disease’, In Kenton Kroker, Jennifer Keelan & Pauline Mazumdar (Eds.), Crafting Immunity: Working Histories of Clinical Immunology (London: Ashgate, 2008), 107–144; ‘“A Most Protean Disease”: Aligning Medical Knowledge of Modern Influenza, 1890–1914’, Medical History 56 (2012), 481–510; ‘Uses of a Pandemic: Forging the Identities of Influenza and Virus Research in Interwar Britain’, Social History of Medicine 25.2 (2012), 400–424; ‘Fighting Flu: Military Pathology, Vaccines, and the Conflicted Identity of the 1918–19 Pandemic in Britain’, Journal of the History of Medicine and Allied Sciences 68 (2013), 87–128; ‘“Saving the Lives of Our Dogs”: The Development of Canine Distemper Vaccine in Interwar Britain’, British Journal for the History of Science 47 (2014), 305–334. Writing this book has depended upon support from those closest to me. Sarah Dry and Rob Iliffe have been the best pillars a friend could ask for. They always had time to discuss this project, to share their remarkable breadth of knowledge as gifted historians of science, and to make sure any discussion was served up with great food, drink, and cheer. Rob read early versions of the manuscript and asked all the right questions. Sarah has never pulled punches when it came to the urgency of getting this monkey off my back and, to my eternal gratitude, she agreed to be my Zoom ‘writing buddy’ while I was finishing up. Though our buddy-system was meant to work both ways, at a critical juncture Sarah put aside her own project to help pull mine across the line. Many others have taken time to listen to or discuss germinating ideas, dead-ends, and frustrations. Thanks to Steve Brearton, Mark Bostridge, Tatjana Buklijas, John Graham, Havi Carel, Samir Okasha, Jonathan Reinarz, Ana Carden-Coyne, Jean-Marc Dreyfus, and Chris Mikton. My family in Canada have been a constant source of support. Long ago, my mother, Sheila Hurtig Robertson, instilled a passion for history and the written word. A writer, historian, and editor herself, neither she nor I could ever have imagined that one day she would copy-edit a book of mine. I am enormously grateful for the many hours she devoted to fine-tuning every sentence. Any errors or oversights are solely my responsibility.

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I owe most to three people who have lived under the sun and clouds of this project. Sarah Peat, my life partner and true historical passion, has sustained the love, tolerance, and impatience needed. Every day I marvel at all she brings to our little clan, her wicked wit, razor-sharp insights, and remarkable achievements. Our children, Max and Beatrix, have brought endless joy and an uncanny appreciation of the preciousness of time. Max’s impersonations of my academese have been a hilarious reminder not to take things too seriously. Beatrix took a keen interest in this book as it neared completion, asking when it would be done, musing on why made-up stories are better than history, and not hesitating to remind me that this book will never sell as many copies as Harry Potter! The weeks, months, and years spent on this project have been as much theirs as it has been mine. Almost every weekend, for nearly a decade, I had the pleasure of heading out of Bristol on road bikes with Nick Wharton and Will Sefton to the Mendips, Cotswolds, the Wye Valley, and beyond. And almost every weekend, they’d jibe me about when the book would be done, when they’d get their acknowledgements, when they’d get to read the damn thing. Our cycling kept me sane and brought much needed levity to a project that weighed on me most weeks. After Nick was diagnosed with a rare cancer, finishing this book took on greater urgency. I wanted to share it with him. But I missed my chance. I dedicate this book to Nick and to my father, Dr. Seymour Bresalier, two people who I wish were around to read it.

Contents

1

1

Historicising Flu: Viral Identities of Influenza

2

Naming Flu: Classification and Its Conflicts 1 Naming Influenza 2 New Classifications 3 Epidemic Catarrh 4 Hippocratic and ‘Heroic’ Treatments 5 Epidemic Identities

3

Modernising Flu: Re-aligning Medical Knowledge of the ‘Most Protean Disease’ 1 Making Influenza Communicable 2 Proteus in the Clinic 3 The Influenza Germ 4 A New Influenza 5 Re-aligning Clinical, Public Health and Laboratory Medicine

100

Fighting Flu: Military Pathology and the 1918–1919 Pandemic 1 The War and the Pandemic 2 War Pathology 3 A New Disease? 4 Disputed Germs 5 Mixed Vaccines

107 111 117 125 132 144

4

25 26 29 33 39 42 49 51 71 86 96

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CONTENTS

6 5

Reckoning and Reconstruction

157

Mobilising Flu: The Medical Research Council and the Genesis of British Virus Research 1 Competing Visions 2 New Agents, Old Problems 3 Experimentalising Pathology 4 The Virus Scheme 5 Uses of the Pandemic

161 165 173 189 196 204

Modelling Flu: Dog Distemper and the Promise of Virus Research 1 Making Virus Instruments 2 A Proxy Disease 3 Translating Viruses into Vaccines 4 The ‘Flu Problem’ 5 Limits of Control

209 214 221 236 240 244

7

Viralising Flu: Towards a New Medical Consensus 1 Virus Neutralization 2 Ferret Flu 3 Putting Mice to Work 4 A Virus Disease? 5 Collaboration and Consensus

253 259 270 295 307 311

8

Globalising Flu: Systems of Surveillance and Vaccination 1 ‘A New Complicating Factor’ 2 Experimental Vaccines 3 Harnessing the Chick Egg 4 American Methods 5 World Influenza Programme 6 Test and Tensions

315 321 325 330 337 339 349

9

Conclusion: ‘The Most Protean Disease’

355

10

Coda: Influenza and Covid-19 1 Which Influenza? 2 Challenges of Control 3 Zoonotic Connections 4 System Failures 5 Cautionary Lessons

375 376 381 385 392 394

6

CONTENTS

xiii

Select Bibliography

397

Index

445

Abbreviations

AMS BEF BMA CCS COI DGAMS DRC ERC FDC FDF IHD LCC LGB MAB MOH MoH MOHs MRC NIMR RAMC RIH RIMR RNC RSM SMOH WEHIMR

Army Medical Services British Expeditionary Force British Medical Association Casualty Clearing Stations Commission on Influenza Director-General of the Army Medical Services Distemper Research Committee Emergency Research Committee Field Distemper Council Field Distemper Fund International Health Division London County Council Local Government Board Metropolitan Asylums Board Medical Officer of Health Ministry of Health Medical Officers of Health Medical Research Committee/Council National Institute for Medical Research Royal Army Medical Corps Rockefeller Institute Hospital Rockefeller Institute for Medical Research Royal Naval College Royal Society of Medicine Society of Medical Officers of Health Walter Eliza Hall Institute for Medical Research xv

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ABBREVIATIONS

WHO WIC WIP WO

World Health Organization World Influenza Centre World Influenza Programme War Office

List of Figures

Chapter 3 Fig. 1

Fig. 2

Fig. 3

Deaths from Influenza (London). The table demonstrates the degree to which influenza deaths in London had declined from a peak in 1848 to ‘quite insignificant proportions’ by 1889 (Source Henry Parsons, Report on the Influenza Epidemic of 1889–1890, Local Government Board [London: HMSO, 1891], 4) Annual Influenza Death-Rate per million in England and Wales, 1847–1905. With the exception the epidemic year of 1847–1848, and lesser outbreaks in 1850–1851 and 1857–1858, mortality-rates attributed influenza in England and Wales declined in the second half of the nineteenth century. The 1889–1890 epidemic set in train consistently higher levels of mortality than in the preceding three decades (Source A. Newsholme, ‘Influenza for the Public Health Standpoint’, The Practitioner, LXXVII [1907], 118) Questionnaire on the Origin and Spread of Influenza, 1890. Distributed by Henry Parson to collect “information on a uniform plan” (Source Report on the Influenza Epidemic of 1889–1890 [1891], 120)

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xviii Fig. 4

Fig. 5

Fig. 6

Fig. 7

Fig. 8

LIST OF FIGURES

Influenza across the World ‘Map showing recorded date of Influenza Epidemic in 1890 and 1891,’ Report on the Influenza Epidemic of 1889–1890 (1891) (Credit Wellcome Collection. Attribution 4.0 International [CC BY 4.0]) ‘Uncomplicated influenza’. First recognised case at Barts, 30 December 1889. Fever chart of Bedford Pierce, 28, house physician, who awoke on 30 December with a high fever. Warded on 31 December. Returned home on 3 January 1890, two weeks after which he ‘was not up to the mark’ (Source Samuel West, ‘The Influenza Epidemic of 1890’, St. Bartholomew’s Hospital Reports, XXVI [1890], 212) Relapsing Fever. A standard reference was Otto Frentzel, ‘Zur Kenntnis des Fieberganges bei Influenza’, Centralblatt fur klinische Medicin (11 January 1890), who characterised three types of fever in the 1889–1890 epidemic in the Municipal General Hospital at Friedrichshain. Type II, shown here, was a relapsing fever that could last for a week, with significant temperature fluctuations, in which the patient might appear to recover, only for the fever to return (Source J.W.S. Moore, ‘Influenza’, in J.W. Ballantyne [Ed.], Encyclopaedia Medica [Edinburgh and London: Green & Son, 1919], 517) Apyretic Fever. From Frentzel (1890). Type III ‘apyretic’ fever, marked by a sudden fall in temperature below normal, indicative of the onset of serious secondary complications, especially pneumonia (Source J.W.S. Moore, ‘Influenza’ [1919], 517) ‘Aetiology of Influenza’. Walter Hall’s Pfeiffer Bacillus. Cover-glass specimen of Hall’s sputum taken on 2 February, 1892, showing ‘an almost pure culture of the specific bacillus.’ The sputum was permeated by different forms of the bacilli, ‘singly’ in ‘dumbbells’ and ‘in larger and smaller groups’ (Source E.E. Klein, ‘Report on Influenza in Its Clinical and Pathological Aspects’, in Local Government Board, Further Report and Papers on Epidemic Influenza, 1889–92 [London: HMSO, 1893], 120)

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LIST OF FIGURES

Fig. 9

Fig. 10

a and b Standard culture preparations of Pfeiffer’s bacillus. Left: B. influenzae in blood agar, indicated by small pocks. Right: photomicrograph of B. influenzae in pure culture (Source Richard Pfeiffer, ‘Influenza und die Gruppe der häemoglobinphilen Bakterien’, in E. Friedberger and R. Pfeiffer (Eds.), Lehrbuch der Mikrobiologie (Jena: Verlag Von Gustav Fischer, 1919 [originally published in 1893], 743. Photograph by Wellcome Library) A new influenza bacillus? Micrococcus Catarrhalis isolated and identified by Mervyn H. Gordon as the cause of clinical cases of “influenza” in Hertford, January 1905 (Source R.A. Dunn and M.H. Gordon, ‘Remarks on Clinical and Bacteriological Aspects of an Epidemic Simulating Influenza Which Recently Occurred in East Herts District’, British Medical Journal [26 August 1905], 425)

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Chapter 4 Fig. 1

Fig. 2

Fig. 3

(Sir) Walter Morley Fletcher, F.R.S., (1873–1933) (Source: Obituary Notices of Fellows of The Royal Society, Vol. 1 No. 2 [December] 1933) Motor Laboratory—interior, circa 1917 (Source: Medical Research Committee, Bacteriological Studies in the Pathology and Preventive Control of Cerebro-Spinal Fever Among the Forces During 1915 and 1916 [London: HMSO, 1917], 100) McIntosh and Fildes’ Influenza Bacillus. Diagrammed section of human bronchus of a fatal case of influenza. Scores of B. influenzae are drawn as minute black dots at the surface of the section. Following standard practice of the ‘Pfeiffer School’, McIntosh and Fildes used histopathological images to demonstrate the association between the bacillus and influenza (Source Plate from James McIntosh, Studies in the Aetiology of Epidemic Influenza, Medical Research Council Special Report Series, no. 63 [London: HMSO, 1922])

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LIST OF FIGURES

Fig. 4

Fig. 5

Heliotrope Cyanosis. ‘It is impossible for a heliotrope cyanosis patient to recover’ (Source A. Abrahams, N. Hallows, and H. French, ‘A further investigation into influenzo-pneumococcal and influenzo-streptococcal septicaemia: Epidemic influenzal “pneumonia” of highly fatal type and its relation to “purulent bronchitis”’, Lancet [4 January 1919], 1–11 [Illustrator: W. Thornton Shiells; Originally published as a grayscale]) Anti-catarrh vaccine, prepared by Almorth Wright’s Inoculation Department and marketed and distributed by Parke, Davis and Company. The advertisement refers readers to the Department’s Mixed Anti-Influenza Vaccine, which had been in production since 1915 (Source: Journal of Laryngology and Otology, 37.9 [1922], vi)

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Chapter 5 Fig. 1

Fig. 2

Fig. 3

Fig. 4

Abbeville Filter-passer. Photomicrograph taken for Gibson and his colleagues by the MRC microscopist, J.E. Barnard in February 1919. Gibson’s co-worker, F.B. Bowman, sent it to W.M. Fletcher on 11 February: ‘I am enclosing a photo of our “bug” which we have isolated from filtered material. It is practically identical with John R[ose] B[radford]’s’ (Source NA FD1/529, Bowman to Fletcher, Medical Research Committee, Influenza Research by Colonel Cummings with British Forces in France, 11 February 1919. Used with permission from the National Archives) Étaples Filter-passer. Étaples workers’ virus in Noguchi cultures at (1) 3 days’ growth, (2) 5 days’ growth, (3) 7 days’ growth. Filtrates of the culture material were inoculated into guinea-pigs and monkeys (Source John R. Bradford, E.F. Bashford and J.A. Wilson, ‘The Filter-passing Virus of Influenza’, Quarterly Journal of Medicine, no. 12 [1919], 307) Étaples Filter-passer Films. Prepared from cultures, in films the organism had ‘the appearance of a minute, rounded, or slightly oval, undifferentiated coccus-like body, arranged in colonies of twenty to sixty elements’ (Source Bradford, Bashford, Wilson [1919], 308) National Institute for Medical Research—Hampstead (Front View) (Source Wellcome Library)

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LIST OF FIGURES

Fig. 5

Fig. 6

‘To Illustrate “The Filter Passer of Influenza”’. Photomicrograph taken for M.H. Gordon by J.E. Barnard at the NIMR in early 1922, of a film of Gordon’s filter-passer grown ‘in pure culture’ in Noguchi medium, which had been inoculated with filtrates of diluted nasal secretions from a nurse at Barts suffering from flu. After a fortnight, material from the base of the culture was examined for bacteria, diluted, spread on a coverslip and dried. The film was fixed and stained, before being photographed (Source M.H. Gordon, ‘The Filter Passer of Influenza’, Journal of the Royal Army Medical Corps, 39 [1922], 11) Patrick Playfair Laidlaw, F.R.C.P., F.R.S. (1881–1940), Obituary Notices of Fellows of the Royal Society, 3.9 (1941), 427–447

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Chapter 6 Fig. 1

Fig. 2

Barnard’s Ultraviolet microscope (Note A1 and A2 are screws for course and fine adjustment. O1 carries the objective, while O2 carries the ocular. O3 is the combined dark-ground and ultraviolet illuminator, moved by a screw controlled by a large graduate head, A3. A4 are milled heads to control movements of the object on the stage. M1 is a mercury-vapor lamp mounted on an optical bench. At M3, a reflecting prism is mounted on a swing to enable the beam of light from the mercury vapor-lamp to be projected into the microscope. The spark S1 is projected by a quartz lens S2 through a quartz prism S3 into the central part of the microscope condenser. Source J.E. Barnard ‘The Microscopical Examination of Filterable Viruses’, Lancet [18 July 1925], 121) Dog distemper isolation compound, Mill Hill ‘Farm’ Laboratories (Note The entrance and disinfection house are at the left corner. A kennel maid’s bungalow is in the foreground, behind the tree, with the kennels in the background. Source P.P. Laidlaw and G.W. Dunkin, ‘A Report Upon the Cause and Prevention of Dog Distemper’, In Field Distemper Fund, Progress Report of the Distemper Research Committee [1928], 12)

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Fig. 4

LIST OF FIGURES

Animal Hospital, Mill Hill ‘Farm’ Laboratories (Source Laidlaw and Dunkin, ‘A Report Upon the Cause and Prevention of Dog Distemper’, In Field Distemper Fund, Progress Report of the Distemper Research Committee [1928], 14) Purpose-bred ferrets at Mill Hill. Date unknown (Source NA FD1/1284)

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Chapter 7 Fig. 1 Fig. 2

Fig. 3

Fig. 4

Fig. 5

Fig. 6

Fig. 7

Wilson Smith M.B., F.R.S. (1897–1965) (Source Obituary Notices of Fellows of the Royal Society, 12 [1966], 478–487) Christopher Howard Andrewes, M.B., F.R.S. (1896–1987) (Source MRC National Institute for Medical Research, https://commons.wikimedia.org/wiki/File:Christopher_ Howard_Andrewes.jpg#filelinks) Infecting a ferret. The original caption read: ‘An Experiment in the Fight against Influenza: A Ferret is Injected.’ C.H. Andrewes (with the pipette) and an unidentified technician demonstrate the technique of ‘instilling’ virus material into the nose of a ferret. The ferret was anaesthetised with ether to ease injection of virus material (Source ‘Can We Beat ‘Flu?’, Picture Post [2 February 1946], 10). Licensed and used with permission from Getty Images (3401341) Has the Ferret Got Influenza? Ferret, forty-eight hours after nasal instillation (Source Picture Post [2 February 1946], 10) ‘Ferret Flu’ (Source Wilson Smith, C.H. Andrewes, and P.P. Laidlaw, ‘A Virus Obtained from Influenza Patients’, Lancet [8 July 1933], 67) Ferret Flu Neutralized. Upper chart—Ferret (F131) infected with a mixture of virus and normal ferret serum. Lower chart—Ferret (F101) infected with a mixture of virus and immune ferret serum. Virus neutralization was demonstrated in the lower chart (Source Wilson Smith, C.H. Andrewes, and P.P. Laidlaw, ‘A Virus Obtained from Influenza Patients’, Lancet [8 July 1933], 68) ‘British Doctors’ Discovery’ (Source Daily Telegraph [Friday, 7 July 1933], 7)

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LIST OF FIGURES

Fig. 8 Fig. 9

Fig. 10 Fig. 11

‘How the Virus Was Tracked Down’ (Source Daily Telegraph [Friday, 7 July 1933], 10) Neutralizing Antibody Levels in Londoners. Each vertical column represents a serum. The height of shading indicates the quantity of influenza virus antibody in the serum. Sera were graded as better than S (standard IH2 or IH4 horse-antiserum), equal S, S/5 (one-fifth the neutralizing power of S), or S/25 (one twenty-fifth the neutralizing power of S). Spaces marked O indicate sera with no antibody or with less than S/25 (Source Christopher H. Andrewes, Patrick P. Laidlaw, and Wilson Smith, ‘Influenza: Observations on the Recovery of Virus from Man and on the Antibody Content of Human Sera’, British Journal of Experimental Pathology, XVI [1935], 577) ‘Flying Squad’ Collects Virus (Source Daily Herald [5 January 1937], 3) ‘Ferret Flu in Man’. Fever chart of Stuart-Harris after contracting influenza from ferrets while studying a small epidemic in army personnel at Woolwich in February 1936. On 6 March ‘one ferret sneezed violently at close range while being examined.’ Forty-five hours after contact, Stuart-Harris came down with a ‘typical attack’ of influenza. On 9 March, the first day of symptoms, he reported ‘very abrupt onset with coryza; sleeplessness and stiffness of joints during the night. Second day: Malaise, coryza, severe backache and frontal headache … Third day: Malaise, headache, severe backache in sacral region, aching pains in the hamstrings; sweating, coryza, giddiness on standing. Fourth day: … onset of acute mental depression … Later in day … exacerbation of symptoms … Fifth day: Steady improvement with fall of temperature, giddiness. Fifth to eleventh days: Steady improvement; muscular weakness remained until eleventh day’ (Source Wilson Smith and C.H. Stuart-Harris, ‘Influenza Infection of Man from the Ferret’, Lancet [1936], 121)

xxiii

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299 301

305

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Fig. 12

Identifying Flu. Differential diagnosis suggested to MOHs and medical practitioners by the Ministry of Health in 1939. Based on the NIMR’s Study of Epidemic Influenza (1938). While the presence of virus became a key diagnostic marker, its relation to specific clinical symptoms and epidemiological characteristics was crucial for its differentiation from febrile catarrhs (Source Ministry of Health Memorandum on Influenza (Revised Edition) [London: HMSO, 1939], 6)

308

Chapter 8 Fig. 1

Fig. 2

Fig. 3

Fig. 4

Fig. 5

Sketch of the proposed influenza laboratory network. C.H. Andrewes’ diagram of the influenza virus tracking system proposed to the World Health Assembly in September 1947 (Source National Archives FD1/ 544 ‘Memorandum—International Collaboration in the Influenza Field’, 1947) Diagram showing membranes and cavities of the 12–15 day old developing chick egg. The diagram is from F.M. Burnet and W.I.B. Beveridge, The Cultivation of Viruses and Rickettsiae in the Chick Embryo. An updated version of Burnet’s 1936 manual, the text became a standard reference for egg-based virus work (Source F.M. Burnet and W.I.B. Beveridge, The Cultivation of Viruses and Rickettsiae in the Chick Embryo [London: HMSO, 1946], 9) Diagrams of Burnet’s amniotic and allantoic techniques (Source ‘Recent epidemics and the World Influenza Centre’, World Health Organization Chronicle, 5 [2 February 1951], 51–53) World Influenza Programme ca. 1953. Each dot represents an affiliated laboratory. The NIMR is the ‘World Centre’, while Montgomery, Alabama is represented as the ‘Regional centre’ for the Americas (Source A.M.-M. Payne, ‘The Influenza Programme of the WHO’, Bulletin of the World Health Organisation, 8 [1953], 576) Manufacturing influenza vaccine ca. 1951. Female technician injects virus material into 10-to-12-day-old chick eggs at Philips-Roxane (Source ‘The Manufacture of Virus Vaccine Against Influenza’, Philips Technical Review, 12 [April 1951], 278)

317

331

335

345

350

LIST OF FIGURES

Fig. 6

Wright-Fleming Institute. Egg-based Influenza vaccine, ca. 1957 (Source World Health Organization Archives. WHO_A_012550)

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Chapter 9 Fig. 1

‘Can we beat influenza?’ Photograph of a haemagglutination test (Source Picture Post [2 February 1946], 9)

363

List of Tables

Chapter 6 Table 1 Table 2

Annual Flu Morbidity Rates per 100,000 in England (and Wales), Germany and the United States, 1920–1929 Deaths from the three leading notifiable infectious diseases, 1926–1929

240 242

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CHAPTER 1

Historicising Flu: Viral Identities of Influenza

The doctor handed me a small bottle, carefully stoppered. Brought from Berlin by courier the day before, it contained a few drops of fluid matter from the back of a British soldier’s throat. He had been ill – a sharp attack, a good deal worse than a cold. Was it influenza? With an Occupation Army spread over a defeated land, where hunger and cold stalked the shifting populations, the question was of more than academic interest.1

‘Was it influenza?’ The question was hardly new, though it had undergone many changes in meaning. Generations of medical practitioners had asked it, but with widely varying responses. When ‘influenza’ first became a commonly used medical term in the late eighteenth century, physicians sought answers in widespread catarrhal fevers, the heavens, the atmosphere, or the weather. Through the nineteenth century, attention turned to patients’ bodies and the plethora of respiratory, nervous, or gastral symptoms expressed during bouts of sickness. Victorian doctors increasingly defined the disease through its ability to suddenly explode across vast geographic areas. By the end of the century, their focus shifted to the array of bacteria found in the noses, throats, and lungs of sufferers and that spread through communities and nations, with various germs posited as the causative agent and key to identifying the disease. At the dawn of the 1 Clifford Troke, ‘Can we beat flu?’, Picture Post (2 February 1946), 8.

© The Editor(s) (if applicable) and The Author(s), under exclusive licence to Springer Nature Limited 2023 M. Bresalier, Modern Flu, Medicine and Biomedical Sciences in Modern History, https://doi.org/10.1057/978-1-137-33954-6_1

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twentieth century, a single bacillus was widely believed to hold the means to diagnosis, as well as treatment and prevention, but in the aftermath of the First World War and the 1918–1919 pandemic its role had been cast in doubt. For over a century, moments of certainty about what counted as influenza gave way to periods of uncertainty. This historical cycle came to an apparent end in the early 1930s, with the development of a new way of identifying the disease. It sprang from medical science laboratories, where novel methods had been generated to demonstrate that influenza was caused by a virus which infected the cells of the human respiratory tract. With these methods, researchers across the world showed that when the virus multiplied and setup infection in a person, it produced an acute disease, marked by high fever, crippling body aches, nausea, and delirium that lasted days or sometimes weeks. In some, influenza could morph into a more severe or fatal pneumonic condition, as the virus weakened the lungs and made them vulnerable to secondary infections. Highly contagious, the virus was soon shown to spread through the air by droplets through coughs, sneezes, spitting, and close contact, enabling it to rapidly infect large numbers of people. Testing for its presence in samples taken from a sick person became essential to determining whether the disease was influenza, while the biology and epidemiology of the virus held the keys to its control. In other words, what had long been called ‘influenza’ was transformed in the 1930s into something resembling what we know of the disease today. It took little over a decade for these developments to unfold. When the renowned British photo-journal, the Picture Post, came to tell their story in 1946, an increasingly certain way to answer the question—‘Was it influenza?’—had been put in place: it now rested on identifying the virus in individuals and populations. The Picture Post story, the source of my opening quote, vividly detailed the innovative techniques that had been used to establish influenza as a viral disease. The story focused on the National Institute of Medical Research (NIMR), the flagship laboratory of Britain’s Medical Research Council (MRC). Located in the leafy north London suburb of Hampstead, it was here, readers were told, that in 1933 a team of researchers developed a way to produce human influenza in ferrets and to isolate a virus from the experimental disease that developed in these animals. The discovery placed the NIMR at the vanguard of monumental changes in the science of influenza and in the modern biological sciences in general. Within a few years, researchers in Princeton, New York, Melbourne, Moscow, and elsewhere confirmed and built on

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their findings. The virus isolated in ferrets was quickly established as the primary cause and influenza was reclassified: no longer was it a disease defined by symptoms or environments, by airs, constitutions, or bacteria; it was now defined by a virus. The pathogenesis of influenza, from the onset of symptoms to their resolution in mild cases or resulting complications in severe cases could be traced back to initial infection with the virus. The medical identity of influenza would become viral. Behind this transformation was the institutional positioning of virology—and virologists—as arbiters of the new medical identity of influenza. Other medical professionals—clinicians, epidemiologists, veterinarians—would still have key roles in diagnosis, treatment, and prevention, but in the decades that followed, virologists had the final say on what was—and was not—influenza. Through the 1930s and 1940s, virus researchers developed, tested, and standardised ways of identifying and investigating influenza viruses, enabling laboratories in different corners of the globe to verify cases, outbreaks, and epidemics. Their innovations paved the way for new approaches to prevention, with priority given to vaccines. Fears that the Second World War would create conditions for a catastrophic pandemic of the kind experienced at the end of the First World War accelerated the pace of research. Through the 1940s, American scientists, collaborating with British and Australian counterparts, produced the first effective vaccines for large-scale inoculation of troops, marking the beginning of mass immunisation against influenza as an essential public health intervention. The Picture Post ’s story revealed how powerful ways of knowing and controlling influenza had come to revolve around the virus discovered at the NIMR thirteen years earlier.2 With a strong dose of national pride, it highlighted the Institute’s crucial role in shaping the medical future of influenza. At the time, the Institute’s director of virus research, Charles Herbert (C.H.) Andrewes, who was a member of the team that made the original breakthrough, was laying the groundwork for an international system of influenza virus surveillance, which would come under the auspices of the newly formed World Health Organization in 1948. Andrewes was likely the ‘doctor’ with the bottle from Berlin mentioned in the Picture Post story; yet unlike a rank-and-file doctor, he possessed 2 For the concept of ‘ways of knowing’, see John V. Pickstone, Ways of Knowing: A New History of Science, Technology and Medicine (Manchester: Manchester University Press, 2000).

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a novel form of expertise that enabled him to determine the presence of influenza virus in samples sent to his laboratory, and to test whether the virus was a familiar seasonal subtype or an unfamiliar strain that might give rise to a major epidemic. Andrewes was the embodiment of the new authority virologists had gained in shaping the medical identity of influenza. He had been one of a handful of researchers who had participated in establishing the study of viruses—what would be called virology in the 1940s—as a distinct medical scientific specialty in interwar Britain and who had used their expertise to define a number of significant infections as virus diseases.3 Their work on influenza was part of a larger process of developing and legitimising virus research as vital to the health of the nation and Empire. The end of the Second World War and the creation of the WHO opened new opportunities to position virology and virologists as integral to the health of the world. The coming of virology, with influenza research at its centre, was not just shaping the medical future of influenza, but also its medical past.4 The discovery of the virus and the forging of its identity as the primary cause of influenza prompted researchers to speculate on and explore its possible role in previous epidemics. Many wondered if the virus or a close relative had been the agent behind the catastrophic 1918–1919 pandemic, which at the time was thought to have killed over 20 million worldwide.5 The prolific Australian virologist, Frank Macfarlane (F.M.) Burnet, who had witnessed the discovery at the NIMR and became one of the leading experts on influenza virus, suggested that, not only were scientists in a position to answer major questions about the 1918–1919 pandemic, but it was also possible to delve into the viral origins of more distant influenza pandemics.6 With the developments that had been put in place 3 ‘Virus disease’ was the general term used in English-language medical and scientific publications and textbooks from the turn of the centuty until the late 1940s, when ‘viral disease’ became more widely used. 4 Andrew Cunningham has traced how the bacteriological transformation of the identity of plague involved a transformation of its history; a similar process occurred with the viralization of influenza. Andrew Cunningham, ‘Transforming Plague: the Laboratory and the Identity of Infectious Disease’, in A. Cunningham and P. Williams (Eds.), The Laboratory Revolution in Medicine (Cambridge: Cambridge University Press, 1992), 209–244. 5 P.P. Laidlaw, ‘Epidemic Influenza: A Virus Disease’, The Lancet (11 May 1935), 1123. 6 F.M. Burnet and E. Clark, Influenza: A Survey of the Last 50 years in the Light of Modern Work on the Virus of Epidemic Influenza (Melbourne: Macmillan, 1942).

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since 1933, it was now feasible to imagine writing the history of influenza in terms of the history of influenza viruses. Influenza’s past would soon be viralised. This book tells the story of how the past, present, and future of influenza became viral in the first half of the twentieth century. Virologists, influenza experts, and many historians take it for granted that influenza has always been a viral disease. In strictly biological terms, of course, this is probably true. The biological history of influenza viruses is likely thousands of years old, and it is widely assumed that they co-evolved with and have been infecting humans since the transition from nomadic to agricultural settlements.7 By contrast, however, medical and scientific knowledge of influenza as a viral disease is historically recent, contingent on and contextualised through developments from the late nineteenth century to the 1940s. This book is a history of the making of a virological way of knowing that was slowly constructed in Britain from the end of the nineteenth century and through the first half of twentieth century, and how it became essential to identifying and controlling influenza.8 It traces the emergence and positioning of virus research as a new medical scientific field, which sought to master influenza viruses as crucial scientific objects and problems. It explains how the virus became central to the medical identity of influenza and to the clinical, public health and laboratory systems organised to tackle the disease in the twentieth century. And it shows how, despite these significant transformations, influenza virus continued to challenge, resist, and propel changes in the science, surveillance, and control of influenza. Modern Flu starts from the premise that virological ideas and practices have a history and that without them it would be impossible to

7 Genomic studies suggest that influenza viruses have existed for hundreds of millions

of years. See, M. Shi, X.D. Lin, X. Chen, J.H. Tian, et al., ‘The Evolutionary History of Vertebrate RNA Viruses’, Nature, 556 (2018), 197–202; J.K. Taubenberger and D.M. Morens, ‘1918 Influenza: The Mother of All Pandemics’, Emerging Infectious Diseases, 12 (2006), 15–22; C.W. Potter, ‘A History of Influenza’, Journal of Applied Microbiology, 91.4 (2001), 572–579; W.I.B. Beveridge, ‘The Chronicle of Influenza Epidemics’, History and Philosophy of the Life Sciences, 13.2 (1991), 223–234; Youri Ghendon, ‘Introduction to Pandemic Influenza Through History’, European Journal of Epidemiology, 10.4 (1994), 451–453. 8 I follow Pickstone’s characterisation of ‘ways of knowing’ as also ‘ways of working’, in which concepts and practice operate together. John V. Pickstone, ‘A Brief Introduction to Ways of Knowing and Ways of Working’, History of Science, 49.3 (2011), 235–245.

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speculate upon—let alone retrospectively explore—the biological origins of influenza viruses and much else about the disease.9 This approach presents a number of methodological challenges, in particular: how to tell the history of a new way of knowing a disease? Conventional histories put much emphasis on discoveries as crucial catalysts for change in medicine and science. A standard narrative for influenza pinpoints the 1933 discovery at the NIMR as the definitive moment when it became possible to know and control the disease virologically.10 The story goes that, once the necessary methods for isolating the virus were developed, refined, and replicated to demonstrate its primary role in the disease, virus-based diagnoses and prevention methods were quickly adopted as standard parts of medicine and public health, radically transforming them in the process. Long-standing problems were opened to new lines of investigation and potential resolution. The discovery is seen to have revealed a fundamental truth about influenza and set in train further breakthroughs that made its virus aetiology, pathology, epidemiology, and ecology among the most widely and extensively studied problems in modern biomedical science. Such accounts contain some truth. There is no doubting that change in virus research occurred rapidly. But they also leave out much and are misleading. A focus on a single discovery or series of milestones fails to address the conditions that made it possible to envision and then establish 9 Retrospective diagnoses of past influenza outbreaks or epidemics tend to ignore two important historical contingencies: first, that virological concepts and tools have histories and carry certain assumptions about the identity of a disease and its causes; and second, earlier classifications of influenza referred to or included other diseases and their different causes. For discussions of the pitfalls and prospects of retrospective disease history, see: Adrian Wilson, ‘On the History of Disease-Concepts: The Case of Pleurisy’, History of Science, xxxviii (2000), 271–319; Andrew Cunningham, ‘Identifying Disease in the Past: Cutting the Gordian Knot’, Asclepio, LIV (2002), 13–34; John Arrizabalaga, ‘Problematizing Retrospective Diagnosis in the History of Disease’, Asclepio, LIV (2002), 51–70; Mark, Jackson, ‘Perspectives on the History of Disease’, in idem., The Routledge History of Disease (London: Routledge 2016), 1–18. 10 For example, W.I.B. Beveridge, Influenza: The Last Great Plague, An Unfinished Story of Discovery (London: Heinemann, 1977); F.M. Burnet, ‘A Portrait of Influenza’, Intervirology, 2 (1979), 201–214; E.D. Kilbourne, ‘Pandora’s Box and the History of the Respiratory Viruses: A Case Study of Serendipity in Research’, History and Philosophy of the Life Sciences, 14 (1992), 299–308; D.A.J. Tyrell, ‘Discovery of Influenza Viruses’, in K.G. Nicholson, R.G. Webster and A.J. Hay (Eds.), Textbook of Influenza (Oxford: Blackwell 1998), 19–26; T. Quinn, Flu: A Social History of Influenza (London: New Holland, 2008).

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influenza as a ‘virus disease’. It oversimplifies historical change. Modern Flu seeks answers to questions that demand looking beyond a small group of scientists attempting to conquer a complex disease and beyond the annus mirabilis of 1933. De-centring the narrative of discovery leads us to a series of new questions about the history of influenza: what were medical and public health approaches to influenza before the discovery of the virus? What had to be put in place for a virus to be identified and established as the cause of influenza? Through what contexts was virus research built? How was the virus—and virological ideas and practices— incorporated into existing approaches to the disease in clinical, laboratory, and public health medicine? And in what ways was the medical identity of influenza transformed? Historians building on the work of the bacteriologist and philosopher, Ludwik Fleck, have problematised the idea of scientific discovery as a singular and transformative event and have directed attention to the long process of producing, legitimising, and consolidating medical and scientific facts.11 Fleck challenged what he called the ‘individualistic point of view’ of discovery because it hides the extensive labour and time that goes into its making and legitimisation. ‘Every experimental scientist,’ argued Fleck in his 1935 classic, Genesis and Development of a Scientific Fact, ‘knows just how little a single experiment can prove or convince. To establish proof, an entire system of experiments and controls is needed, setup according to an assumption or style and performed by an expert.’12 Fleck insisted that ‘discovery must be regarded as a social event,’ one dependent on the construction and reproduction of a research system or ‘style’ with a working culture shared by specially trained experts. But it also depends on the movement of knowledge and practices between specialist and nonspecialist settings—between, for example, the esoteric realm of the NIMR laboratories where influenza viruses were studied in ferrets and mice and the hospitals, clinics or homes where doctors engaged with people

11 Ludwick Fleck, Genesis and Development of a Scientific Fact (Chicago: University of Chicago Press, [1935], 1979). Ilana Löwy and her colleagues have done invaluable work to develop Fleckian analyses of (bio)medical knowledge production. Ilana Löwy, ‘Ludwik Fleck’s Epistemology of Medicine and Biomedical Sciences’, Studies in History and Philosophy of Biological and Biomedical Sciences, 35C (2004), 437–446; Ilana Löwy, ‘Ludwik Fleck on the Social Construction of Medical Knowledge’, Sociology of Health & Illness, 10.2 (1988), 133–155. 12 Fleck, Genesis and Development of a Scientific Fact, 96.

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suffering from the disease.13 This movement is not unidirectional, from laboratory to clinic, but rather back-and-forth, with laboratory science shaping and being shaped by the needs or problems of clinical and public health medicine. Fleck argued that as basic research becomes more widely communicated, shared, and applied, uncertainties or disagreements about it tend to be diminished or stripped out altogether.14 A complex problem becomes increasingly simplified. The outcome is that a scientific claim— in this case that post-1933 ‘influenza is caused by a virus’—which at one point was disputed becomes undisputed; a claim becomes a fact. Modern Flu tells the story of how and why this came about with influenza. This conceptualisation of discovery reminds us that medical knowledge is a social and historical product and shaped by, among other things, professional, disciplinary, economic, political, social and cultural forces and interests.15 It calls for a long-term perspective on what made it possible to establish a virus as the cause of influenza, to determine its virus identity, to harness virus research to address the complex medical and public health problems associated with the disease, and to win the support and acceptance of medical professionals and policy makers. Taking this perspective means tracing the creation and adoption of methods, materials, and technologies to investigate viruses and the creation of medical researchers and institutions that came to be positioned as necessary to understanding and tackling the role of viruses as causative agents of major diseases. Much had to be built in the decades before 1933; much also had to change afterwards. When the NIMR workers announced their discovery in 1933 it was against a historical backdrop shaped by other approaches that already laid claim to understanding and managing influenza. Rather than a straightforward story of scientific progress, making influenza viral took many years and was marked by negotiations, conflicts, and exchanges between different medical professionals over the kinds of expertise needed to identify and control influenza.

13 Fleck, Genesis and Development of a Scientific Fact, 76. 14 For a summary of this process, see Jan Golinski Making of Natural Knowledge:

Constructivism and the History of Science (Cambridge: Cambridge University Press, 1998), 32–45. 15 Charles E. Rosenberg, ‘What Is Disease? In Memory of Owsei Temkin’, Bulletin of the History of Medicine, 77 (2003), 491–505; Keith Wailoo, ‘Introduction’, in idem., Dying in the City of the Blues: Sickle Cell Anemia and the Politics of Race and Health (Chapel Hill: University of North Carolina Press, 2001), 1–24.

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Among virus researchers themselves, sorting out the virus identity of influenza was itself part of sorting out the basic nature of viruses, which were still novel and contested entities in the 1930s. Ultimately, making influenza viral was about the process of aligning different interests and building a medical scientific consensus on the virus identity of influenza. This involved creating new social relations between medical scientists, clinicians, doctors, public health experts, policymakers, patients, and the public. If making influenza viral was the outcome of a long process of change, when did it begin? My contention is that its roots can be traced back to medical and scientific approaches that emerged at the end of the nineteenth century which transformed understandings of the disease. A crucial catalyst was an epidemic that swept the world in waves between 1889 and 1894. Not only was this the first truly global influenza epidemic, it also marked the first time that governments across Europe were in a position to launch large-scale investigations of the disease at home and across their empires.16 Novel in size and organisation, investigations in Germany, France, Britain and elsewhere took the pandemic as an opportunity to define influenza in terms of the principles and practices of what they deemed as scientific medicine, which encompassed knowledge and materials produced experimentally in the laboratory with specialised instruments and controlled methods.17 By the late nineteenth century, bacteriology was taking its place alongside experimental physiology and cellular pathology as an emblem of scientific medicine, and transforming

16 Most contemporary accounts in the 1890s used the term ‘epidemic’ instead of ‘pandemic. The term ‘pandemic’ came into wide use in the early nineteenth century to characterise the spread of cholera. August Hirsch was among the first to apply the term to influenza, noting in his 1883 Handbook that influenza ‘always occurs as an epidemic or pandemic’. August Hirsch, Handbook of Geographical and Historical Pathology, Volume I. Trans. Charles Creighton (1883), 18. The term started to be generally applied to influenza in accounts of the 1918–1919 pandemic, and then retrospectively applied to earlier epidemics. 17 W.F. Bynum, Science and the Practice of Medicine in the Nineteenth Century

(Cambridge: Cambridge University Bynum 1994), 92–117; William Bynum, ‘Medicine in the Laboratory’, in idem., History of Medicine: A Very Short Introduction (Oxford: Oxford University Press, 2008), 73–74. For an overview, of the relation between science and medicine, see John Harley Warner, ‘The History of Science and the Sciences of Medicine’, Osiris, 10 (1995), 164–193.

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it in the process.18 Among the most influential investigations of influenza were those carried out in Britain by the Medical Department of the Local Government Board, which had loosely coordinated the nation’s public health system since the 1870s. Two reports issued during the epidemic were hailed as landmarks in drawing influenza into a new bacteriological framework, which led to its classification as an infectious disease. Hereafter, London became an important centre for influenza research, where ways of knowing influenza were refashioned through the practical and epistemological resources of bacteriology. British researchers hardly acted alone. They interacted and engaged with research carried out in Germany, France, the United States and elsewhere. Determining the specific aetiology of the disease was an international phenomenon, in which identifying the ‘germ’ of influenza became increasingly important to understanding and managing its epidemiological, clinical, and pathological characteristics. At the same time, local contexts shaped how this imperative developed and played out. Innovations made in Berlin were not readily recognised or taken up in London. For some contemporaries, the ways of knowing that took hold during the 1889–1894 epidemic represented a fundamental break in the medical history of influenza, where ‘traditional’ concepts of the disease were swept away by ‘modern’ concepts and methods embodied by scientific medicine. As influenza became an object of scientific medicine, it also gained an increasingly important role in the affairs of nations as a malady of modern life. Some went so far as to claim that the pandemic marked the birth of a new disease altogether, ‘modern influenza’. This demarcation is attractive and, as the title of this book suggests, has heuristic value. But it needs to be qualified. Close attention has to be paid to how the meaning of influenza changed over time. By 1890, the term ‘influenza’ had been part of the medical lexicon for over a century, during which time it had become widely used but also much contested. Some agreement had been forged on a general clinical picture and many medical observers

18 Michael Worboys, ‘Practice and the Science of Medicine in the Nineteenth Century’,

Isis, 102.1 (2011), 109–115; William F. Bynum, ‘The Rise of Science in Medicine, 1850– 1913’, in W.F. Bynum, A. Hardy, S. Jacyna, C. Lawrence and E.M. Tansey (Eds.), The Western Medical Tradition: 1800 to 2000 (Cambridge: Cambridge University Press 2006), 111–239; Christoph Gradmann, Laboratory Disease: Robert Koch’s Medical Bacteriology. Trans. Elborg Forster (Baltimore: Johns Hopkins University Press, 2009).

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viewed influenza as a specific entity. However, there were sharp disagreements on questions about its characteristics, origins (cause), and how it spread. Epidemics through the nineteenth century were epistemological battlegrounds over these questions, with individual observers offering all manner of explanation depending on their commitments to miasmatic, contagionist, telluric or a combination of these and other perspectives. The 1889–1894 epidemic was no different. The first to strike Europe in more than forty years, large-scale investigations were seen as opportunities to use approaches developed in the intervening decades to settle disagreements and generate new knowledge. And yet, at least initially, they tackled the same questions and arrived at similar conclusions as before. Older concepts were not suddenly overturned, as some hoped or believed. Nonetheless, the 1889–1894 epidemic marked a turning point. By the mid-1890s, influenza was being reframed as a specific infection, caused by a ‘germ’ that spread from person-to-person. What set ‘modern influenza’ apart from ‘traditional influenza’ was that its identity was now intimately connected to the growing importance of bacteriology in determining the nature and cause of infectious diseases, how they spread, the symptoms and pathologies they produced, and how best to treat and prevent them. Modern influenza was, in many respects, born with bacteriology. But the relationship was troubled from the start. First, other approaches, notably epidemiological case-tracking methods, played a crucial role in framing influenza as an infectious disease. While bacteriological concepts and practices were important resources, they were unevenly incorporated into medicine and public health. Modern influenza was not the product of a ‘bacteriological revolution’ that swept aside other approaches but of a combination of new ways of knowing that linked together pathogens, patients, and populations and formed the foundations of scientific medicine.19

19 My analysis is allied with revisionist accounts of the so-called bacteriological revolution. Michael Worboys, ‘Was There a Bacteriological Revolution in Late Nineteenth Century Medicine?’ Studies in History and Philosophy of Biological and Biomedical Sciences 38 (2007), 20–42. However, I also draw on important studies that have historicised the bacteriological revolution. Bruno Latour, The Pasteurization of France (Cambridge, MA: Harvard University Press, 1988); Andrew Cunningham, ‘Transforming Plague: the Laboratory and the Identity of Infectious Disease’, in A. Cunningham and P. Williams (Eds.), The Laboratory Revolution in Medicine (Cambridge: Cambridge University Press, 1992), 209–244.

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Second, while bacteriology provided an important framework for understanding influenza, it also provided the wrong agent around which the medical community came to be organised for more than a generation. First identified in 1892 by the German bacteriologist, Richard Pfeiffer, the so-called ‘influenza bacillus’ (or ‘Pfeiffer’s bacillus’) was characterised as the primary cause of influenza for nearly forty years. In hindsight, modern influenza initially rested on an error. It would be easy to dismiss the bacillus as an erroneous object that led medicine and public health astray, as has been the case in most histories. We now know that influenza is a viral not a bacterial infection. However, to understand why and how this distinction came to matter, we need to track back to how a bacillus was established as the causative agent, its role in reframing influenza as a specific infection, and how it shaped late nineteenth and early twentieth-century laboratory, clinical, and public health approaches to the disease. Paying attention to this history is essential for understanding how the bacillus and the general conception of influenza as a bacterial disease came to be challenged, and how such challenges played a role in reframing influenza as a viral disease. Bacteriological failures, as historians have shown, were as important as successes in changing approaches to infections.20 Challenges to the bacillus and bacteriology first surfaced in the early 1900s, but they crystallised during the devastating 1918–1919 pandemic. Much historical work has retrospectively linked the emergence and virulence of the pandemic to war conditions—troop movements, trench warfare, the massing of soldiers in camps.21 But as Roger Cooter has suggested, the relationship between wars and epidemics has often been 20 For example, see Michael Worboys, Spreading Germs: Disease Theories and Medical Practice in Britain, 1865–1900 (Cambridge: Cambridge University Press, 2000), 108– 149; Christoph Gradmann, ‘Robert Koch and the Pressures of Scientific Research: Tuberculosis and Tuberculin’, Medical History, 45.1 (2001), 1–32. For failure in science and medicine more generally, see Jutta Schickore, ‘“Through Thousands of Errors We Reach the Truth”—But How? On the Epistemic Roles of Error in Scientific Practice’, Studies in History and Philosophy of Science, 36.3 (2005), 539–556; Thomas Schlich, ‘Making Mistakes in Science: Eduard Pflüger, His Scientific and Professional Concept of Physiology, and His Unsuccessful Theory of Diabetes (1903–1910)’, Studies in History and Philosophy of Science, 24 (1993), 411–441. 21 Margaret Humphreys, ‘The Influenza of 1918: Evolutionary Perspectives in a Historical Context’, Evolution, Medicine, and Public Health, 1 (2018), 219–229; Mark Osborne Humphries, ‘Paths of Infection: The First World War and the Origins of the 1918 Influenza Pandemic’, War in History, 21.1 (January 2014), 55–81; John S. Oxford et al.,

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taken as self-evident and rarely historicised.22 In the case of the 1918– 1919 pandemic, little attention has been given to how people at the time understood or explained connections between the First World War and influenza. My analysis highlights ways in which the epidemic-and-war couplet was constructed through laboratory practices and their wartime organisation. In combatant nations such as Britain, the mass mobilisation of medicine for the war fundamentally shaped approaches to influenza. In particular, it facilitated an unprecedented outpouring of medical and scientific research, the vast majority of which was bacteriological in orientation. Medical and bacteriological interventions were closely allied with wartime imperatives, with strategic priority given to the production of vaccines to protect military populations. Yet despite the enormity of effort, scientific medicine—and bacteriology in particular—had only limited effect on the course the pandemic. Bacteriologists were unable to consistently identify Pfeiffer’s bacillus or any other bacterial agent as the cause of the epidemic. Vaccines made with different bacteria offered little or no protection. In some quarters, the inability to halt the pandemic in any significant way represented a monumental failure of scientific medicine. For some time now, historians have argued that a common response to the 1918 pandemic was for societies and medical professionals to either wilfully forget the event by erasing it from public memory or to keep memories private.23 The ‘forgotten pandemic’ remains a dominant

‘World War I May Have Allowed the Emergence of “Spanish” Influenza’, The Lancet Infectious Diseases Journal, 2.2 (2002), 111–114; Robert J. Brown ‘The Great War and the Great Flu Pandemic of 1918’, Wellcome History, 24, 5–7; John S. Oxford, ‘The So-Called Great Spanish Influenza Pandemic of 1918 May Have Originated in France in 1916’, Philosophical Transactions of the Royal Society of London, B, 336 (2001), 1857–1859; Andrea Tanner ‘The Spanish Lady Comes to London: The Influenza Pandemic 1918– 1919’, London Journal, 27 (2002), 51–76; Carol R. Byerly Fever of War: The Influenza Epidemic in the U.S. Army during World War I (New York: New York University Press, 2005). 22 Roger Cooter ‘Of War and Epidemics: Unnatural Couplings, Problematic Conceptions’, Social History of Medicine, 16 (2003), 283–302. 23 Alfred Crosby, America’s Forgotten Pandemic—The Influenza of 1918 (Cambridge: Cambridge University Press, 1989), argued, in passing, that memories of the pandemic in America were largely preserved in private memoirs of survivors and of some medical researchers. Nancy Bristow has developed this observation, highlighting how doctors, nurses and survivors also remembered, memorialized and forgot the pandemic. Nancy K.

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trope.24 Yet an equally common response, generally neglected by historians, was to turn the existential challenges of the pandemic into new opportunities.25 This is exactly what the British Medical Research Council did in the 1920s. Under the direction of its secretary, Walter Morley Fletcher, the problems posed by influenza were translated into the development of new areas of basic scientific research. The MRC mobilised the pandemic as part of a larger agenda to scientifically modernise approaches to infectious disease.26 In 1922, it established a programme of virus research tasked with unravelling the causes of diseases that had stymied bacteriologists. The pandemic was pivotal to this development. The failures of bacteriology ignited interest in the possible role of other agents, with priority given to so-called ‘filterable viruses’. French and British researchers had started to study the possible roll of a filterable virus during the pandemic, but with poor methods and results. Nonetheless, in Britain, these investigations not only connected the pandemic to a filterable virus, but they also connected virus research to the wartime organisation of pathology. Both were used by the MRC as a rationale for developing virus research in the 1920s. Fletcher and his colleagues were convinced that virus research was not just a new way into solving influenza but a way to shape the development of a novel medical scientific field through Bristow, American Pandemic: The Lost Worlds of the 1918 Influenza Epidemic (Oxford: Oxford University Press, 2012). 24 Samuel K. Cohn has recently addressed this issue. Samuel K. Cohn, Epidemics: Hate and Compassion from the Plague of Athens to Aids (Oxford: Oxford University Press, 2018), 423–424. 25 For a reassessment of the role of medicine and science in remembering the pandemic, see Guy Beiner, ‘The Great ‘Flu Between Remembering and Forgetting’, in idem. (Ed.), Pandemic Re-awakenings: The Forgotten and Unforgotten ’Spanish’ Flu of 1918–1919 (Oxford: Oxford University Press, 2021), 14–18; Jeffrey S. Reznick, ’The Past, Present and Future of Memory: Medical Histories of the 1918–19 Influenza Epidemic in the United States’, in Guy Beiner (Ed.), Pandemic Re-awakenings, 234–243. 26 Joan Austoker and Linda Bryder, ‘The National Institute for Medical Research and Related Activities of the MRC’, in J. Austoker and L. Bryder (Eds.), Historical Perscpectives on the Role of the MRC: Essays in the History of the MRC of the United Kingdom and its Predecessor, the Medical Research Committee, 1913–1953 (Oxford: Oxford University Press, 1989) 39; A.L. Thomson, Half a Century of Medical Research. The Programme of the Medical Research Council (UK), Vol. 2 (London: HMSO, 1975), 114; Roger Cooter, ‘Keywords in the History of Medicine: “Teamwork”’, Lancet, 363.9416 (April 10, 2004), 1245; Andrew Hull, ‘Teamwork, Clinical Research, and the Development of Scientific Medicines in Interwar Britain: The “Glasgow School” Revisited’, Bulletin of the History of Medicine, 81 (2007), 569–593.

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British leadership. If questions about influenza’s virus identity—and more general questions about virus diseases—were to be successfully investigated, new researchers and institutions had to be created. By translating the influenza pandemic into a crucial matter for modern medical science and the state, the MRC ensured that influenza figured in the construction of virus research and, with it, the creation of virus diseases as a new class of medical problem that would be shown to be major factors in contemporary health. At the time, yellow fever, polio, and smallpox were the only human infections in this category. A decade later, on the back of these developments, influenza would be reframed as a virus disease, and the reputation of the MRC and Britain as a world leader in virus research would be firmly established. The NIMR was the institutional home of the virus programme and served as the flagship for the MRC’s modernising agenda. At the heart of this agenda was a commitment to making laboratory-based experimental science the foundation of British medicine.27 Fletcher and his colleagues were convinced that the existing professional and epistemological structures of medicine constrained scientific research they deemed essential to effectively combatting threats to national health.28 The influenza pandemic underscored the urgent need to change these structures and virus research was viewed as one way to do so. In particular, virus research was enrolled to remake pathology as a stand-alone experimental science freed from the traditional service demands of clinical and public health medicine.29 Virus diseases were among a core set of problems that demanded a new experimental pathology that rested on

27 Steve Sturdy, ‘War as Experiment: Physiology, Innovation and Administration in Britain, 1914–1918: The Case of Chemical Warfare’, in R. Cooter, M. Harrison and S. Sturdy (Eds.), War, Medicine and Modernity (London: Sutton), 79; Robert E. Kohler, ‘Walter Fletcher, F.G. Hopkins, and the Dunn Institute of Biochemistry: A Case Study in the Patronage of Science’, Isis, 69 (1978), 331–355. 28 Christopher C. Lawrence, ‘Still Incommunicable: Clinical Holists and Medical Knowledge in Interwar Britain’, in C. Lawrence and G. Weisz (Eds.), Greater Than the Parts: Holism in Biomedicine, 1921–1950 (Oxford: Oxford University Press 1998), 94–111. 29 Steve Sturdy, ‘The Political Economy of Scientific Medicine: Science, Education and the Transformation of Medical Practice in Sheffield, 1890–1922’, Medical History, 36 (1992), 125–159; Steve Sturdy and Roger Cooter, ‘Science, Scientific Management, and the Transformation of Medicine in Britain c. 1870–1950’, History of Science, 36 (1998), 421–466.

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broad collaboration between experts from a range of fields, including physiology, chemistry and physics.30 Through a combination of strategic recruitment, network building, and departmental organisation, the NIMR created the necessary conditions for collaboration that would underpin this programme. Collaboration was not just internal to experts at the Institute but extended beyond its walls. The NIMR built relations and partnerships with hospital clinicians, military and public health doctors, municipal and voluntary hospitals, public schools, patrons, pharmaceutical companies, the popular press, and public bodies that supported and wanted to be involved in the enterprise. Through the 1920s, NIMR workers approached influenza indirectly through the study of other virus diseases. The most notable and important was the dog disease, canine distemper. The main reason for this approach was that influenza research was hampered by the lack of a suitable experimental animal in which to test, grow, and visualise suspected viruses. Unlike bacteria, at the time viruses could not be grown in artificial media, but only directly in the cells and tissue of living organisms—occasionally humans, but mostly laboratory animals. This characteristic came to be widely recognised in the 1920s, along with two other defining properties: viruses passed through standard bacterial filters—hence the term, ‘filterable virus’—and they could not be made visible by standard methods of light microscopy. Until effective tissue culture techniques were developed in the 1950s, human and animal viruses could only be studied experimentally through diseases produced in laboratory animals. To address the lack of such an animal, NIMR workers turned to canine distemper as a proxy for influenza. The decision proved to be remarkably successful. Dog distemper served as the principal focus of virus research at the Institute for over a decade. It gave rise to a distinctive style of research

30 For the centrality of collaboration in early twentieth century biomedicine, see Ilana Löwy, ‘Historiography of Biomedicine: ‘Bio,’ ‘Medicine,’ and In Between’, Isis, 102.1 (2011), 116–122; Viviane Quirke and Jean-Paul Gaudillière, ‘The Era of Biomedicine: Science, Medicine, and Public Health in Britain and France After the Second World War’, Medical History 52.4 (2008), 441–452; Jean-Paul Gaudillière, Inventer la biomédicine: La France, l’Amerique et la production des savoirs du vivant (Paris: La De´couverte, 2002); Soraya de Chadarevian and Harmke Kamminga, eds., Molecularizing Biology and Medicine: New Practicesand Alliances, 1910s–1970s (Amsterdam: Harwood, 1998).

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that would become the hallmark of the NIMR approach.31 First, it was broadly comparative and involved working analogically between different species and virus diseases—human and animal—to develop new skills, techniques, and knowledge necessary for studying viruses. The ferret, which would be so critical to influenza research in the 1930s, first became a laboratory animal in work on distemper. Second, as noted above, it was broadly collaborative, drawing together and integrating disparate kinds of expertise to tackle fundamental problems posed by viruses, including their cultivation, visualisation, and filtration. Third, it was broadly cooperative and involved building and sustaining partnerships with a heterogenous ensemble of ‘lay’ constituencies who would play vital roles in the research process and in the broader legitimisation of virus work and virus diseases as major health problems. Fourth, it became broadly commercial and involved translating basic laboratory research into widely used diagnostics, therapeutics, and vaccines mass-produced by large pharmaceutical companies. And finally, it was international in scope, with support coming from across the British empire and the United States of America, with researchers exchanging results, and with research products used to treat and protect canine populations circulating around the world. These characteristics were not unique to the distemper work or the NIMR research programme.32 But in specific ways, dog distemper was critical for laying the foundations of virus research at the NIMR and would become a key organisational model for influenza research in the 1930s. Wider developments in human and animal virus research were also important. The NIMR programme was part of a small but burgeoning international network of medical and veterinary virus research that was 31 For general details, see, Michael Bresalier and Michael Worboys. ‘Saving the Lives of Our Dogs: The Development of Canine Distemper Vaccine in Interwar Britain’, British Journal for the History of Science, 47 (2014), 305–334. 32 For example, Sabina Clarke ‘Pure Science with a Practical Aim: The Meanings of Fundamental Research in Britain, Circa 1916–1950’, Isis, 101 (2010), 285–311; Viviane Quirke, Collaboration in the Pharmaceutical Industry: Changing Relationships in Britain and France, 1935–1965 (London: Routledge, 2007); John Liebenau, ‘The MRC and the Pharmaceutical Industry: The Model of Insulin’, in J. Austoker and L. Bryder (Eds.), Historical Perspectives on the Role of the MRC (Oxford: OUP, 1989); Christopher Lawrence, Rockefeller Money, the Laboratory, and Medicine in Edinburgh, 1919–1930: New Science in an Old Country (Rochester, NY: University of Rochester Press, 2005); Ilana Löwy and Patrick Zylberman, ‘The Rockefeller Foundation and the Biomedical Sciences’, Studies in History and Philosophy of Biological and Biomedical Sciences, 31c (2000), 365–509.

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supported and financed but only loosely coordinated by the Americanbased but globally-reaching Rockefeller Foundation.33 NIMR workers maintained close ties with Rockefeller Foundation researchers and institutions through various forms of research exchange. These proved to be critical to the NIMR’s influenza virus work.34 An important spur for the Institute’s decision to work directly on human influenza came from a discovery made by Richard E. Shope at the Rockefeller Foundation’s Animal Pathology Laboratories at Princeton University. In 1931, Shope determined that a filterable virus was the causative agent of swine influenza, a highly contagious disease that affected pig populations and was widely thought to be closely related to human influenza. When Patrick Laidlaw, C.H. Andrewes, and Wilson Smith embarked on their influenza virus work at the NIMR a year later, the relationships they developed and maintained with Shope and other Rockefeller researchers would be key to the rapid pace that research on human and swine influenza unfolded. Scientific exchanges and developments were not the only factors that drove the NIMR’s move into influenza virus research. Through the 1920s and early 1930s, recurring influenza epidemics invoked memories and fears of the 1918–1919 pandemic. The MRC used these to garner support for the virus programme. But political and public concerns about influenza, filtered through the popular press, also concentrated attention on and added urgency to finding new ways to address the disease. While influenza had emerged as an inescapable malady of modern life at the turn of the century, after 1918 it was widely perceived as a major threat to modern life itself. Its heightened profile was reflected in the growing use of ‘flu (rather than influenza) as a popular term. Originating in the midnineteenth century, the term proliferated in the 1920s, with doctors and

33 Barbara Canavan, ‘Collaboration Across the Pound: Influenza Virus Research, Interwar United States and Britain’, Rockefeller Archive Center Research Reports Online, 31 December 2014; William H. Schneider, ed., Rockefeller Philanthropy and Modern Biomedicine: International Initiatives from World War I to the Cold War (Bloomington: University of Indiana Press, 2002). 34 With the exception of Patrick Laidlaw, all of the members of the NIMR team that worked influenza in the 1930s had received training from or had visited Rockefeller Foundation institutions.

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patients using it as a catchall for a host of respiratory, gastric, and neurological conditions.35 The spreading of ‘flu gained currency as a metaphor for a variety of political and economic anxieties of the age: not just epidemics, but financial crises, Bolshevism, crime, national degeneration, and inefficiency. Initially, there was little agreement on how best to tackle the ‘flu problem. Sharp divisions existed between the MRC and the Ministry of Health, both of which government looked to for new approaches after 1918. Whereas the Ministry framed influenza as a complex epidemiological problem requiring a broadly holistic approach, the MRC framed it as a basic research problem requiring systematic experimentation to determine the specific cause of the disease. The MRC promoted virus research as vital and redefining influenza as a virus disease was central to this project. Yet, only in the 1930s did the MRC vision start to become a reality. Even then, the process was hardly straightforward. It entailed re-organising medicine and public health around influenza viruses as tangible pathogens that caused outbreaks and epidemics which burdened the nation, empire , and wider world. For this to happen, a new medical consensus had to be built. Revisionist histories of the adoption and use of laboratory knowledge and practices have demonstrated the evolutionary rather than revolutionary nature change in modern medicine.36 However, as Steve Sturdy has argued, a strong tendency has been to examine this dynamic through the prism of the ‘essential tension’ between medical practice and medical science.37 Conflict has been the status quo ante in studies of the relations between the laboratory, the clinic, and the field, with each domain characterised as having distinctive, if not incommensurable, institutional

35 The OED dates the first use of the term to 1839. Chambers Journal referred to the ‘flu season’ in 1911. General use became frequent in the 1920s and 1930s, especially in patent medicine advertising, and NIMR workers used it in the vernacular. Its medical use in the Lancet and BMJ began in the early 1940s. 36 For example, Christopher Lawrence, ‘Incommunicable Knowledge: Science, Technology and the Clinical Art in Britain, 1850–1914’, Journal of Contemporary History, 20 (1985), 503–520; J.D. Howell, Technology and the Hospital: Transforming Patient Care in the Early Twentieth Century (Baltimore: Johns Hopkins University Press, 1995). 37 Steve Sturdy, ‘Looking for Trouble: Medical Science and Clinical Practice in the Historiography of Modern Medicine’, Social History of Medicine, 24, 3 (2011), 739–757.

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commitments, interests, values, skills, norms of practice, and evidence.38 One consequence of this focus is that other kinds of negotiation, particularly those involving collaboration between laboratory, clinical, and public health practitioners, have been cast as exceptional rather than intrinsic to the making of modern medicine. As a corrective, recent historical work has pointed to important patterns of convergence, in which clinical and epidemiological knowledge shaped and was shaped by laboratory knowledge.39 This pattern has been well demonstrated for the integration of bacteriology into different realms of medical practice, and its role in changing definitions of disease at the end of the nineteenth century. This book shows that with virus research the pattern continued to evolve and became more complex in the twentieth century. Modern Flu approaches the process of redefining influenza as an example of how aligning different forms of knowledge was integral to creating the identity of a viral disease. Examining patterns of convergence between the different professions, specialisms, disciplines, institutions, and practices around which modern medicine has been organised yields a more rounded and empirically rich picture of the dynamics of producing medical scientific knowledge, in which consensus-building was central. In the case of influenza, consensus-building depended on the alignment and integration of virological knowledge with existing epidemiological, clinical, and pathological knowledge.40 The ideas and practices of virus research had to be legitimised among those constituencies who claimed authority over influenza—clinicians, pathologists, epidemiologists, and public health officials. These constituencies understood influenza from

38 For an overview, see Morten Hammerborg, ‘The Laboratory and the Clinic Revisited: The Introduction of Laboratory Medicine into the Bergen General Hospital, Norway’, Social History of Medicine, 24.3 (2011), 758–775. 39 For general approaches to aligning different medical knowledge, see Ilana Löwy, ‘Medicine and change’, in I. Löwy and J.-P. Gaudillière (Eds.), Medicine and Change: Historical and Sociological Studies of Medical Innovation (Montrouge, France: John Libbey Eurotext, 1993), 1–19; Annemarie Mol, ‘Pathology and the Clinic: an Ethnographic Presentation of Two Atheroscleroses’, in M. Lock, A. Young and A. Cambrosio (Eds.), Living and Working with the New Medical Technologies. Intersections of Inquiry (Cambridge: University of Cambridge, 2000), 82–102. 40 For the importance of alignment, see Joan H. Fujimura, ‘Constructing “Do-able” Problems in Cancer Research: Articulating Alignment’, Social Studies of Science, 17 (1987), 257–293.

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different viewpoints and connected disease definitions to their own scientific, clinical, social, and political agendas. Modern Flu details the varied ways in which physicians and pathologists, clinical, public health, and scientific institutions, and medical and popular media shaped the reception, meanings, and uses of a new virus disease. Only by demonstrating the value of the influenza virus for explaining the cause, clinical picture, pathology, and epidemiology of the disease could virus workers make it indispensable to medical and public health knowledge and practices in Britain and beyond. A key methodological framing of the history of influenza in the twentieth century is ‘viralisation’, a concept that underpins scientific as well as cultural meanings. Viralisation denotes the complex and uneven ways in which influenza virus was incorporated into medicine and public health in the 1930s and 1940s. While changing medicine in significant ways, the process did not result in the reduction of all aspects of the disease to a single causative agent framed exclusively in virological terms. What is fascinating and important to understand is that as significant as virology would become in approaches to influenza after the Second World War, it never completely colonised meanings or experiences of the disease. Viralisation was a productive rather than reductive process: it involved the creation of a new disease entity and new medical experts, ideas, methods, social relations, and institutions for recognising influenza as viral. Virological concepts and techniques were at once adapted to and selectively incorporated into different medical fields. Agreement on the specific role of influenza viruses was the outcome of a process of mutual alignment and accommodation, in which virological, clinical, pathological, and epidemiological approaches were modified and made commensurable.41 Modern Flu tells the story of how the greatest pandemic threat of the twentieth century was made viral between 1890 and 1945. While intimately connected to the increasingly important role of virus research 41 Similar dynamics have been identified in histories examining the relationship between the ‘bench’ and the ‘bedside’ in constructions of cardiac disease, cancer, aphasia, and allergy. See, for example Ilana Löwy, Between Bench and Bedside: Science, Healing and Interleukin-2 in a Cancer Ward (Cambridge, MA: Harvard University Press, 1997); L.S. Jacyna, Lost Words: Narratives of Language and the Brain, 1825–1926 (Princeton, NJ: Princeton University Press, 2000); Mark Jackson, ‘“A Private Line to Medicine”: The Clinical and Laboratory Contours of Allergy in the Early Twentieth Century’, in K. Kroker, J. Keelan and P.M.H. Mazumdar (Eds.), Crafting Immunity: Working Histories of Clinical Immunology (Aldershort: Ashgate, 2008), 55–76.

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in efforts to scientifically modernise medicine, equally important were pandemics, wars, and the modernising state. Pandemics in the 1890s and in 1918 presented novel conditions and opportunities for governments and researchers to carry out large-scale studies on the most pressing questions concerning the identity and control of influenza. Failures to resolve such questions may have resulted in moments of epistemological crisis but they were quickly translated into new opportunities that drove the development of virus research. Wars were also important contexts of experimentation, but, more importantly, wartime organisation of medical science fundamentally shaped strategies for tackling influenza, with priority in both the First and Second World Wars given to identifying causative agents and mass-producing vaccines for military populations. In the aftermath of the 1918 pandemic, and between the two wars, state-sponsored and organised virus research would become crucial to establishing influenza’s identity as a viral disease. During the Second World War, fears that war conditions would give rise to another pandemic spurred efforts to translate interwar developments into systems for mass-producing and testing influenza virus vaccines. The key organisational model came from the United States Commission on Influenza (COI), with American researchers working in collaboration with British and allied researchers in developing effective vaccines for mass immunization of allied troops. The COI programme made the prospect of controlling influenza through immunization a postwar reality for some highly developed nations. Yet, at the same time, mass vaccination systems put a spotlight on a major practical problem, which had been first identified in the late 1930s: antigenic variation among influenza viruses. Rather than being stable entities, influenza viruses were shown to be highly susceptible to evolutionary and genetic change, constantly yielding new variants or subtypes. Such variation posed a significant problem for vaccine manufacture. It became clear to researchers such as C.H. Andrewes that because new strains could appear from any part of the world, vaccine systems had to be underpinned by a world-wide system of influenza virus surveillance. In 1947, Andrewes and leading virus researchers from around the world proposed establishing such a system as part of the agenda of the newly formed World Health Organization (WHO). The World Influenza Programme (WIP) came into being in 1948 with the combined task of collecting, characterising, and sharing influenza viruses from every corner of the globe. Its connected aims were to make it possible to ‘forecast’ epidemics and rapidly provide vaccine

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makers with the right virus strains. The viralisation of influenza would be internationalised under the WIP. Controlling influenza now would be based on the close integration of world-wide virus surveillance and vaccine production. Through the second half of the twentieth century and into the twenty-first century, the programme evolved, expanded, and changed to become the model not just for controlling human and animal influenza viruses, but for responding to the threats posed by so-called emerging infections.42 Indeed, the global systems that were built to control influenza over the last seventy-five years were vital to the global response to Covid-19. But as with so many post-war world health projects, the process of globalising influenza control would be riven by contradictions, revealing as well as reproducing marked divisions and inequities between so-called ‘developed’ and ‘developing’ nations. While the architects of the WIP aspired to create a system for freely sharing influenza viruses among WHO member states, vaccine production capacity and vaccine programmes remained largely concentrated in high-income countries, which prioritised their own populations. Forms of vaccine nationalism co-existed alongside the internationalisation of influenza virus surveillance. Influenza was made viral through a conjunction of two pandemics, two world wars, government research and international connexions that spurred forty years of scientific development and innovation. Success came so quickly in 1933 only because so much had been put in place in the decades before. The transformations in medical knowledge of the 1890s, the experience of 1918, the post-pandemic modernising agenda of the MRC, the development of virus research at the NIMR in the 1920s, American patronage and partnerships before and during the Second World War, political and public support, and the formation of the World Health Organization, created the conditions for success. Nevertheless, no one in 1890, let alone 1918 or 1933, could have foretold that by the end of the Second World War the identities of influenza would pivot on the identities of a virus. Modern Flu is a history of unanticipated outcomes and their consequences.

42 Carlo Caduff, The Pandemic Perhaps: Dramatic Events in a Public Culture of Danger (Berkeley: University of California Press, 2015); Lorna Weir and Eric Mykhalovskiy, Global Public Health Vigilance: Creating a World on Alert (New York: Routledge, 2010).

CHAPTER 2

Naming Flu: Classification and Its Conflicts

In his famous opening to War and Peace, Leo Tolstoy set the manners and intrigues of the Russian court against the backdrop of two great new menaces, Napoleon Bonaparte and influenza. The disease enters at the outset of the novel during a reception hosted in 1805 by Anna Pavlovna, ‘maid of honour and favourite of the Empress….’ As Anna Pavlovna and her guests worry over Bonaparte’s imperial ambitions, she confides that she has been suffering from a bout of ‘grippe’. This was ‘a new word in St Petersburg, used only by the elite’ for a debilitating malady associated with a bewildering array of constitutional symptoms that physically gripped the sufferer with fever, bodily aches, and severe prostration.1 The term ‘grippe’ came from France, where it had become part of medical discourse from the end of the eighteenth century. English physicians had identified a similar condition earlier, naming it influenza. But French terms were preferred and fashionable in the Russian court.2 In Tolstoy’s aristocratic Russia, grippe was a marker of social status and distinction. While quickly disappearing from the story, its brief appearance reflected an important change in the place of the disease in nineteenth-century

1 Leon Tolstoy, War and Peace (Oxford: Oxford University Press, 2010), 3. 2 Derek Offord, Larissa Ryazanova-Clarke, Rjéoutski Vladislav, and Gesine Argent

(Eds.), French and Russian in Imperial Russia. Volume 1, Language Use Among the Russian Elite (Edinburgh: Edinburgh University Press, 2015).

© The Editor(s) (if applicable) and The Author(s), under exclusive licence to Springer Nature Limited 2023 M. Bresalier, Modern Flu, Medicine and Biomedical Sciences in Modern History, https://doi.org/10.1057/978-1-137-33954-6_2

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European medicine and society. When Tolstoy’s epic begins in 1805, grippe and its English equivalent were just becoming common terms in European medicine, accessible to medical and literate elites. By the 1860s, when Tolstoy published War and Peace, these terms not only had become generally commensurable but, crucially, increasingly part of everyday language, which medical practitioners and lay people from different social strata used to characterise and explain severe cold-like symptoms, with fever, fatigue, crippling body pain and headaches. The use of influenza as a commonplace medical term in the early nineteenth century was entirely new. It had only become part of medical discourse at the end of the eighteenth century. Before then, it did not exist in the medical lexicon. Doctors did not use it as term to capture a complex array of symptoms in their diagnoses. It was not something they studied or sought to know because it had yet to be classified as a disease. As Charles Rosenberg argued, ‘in some ways disease does not exist until we have agreed that it does, by perceiving, naming, and responding to it.’3 Influenza only came into being as an object of medical knowledge and something to have and suffer from when it was named.

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Naming Influenza

Medical practitioners in England and Scotland started using ‘influenza’ to denote an epidemic disease that began visiting the British Isles in the 1740s. Its emergence as a medical term in the mid-eighteenth century corresponded with the development of a new Enlightenment medical epistemology, which approached diseases as entities with distinctive and specific properties—symptoms and signs—that could be used as the basis for comparison and classification. Some historians argue that this ‘natural historical’ approach marked the beginning of modern medical understanding of disease.4 It was crucial to establishing influenza as both a 3 The classic analysis of the role of naming in ‘framing’ disease is Charles Rosenberg, ‘Introduction: Framing Disease: Illness, Society and History’, in Charles Rosenberg and Janet Golden (Eds.), Framing Disease (New Brunswick, NJ: Rutgers University Press; 1992), xiii. See also, Charles Rosenberg, ‘Framing Disease: Illness, Society, and History’, in idem., Explaining Epidemics and Other Studies in the History of Medicine (Cambridge: Cambridge University Press, 1992), 305–318. 4 John V. Pickstone, ‘Natural Histories, Analyses and Experimentation: Dissecting the Working Knowledges of Chemistry, Medicine and Biology Since 1750’, History of Science, 49 (2011), 235–376.

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name doctors used to identify and characterise a specific disease and as an object of medical investigation. Yet, influenza also came to be an example of a number of diseases that challenged ideas of specificity because it seemed to take on so many different forms and, indeed, to change forms altogether. Thus, while influenza was constituted as a medical entity in the context of Enlightenment medicine that took hold in England and Scotland in the mid-eighteenth century, its identity was hardly fixed. ‘Influenza’ could mean many things. When exactly the term was first introduced into the medical lexicon is unclear. The Victorian historical epidemiologist, Charles Creighton, traced its first usage to England during an epidemic in 1730. Others have claimed that English and Scottish physicians began using it in 1743 to describe a fever that seemed to suddenly spring upon the British Isles and continental Europe.5 The appearance of the fever corresponded with reports from Rome of ‘a contagious Distemper raging there, call’d the Influenza.’6 Whatever the exact date, the term likely derived from two Italian phrases, influenza di freddo and influenza coeili, which had been in use in Italian states from the early sixteenth century and were tied to Hippocratic medical systems.7 Rather than specific things, Hippocratic systems viewed diseases as imbalances, the result of one or a combination of factors related to individual constitutions or behaviours.8 Likewise, epidemics were attributed to imbalances in the constitution of a local environment or atmosphere, related to qualities of climate, air, humidity,

5 Charles Creighton, A History of Epidemics in Britain, Vol. II (London: Cambridge University Press, 1894), 345; Francis Graham Crookshank, ‘The Name and Names of Influenza’, in Francis GrahamCrookshank (Ed.), Influenza: Essays by Several Authors (London: Heinemann, 1922), 67. 6 The London Magazine ‘Article of News from Rome’ (1743), 145. 7 W.I.B. Beveridge, Influenza: The Last Great Plague, An Unfinished Story of Discovery

(London: Heinemann, 1977), 24–25; David Cantor, ‘Western Medicine Since the Renaissance’, in P. Promann (Ed.), The Cambridge Companion to Hippocrates (Cambridge: Cambridge University Press, 2008), 362–383. 8 Andrew Wear, ‘Place, Health, and Disease: The Airs, Waters, Places Tradition in Early Modern England and North America’, Journal of Medieval and Early Modern Studies, 38 (2008), 443–465; Frederick Sargent II, Hippocratic Heritage: A History of Ideas About Weather and Human Health (New York: Pergamon Press, 1982); Jan Golinski, British Weather and the Climate of Enlightenment (Chicago: University of Chicago Press, 2007).

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temperature, and other variables.9 The original meanings of ‘influenza’ were rooted in these traditions. It was not a specific disease but an ‘influence’. Influenza coeili meant influence of the heavens and stars and referred to a general astral or occult phenomenon that assailed large numbers of people at the same time.10 Influenza di freddo meant influence of the cold and explained disease-states in terms of general climatic or weather conditions, especially those associated with autumn and winter. Early uses of the term in English medicine followed the spirit of these explanations.11 The Devon physician, John Huxham, whose 1750 Essay on Fevers is thought to be among the first texts to formally adopt ‘influenza’, emphasised its connection to atmospheric states, noxious gases released by volcanic eruptions and earthquakes, and the influence of planets, comets, or meteors.12 Huxham and his contemporaries readily invoked the idea of an ‘epidemic constitution’, which had been popularised in the seventeenth-century writings of the ‘English Hippocrates’, Thomas Sydenham, and they associated influenza with changes in local conditions, including temperature, moisture, qualities of the air, and the density of fogs.13 These older meanings retained their currency and appeal through the nineteenth century. But as influenza was adopted as a general medical term, they were also challenged.

9 Andrea A. Rusnock, ‘Hippocrates, Bacon, and Medical Meteorology at the Royal Society, 1700 –1750’, in D. Cantor (Ed.), Reinventing Hippocrates (Aldershot, Hampshire: Ashgate Press, 2002), 136–153. 10 Beveridge, Influenza: The Last Great Plague, 24. 11 The first historical chronology of influenza to trace the name was Theodiphilus

Thompson, Annals of Influenza or Epidemic Catarrhal Fever in Great Britain from 1510– 1837 (London: The Sydenham Society London, 1852). 12 August Hirsch, Handbook of Geographical and Historical Pathology (London: New Sydenham Society, 1883), 4–36. 13 Donald Bates, ‘Thomas Sydenham: The Development of His Thought, 1666–1676’ (Unpublished Doctoral Thesis, Johns Hopkins University, 1975), 146–152.

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New Classifications

Changes in European medicine in the eighteenth century gave rise to new approaches to defining influenza.14 Of particular importance was the growing interest with developing medical classification systems—nosologies—based on understanding diseases as specific entities.15 Doctors working in Hippocratic medicine viewed health and disease in terms of the balance or imbalance of the four humours in the body. They resisted grouping diseases into general categories because each disease was viewed as being unique to each patient or locality in which it developed. Humoralism presupposed that every form of a disease was different. Breaking with this tradition, Enlightenment medical practitioners began to approach diseases as natural kinds, akin to species of plants or animals, with characteristic and uniform symptoms that could be used as the basis for classification.16 English advocates traced the origins of this approach to Sydenham, who, along with promoting a constitutional approach to the origins of epidemics, also promoted viewing diseases as distinctive entities with distinctive cures.17 Interest in classifying diseases in this way stemmed from the general development of taxonomy in natural history, influenced by the Swedish botanist Karl von Linné (Linnaeus), author of Systema naturae (1735) and inventor of the binomial system of biological classification.18 Physicians who applied methods of natural history to

14 Christopher Lawrence, ‘The Enlightenment’, in idem., Medicine and the Making of Modern Britain (London: Routledge, 1994), 7–25; Roy Porter, ‘The Eighteenth Century’, in L. Conrad, M. Neve, V. Nutton, R. Porter and A. Wear (Eds.), The Western Medical Tradition 800BC to AD 1800 (Cambridge: Cambridge University Press, 1995), 371–475; Guenther Risse, ‘Medicine in the Enlightenment’, in A. Wear (Ed.), Medicine in Society: Historical Essays (Cambridge: Cambridge University Press, 1992), 149–196. 15 Knud Faber, Nosography: The Evolution of Clinical Medicine (New York: Paul B. Hoeber, 1930); Margaret Delacy, ‘Nosology, Mortality, and Disease Theory in the Eighteenth Century’, Journal of the History of Medicine and Allied Sciences, 54.2 (1999), 261–284. 16 Lester King, The Medical World of the Eighteenth Century (Chicago: University of Chicago Press, 1958), 194–196. 17 Andrew Cunningham, ‘Thomas Sydenham: Epidemics, Experiment and the ‘Good Old Cause’’, in Roger French and Andrew Wear (Eds.), The Medical Revolution of the Seventeenth Century (Cambridge, 1989), 164–190; Harold J. Cook, ‘Physicians and the New Philosophy: Henry Stubbe and the Virtuosi-Physicians’, in French and Wear (Eds.), Medical Revolution, 246–247. 18 Roy Porter, The Greatest Benefit to Mankind (New York: Norton, 1997), 260–262.

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medicine did so as part of a general rejection of humoralism. Observing diseases and making nosologies (disease classifications) became the order of the day.19 In France, physician-naturalists led by François Boissier de Sauvages developed complex systems that divided diseases into numerous classes, genera, and species, with the aim of creating universal nosologies to guide the physician through the labyrinth of diseases they encountered with patients.20 But the most influential nosological work came from more parsimonious Scottish and English physicians. Leading the way was a small group of acquaintances trained at the new medical school at Edinburgh University. Informed by the teachings of Herman Boerhaave, the renowned Leiden Professor of Medicine, William Cullen, John Pringle, John Fothergill, William Heberden, and William Rutty were among the pioneers of an approach that took correct classification as a principal aim of medicine. As Margaret DeLacy has shown, their approach relied on the collection and exchange of observations and experiences of fellow practitioners through local surveys.21 Viewing each disease as an unique entity, which exhibited the same basic characteristics in every place it appeared, the systematic definition of what constituted a case was crucial. Cullen and his colleagues became enthusiastic practitioners of survey and case-based methods.22 Most notably, they used these methods to untangle the many maladies defined as Pyrexia or fevers, which plagued eighteenth century men and women.23 Out the mangle of fevers they carved out such clinical entities as typhus, measles, scarlet fever, and pneumonia.24 This work became the basis for Cullen’s authoritative 19 Roy Porter, ‘Cleaning Up the Great Wen: Public Health in Eighteenth-Century London’, Medical History, Suppl. 11 (1991), 69–70. 20 Anne Kveim Lie and Jeremy A Greene, ‘From Ariadne’s Thread to the Labyrinth Itself—Nosology and the Infrastructure of Modern Medicine’, The New England Journal of Medicine, 382.13 (2020), 1273–1277. 21 Margaret DeLacy, ‘The Conceptualization of Influenza in Eighteenth Century Britain: Specificity and Contagion’, Bulletin of the History of Medicine, 67 (1993), 74–118. 22 Margaret DeLacy, ‘Influenza Research and the Medical Profession in EighteenthCentury Britain’, Albion: A Quarterly Journal Concerned with British Studies, 25.1 (1993), 37–66. 23 William F. Bynum, ‘Cullen and the Study of Fevers in Britain, 1760–1820’, in W.F. Bynum and V. Nutton (Eds.), Theories of Fever from Antiquity to the Enlightenment, Medical History Supplement (1981), 135–147. 24 Chris Hamlin, More Than Hot: A Short History of Fever (Baltimore: Johns Hopkins University Press, 2014).

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Synopsis nosologiae methodicae, first published in 1769, in which he divided diseases into four basic classes.25 Partly because of its simplicity, his system shaped the ideas and practices of doctors in the English-speaking world through the second half of the eighteenth century.26 The first systematic descriptions of influenza emerged from studies of five epidemics between 1758 and 1789. Typically, descriptions combined accounts of doctors’ own experiences with those of their patients. The Leiden-trained physician, John Pringle, initiated the earliest survey in 1758; others soon followed. Drawing on his own bout with the disease during a particularly severe epidemic in Europe and the British Isles in 1775, Pringle provided one of the more succinct accounts of its basic symptoms: ‘The species I had of Influenza was a sore throat, with fever, and shooting pain through the back part of my head; but these symptoms were never followed by a cough.’27 As doctors moved from recounting their own experiences to observing their patients, they identified different ‘varieties’ of influenza. William Heberden, the eminent London physician, renowned for his case histories, detailed its complex symptomatology: In some it began with a sickness and perpetual vomiting, which were the forerunners of a severe degree of this illness; in others the first symptoms were sneezing, and a copious defluxion from the nose and eyes, and were sooner recovered. Many complained of a hoarseness and sore throat, and of a tightness, oppression, and heat of their breasts, and feeling of pains in various parts, particularly their heads, sides, and backs. Almost every one of these patients was afflicted with a racking cough; with a sense of coldness, frequently returning upon them; with a failure of appetite and of sleep, and with a languor and weakness much greater than might have been expected from the effects of any other symptoms.28

25 William Cullen, Synopsis nosologiae methodicae (Edinburgh, 1769). 26 William F. Bynum, Science and the Practice of Medicine in the Nineteenth Century

(Cambridge: Cambridge University Press), 14–19; see also Porter, The Greatest Benefit, pp. 260ff. 27 Sir John Pringle, in Thompson, Annals of Influenza or Epidemic Catarrhal Fever (1852), 89–90. 28 William Heberden, ‘The Epidemical Cold in June and July 1767’, Medical Transactions, vol I, 3rd edition (1785), 437; op. cit. ‘Epidemic of 1767-Hederden’, in Edmund Symes Thompson Influenza, or Epidemic Catarrhal Fever: An Historical Survey of Past Epidemics in Great Britain from 1510 to 1890 (London: Percival & Co., 1890), 73.

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Collections of experiences and observations were the raw material from which physicians delineated the typical case of influenza.29 This was characterised by a particular set of symptoms—chills, headaches, muscle aches, watery eyes, cough, intense prostration, profuse sweating, and great lassitude. Physicians also started to map the clinical course of influenza—its onset, how it progressed, and how and when it ended. They noted that in some people—especially the old, the infirm and those with certain dispositions—it could quickly turn into graver respiratory conditions, including pneumonia, bronchitis, and pleurisy, or to aggravate existing ones, such as consumption.30 Despite the new focus on identifying diseases as uniform species, diagnosis was rarely based on a single characteristic sign of a particular disease, such as the pock-lesion associated with smallpox or the bubo in plague. Instead, physicians detailed and ordered all possible symptoms of a disease to generate an ideal-typical picture, which then could be compared with other diseases.31 This formed the basis of classification. Influenza posed challenges to this enterprise because its symptoms seemed inexhaustible. ‘It would be an endless task,’ noted Edward Gray, ‘to describe, minutely, the various forms which in different persons, the disorder put on.’32 The protean array of symptoms lent themselves to an equally protean number of classifications. The clinical identities of influenza proliferated. Some agreement emerged in the early 1770s when influenza started to be categorized as a type of catarrh, a cluster of conditions characterised by the inflammation of the upper respiratory tract, with consequent discharge of copious amounts of mucous through the mouth and nose.33 29 Volker Hess and Andrew J. Mendelsohn, ‘Sauvages’ Paperwork: How Disease Classification Arose from Scholarly Note-Taking’, Early Science and Medicine, 19 (2014), 471–503; G. Pomata, ‘Sharing Cases: The Observations in Early Modern Medicine’, Early Science and Medicine, 15 (2010), 193–236. 30 Delacy, ‘The Conceptualization of Influenza in Eighteenth Century Britain’, 79–92. 31 For analysis of the ideal-typical in eighteenth century medical atlases, see Lorraine

Daston and Peter Galison, ‘The Image of Objectivity’, Representations, 40 (1992), 87–95. 32 Edward Gray, ‘An Account of Epidemic Catarrh of the Year 1782’, Medical Communications—Society for Promoting Medical Knowledge, vol. i (1782); op. cit. ‘The Epidemic Catarrh of 1782—Edward Gray, M.D.., F.R.S.’, in Thompson, Influenza, or Epidemic Catarrhal Fever (1890), 118. 33 Margaret DeLacy, ‘Influenza Research and the Medical Profession in EighteenthCentury Britain’, Albion: A Quarterly Journal Concerned with British Studies, 1 (1993), 37–66.

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Catarrh was viewed as a form of fever and included many acute coldlike ailments. As part of their work of delineating fevers, Cullen and his Edinburgh colleagues sought to re-classify catarrhs into definite types.34 What we now know as influenza came from this work. Yet, setting influenza apart from other forms of catarrh on the basis of symptoms was almost impossible. Catarrhal symptoms were encountered in many other conditions, and thus lacked specificity. Physicians found that the best way to distinguish influenza was by its epidemiological characteristics and particularly its visits in epidemic years. They recognised that, unlike all other catarrhs, influenza demonstrated a unique ability to suddenly become epidemic and to rapidly engulf a town, city, nation, or continent. Influenza was thus first and foremost an epidemic disease. Investigations described it as the grandest of all epidemics, with the potential of reaching every corner of the inhabited globe. When catarrh became epidemic, late eighteenth-century physicians could be confident that it was influenza. The common English term for it became epidemic catarrh.

3

Epidemic Catarrh

Once physicians agreed on how to identify a case of influenza, they turned to studying epidemics in order to understand where it came from and how it spread.35 On these questions, medical opinion was sharply divided. Some attributed its origins and spread to the influence of the stars, the atmosphere, or the weather. A large contingent of European and English doctors viewed it as a miasma, in which air contaminated by some special means—rotting vegetative matter, urban filth, or extreme environmental conditions such as volcanic eruptions— was carried through cities and towns by prevailing winds. Miasmas could act at a distance, whereby remotely corrupted air caused spontaneous internal bodily changes in those who inhaled it. Miasma theories were attractive because they provided a ready explanation for the apparent ability of influenza to explode upon a population as an epidemic. But not all were convinced. A growing number of medical observers, many of whom took to the new methods of classification being developed in 34 William F. Bynum, ‘Cullen and the Study of Fevers in Britain, 1760–1820’, Medical History, Supp.I (1981), 135–147. 35 For these efforts, see Margaret DeLacy, Contagionism Catches On: Medical Ideology in Britain, 1730–1800 (Basingstoke: Palgrave, 2017), 125–164.

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Edinburgh, came to view influenza as a contagious disease, spread personto-person by direct or indirect contact. From the second edition of his Synopsis nosologiae methodicae, published in 1772, Cullen began characterising a ‘Catarrhus a contagio’, a contagious catarrh, and a ‘Catarrhus epidemicus ’, both of which were later taken to refer to influenza.36 While these definitions gained prominence in late eighteenth century medical circles, framings of influenza as a contagion would come under attack in the nineteenth century. Contagionists built their arguments using case-tracking methods.37 Developed in studies of smallpox and plague, the methods involved identifying first cases of a disease in a locality and then tracing its spread through a population. In turn, the method yielded insights into patterns of incidence, which often led to hypotheses about the cause of a disease. Case-tracking not only depended on an agreed clinical definition, and the idea that a species of disease manifested in the same way in different places, but also on the ability to widely circulate and exchange medical knowledge. Growth in new forms of medical communication in the eighteenth century provided improved conditions for case-tracking. Specialised medical journals increased the flow of medical information within and between nations, as did the expansion of the general press and secular publishing. Improvements in mail service, which accompanied innovations in shipping and inland transportation, strengthened and increased networks of correspondence, which were crucial to the sharing of medical and scientific information. As DeLacy shows, these exchanges were important for forging consensus on medical classifications, and they facilitated efforts to make commensurate the English ‘influenza’ with new names associated with the disease in other languages, such as ‘grippe’.38 Improved medical communication meant that epidemics could be studied prospectively rather than just retrospectively. Through press and correspondence networks, doctors could be alerted to expect cases of

36 William Cullen, Synopsis Nosologiae Methodicae Vol. 1 (1772), 248; William Cullen, Synopsis Nosologiae Methodicae Vol. 1 in The Works of William Cullen, ed. John Thompson (Edinburgh: William Blackwood, 1785), 290. It remains unclear when Cullen used ‘influenza’ as a term in his Synopsis. 37 DeLacy, Contagionism Catches On, 125–164. 38 According to M. Saillant, Sauvage named the disease ‘grippe’ in 1743; op. cit., M.

Saillant, Tableau Historique et Raisonné des Épidemies Catarrhales , Vulgairement dites La Grippe (Paris, 1780), 63.

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the disease. These developments made it possible to follow influenza in different parts of the world. Cities and towns were the key sites for such surveys. London, Edinburgh, Paris, Vienna, Berlin, and Philadelphia were especially important because of their concentration of doctors, medical institutions, and links to international commerce and communication. Following influenza through a city formed the basis of the new way of thinking about its epidemiology. One of the earliest examples came from the Edinburghtrained and Quaker physician, John Fothergill, in his ‘Sketch of the Epidemic disease in London’ in December 1775.39 1. About the beginning of the last month, it was mentioned to me in many families that most the servants were sick; that they had colds, coughs, sore throats, and various other complaints. 2. In the space of a week these complaints became more general; few servants escaped them, especially the men, who were abroad; many of the other sex, likewise, and people of higher condition, were attacked; nor were children exempted. 3. The disease … now claimed the attention of the [medical] faculty, and, for the space of near three weeks, kept them, for the most part, universally employed. Descriptions of this kind provided specific information about how the disease spread. A practising natural historian as well as a physician, Fothergill was known for his conviction in approaching diseases as species.40 His account of influenza developing incrementally through London suggested person-to-person transmission and thus directly challenged the miasmatic idea of the disease suddenly exploding upon the city. Often, practitioners of case-tracking also emphasised the contagious nature of epidemics. While Fothergill did not immediately decide on whether influenza was a true contagion, within a decade, similar studies led many to this view.

39 John Fothergill, ‘A Sketch of the Epidemic Disease Which Appeared in London Towards the End of the Year 1775’, in E. Symes Thompson, Influenza or Epidemic Catarrhal Fever (1890), 74. 40 See DeLacy, ‘The Conceptualization of Influenza in Eighteenth Century Britain’, 89–90.

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A crucial juncture came in 1782. An epidemic that, in hindsight, would rank among the greatest of the eighteenth century, provoked a spate of investigations. Two influential reports were organised in London, one by the physician, Edward Gray, for the Society for Promoting Medical Knowledge, and another by the London College of Physicians.41 Both made use of Britain’s imperial networks to track the epidemic. Gray was especially keen to reconstruct its progression across Europe to demonstrate that influenza was a contagion. He traced the first reported European cases to Tobolsk, the ancient capital of Siberia. From Tobolsk, where it had simmered through autumn 1781, it moved northward and westward to Moscow and Saint Petersburg in January 1782, then to Copenhagen in April. Vienna, Warsaw, and Hungary were struck in April. It arrived in London in early May, after which it spread to other parts of England, and then to Scotland and Ireland. It appeared in northern France in June, striking Lille and then Paris in July. It made its way to Spain and Portugal in August, and eventually to Geneva and several cities in northern Italy in October, where it reached its full extent in Europe. Soon thereafter it was widespread along the eastern seaboard of the America. The scale of the epidemic was unprecedented. Just as novel were epidemiological reconstructions that made it possible to conceive of influenza as a global disease. New ideas about its origins also emerged. Some observers speculated that the epidemic had been brought to Russia from China, India, or the East Indies. Russians referred to it by a term roughly translated as ‘Chinese catarrh’. In much of Europe, however, Russia was viewed as the seat or geographical origin of the epidemic. It was popularly referred to as ‘La Russe’, ‘catarro russo’, ‘russischer Katarrh’, and reports reaching London in 1782 called it ‘Russian catarrh’.42 Attributing influenza to a specific geographical origin began with this epidemic and became common practice through the nineteenth century. 41 Edward Gray, ‘An Account of the Epidemic Catarrh of the Year 1782’, Society for the Promotion of Medical Knowledge (London, 1782); ‘An Account of the Epidemic Disease, Called the Influenza, of the Year 1782 College of Physicians, Medical Transactions, vol. iii [25 June 1782]). Both were reproduced in Theophilus Thompson, Annals of Influenza or Epidemic Catarrhal Fever in Great Britain from 1510–1837 (1852). 42 D.K. Patterson, Pandemic Influenza, 1700–1900: A Study in Historical Epidemiology (Totowa, NJ: Rowman & Littlefield, 1986), 22; Edward Gray in Thompson, Annals of Influenza or Epidemic Catarrhal Fever (1852), 137.

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Miasmatists and contagionists were both attracted to the idea that influenza had a place of origin, but for different reasons. Some miasmatists believed that influenza arose from regions with special weather or atmospheric conditions. But they could never agree on the exact birthplace. The Faculté de Médicine in Paris insisted that ‘La Grippe’ originated from ‘les variations de l’atmosphere’ [variations of the atmosphere] in different parts of Europe. Shifting the locus, the American lexicographer and epidemiologist, Noah Webster, argued that the epidemic started along the Atlantic Coast of the United States in Spring 1781 and spread westward over the Pacific to China and Kamchatka, and then onwards to Europe.43 For contagionists, the notion that the pandemic began in a city in the Russian steppe provided an index for tracking its spread. Evidence in support of the contagionist view came directly from mapping the ‘general progress of influenza’ across Europe. ‘When its character has been so well ascertained,’ Gray argued, ‘and its progress from Russia to England, and from thence to the south of Europe, has been so clearly traced, and is so generally acknowledged, it would be superfluous to endeavour to prove that which everyone admits.’ The incremental development of the pandemic led Gray to the conclusion that it was ‘propagated by personal intercourse.’ This explained why it took time to travel. The best evidence came from observations identifying the first cases and their subsequent spread in a town or city. ‘In many instances the introduction of it into a place seems to be pretty clearly traced to some particular person or persons … It was generally observed that someone of a family was first attacked, and then several more of that family.’44 John Haygarth’s observations of the epidemic in Chester, which he submitted to the Royal College of Physicians for its report, led to a similar conclusion: At Chester and most of the towns which surrounded this city, I had the good fortune to discover the individual person who brought it into each place, previous to the general seizure of the inhabitants. The intercourse is greater from the metropolis [London] to Chester than to other towns in its neighbourhood. Again, more people go from Chester to the adjacent market-towns than to the villages and scattered houses which

43 Op. cit., Patterson, Pandemic Influenza, 22–23. 44 Gray in Thompson, Annals of Influenza or Epidemic Catarrhal Fever (1852), 137–

147.

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surround them. The influenza spread exactly in this order of time, from the metropolis to Chester, to the neighbouring towns, and lastly to the villages.45

Contagionists believed that this kind of evidence completely refuted climatic and miasma theories. ‘No hypothesis about the wind, weather, season, or any morbid constitution of the atmosphere whatsoever,’ insisted Gray, ‘can possibly account for such facts. But the progress of the epidemic may be distinctly traced, and explained in the most satisfactory manner, by personal contagion of travellers ill of the distemper, who … conveyed it from place to place.’46 Differences in opinion on the origins and epidemiology of influenza did not disappear. But after 1782, agreement grew in British and European medical circles on the idea that influenza was a specific disease that spread person-to-person, most typically taking the form of epidemics. While occasionally referred to as a ‘contagio a catarrhus ’, it was Cullen’s other term that would become popular. Influenza was the prototypical ‘catarrhus epidemicus ’ or ‘epidemic catarrh’. Defining influenza as a contagion was motivated by the aim of bringing the disease under control. Proponents argued that by their very nature, contagious diseases could be prevented; miasmas could not. ‘Knowledge, in this instance, is power’, argued Haygarth. ‘So far as it can be proved that a disease is produced by contagion, human wisdom can prevent the mischief. But the morbid constitution of the atmosphere cannot possibly be corrected or controlled by man.’47 Yet, despite this grandiose claim, existing control measures were limited. Vaccination was just being developed for smallpox. Quarantine and isolation were the established approaches. Quarantine had proven relatively effective in protecting cities against smallpox and plague, not least because these diseases were relatively slow-moving and easy to identify. But as medical practitioners soon found out, influenza was far less susceptible to such prevention measures. Not only did it spread faster than any other contagion, it generally eluded detection until it reached epidemic proportions. With around a quarter to 45 John Haygarth, ‘Of the Manner in Which the Influenza of 1775 and 1782 Spread by Contagion in Chester and Its Neighbourhood’, in Thompson, Annals (1890), 196. 46 Gray in Thompson, Annals of Influenza or Epidemic Catarrhal Fever (1890), 137. 47 Haygarth, ‘Of the Manner in Which the Influenza of 1775 and 1782 Spread by

Contagion in Chester and Its Neighbourhood’, in Thompson, Annals (1852), 197.

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a half of a city’s population affected, quarantine or isolating the sick from the healthy was pointless. Physicians came up with important explanations for why influenza eluded prevention measures. Unlike smallpox, where infection conferred long-lasting immunity, ‘persons who have had the influenza [were] not exempted from a future attack.’48 Moreover, there seemed to be ‘a shorter latent period between infection and the commencement of the disease,’ which observers deduced to be about forty-eight hours. As a result, the number of people infected and able to spread the disease could grow rapidly. Shorter latency increased the rate of transmission and reduced the window of opportunity for deploying quarantine or isolation measures. Together, these factors meant that ‘a large proportion of persons [were] capable of receiving and propagating’ the disease.49 While late eighteenth-century practitioners recommended the isolation of the sick and those most vulnerable—recognised as the old, the infirm, infants, and pregnant women—they did so knowing that these measures were of limited value. The combination of the lack of lasting immunity, the short latency period, and the resulting high incidence rates of influenza have posed challenges to doctors and governments ever since.

4

Hippocratic and ‘Heroic’ Treatments

The high incidence of influenza and the absence of direct prevention measures made it inevitable that the many who came down with the disease sought some kind of remedy. Treatment choices were as wide and varied as the symptoms of the disease. Eighteenth-century medicine was organised around the marketplace, and nowhere was this more evident than in therapeutics.50 Physicians and apothecaries tailored treatments to individual proclivities and needs.51 Eighteenth-century therapeutic practices have been characterised as a form of ‘heroic medicine’, in which the 48 Haygarth, ‘Of the Manner in Which the Influenza of 1775 and 1782 Spread by Contagion in Chester and Its Neighbourhood’, in Thompson, Annals (1852), 196. 49 Gray in Thompson, Annals of Influenza or Epidemic Catarrhal Fever (1890), 137. 50 Mark S. Jenner, ‘The Medical Marketplace’, in M.S. Jenner and J. Wallis (Eds.),

Medicine & the Market in England & Its Colonies, c.1450–c.1850 (Basingstoke: Palgrave, 2007), 1–23. 51 Ian Burney, ‘Medicine in the Age of Reform’, in A. Burns and J. Innes (Eds.), Rethinking the Age of Reform: Britain, 1780–1850 (Cambridge, 2003), 163–182.

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principle of ‘do less harm’ was supplanted by an almost wanton array of interventions, which rarely worked and sometimes killed.52 If there was a general rule dictating regimens, it was the Hippocratic ideal of restoring the body to a natural balance. What this meant was open to wide interpretation. For every symptom and every type of influenza there was one or more corresponding medication. The typical approach to mild cases combined common sense with remedies aimed at re-balancing the body. Sufferers were advised to take bed rest, keep warm, and drink decoctions of broth, bark, or cordials to flush the system. Profuse perspiration and ‘evacuation’—bowel movements and vomiting—were viewed as ‘natural cures’, and both were aided by the use of emetics and laxatives. While the materia medica still relied heavily on herbal remedies prepared by apothecaries, it was being supplemented by new mineral and metallic drugs manufactured by a burgeoning chemistry industry.53 Calomel, the ‘little blue pill’ made from mercury chloride, was popular as a purgative to cleanse the body of mucous and to encourage perspiration, both of which were thought to reduce fever and catarrh.54 Quinine, a derivative of Peruvian bark, was widely used to control fever. More severe cases of influenza called for different treatments according to the nature of the symptoms. Bleeding was employed to relieve inflammation associated with respiratory complications, especially pleurisy, bronchial congestion, and pneumonia. Some physicians recommended blood-letting for pregnant women, who were thought to be more susceptible to severe influenzal symptoms, despite the general observation that it ‘did more harm than good.’55 Blisters were applied and opiates taken for crippling aches and pains. Patients were advised to swear off wine, popularly thought to encourage perspiration, because it aggravated symptoms and, in some cases, turned influenza into a ‘violent inflammatory fever.’56 Meat was also to be avoided, especially in earlier stages of the disease, because it was too rich and further congested the system. The drug of choice for physicians and sufferers alike

52 Porter, Greatest Benefit, 262. 53 A.-H. Maehle, Drugs on Trial: Experimental Pharmacology and Therapeutic Innova-

tion in the Eighteenth Century (Amsterdam and Atlanta: Rodopi, 1999). 54 Porter, Greatest Benefit, 266–267. 55 Gray in Thompson, Annals of Influenza or Epidemic Catarrhal Fever (1852), 131. 56 Gray in Thompson, Annals of Influenza or Epidemic Catarrhal Fever (1852), 131.

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was opium, used widely for the pain and the persistent coughs accompanying influenza. Opiates, claimed one physician, ‘generally put all the symptoms [of influenza] to flight.’57 Cullen and his classifying colleagues had hoped that their nosologies would make therapeutics more rational by focusing treatment on the specific symptoms of a disease. But when confronted with so protean an entity as influenza, treatments ran amok. What are we to make of these practices? Some historians have judged eighteenth-century ‘heroic medicine’ as hopelessly ineffective and dangerous.58 It may indeed have been so. Symptom-based therapeutics reflected medical Enlightenment’s drive to classify, which also may have been a crucial limitation. The concentration on symptoms meant that little account was taken of specific underlying causes, which, as we shall see, became the focal point of ‘scientific’ medicine and therapeutics in the late nineteenth century. Yet such a criticism misses a crucial point: treatment of symptoms has been and remains central to the management of influenza. While therapeutic tools, practices, and conventions changed, the idea of treating influenza’s multiple symptoms was born in the late eighteenth century. This is not the only important legacy of Enlightenment medicine. Classification practices created a disease identity whose characteristics, origins, and causes could be determined as well as debated. Physicians could now use ‘influenza’ to make diagnoses and to treat. By the late 1770s, Cullen and his colleagues were employing ‘influenza’ in communications with their aristocratic patrons, a practice that spread through the English-speaking world.59 In due course, sufferers themselves would also start to use the term to explain what ailed them. In January 1824, for example, the English essayist Charles Lamb wrote to his friend, the Quaker poet Bernard Barton, describing his on-going struggle with the so-called ‘influenza’.

57 Dr Flint, cited in Gray (1782), op. cit., Thompson, Annals of Influenza or Epidemic Catarrhal Fever (1852), 134. 58 Nicolas D. Jewson, ‘Medical Knowledge and the Patronage System in 18th Century England’, Sociology, 8.3 (1974), 369–385; R.B. Sullivan, ‘Sanguine Practices: A Historical and Historiographic Reconsideration of Heroic Therapy in the Age of Rush’, Bulletin of the History of Medicine, 68.2 (1994), 211–234. 59 See, for example, ‘Influenza’ in The Cullen Project, Letters of Dr William Cullen (1710–1790) at the Royal College of Physicians of Edinburgh. http://www.cullenproject. ac.uk/items/c103/.

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Dear B.B.: Do you know what it is to succumb under an insurmountable daymare – ‘a whoreson lethargy,’ Falstaff calls it – an indisposition to do anything, or to be anything; a total deadness and distaste; a suspension of vitality; an indifference to locality; a numb, soporifical, good-for-nothingness; an ossification all over, an oysterlike insensibility to the passing events; a mind stupor; a brawny to the needles of a thrusting-in conscience? Did you ever have a very bad cold, with a total irresolution to submit to water-gruel processes? This has been for many weeks my lot, and my excuse; my fingers drag heavily over this paper, and to my thinking, it is three and twenty furlongs from here to the demisheet … O for a vigorous spirit of gout, colic, toothache – an earwig in auditory, a fly in my visual organs. Pain is life – the sharper the more evidence of life; but this apathy, this death! Did you ever have an obstinate cold – six or seven weeks’ unintermitting chill and suspension of hope, fear, conscience and every thing? Yet do I try all I can to cure it; I try wine and spirits, and snuff in unsparing quantities; but they all only seem to make me worse instead of better. I sleep in a damp room but it does me no good; I come home late o’ nights but do not find any visible amendment! Who shall deliver me from the body of this death?60

Despite the apparent weakness of his physical and mental state, Lamb’s ability to dramatise his bout of influenza testifies to his literary power and his effective grip on metaphor. But it is also indicative of an important development in the cultural position of the disease. Lamb could dramatise his symptoms precisely because influenza had become a popular term that literate people used to name an experience. Unlike in the previous century, the name and the illness were intelligible and recognisable to many people. Influenza, especially in the English-speaking world, became a common part of medical and popular discourse in the first half of the nineteenth century.

5

Epidemic Identities

By the early nineteenth century, Scottish and English physicians had generated a recognisable clinical entity. The definition of influenza as a catarrhal fever endured through the nineteenth century, with ‘epidemic

60 C. Lamb to Bernard Barton (republished Journal of the American Medical Association, 98.14 [2 April 1932], 30).

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catarrh’ or ‘epidemic catarrhal fever’ commonly used as a synonym.61 The English ‘influenza’ was commensurate with names associated with the disease in other languages, such as grippe, which was widely used in France and in the German lands.62 Naming the disease not only made it part of medical and popular discourse, but also made it possible to reconstruct its history. Chronicling diseases was an ancient craft, but new nosologies enabled nineteenth century chroniclers to retrospectively identify a disease by translating older terms for symptoms or epidemics into new ones. In 1852, Theophilus Thompson, a prominent London physician, who specialised in consumption and diseases of the chest, and was a leading figure of the Sydenham Society, published the first such chronicle of influenza. His Annals of Influenza or Epidemic Catarrhal Fever was a ‘survey of past epidemics in Great Britain’.63 Although ‘influenza’ had not been used as a term until the 1750s, Thompson traced epidemics back to 1510 because, he claimed, the disease demonstrated ‘a grandeur in its constancy and immutability superior to the influence of national habits’. Observations and terms may have varied according to past conventions or customs, but Thompson believed he could make commensurate ‘the present picture of Influenza exactly as … delineated by the original observers.’64 A classic example of Victorian historical epidemiology, the Annals highlight how reconceptualising influenza as a specific entity, with a distinct symptomatology and epidemiology, could be used for retrospective diagnosis. As Mark Honigsbaum notes, the Annals rested on the assumption that new nosologies revealed essential and unchanging qualities about influenza that made it possible to chronicle its deep history seamlessly.65 But while the Annals might be criticised for being typically ‘Whiggish’, it can be read in other ways. The accounts Thompson collected were presented in their original form, with the language evidently unaltered. For the historian, they are 61 For example, Thomas Bevill Peacock, On the Influenza, or Epidemic Catarrhal Fever (London: John Churchill, 1848). 62 D. Finkler, ‘Influenza’, in T.L. Stedman (Ed.), Twentieth Century Practice: An International Encyclopedia of Modern Medical Science (London: Sampson Low, Martson & Co, 1898), 1–249. 63 Thompson, Annals of Influenza or Epidemic Catarrhal Fever (1852), x. 64 Thompson, Annals of Influenza or Epidemic Catarrhal Fever (1852), xi. 65 Mark Honigsbaum, History of the Great Influenza Pandemics: Death, Panic and

Hysteria, 1830–1920 (London: I.B. Tauris, 2014), 14–15.

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valuable because, although selective, they document the emergence and uses of ‘influenza’ as a term from the 1750s onwards. They detail important continuities, variations, and changes in descriptions of influenza’s signs, symptoms, and epidemiology. And finally, they highlight the importance of epidemics as sites for the production and testing of medical ideas, and the shaping of influenza’s identity as an epidemic disease. Almost all the accounts collected in the Annals are observations of epidemics. Along with those of the late eighteenth century, epidemics that swept across Europe and Britain in 1802–1803, 1826–1827, 1830–1831, 1833, 1836–1837, and 1848 helped consolidate influenza’s place in nineteenth century medicine and society. Their frequency meant that most people would have had a bout of influenza at some point in their lives. The satirist and ‘sage of Chelsea’, Thomas Carlyle, captured something of the general experience in a letter to his sister in January 1837, where he described the impact of a severe epidemic in London: All the people have got a thing they call Influenza, a dirty, feverish kind of cold; very miserable and so general as was hardly ever seen. Printing offices, Manufacturies, Tailor shops and such like are struck silent, every second man lying sniftering in his respective place of abode. The same seems to be the rule in the North too. I suppose the miserable climate may be the cause.66

Beyond individual cases, epidemics were objects of investigation, with questions about where influenza came from, how it spread and whom it affected becoming focal points of medical concern and crucial opportunities to refine and develop medical knowledge. If there was some agreement on influenza’s basic clinical features, epidemics often gave rise to disagreement on almost everything else, especially on what caused the disease and how it spread. Many, like Carlyle, blamed the climate. Others pointed to different causes. Nothing attracted more controversy than the idea that influenza might be a contagious disease. ‘There is no department of the subject [of influenza] regarding which there is so great a diversity of opinion among observers,’ noted Thompson in his Annals, ‘as on the much-vexed question of contagion.’67

66 ‘Glimpses of Influenza in the Past’, BMJ (1 February 1919), 138. 67 Thompson, Annals of Influenza or Epidemic Catarrhal Fever (1852), 222.

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The idea that influenza was a contagion was intimately linked to the idea that it was a specific entity. Yet, observations of epidemics in the early nineteenth century challenged symptom-based classifications that posited influenza as a specific disease. Physicians commonly remarked on its protean forms and seeming ability to change from one to another. Rather than a uniform entity, many believed influenza’s clinical and epidemiological characteristics were contingent on the specific time, place, and population in which they developed.68 Medical practitioners were increasingly divided on whether influenza was a contagion, spread personto-person like smallpox, or a miasma, spread like malaria by the morbid contamination of air. Contagion theories that had been dominant in the late eighteenth century gave way to increasingly popular miasma and ‘contingent-contagionist’ theories.69 Such theories attracted nineteenth century physicians because they helped make sense of two outstanding features of influenza: its apparent ability to explode upon and rapidly spread through a population or place faster than any other disease, and the variety and number of symptoms and conditions associated with an epidemic. But, as Margaret Pelling cautioned, contagion and miasma theories were never mutually exclusive and, more often, coexisted in explanations of epidemics in early nineteenth century English medicine.70 Questions about the origins and epidemiology of influenza were revisited episodically during large epidemics. But perplexing as influenza’s identity may have been to nineteenth century observers, it attracted only limited government interest. One exception was William Farr, who, on becoming the first Registrar General of the General Register Office in 1839, innovated sophisticated statistical analyses of demographic and epidemiological phenomena in industrialising Britain.71 Through the 1840s, Farr made the ‘life table’ a vital instrument for measuring and

68 Augustus Hirsch, Handbook of Geographical and Historical Pathology (London: New Sydenham Society, 1883), 4–36. 69 Margaret Pelling, ‘Contagion/Germ Theory/Specificity’, in W.F. Bynum and R. Porter, (Eds.), Companion Encyclopedia of the History of Medicine (London: Routledge, 1992), 309–334. 70 Margaret Pelling, Cholera, Fever and English Medicine, 1835–1865 (Oxford: Oxford University Press, 1978); Christoph Hamlin has made similar observations. Christoph Hamlin, ‘Predisposing Causes and Public Health in Early Nineteenth-Century Medical Thought’, Social History of Medicine, 5.1 (1992), 43–70. 71 Honigsbaum, A History of the Great Influenza Pandemic, 18–23.

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assessing health, disease, and death. His life tables eventually incorporated a systematic method for classifying so-called ‘zymotic diseases’, which were associated with chemical poisons (ferments) that could spontaneously arise from rotting vegetable or animal matter, from filth or from an animal or human body and then ‘infect’ individuals and spread through populations.72 Farr classified major epidemic diseases such as cholera, typhus, and smallpox as ‘zymotic’, which in turn not only allowed him to track their prevalence but also to align them with emerging sanitary ideas that aimed to remove the filth from which they originated.73 The 1848 influenza epidemic allowed Farr to categorise influenza as a zymotic disease and thus make it visible as a significant epidemiological and public health problem. Farr issued weekly mortality returns that recorded the incidence of influenza in different age groups and localities, highlighting those most affected. He also devised a method to determine the excess mortality associated with influenza, as way to demonstrate its general impact. And yet, despite Farr’s efforts, influenza generally escaped the interest of sanitary science and reformers.74 The short duration of epidemics combined with the general lack of organised medical and public health systems constrained inquiries. Equally important, there was little perceived need for systematic investigations. Despite its hoary reputation as the grandest of all epidemic diseases, influenza generally was not viewed as a threat to the emerging nation-state. Unlike cholera, smallpox, or tuberculosis, it did not arouse general fear, nor did it ignite social or class tensions. As a result, it played no significant role in galvanising public attention or provoking changes in the organisation and practice of medicine and public health. As industrialising nations constructed what

72 Michael Worboys, Spreading Germs, 34–38. 73 William Farr, Tenth Annual Report of the Registrar-General of Births, Deaths, and

Marriages in England (London: HMSO, [1847] 1852) xxxiv; Sixteenth Annual Report of the Registrar General of Births, Deaths, and Marriages in England (London: HMSO, 1856), xv, 1. For Farr’s philosophy and methods, see John M. Eyler, Victorian Social Medicine: The Ideas and Methods of William Farr (Baltimore: Johns Hopkins University Press, 1979). 74 Honigsbaum, A History of the Great Influenza Pandemic, 22–23.

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became the institutions and systems of modern public health, influenza all but disappeared as an epidemiological factor in Britain. After the 1848 epidemic, Victorians rarely concerned themselves with the disease. This would all change at the end of the century.

CHAPTER 3

Modernising Flu: Re-aligning Medical Knowledge of the ‘Most Protean Disease’

‘[S]uch phrases as the return of influenza, the reimportation of influenza, etc., are mere figures of speech; we have never lost it again since 1889.’1 So wrote the London epidemiologist, Major Greenwood, in 1920. Like many epidemiologists, he was trying to contextualise the pandemic that had devastated the world two years earlier. For Greenwood, the 1918– 1919 pandemic represented the culmination of a ‘new cycle’ in influenza’s history, which had begun when four epidemics swept most of the globe between 1889 and 1894. Through its recorded history, Greenwood argued, influenza had appeared episodically, visiting Britain and Europe once or twice a generation. But in the 1890s this pattern changed radically, with influenza becoming ‘endemic’ in industrial nations.2 The epidemics of the early 1890s inaugurated what Greenwood called the ‘modern period’ of influenza, when it became ‘a factor of great importance in the causation of mortality’ and an inescapable part of modern life.3 Greenwood assumed, as did most of his contemporaries, that the signs, symptoms, and pathology of influenza had been essentially constant 1 Major Greenwood, ‘The History of Influenza, 1658–1911’, in Ministry of Health, Report on the Pandemic of Influenza, 1918–19, Reports on Public Health and Medical Subjects, No. 4 (London: HMSO), 20. 2 Greenwood, ‘History of Influenza’, 23–24. 3 Ministry of Health, Report on the Pandemic of Influenza, vi.

© The Editor(s) (if applicable) and The Author(s), under exclusive licence to Springer Nature Limited 2023 M. Bresalier, Modern Flu, Medicine and Biomedical Sciences in Modern History, https://doi.org/10.1057/978-1-137-33954-6_3

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through history and that what had changed since 1890 was the epidemiology of the disease. Yet medical professionals were not simply mapping new behaviours of an old disease, but those of a new influenza whose identity had been established in the last decade of the nineteenth century. ‘Modern influenza’, as some called it, was defined through a combination of epidemiological, clinical, and bacteriological knowledge and practices that would come to form the foundations of modern medicine at the end of the nineteenth century.4 Otto Leichtenstern, the Munich clinician and pathologist, explained in his influential 1898 manuscript on influenza that the medical profession across Europe had confronted the 1889– 1894 pandemic as a ‘new disease’ and, by applying ‘the progress and the acquisitions of modern medicine, advanced… knowledge of influenza in every direction.’5 Crucially, modern medical knowledge adhered to ‘the doctrine of the contagious nature of influenza, of its transmission from person to person, and its dissemination through human intercourse.’6 Modern influenza was no longer a mysterious product of poisoned air, cold weather, atmospheric changes, or the cosmos; it was an infectious disease. This new influenza was rooted in the general transformation of medical ways of knowing by bacteriological ideas and practices at the end of the nineteenth century. Between 1890 and the outbreak of the First World War, medical officers of health (MOHs), hospital physicians, and pathologists drew upon bacteriology as a conceptual and practical resource to forge agreement on the nature and identity of influenza. This process involved aligning epidemiological, clinical, and bacteriological knowledge produced in public health, in hospital medicine, and in laboratories. Basic differences in the institutional, cultural, and professional orientations of each form of knowledge meant that there existed different ‘influenzas’ for each group. But over the next two decades, the problems, interests,

4 For the historiography and specific changes in Britain, see Michael Worboys, Spreading

Germs: Disease Theories and Medical Practice in Britain, 1865–1900 (Cambridge: Cambridge University Press, 2000), 1–15. 5 Oswald Leichtenstern, ‘Influenza’, in Julius Mannaberg and Oswald Leichtenstern (Eds.), Malaria, Influenza and Dengue (Philadelphia and London: W.B. Saunders & Co., 1898), 523. 6 Leichtenstern, ‘Influenza’, 523.

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and practices of these medical professionals were slowly made commensurable, such that by the early 1900s, influenza was generally characterised as a specific infectious disease. The alignment of public health, clinical, and bacteriological expertise and knowledge in the wake of the 1889–1890 epidemic was integral to establishing the modern identity of influenza. This chapter shows how each provided the other with specific problems to solve and with conceptual and practical resources to do so. Increasing trust in bacteriological ideas and methods in British medicine, especially after 1900, was a crucial factor. But it would be wrong to give all the credit to bacteriology. No less important were large-scale ‘collective investigations’ organised by Britain’s central public health authority, the Medical Department of the Local Government Board.7 These investigations integrated epidemiological, clinical, and bacteriological evidence into the definition of influenza as a specific infection, in which a new germ—Bacillus influenzae—was eventually determined to play a necessary role in its aetiology, transmission, and pathogenesis. In the characterisation of ‘modern influenza’, bacteriological concepts and techniques were simultaneously adapted to and incorporated into clinical, pathological, and epidemiological frameworks. The Medical Department was uniquely positioned to draw together such evidence and its relative success in doing so demonstrates the importance of a government body in shaping the identity of influenza as an infectious disease and the relationships between laboratory, clinical, and public health medicine on which this identity was based.

1

Making Influenza Communicable

Through most of the nineteenth century influenza played only a minor role in the affairs of government, medicine, public health, and everyday experiences of illness. It existed on the fringes of Victorian life. Mortality statistics told part of this story. From the 1740s to the 1850s, epidemics had visited London at least seven times.8 But after 1848, influenza slipped

7 For a definitive account of the Medical Department’s epidemiological investigations see, Jacob Steere-Williams, The Filth Disease: Typhoid Fever and the Practices of Epidemiology in Victorian England (Rochester, NY: University of Rochester Press, 2020). 8 David K. Patterson, Pandemic Influenza, 1700–1900: A Study in Historical Epidemiology (Totowa, NJ: Rowman & Littlefield, 1986).

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off the epidemiological map.9 For the next four decades, with the exception of small outbreaks in 1855 and 1858, its prevalence steadily declined. Between 1870 and 1888 outbreaks had almost disappeared from England and the rest of Europe (Fig. 1).10 This period of decline ended abruptly in autumn 1889, when a massive epidemic swept across Europe and much of the world. Three ‘recrudescences’, one less widespread but more deadly in 1890–1891, another in 1892, and a third in 1892–1893, followed the 1889 epidemic. Influenza killed no fewer than 57,980 in Britain between 1890 and 1891. Unlike in the past, however, it did not abate. In no year between 1890 and 1915 did fewer than 496 Londoners die from it; in ten of these years more than a thousand deaths were allotted to influenza. Major epidemics struck London in 1895, 1899–1900, and 1908–1909.11 In the decade after 1890, the number of deaths attributed to influenza in England and Wales averaged 11,050 per year, and never went below 3,753 (Fig. 2).12 The rest of Europe experienced a similar escalation. Raw numbers underscored influenza’s changing presence in the social experience of health and illness.13 The epidemics of the early 1890s captivated medical and popular attention on the disease. But initially, while generally called ‘influenza’, neither public health professionals relying on epidemiological knowledge nor medical practitioners relying on clinical knowledge could agree on its identity. Agreement only came slowly and because of state-organised investigations that mapped and redefined its epidemiological, clinical, and aetiological characteristics. The 1889– 1890 epidemic spurred public health bodies across Europe to organise the first ever large-scale studies of influenza, with the general aim of 9 Patterson, Pandemic Influenza, 29–48. For contemporary accounts, see Charles Creighton, ‘Influenzas and Epidemic Agues’, in idem., A History of Epidemics in Britain, Vol. II (London: Cambridge University Press, 1894), 306–433; Theodophilus Thompson, Annals of Influenza or Epidemic Catarrhal Fever in Great Britain from 1510–1837 (London: The Sydenham Society, 1852). 10 From 1861 until 1888, influenza deaths in London went above 50 once (1864); in the 1870s, they exceeded 25 once (1870); from 1880 to 1888, they averaged 7.7 per year. Registrar-General, Fifty-Fourth Annual Report of the Registrar-General, 1891 (London: HMSO, 1892), xiii–xiv. 11 Ministry of Health, Report on the Pandemic of Influenza, 23. 12 All figures are from the Sixty-Third Annual Report of the Registrar General, 1900

(London: HMSO, 1902), ixvi. 13 Ministry of Health, Report on the Pandemic of Influenza, 23–24.

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Fig. 1 Deaths from Influenza (London). The table demonstrates the degree to which influenza deaths in London had declined from a peak in 1848 to ‘quite insignificant proportions’ by 1889 (Source Henry Parsons, Report on the Influenza Epidemic of 1889–1890, Local Government Board [London: HMSO, 1891], 4)

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Fig. 2 Annual Influenza Death-Rate per million in England and Wales, 1847– 1905. With the exception the epidemic year of 1847–1848, and lesser outbreaks in 1850–1851 and 1857–1858, mortality-rates attributed influenza in England and Wales declined in the second half of the nineteenth century. The 1889– 1890 epidemic set in train consistently higher levels of mortality than in the preceding three decades (Source A. Newsholme, ‘Influenza for the Public Health Standpoint’, The Practitioner, LXXVII [1907], 118)

resolving questions about its origins, causes, modes of spread, and what constituted a case of the disease. In Britain, the LGB’s Medical Department launched investigations that resulted in two influential reports.14 Drawing on methods of case-based epidemiology and the epistemological

14 Local Government Board, Report on the Influenza Epidemic of 1889–1890, Vol. XXXIV (London: HMSO, 1891); Local Government Board, Further Report and Papers on Epidemic Influenza, 1889–92, Vol. VLII (London: HMSO, 1893).

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resources of bacteriology, they were widely heralded for producing a new understanding of influenza. The first report, published in early 1891, analysed the 1889–1890 epidemic and highlighted the Department’s leading role in the use of modern epidemiological methods, which it had established in the preceding decades. The second report, published in late 1892, examined the recrudescences of 1891 and 1892. It demonstrated the Department’s key role in drawing together epidemiological, clinical and laboratory evidence to transform influenza into a specific infectious disease and to make it a vital part of the calculus of government, medicine, and public health and an inescapable facet of modern health and disease. The Department’s reputation for epidemiological investigations was already well established among European public health bodies when influenza returned in 1889.15 Created out of the Board of Health in 1858, it was incorporated into the LGB in 1871, which was established to administer England and Wales’ public health system under the 1872 Public Health Act.16 The Act required urban and rural sanitary districts to appoint a medical officer to monitor all aspects of public health. The Medical Department functioned as one of two centres producing epidemiological information for the system, the other being the General Register Office (GRO). London’s first medical officer, John Simon, headed the Department until 1876, and oversaw a small professional staff authorised to produce and disseminate epidemiological information specifically aimed at advising and directing prevention approaches. Rooted in traditions of Victorian epidemiology, it combined statistical analyses, case-tracking, and judicious observations of local environmental factors.17

15 Anne Hardy, ‘On the Cusp: Epidemiology and Bacteriology at the Local Government Board, 1890–1905’, Medical History, 42 (1998), 330–335; Jacob Steere Williams, ‘Performing State Medicine During Its ‘Frustrating’ Years: Epidemiology and Bacteriology at the Local Government Board, 1870–1900’, Social History of Medicine, 28.1 (2015), 82–107. 16 Anne Hardy, ‘Public Health and the Expert: The London Medical Officers of Health, 1856–1900’, in Roy Macleod (Ed.), Government and Expertise: Specialists, Administrators and Professionals, 1860–1919 (Cambridge: Cambridge University Press, 1988), 128–142. For the GRO, see Simon Szreter, ‘The GRO and the Public Health Movement in Britain, 1837–1914’, Social History of Medicine, 4 (1991), 435–464. 17 William Coleman, Death Is a Social Disease: Public Health and Political Economy in Early Industrial France (London: University of Wisconsin Press, 1982); John M. Eyler, Victorian Social Medicine: The Ideas and Methods of William Farr (Baltimore: Johns Hopkins University Press, 1979).

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Initially, epidemiological work remained separate from laboratory work, with so-called ‘auxiliary scientific investigations’ introduced in 1865 and the relevance of bacteriology viewed as suspect.18 The Department did not have its own laboratory facilities until the 1910s. Instead, it relied on researchers working in pathology laboratories at the Brown Animal Sanatory Institution, St. Bartholomew’s Hospital, St Thomas’ Hospital and King’s College Hospital, where medical bacteriology was being pioneered in Britain.19 By the 1880s, bacteriology was becoming increasingly important in the production of epidemiological knowledge of major diseases such as typhus, typhoid, diphtheria, smallpox, scarlet fever and tuberculosis.20 Edward Klein, the Vienna-trained histologist and a reputed founder of British bacteriology, played a leading role in introducing bacteriological methods into the Department.21 The Department’s traditional focus on ‘inclusive’ public health measures, guided by an older sanitary vision and widely directed at the general environment of disease, slowly gave way to ‘exclusive’ measures, specifically directed at disease agents, people who carried them, and their social interactions.22 Its investigations into influenza in the early 1890s were important to the process of integrating these changes into its approaches. Alongside developments in bacteriology, the Medical Department’s epidemiological work also had been transformed by the revolution in telegraphy.23 A rudimentary technology when influenza last became epidemic in 1848, and still in development when the Department had been established, by the late 1880s Britain’s telegraphic cables girdled the

18 Christopher Hamlin, A Science of Impurity: Water Analysis in Nineteenth Century

Britain (Bristol: Hilger, 1990), Chps., 9, 10. 19 W.D. Foster, Pathology as Profession in Great Britain and the Early History of the Royal College of Pathologists (London: E&S Livingstone, 1965), 60–67. 20 See, for example, Steere-Williams, The Filth Disease, 172–223; Joanne L. Brand, Doctors and the State: The British Medical Profession and Government Action in Public Health, 1870–1912 (Baltimore: Johns Hopkins Press, 1965), 73–75. 21 Hardy, ‘On the Cusp’, 330–335. 22 Worboys, Spreading Germs, 234–276. 23 William Coleman, Yellow Fever in the North: The Methods of Early Epidemiology (Madison: University of Wisconsin Press, 1987), 186.

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globe, with London functioning as the centre of a world-wide communications system.24 The Medical Department, like every government body, was wired into the system, as were all major news and medical media.25 Telegraphy made it possible to almost simultaneously track the development and spread of epidemic diseases across the nation, empire, and the rest of the world, and it was readily mobilised for tracking influenza in late 1889. Through telegraphed news reports, Londoners and most Britons living in other major cities knew about the disease well before it struck; medical experts, observers, and commentators were able to anticipate its appearance and to speculate on its identity, characteristics, and course. This ability to follow influenza was crucial to framing it as a communicable infection and to tracking its spread across the world. Telegraphy helped make influenza intelligible as a global epidemic. The first news of the 1889 epidemic came from St. Petersburg, where a massive outbreak was reported to the Times in late November and by the Lancet in early December 1889.26 Days after, further reports announced that the disease had moved west across Poland, Germany, and AustroHungary, south to Italy, Greece, and Spain, north to Scandinavia, and into France. By early December, all of Paris was said to have ‘la grippe’, prompting fears and speculation of its imminent arrival in London. ‘It is more than probable,’ the Lancet warned, ‘that we will be visited by this epidemic … When it does come it will speedily make its presence felt, and the difference between an ordinary or even an unusual prevalence of catarrh and of true epidemic influenza will soon be appreciated.’27 The epidemic struck the capital just after Christmas 1889 and conformed to fears and expectations. Social and economic life in London was severely disrupted. Between January and early February 1890, about one-third of its four million

24 Mark Honigsbaum, A History of the Great Influenza Pandemics: Death, Panic and Hysteria, 1830–1920 (London: I.B. Tauris, 2014), 32–80. 25 On mass print media in the pandemic, see James Mussell, ‘Pandemic in Print: The Spread of Influenza in the Fin de Siècle’, Endeavour (2007), 12–17. 26 ‘Russia’, The Times (25 November, 1889), 6; ‘Russia’, The Times (30 November, 1889), 5; ‘The Epidemic of Influenza in St. Petersburg’, Lancet (7 December 1889), 1194–1195. 27 ‘Influenza’, Lancet (21 December 1889), 1293–1294.

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inhabitants were immobilised.28 Hospitals, dispensaries, and clinics were overrun. Public institutions and large private establishments were among the worst hit. The Post Office reported 1,346 employees absent from work in January—nearly 25%—for an average of fifteen days. Bank branches in central London reported absentee rates of 20%; 1,600 Metropolitan policemen were sick in January; normal rates were between 500 and 600. London railway services stalled. Scores of booking clerks and carriage department men were unable to work.29 The epidemic escalated death rates associated with respiratory diseases, such as whooping cough, tuberculosis, measles, diphtheria, bronchitis, and pneumonia, which preyed especially upon the poor.30 Unparalleled in its scale and scope, the epidemic spread more widely and precipitously than any before, affecting almost every corner of Britain, the empire, and the inhabited world. Historical epidemiologists have suggested that the development of faster and more efficient railway systems and steamships in the second half of the nineteenth century accelerated and globalised the pandemic, allowing ‘influenza to move from city to city and into the countryside at unprecedented speeds.’31 David Patterson noted in his pioneering study that ‘the rapid diffusion of influenza [in 1889–90] provides a graphic illustration of how the world was becoming a single interconnected entity.’32 A.H. Gale argued in his survey of Epidemic Diseases, that these changes marked ‘the beginning of a new chapter in the history of the disease, not only in [Britain], but also in Europe and America, and probably throughout the world.’33 Yet, while we now accept that the pandemic was intimately connected to the revolution in steam travel, this was not immediately evident to contemporary observers. Influenza was more likely to be perceived as an air-borne miasma than as a contagion that spread between humans travelling by rail or ship. So how did perceptions change over the next decade and 28 Henry Franklin Parsons, ‘The Epidemiology of Influenza’, BMJ (6 May 1905), 980–982. 29 Henry Franklin Parsons, ‘The Influenza Epidemics of 1889–90 and 1891, and Their Distribution in England and Wales’, BMJ (8 August 1891), 303–308. 30 F.B. Smith, ‘The Russian Influenza in the United Kingdom’, Social History of Medicine 8 (1995), 60. 31 Patterson, Pandemic Influenza, 8. 32 Patterson, Pandemic Influenza, 8. 33 A.H. Gale, Epidemic Diseases (London: Penguin Books, 1959), 47.

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how was influenza connected conceptually to the material conditions of modernity? Part of the answer lies with the decisive role of the Medical Department. At the height of the epidemic in December 1889, the LGB’s Medical Officer, George Buchanan, asked his assistant, Henry Franklin Parsons, to organize a ‘collective’ epidemiological investigation, with the aim of determining its origins and modes of spread—issues that sharply divided medical observers.34 Collective investigations, as Harry Marks has shown, were first proposed by elite physicians in Britain as a way to transcend the study of diseases in hospitals and to involve general practitioners in reconstructing their ‘life-history’ through populations.35 A key aim was to standardise the production and use of medical knowledge, particularly diagnostic categories and practices. While the collective investigation had limited popularity as a tool for clinical research, the basic principle of mobilising practitioners to study and to help generate a standard picture of a disease was one that the Medical Department put into practice in its own studies. Its style of collective inquiry, which it had already honed in investigations of cholera and smallpox, involved the entire public health system, gathering information from medical officers, general practitioners, the War Office, the Colonial Office and various other sources.36 Parsons was one of the leading practitioners of the Department’s style of epidemiological investigation. Four years after obtaining his M.D. from the University of London in 1870, he became a Medical Officer of Health in Yorkshire, during which time he also pursued a public health degree at the University of London and, in 1876, a Doctorate of Public Health at the University of Cambridge. In 1879, he was invited to become a medical inspector for the LGB, ‘on account of the profound knowledge displayed in his reports on the sanitary circumstances of the districts in his charge.’37 Immersing himself in the ‘mass of routine work’ of the Medical Department, his mastery of epidemiological methods led to his appointment as President of the Epidemiological Society of 34 ‘Henry Franklin Parsons’, BMJ (8 November 1913), 1263–1264; ‘Henry Franklin Parsons (1846–1913)’, Lancet ii (8 November 1913), 1355–1356. 35 Harry Marks, ‘Until the Sun of Science…the True Apollo of Medicine Has Risen’: Collective Investigation in Britain and America, 1880–1910’, Medical History 50 (2006), 147–166. 36 Coleman, Yellow Fever, 186. 37 ‘Henry Franklin Parsons (1846–1913)’, 1355.

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London. Of the numerous reports Parson produced for the Department, his first report on influenza consolidated his reputation among his peers and became, as one observer put it, ‘a classic on the subject which will be referred to as long as this plague continues to exist.’38 In early January 1890, from his office in Whitehall, Parsons issued a questionnaire to 1,777 sanitary districts, all government departments, and heads of public and quasi-public bodies, including military and imperial offices, medical and public health journals, and the daily press (Fig. 3).39 The questionnaire aimed to prompt the uniform collection of epidemiological information on influenza. Comprised of six questions, it was a model of case-based epidemiology. Accurately identifying influenza was key to determining its first occurrence, how it spread and when it became epidemic. But the method depended on an agreed clinical definition of the disease. The problem for Parsons was that most medical practitioners were unfamiliar with what constituted a case of influenza. While he provided a short list of standard symptoms as diagnostic guide, these were based on older classifications and, as we shall see, did not match the ‘influenza’ many practitioners actually encountered in 1889–1890. Despite this obstacle, Parsons proceeded to gather views on the ‘commencement’, ‘the mode of origin of introduction of the disease’, ‘its method of spread’, and its ‘dissemination’ through households, communities, and localities.40 He also asked for observations on similar outbreaks in domestic animals, among which there had been reported epizootics of influenza-like disease, particularly in horses, prompting speculation about their relationship to human disease. Some 1,150 reports were returned. Parsons’ first impression on reviewing them was ‘bewilderment. There is scarcely a single proposition made which was not contradicted by different observers.’41 The avalanche of reports revealed deep fissures on crucial questions about the influenza’s identity, the factors that caused the epidemic, how it spread, and the speed it travelled. Part of the problem stemmed from the distinct epidemiological nature of the disease itself. Influenza’s ‘mode of diffusion stands almost alone among epidemic diseases,’ the Lancet noted:

38 ‘Henry Franklin Parsons (1846–1913)’, 1356. 39 Parsons, Report on the Influenza Epidemic of 1889–1890, 13. 40 Parsons, Report on the Influenza Epidemic of 1889–1890, 120. 41 Frank Clemow, ‘Epidemic Influenza’, Public Health, 24 (1890), 358–366.

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Fig. 3 Questionnaire on the Origin and Spread of Influenza, 1890. Distributed by Henry Parson to collect “information on a uniform plan” (Source Report on the Influenza Epidemic of 1889–1890 [1891], 120)

In the first place, it spreads with remarkable rapidity once it is established in a centre. Secondly, it tends more or less rapidly to become pandemic … its liability to diffusion over whole continents, and indeed from one hemisphere to the other, is one of the best-known facts concerning it. The disease therefore has no geographical limitation … and its virus travels

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over seas and land in manner so baffling and contradictory to the ordinary conceptions of the transmission of infection as to render any simple explanation of its nature almost impossible.42

But the challenges posed by the nature of influenza were not the only reason for disputes over its epidemiology; they were also rooted in competing medical ideas and practices. A priority for public health officials was to understand how the disease spread so quickly and suddenly. Yet at first, disagreement reigned. Some medical observers invoked theories based on the original meaning of ‘influenza’, which presupposed an external influence—occult, telluric, astral, or meteorological—that conspired to excite an epidemic.43 A long history of associating influenza with the weather had wide appeal because it resonated with popular perceptions of its apparent affinity for colder and damper months of the year. Reports in the daily press attributed the epidemic to miasmas activated by elemental forces, such as floods, droughts, earthquakes, volcanoes, or electrical magnetic waves and suggested that, by these means, influenza traversed continents, countries and cities faster than any other epidemic disease.44 Historians have focused on rivalries in nineteenth century epidemiological thinking between supporters of miasma and contagion theories, but in practice the dominant view in Britain was that of contingent contagionism and there were different models for different diseases.45 By 1890, bacteriological ideas were reshaping, albeit unevenly, epidemiological models, with more emphasis on the modes by which diseases were transmitted and role of living pathogens in epidemic diseases.46 At the beginning of the epidemic in January 1890, a British Medical Journal editorial argued that, ‘like other epidemic diseases, influenza is spread by a contagium, and must be due to a living organism, a microbe,’ but disagreement remained over whether the stunning diffusion of influenza was the product of ‘microbes

42 ‘Influenza’, Lancet (21 December 1889), 1293. 43 Margaret DeLacy, ‘The Conceptualization of Influenza in Eighteenth Century

Britain: Specificity and Contagion’, Bulletin of the History of Medicine, 67 (1993), 74–118. 44 See Smith, ‘Russian Influenza’, 62. 45 Margaret Pelling, ‘Contagion/Germ

Theory/Specificity’, in Companion Encyclopaedia of the History of Medicine (London: Routledge, 1993), 309–334. 46 Worboys, Spreading Germs, 212.

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carried in the air’, microbes spread from person to person, or a combination of the two.47 For many observers, influenza defied explanation as a strictly contagious disease. They concurred with mid-nineteenth century observations that conceptualising influenza as a strict contagion could not account for the speed epidemics spread, how they struck countries ‘as if at one blow’ and extended over ‘the whole of the inhabitable globe.’48 Early reports of the 1890 epidemic reinforced this view. ‘The most remarkable phenomenon of [the epidemic’s] progress,’ noted the Lancet, ‘was the rapidity, almost suddenness, with which large numbers of persons, or entire communities, were attacked, exceeding anything observed in the case of other infectious diseases, and not easily explicable on the ordinary theory of contagion, but apparently suggesting an aerial conveyance of some kind.’49 The medical geographer and physician, Frank Clemow, who had been working at the English Hospital in Kronstadt near St. Petersburg when the 1889 epidemic had broken out there, outlined the standard ‘contingent-contagionist’ position supported by the Lancet.50 At a meeting of the Society of Medical Officers of Health (SMOH) in February 1890, he argued that influenza’s capacity to simultaneously affect numerous people over a vast country demonstrated that its causative agent was ‘carried by the air, and that the primary mode of spread …[was] through the atmosphere.’ Once the epidemic was established in a locale, ‘direct infection from person to person’ became ‘a secondary mode of spread.’51 He thus divided the epidemic into a primary wave, in which people were attacked by air saturated with highly infective material, and a

47 Parsons, Report on the Influenza Epidemic of 1889–1890, 78. 48 Registrar General, Tenth Annual Report of the Registrar-General of Births, Deaths,

and Marriages in England (London: HMSO, 1852), xxxiv; Registrar General, Fourteenth Annual Report of the Registrar-General of Births, Deaths, and Marriages in England (London: HMSO, 1856), xv; August Hirsch, Handbook of Geographical and Historical Pathology, trans. Charles Creighton (London: New Sydenham Society, 1883), 18. 49 ‘Society of Medical Officers of Health: Epidemic Influenza’, Lancet (5 April 1890),

754. 50 Frank Clemow, ‘Epidemic Influenza’, Public Health, 24 (April 1890), 358–366. 51 Clemow, ‘Epidemic Influenza’, 362.

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secondary wave, when it turned into a contagious disease, which spread slowly from distinct centres.52 Many medical officers criticised Clemow’s theory. John Sykes, MOH for St. Pancras and Secretary of the Society of Medical Officers of Health, suggested that the difference between aerial transmission and contagion was one of degree—the distance travelled by the contagion.53 The germs of infectious diseases such as smallpox, measles, and diphtheria were known to spread through the air, but only over relatively short distances; no living germ was known to travel the distances Clemow claimed for influenza. Bacteriological studies in the 1880s gave air-borne germs a notoriously short life-span, since the properties of the air could not support them and factors such as light quickly destroyed them.54 Edward Willoughby, another London MOH, argued that if the aerial germ of influenza was a living agent it must be uniquely able to multiply in the air or, as was more likely, it would ‘simply die out.’ If influenza followed the established modes of transmission of air-borne diseases, which bacteriological studies delimited to interactions between people in specific places, there was, according to Willoughby, no reason to think that it did not adhere to ‘the theory of infection’.55 When MOHs employed epidemiological methods to identify first cases of influenza and to reconstruct its spread, many became convinced that it was primarily contagious. W. Bezley Thorne, MOH for South Kensington, described how his ideas evolved in the process of his investigations: ‘Some five weeks ago I might have been inclined to support the view that this malady is not infectious … but observation of the manner in which it spread in households … has compelled me to adopt the opposite opinion.’56 Thorne was not alone in his view. Similar observations lead the Medical Officers of Schools Association in London to conclude in late April 1890 that influenza was primarily disseminated by ‘personal intercourse.’57

52 Frank Clemow, ‘The Recent Pandemic of Influenza: Its Place of Origin and Mode of Spread’, Lancet (20 January 1894), 140–143. 53 ‘Discussion: Epidemic Influenza’, Public Health, 24 (April 1890), 367. 54 See, for example, Tomes The Gospel of Germs, 80–81. 55 ‘Discussion: Epidemic Influenza’, Public Health, 24 (April 1890), 366. 56 ‘Letter to the Editor’, The Times (13 January 1890), 10. 57 ‘The Spread of Influenza’, BMJ (3 May 1890), 1026.

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Parsons’ Report on the Influenza Epidemic of 1889–1890, published in July 1891, assessed the different aetiological theories and concluded that the growing body of evidence indicated that this was a contagious disease. Parsons was well positioned to make such a judgement. The Department put at his disposal epidemiological information from most corners of the globe. Along with the responses he received from his official questionnaire, he had also accumulated scores of reports from colonial and European health authorities. Turning this mountain of material into an evidence base took considerable time, but when completed his Report presented the most thorough analysis of the epidemiology of influenza of its day. In building the case for recognising influenza as a contagious disease, Parsons first dismantled competing theories. He disposed of those attributing the epidemic to specific weather states by showing that influenza occurred in all climates, under a variety of conditions. Its simultaneous prevalence in northern and southern hemispheres at nearly the same time undermined the notion that it depended on a specific season.58 Miasma theories were harder to discount. Many authorities turned to them to explain the epidemic’s rapid spread and its alleged tendency to affect large numbers of people simultaneously. Parsons argued that its explosiveness was exaggerated on both counts. Accepting the idea that the ‘exciting organism’ was capable of ‘multiplication within the human body as well as outside’, he nonetheless doubted whether germs could exist for long in pure air or be spread over great distances.59 His own observations and those of many MOHs suggested that, if the suspected microbe was indeed air-borne, it thrived only in the air of ‘crowded establishments’, homes, and modes of urban transportation where people interacted. Case-tracking surveys of MOHs and other medical practitioners contradicted the notion that the epidemic exploded all at once in different places. They consistently showed, according to Parsons, that outbreaks were preceded by early cases and as influenza progressed into an epidemic, its incidence increased incrementally. This pattern was most evident in so-called ‘household’ outbreaks, which also revealed how the epidemic moved between public into private realms. Breadwinners and school children were often found to be the first to contract influenza. In many

58 Parsons, Report on the Influenza Epidemic of 1889–1890, 76–80. 59 Parsons, Report on the Influenza Epidemic of 1889–1890, 81.

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instances, their exposure to infection could be traced to a previous case at an infected workplace or locality. In counties such as Middlesex, Essex, Surrey and Kent, household outbreaks were directly linked to men who had returned from jobs in London and introduced the disease ‘to the wife and afterwards the [younger] children’ and the servants.60 Social and gender hierarchies were mapped onto urban hierarchies. ‘There is no part of England and Wales,’ argued Parsons, ‘that cannot be reached by a traveller in twenty-four hours.’61 Rather than exploding across England, the epidemic radiated outwards from London, along the railways to the suburbs, the great cities of the midlands, and then to increasingly remote areas. Such evidence convinced Parsons that influenza was ‘an eminently infectious complaint, communicable in the ordinary personal relations of individuals, one with another,’ in cities, institutions, and homes.62 He posited a ‘germ’ as the contagion, likely communicated directly from person to person. The germ’s short incubation period made it highly transmissible and was the reason influenza spread more rapidly and extensively than any epidemic disease.63 While influenza seemed to explode suddenly, it was always preceded by a succession of early cases, which then multiplied into an epidemic that exploited the material conditions of modern life.64 Parsons did not stop at drawing a picture of how influenza spread across Britain. Using reports from European authorities, the colonies, and the press, he also traced its progress across the globe. From the dates of the first recorded cases or outbreaks, he located the geographical index of the epidemic in the Russian steppe and then reconstructed its movement westward across Russia and Eastern Europe, from where, once gaining a foothold on railway networks, it spread rapidly in every direction across the continent and outwards through ports to the rest of world. Parsons

60 Parsons, Report on the Influenza Epidemic of 1889–1890, 87. 61 Clemow, ‘Epidemic Influenza’, 366. 62 Parsons, Report on the Influenza Epidemic of 1889–1890, x. 63 Parsons, Report on the Influenza Epidemic of 1889–1890, 52. 64 Parsons, Report on the Influenza Epidemic of 1889–1890, 52; Patterson, Pandemic

Influenza, 60.

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contributed to the popular conceptualisation of the epidemic as originating in Russia and to it being named the ‘Russia influenza’.65 But his Report also importantly provided an evidence-base for envisioning influenza as a worldwide phenomenon. Along with a detailed written account, the Report included the first detailed map of its movement across the world. The most notable feature of the map was how it correlated the temporal and spatial spread of the epidemic. Rather than exploding simultaneously in different countries or moving like a vast miasmatic cloud, by pinpointing exactly when and where it appeared, Parsons demonstrated that influenza spread incrementally between towns, cities, countries and continents, and only as fast as existing transportation systems could carry it (Fig. 4). The publication of the Report in July 1891 was much anticipated and well received. The BMJ noted that although ‘the theory that influenza is mainly if not entirely spread by contagion is no new one … [it] had needed to be born again.’66 In a significant turn, the Lancet endorsed the new concept: ‘there does appear to be an abundance of evidence to show that [the epidemic] travelled mainly along the lines of human intercourse, attacking large towns and population centres first … and that the disease travelled only just as fast as any humanly conveyed infection … might have expected to travel.’67 A survey of London Medical Officers found that only one of nineteen held that influenza was a miasma; another remained undecided; the rest supported its identity as an infectious disease.68 In late January 1892 the Society of Medical Officers of Health passed a resolution defining influenza as a ‘dangerous infectious disease’69 and considered including it under the 1889 Infectious Diseases Notification Act.70

65 Smith, ‘Russian Influenza’, 66–67; Honigsbaum, A History of the Great Influenza Pandemics, 32–33. 66 ‘Concerning Influenza’, BMJ (23 January 1892), 183. 67 ‘Official Report on Epidemic Influenza’, Lancet (11 July 1891), 80. 68 ‘The Influenza Epidemic’, BMJ (30 January 1892), 243–250. 69 ‘Concerning Influenza’, BMJ (23 January 1892), 184. 70 Richard Sisley, A Study of Influenza and the Laws of England Concerning Infectious

Diseases (London: Longman’s, Green, and Co., 1892).

Fig. 4 Influenza across the World ‘Map showing recorded date of Influenza Epidemic in 1890 and 1891,’ Report on the Influenza Epidemic of 1889–1890 (1891) (Credit Wellcome Collection. Attribution 4.0 International [CC BY 4.0])

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Not all the medical or public health profession was ready to endorse this new way of defining influenza.71 When Parsons presented his findings at the annual British Medical Association meeting in Bournemouth in August 1891, he faced a number of critics. Military physicians, in particular, argued that influenza’s epidemiological characteristics had greater affinities with ‘malaria fever’ than any contagious disease.72 Such views were not uncommon, and questions about influenza’s epidemiology were debated through the 1890s.73 But anti-contagionist perspectives increasingly ran against official opinion, promoted by the Medical Department and supported by the BMJ , the Lancet, and leading professional bodies such as the Society of Medical Officers of Health. By 1892, Parsons’ perspective was already being legitimised within British public health and hygiene manuals and textbooks.74 Similar studies by German, French and other European health authorities confirmed and embraced the Department’s report. Influenza was being drawn into a new discourse that associated risk of infection with specific conditions of the modern city. Catching and spreading influenza was attributed to increasing urban interconnection and propinquity. ‘The assembly of people in churches, chapels, the Houses of Parliament, places of business, or other institutions’ involved what the Lancet described as the ‘exceptional risk of contracting the disease, the risk depending in part on the closeness of aggregation.’75 Subsequent epidemics in 1890–1891, 1892, and 1893–1894 confirmed this general picture. They demonstrated how people living in close proximity or in overcrowded conditions, and increasingly concentrated in everlarger industries, offices, institutions, and schools provided constantly fresh ‘soil’ for influenza.76 The centrifugal growth of suburbs, facilitated and serviced by railways, created a continuous flow of people travelling in and out of cities, and kept influenza in constant circulation. Britain’s vast 71 Parsons, Report on the Influenza Epidemic of 1889–1890, 118. 72 Peter Eade, ‘Influenza in 1891’, BMJ (8 August 1891), 309. 73 Smith, ‘Russian Influenza’, 68. 74 Louis Parkes, Hygiene and Public Health (London: H.K. Lewis, 1892); B.A. Whitelegge, Hygiene and Public Health (London: Cassell, 1894). 75 ‘Official Report on Epidemic Influenza’, Lancet (11 July 1891), 79. 76 Major Greenwood, ‘A General Discussion of the Epidemiology of Influenza’, in

Report on the Pandemic of Influenza, 1918–19, Ministry of Health, Reports on Public Health and Medical Subjects, No. 4 (London: HMSO, 1920), 190.

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commercial and imperial connections meant that an outbreak in a distant part of world could be carried by steamship into any one of its major ports in Liverpool, Southampton, or London. As Greenwood would observe years later, the ‘steady increase of movement and intermingling of populations associated with the improvement of communications’ made influenza intractable.77 What was new here was not just the epidemiological conditions but the way in which they were being attached to a new epidemiological framework for understanding influenza. In this framework, the conditions of the modern city and communications fostered the disease and its dangers. Yet unlike with cholera or tuberculosis, which sharply revealed class divisions, this risk was presented as being shared by all. Influenza was, in the words of the Times, an ‘essentially democratic’ disease that embraced ‘all the people, not just the lower section of them.’78 The concept of influenza as ‘democratic’ became a trademark of its modern identity. Its democratisation was closely tied to its definition as an infectious disease, which placed it under the aegis of preventive medicine and its focus on risks associated with regular interactions between germs, people and particular environments. Crucially, however, it was the fact that influenza eluded prevention that democratised its danger. Louis Parkes, MOH for Chelsea and author of a widely read manual on Hygiene and Public Health, noted that, ‘theoretically, notification of cases, isolation of the sick, and disinfection of premises, should be, as for other infectious diseases, the proper means of checking or stamping out an [influenza] epidemic.’79 But there was considerable doubt about the effectiveness of these standard prevention measures against influenza. In his introduction to Parsons’ Report, George Buchanan admitted that, ‘from what we have thus far seen of the specialities of influenza, we cannot feel particularly confident, under the existing conditions of society, to successfully defend ourselves against a further outbreak.’80 Isolation was unimaginable during epidemics: ‘When two-thirds of the households, and perhaps not far short of a fourth of the adult population, are suffering from the disease,’ asked the BMJ , ‘is isolation of the sick anything more

77 Greenwood, ‘History of Influenza’, 27. 78 ‘The Epidemic of Influenza’, The Times (28 December 1889), 7. 79 Parkes, Hygiene and Public Health, 460. 80 Parsons, Report on the Influenza Epidemic of 1889–1890, x.

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than a dream?’81 Influenza’s incubation rate was so short that it became rapidly infectious in its early stages and, coupled with its non-specific symptoms, this meant practitioners had great difficulty recognising first cases. While disinfection might have limited influenza’s spread, no one knew what to disinfect. Public health authorities needed answers to two crucial questions: what constituted a case of influenza and what was its disease agent?82 In short, as Buchanan summed up the problem, prevention measures needed ‘more authentic methods of identifying Influenza proper.’83 For these, they turned to clinicians and bacteriologists.

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Parsons’ first report relied on descriptions of influenza supplied by general practitioners, consultant physicians, and medical officers, but it revealed significant gaps in existing clinical knowledge. Few medical practitioners had experience identifying or managing influenza. It did not fall under the 1889 Infectious Diseases Notification Act, so doctors were not obligated to report it.84 Since it had not registered as a serious medical problem for decades, most general practitioners had no reason to learn how to recognise its signs and symptoms, or to distinguish these from other diseases. This not only challenged epidemiological understandings, but it also had implications for medical practice. The construction of specific disease entities had become one of the hallmarks of modern medicine in the nineteenth century. Such entities grounded medical authority and its role in establishing and maintaining natural and social order.85 Authority rested on the ability of physicians 81 ‘Concerning Influenza’, BMJ (23 January 1892), 184. 82 Parsons, Report on the Influenza Epidemic of 1889–1890, xi. 83 Parsons, Report on the Influenza Epidemic of 1889–1890, xi. 84 Richard Sisley, ‘Influenza and the Laws of England Concerning Infectious Diseases: Proceedings of Society of Medical Officers of Health’, Public Health, 4 (1892), 136–142. 85 Charles Rosenberg, ‘The Tyranny of Diagnosis: Specific Entities and Individual Experience’, Milbank Quarterly, 80.2 (2002), 237–260; Charles Rosenberg, ‘Framing Disease: Illness, Society, and History’, in idem., Explaining Epidemics and Other Studies in the History of Medicine (Cambridge: Cambridge University Press, 1992), 310; Robert Aronowitz, Making Sense of Illness: Science, Society, and Disease (Cambridge: Cambridge University Press, 1998); Annemarie Jutel, Putting a Name to It: Diagnosis in Contemporary Society (Baltimore: Johns Hopkins University Press, 2011). For classic accounts, see Nicolas D. Jewson, ‘The Disappearance of the Sick-Man from Medical Cosomology,

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to render a specific diagnosis with established clinical methods, which in turn facilitated treatment and prevention. The inability of physicians to identify a case of influenza thus represented a potential challenge to this professional pillar. Without first-hand experience of the disease, practitioners were forced to turn to existing textbooks for guidance. Yet the descriptions they found had not been revised since the 1850s. Significant gaps emerged between physicians’ own observations and the status quo of an earlier generation. One striking discrepancy was the relative absence of ‘catarrh’ in 1890.86 Following a practice that dated back to William Cullen’s classification of influenza as a ‘catarrhus a contagio’ in the 1780s, clinical accounts through most of the nineteenth century made catarrh—general inflammation of the respiratory tract—a defining symptom, and textbooks categorized influenza as an epidemic ‘catarrhal fever.’87 In contrast, physicians in the 1890s highlighted the predominance of ‘respiratory’ and ‘nervous’ symptoms, and increasingly explained them as products of an underlying infection. Such gaps raised questions about the state of medical knowledge: if older textbooks were out-dated, what constituted a reliable basis for diagnosis? Physicians attributed the change in influenza’s predominant symptoms to its clinical variations, a fact demonstrated in historical records and past medical observations. But gaps in clinical knowledge also stemmed from significant changes in the social organisation and epistemology of medicine since epidemic influenza last appeared in 1848. To learn how to identify influenza, the profession had to re-shape its clinical identity to fit contemporary medical knowledge and practice, which was being transformed by the incorporation of new clinical instruments and new bacteriological ideas and practices. In the early 1890s, influenza would no longer be clinically defined as a species of ‘catarrh’ but as an acute disease in which catarrh and fever were symptoms of an underlying respiratory infection.

1770–1870’, Sociology, 10 (1976), 225–244; Michel Foucault, The Birth of the Clinic: An Archaeology of Medical Perception (New York: Vintage, 1973); Edwin H. Ackernecht, Medicine at the Paris Hospital (Baltimore: JohnsHopkins University Press, 1967). 86 Parsons, Report on the Influenza Epidemic of 1889–1890, 54. 87 Thomas B. Peacock, On the Influenza, or Epidemic Catarrhal Fever of 1847–1848

(London: J. Churchill, 1848); Thomas S. Watson, Lectures on the Principles of Physic (London: Longmans, Green and Co., 1871).

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The practical transformation of influenza’s clinical identity in the medical profession was rooted in London’s voluntary and teaching hospitals, where elite clinicians codified clinical knowledge and practice.88 Although general practitioners developed their own ‘influenzas’, clinicians had the power to produce a standard diagnostic picture. Voluntary hospitals were the institutional base for their authority. In epidemics of the 1830s and 1840s hospitals were generally for London’s paupers and viewed as a last resort. Medical care and treatment took place at home, with physicians attending those who could pay for their services.89 By 1890, reforms in hospital organisation and administration positioned hospitals at the centre of London’s burgeoning health-care system.90 Although most influenza sufferers still relied on home care and local practitioners, a cross-section of working class and, increasingly, middle class patrons visited outpatient clinics. The availability of hospital patients made it possible for clinicians and their students to observe and classify the varieties of influenza, to follow its pathogenesis and to analyse its morbid anatomy and clinical pathology. Increasing technological sophistication of hospitals provided a range of tools with which to trace influenza’s extensive constitutional symptoms and complications. Most crucial was thermometry, which enabled clinicians to standardise fevers associated with particular diseases.91 Hospitals drew together different

88 Elisabeth Heaman, St. Mary’s: The History of a London Teaching Hospital (Montreal: McGill Queen’s University Press, 2003), 89–118; Keir Waddington, Medical Education at St Bartholomew’s Hospital 1123–1995 (London: Boydell Press, 2003), 115–145; for the reception and use of bacteriology, see Rosemary Wall, Bacteria in Britain: 1880–1939 (London: Pickering & Chatto, 2013). 89 For general patterns, see Joan Lane, A Social History of Medicine: Health, Healing and Disease in England, 1790–1950 (London: Routledge, 2001), 87ff. 90 Geoffrey Rivett, The Development of the London Hospital System, 1823–1982 (London: King’s Fund, 1986); Lindsay Granshaw, ‘The Rise of the Modern Hospital’, in Medicine in Society (Cambridge: Cambridge University Press, 1992), 197–218. Lindsay Granshaw and Roy Porter (Eds.), The Hospital in History (London: Routledge, 1989); Steven Cherry, Medical Services and the Hospitals in Britain, 1860–1939 (Cambridge: Cambridge University Press, 1992); Keir Waddington, Charity and the London Hospitals (Woolbridge: Boydell Press, 2000), Francis Fraser, ‘The Rise of Specialism and the Special Hospitals’, in F.N.L. Poynter (Ed.), The Evolution of Hospitals in Britain (London: Pitman Medical Publishing, 1964), 169–185. 91 Volker Hess, ‘Standardizing Body Temperature: Quantification in Hospitals and Daily Life, 1850–1900’, in Gerard Jorland, Annick Opinel, and George Weisz (Eds.),

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kinds of knowledge in one institution.92 The epidemics demonstrated the extent to which the production of medical knowledge was becoming collective.93 At the outset of the 1889–1890 epidemic, London’s leading medical bodies put the production of ‘exact clinical records’ of influenza at the forefront of the medical agenda. The Lancet led the push: ‘[W]e…suggest, in the interest of scientific medicine, that, as nearly half a century has elapsed since the last outbreak of the disease in England, no means should be left untried to ensure full records of the occurrences of cases….’94 Leaders of the profession saw the pandemic as an opportunity to order the clinical picture of influenza. Standardisation of diagnoses had become a platform for those seeking reform.95 It represented a way to unify and assert control over practices and meanings assigned to diseases, and especially for one that showed as much heterogeneity as influenza. But rather than clarify influenza’s clinical picture, the call to collect new information initially complicated it. As the first epidemic reached its apex in early January 1890, clinical descriptions filled the pages of the medical and general press.96 Physicians identified a profuse number of symptoms in the patients they saw. Richard Sisley, a Harley Street physician who produced two studies of the epidemic, surmised that, ‘to sum up accurately all the symptoms of influenza in a single sentence is impossible.’97 James Goodhart, a physician at Guy’s Hospital, insisted that

Body Counts: Medical Quantification in Historical and Sociological Perspective (Montreal: McGill-Queen’s University Press, 2005), 109–126. 92 Lindsay Granshaw, ‘“Fame and Fortune by Means of Bricks and Mortar”: The Medical Profession and Specialist Hospitals in Britain, 1800–1948’, in The Hospital in History, 199–220. 93 Christopher Lawrence, ‘Incommunicable Knowledge’, 503–520; Steve Sturdy and Roger Cooter, ‘Science, Scientific Management, and the Transformation of Medicine in Britain c. 1870–1950’, History of Science, 36 (1998), 435. 94 ‘Influenza’, Lancet (21 December 1889), 1293–1294. 95 Mildred Jeanne Peterson, The Medical Profession in Mid-Victorian London (Berkeley:

University of California Press, 1978), 88–89. 96 ‘The Epidemic of Influenza’, The Times (1 January 1890), 3; ‘The Epidemic of Influenza’, The Times (7 January 1890), 5; ‘The Gresham Lectures on Influenza’ (23 January 1890), 14. For a full account of press responses, see, Mark Honigsbaum ‘The Great Dread: Cultural and Psychological Impacts and Responses to the “Russian” Influenza in the United Kingdom’, Social History of Medicine, 23.2 (2010), 299–319. 97 Richard Sisley Epidemic Influenza, 6.

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influenza stood above all diseases for ‘the width of its range of action over the human body…. There would appear to be no organ or tissue that has not become the subject of its attack.’98 When Symes Thompson, consulting physician to the Brompton Hospital for Consumption and Diseases of the Chest, reissued his father’s authoritative historical survey of influenza in March 1890, he drew particular attention to the ‘extreme and remarkable diversity’ of symptoms physicians described in the onset of the ‘average type of the disease’ during the 1889–1890 epidemic.99 The breadth and lack of specificity of symptoms meant that influenza was linked to numerous clinical interpretations. Reflecting the persistence of older diagnostic custom, ‘catarrh’ remained a common label.100 However, its use as an indicative symptom became suspect as many practitioners noted its general absence. They concentrated on symptoms more closely allied with contemporary disease categories. The ubiquity of prostration and high fever, uncommon in ‘severe catarrh’, was widely taken as the beginnings of typhoid fever, a persistent epidemic disease with a loose enough clinical definition to make it a popular term for a variety of acute fevers.101 The sudden onset of influenza, especially the crippling body pain, led some physicians to diagnose rheumatic fever, while others drew analogies with the tropical disease, dengue fever.102 Depending on prevailing diagnostic proclivities, the early symptoms of influenza were associated with an endless array of established diseases. The lack of an agreed diagnosis worried the medical establishment. Elite physicians blamed general practitioners’ lack of training and discipline for these difficulties. At the height of the 1889–1890 epidemic it was not unusual for a general practitioner to see two or three hundred patients a day. The majority had only brief encounters; their aim was to provide rapid diagnoses and treatment. Critics claimed that, in their haste

98 John F. Goodhart, ‘Influenza’, in Thomas Clifford Albutt (Ed.), A System of Medicine (London: Macmillan and Co., 1896), 690. 99 Thompson, Influenza, or Epidemic Catarrhal Fever, 6. This was a revised edition of his father’s 1852 manual, Thompson, Annals of Influenza (1852). 100 ‘Influenza’, Lancet (21 December 1889), 1293. 101 Hardy, Epidemic Streets, 151–190. 102 Parsons, Report on the Influenza Epidemic of 1889–1890, 55.

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general practitioners pandered to diagnostic ‘fashions’ and used ‘popular symptoms’ derived from the general press or patients. This resulted in a proliferation of clinical definitions, added confusion to a complex problem, and threatened professional authority.103 ‘It is probable,’ argued Seymour Taylor, Assistant Physician to West London Hospital, ‘that practitioners will overlook or not recognise the earlier cases which come under their observation; and further the public, from an erroneous impression of the disease gathered from accounts in the lay press, are apt to regard influenza as a disease presenting symptoms mainly of catarrh of the eyes and nose, together with aching over the frontal sinuses; and think that such are the main, if not only symptoms.’104 To remedy the problem, Taylor argued that a ‘clinical sketch of the disease should be written from the direct observation of the numerous cases now presenting themselves at the hospitals and in private practice.’105 Besides serving general professional interests, the initiative also served physicians’ practical interest in securing an accurate diagnosis of influenza. The elaboration of influenza’s clinical identity at St Bartholomew’s Hospital in the early 1890s exemplifies how a general diagnostic framework was built.106 While influenza was never the property of one institution, Barts established itself as an important centre of clinical and pathological investigations. Samuel West organised these studies. Oxford educated, he was Assistant Physician to Barts and Physician to the City of London Hospital for Diseases of the Chest. His knowledge of chest diseases put him in a good position to clarify influenza’s respiratory complications. An exponent of the idea that influenza was primarily a respiratory ailment, he was among the first to characterise ‘influenzal pneumonia’, an important complication. Like other London voluntary hospitals, Barts was a major destination for the sick during the 1889– 1890 epidemic. West estimated in the first six or seven weeks of 1890 ‘not

103 Seymour Taylor, ‘Notes on Epidemic Influenza’, Lancet (25 January 1890), 187. 104 Taylor, ‘Notes on Epidemic Influenza’, 187. 105 Taylor, ‘Notes on Epidemic Influenza’, 187. 106 For diagnostic practices at Barts, see Rosemary Wall, ‘“Natural”, “Normal”:

Discourse and Practice at Sr. Bartholomew’s Hospital, London, and Addenbrooke’s Hospital, Cambridge, 1880–1920’, Forum: Qualitative Social Research, 8.1 (2007), http:/ /nbnresolving.de/urn:nbn:de:0114-fqs0701174.

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far short of 8000 cases of influenza were seen and treated’ in the Hospital’s Casualty Department and wards.107 The majority came in the second and third weeks of January, when nearly 6000 patients visited—two-thirds suffering from influenza. Many of the sick described how they suddenly became ill ‘in the midst of their work, and had at once to stop, feeling unable to stand, or even fell in a faint.’108 Medical staff could barely cope. ‘The rush was overwhelming,’ recalled West, ‘and utterly beyond the power of the staff to deal with … [T]he general misery and confusion of those few days may be in a measure conceived, but cannot be adequately described.’109 The epidemic temporarily paralysed the hospital. In the first stages of the epidemic, early symptoms were so indistinct that house physicians failed to identify them. John Ogle, a junior houseman, confessed that he was initially unable to ‘recognise the nature of the disease’; he and his colleagues thought it was ‘pneumonia, scarlet fever, or rheumatic fever.’ Early attacks ‘remained an enigma until the epidemic arrived in full force.’110 Along with standard physical examination and urine analysis, key information came from daily temperature readings, which clinicians used to chart the different fevers associated with influenza, and to identify a new entity, known as ‘influenzal fever’. Corresponding to the acute stage of the disease, it involved a sudden rise in temperature at the onset, which peaked after forty-eight hours, and then fell back to normal within a few days (Fig. 5). The fever gave clues to significant events and changes. A ‘relapsing’ form, in which the patient’s temperature would rise, fall, and rise again, was common (Fig. 6). Most worrisome was a sudden drop in temperature to below normal after the acute stage, called ‘apyretic influenza’, for this often signalled the onset of more severe respiratory complications (Fig. 7).111 Thermometry yielded new physical signs that became crucial to the prognosis of influenza. But clinical tools alone could not identify a single pathognomonic marker on which to anchor diagnosis. Post-mortem was

107 Samuel West, ‘The Influenza Epidemic of 1890’, St. Bartholomew’s Hospital Reports, XXVI (1890), 193. 108 West, ‘The Influenza Epidemic of 1890’, 109 West, ‘The Influenza Epidemic of 1890’, 110 West, ‘The Influenza Epidemic of 1890’, 111 West, ‘The Influenza Epidemic of 1890’,

196. 194–195. 217. 217.

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Fig. 5 ‘Uncomplicated influenza’. First recognised case at Barts, 30 December 1889. Fever chart of Bedford Pierce, 28, house physician, who awoke on 30 December with a high fever. Warded on 31 December. Returned home on 3 January 1890, two weeks after which he ‘was not up to the mark’ (Source Samuel West, ‘The Influenza Epidemic of 1890’, St. Bartholomew’s Hospital Reports, XXVI [1890], 212)

rarely performed, and when it was, little was revealed about the pathogenesis of the disease. Clinicians thus resorted to grouping symptoms into patho-physiological forms. This practice had started in the early nineteenth century, most notably in the work of the London physician, Thomas Peacock, whose classification of three different forms of influenza during the 1848 epidemic remained a touchstone through to the 1890s. Peacock divided influenza into ‘simple catarrhal fever’, ‘catarrhal fever with pulmonary complications’, and ‘catarrhal fever with abdominal complications.’112 Theophilus Thompson followed Peacock in his 1852 Annals of Influenza or Epidemic Catarrhal Fever. As its subtitle indicated, 112 See Peacock, On the Influenza. Peacock’s description was used in Quain’s Dictionary of Medicine until 1894, when it was revised by Dawson Williams.Williams noted that an adaptation of Peacock’s original classification was ‘very widely accepted’. See Richard Quain, A Dictionary of Medicine (London: Longmans, Green and Co, 1894), 960.

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Fig. 6 Relapsing Fever. A standard reference was Otto Frentzel, ‘Zur Kenntnis des Fieberganges bei Influenza’, Centralblatt fur klinische Medicin (11 January 1890), who characterised three types of fever in the 1889–1890 epidemic in the Municipal General Hospital at Friedrichshain. Type II, shown here, was a relapsing fever that could last for a week, with significant temperature fluctuations, in which the patient might appear to recover, only for the fever to return (Source J.W.S. Moore, ‘Influenza’, in J.W. Ballantyne [Ed.], Encyclopaedia Medica [Edinburgh and London: Green & Son, 1919], 517)

it highlighted catarrhal symptoms as a defining and constant characteristic across time and place.113 Physicians encountering the epidemics of the early 1890s used but then modified these classifications. Influenza was typically distinguished into ‘simple’ or uncomplicated and complicated cases. West characterised simple influenza as an acute disease, with an abrupt onset, in which ‘the temperature … rose at once’ and the patient was suddenly crippled by severe prostration, involving a range of constitutional symptoms, the most prominent of which were intolerable pain in the limbs, loins, eyes, back, spine and forehead. As the fever increased, ‘patients lay in a dull, heavy, drowsy state, though sleep was unrefreshing and disturbed by dreams, or even slight delirium.’114

113 Thompson, Influenza, or Epidemic Catarrhal Fever. 114 West, ‘The Influenza Epidemic of 1890’, 196–197.

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Fig. 7 Apyretic Fever. From Frentzel (1890). Type III ‘apyretic’ fever, marked by a sudden fall in temperature below normal, indicative of the onset of serious secondary complications, especially pneumonia (Source J.W.S. Moore, ‘Influenza’ [1919], 517)

Symptoms were grouped according to how they affected the nervous system, respiratory or alimentary organs.115 West identified four varieties: a ‘simple uncomplicated febrile’ form, characterised by mild respiratory symptoms and influenzal fever, which rose quickly in the first forty-eight hours and subsided after three or four days; a ‘gastro-intestinal form’, marked by mild gastric symptoms in addition to fever and prostration; a ‘catarrhal form’, which was ‘singularly infrequent’; and a ‘nervous’ form, which involved excruciating neuralgic pains that produced debilitating paroxysms.116 As clinicians around London produced similar classificatory schemes, the need to make them commensurable was recognised. In 1890, the

115 G. Smith, ‘The Influenza Epidemic’, Transactions of the Medical Society of London, 13 (17 February 1890), 277–306. 116 West, ‘The Influenza Epidemic of 1890’, 196.

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Medical Annual , an indispensable tool for general practitioners that synthesised current medical knowledge into a standard reference, recommended that influenza be grouped into four clinically distinct types: ‘simple catarrhal fever’, pulmonary, gastro-intestinal, and nervous.117 With the epidemic adding urgency to correctly diagnose the disease, versions of this scheme quickly became part of clinical descriptions and of textbook medicine.118 Prevailing medical and social concerns were also important in shaping classifications and the meanings ascribed to key symptoms.119 New categorisations of ‘nervous’ and ‘respiratory’ diseases proved especially popular. Symbolising the exigencies and dangers of modern life, both were major factors in contemporary experience of health and disease, and both were a major focus in clinical medicine. During the 1890s, medical professionals fixated on the astonishing range of neurological symptoms associated with influenza, categorising it among a growing number of neurological disorders that fascinated late Victorians.120 They described patients affected with everything from mild neuralgia and neuritis to hypochondria, melancholia, mania, and general paralysis. Earlier observers had noted such symptoms, but late Victorian doctors were especially drawn to the extensive nervous and muscular depression influenza induced. West readily found examples among his patients: ‘All at once all energy and vigour vanish; the patient feels for nothing and cares for nothing, is completely apathetic, listless, and gloomy, and may hardly have strength enough even to be irritable or sulky.’121 For some observers, nervous exhaustion—‘neurasthenia’— which had its own recent history, became a defining feature of influenza, supplanting catarrhal symptoms. Specialists in nervous diseases argued that neurological symptoms indicated influenza’s propensity to attack the 117 ‘Influenza’, The Medical Annual (London: Simpkin, Marshall, Hamilton, Kent & Co, 1890), 529. 118 Examples can be found in Goodhart ‘Influenza’; Alexander Wheeler and William R. Jack, Wheeler’s Handbook of Medicine and Therapeutics (Edinburgh: E&S Livingstone, 1903); Thomas Dixon Savill, A System of Medicine (London: J&A Churchill, 1903), 645; J.W.S. Moore, ‘Influenza’, in J.W. Ballantyne (Ed.), Encyclopaedia Medica (Edinburgh: Green & Son, 1919), 502–533. 119 See Watson, Lectures on the Principles of Physic, 43–46. 120 Matthew Thomson, ‘Neurasthenia in Britain: An Overview’, in Marijke Gijswijt-

Hofstra and Roy Porter (Eds.), Cultures of Neurasthenia from Beard to the First World War (Amsterdam: Rodofi, 2001), 77–96. 121 Samuel West, ‘An Address on Influenza’, Lancet (28 April 1894), 1047–1052.

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nervous system. Julius Althaus, Senior Physician to the London Hospital for Epilepsy and Paralysis, likened influenza to neuroses seen in syphilis, on which he specialised and had written leading texts.122 Benjamin Ward Richardson, a senior physician and author of the utopian sanitary critique, Hygeia, or City of Health, described influenza as an ‘epidemic neuroparesis’ that directly affected ‘organic nervous function’ and produced ‘intense depression’ in patients.123 Althaus, Richardson and others linked nervous influenza to the demands of the modern city. People exhausted ‘by age, by work, by nervous excitability, by late hours, by anxiety, by mental or physical strain, by confinement in close rooms, by broken rest’ were the most susceptible, while the ‘nervously exhausted’ were the most stricken. Influenza worsened existing neuroses and produced a raft of ‘nerve invalids.’124 ‘Grave neurasthenia’ and ‘grave mental disorders’ remained for weeks or became permanent conditions.125 Bouts of insanity, suicides, and murders were blamed on influenza’s nervous sequelae. Wilfred Harris, a colleague of Althaus’, remarked that, ‘there is scarcely a disease of nerve cell or fibre that has not been ascribed to this most searching of diseases since the last great pandemic of the early nineties.’126 Nervous influenza highlighted fin de siècle obsessions with moral and physical weakness, uncertainty, vulnerability, irrationality and sudden death.127 It became part of a moral discourse in which physicians, politicians, industrialists, engineers, social reformers, and public health authorities drew causal links between nervous disorders and the conditions of modernity.128 As an epidemic disease that drained bodies of energy and that produced mass mental and

122 Julius Althaus, Influenza: Its Pathology, Symptoms, Complications, and Sequels (London: Longmans, 1892), 13–20. 123 Benjamin Ward Richardson, ‘Epidemic Neuroparesis’, Asclepiad, 9 (1892), 19–37. 124 Benjamin Ward Richardson, ‘Influenza as an Organic Nervous Paresis’, Asclepiad,

8 (1891), 178–179. 125 Wilfred Harris, ‘The Nervous System in Influenza’, The Practitioner (August 1907),

85. 126 Harris, ‘The Nervous System in Influenza’, 70. 127 See Honigsbaum, A History of the Great Influenza Pandemics, 82–117. 128 Anson Rabinbach, The Human Motor: Energy, Fatigue, and the Origins of Modernity

(Berkeley: University of California Press, 1990), 146–178.

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physical depression, influenza was perceived as a new threat to industrial capitalist order.129 Yet nervous diseases were perhaps more a symbolic than an epidemiologically significant danger. Chronic and acute respiratory diseases such as tuberculosis, bronchitis, and pneumonia were far more formidable.130 In the spectrum of complications, noted West, ‘the affections of the respiratory organs’ held ‘first place.’131 Most insidious was how easily influenza morphed into serious respiratory conditions. In a matter of days, a simple case could be supplanted by bronchitis, bronchopneumonia, lobar pneumonia, pleurisy, and endocarditis. Influenza paved the way for dangerous respiratory problems, including tuberculosis. Patients with existing pulmonary tuberculosis were especially vulnerable. Respiratory complications often prolonged influenza in previously healthy individuals and often killed ‘those enfeebled by ill-health or age.’132 Clinicians most feared the signs of influenza moving into the lungs, as this often signalled the beginnings of pneumonia. Among the deadliest of nineteenth century respiratory diseases, pneumonia was influenza’s gravest complication. Different kinds of pneumonia were associated with the disease. Bronchopneumonia was the most prevalent. Clinicians also identified a specific ‘influenzal pneumonia’. West led the way in characterising this complication. Studying hundreds of patients at Barts between 1890 and 1894, he noted that although pneumonic complications could appear at the onset, influenzal pneumonia often followed convalescence. It could proceed from bronchitis or attack the lungs directly. Men were more susceptible than women, in part because they often returned to work after the initial fever had fallen and, without having fully recovered, made themselves vulnerable. While it presented typical pneumonic signs—wracking cough, crackling rales, chest pain, and asthenia—in other respects it was ‘atypical and eccentric.’133 Whereas most pneumonias were 129 Thomson, ‘Neurasthenia in Britain’, 80. 130 Histories of respiratory disease have focused on tuberculosis. See, F.B. Smith, The

Retreat of Tuberculosis, 1850–1950 (London: Croom Helm, 1988); Sheila M. Rothman, Living in the Shadow of Death: Tuberculosis and the Social Experience of Illness in American History (Baltimore: Johns Hopkins University Press, 1994); Helen Bynum, Spitting Blood: The History of Tuberculosis (Oxford: Oxford University Press, 2012). 131 West, ‘The Influenza Epidemic of 1890’, 202. 132 West, ‘An Address on Influenza’, 1052. 133 West, ‘An Address on Influenza’, 1049.

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localised, it crept slowly from one part of the lung to the next, making its location difficult to pinpoint. Most strikingly, according to West, studies of its morbid anatomy revealed ‘a marked want of proportion between the general symptoms [which were manifold and variable] and the physical signs [which were few and incidental].’134 This disjuncture between the signs and symptoms of influenzal pneumonia, and their variability in individual cases, made it difficult to diagnose directly. For all their work, physicians still had trouble determining a case of influenza on symptoms alone. Although new classifications ensured continuity in clinical descriptions and became part of textbook medicine, they did little to relieve practical difficulties. In illuminating influenza’s protean identity, new clinical knowledge multiplied rather than reduced the number of possible symptoms and complications that could fall under the name. This had important consequences for the treatment of influenza. Treatment choices were as varied as the symptoms of the disease. As Lori Loeb has argued, little consensus existed about therapeutic or preventive regimes for individual patients.135 Lack of agreement on treatment was often attributed to the lack of understanding of the basic nature of influenza, both its clinical characteristics and underlying cause. ‘Our want of complete knowledge of the nature of the disease,’ lamented the Lancet, ‘renders it difficult to suggest measures of prophylaxis other than the uniform observance of general hygienic rules.’136 Editorials and contributions to the Lancet, BMJ , Practitioner, and bodies such as the Royal College of Physicians, counseled using general precautionary measures established for acute diseases, the cornerstones of which were isolation, bed rest, and good nutrition.137 Faced with such a protean disease, practitioners approached treatment on a caseby-case basis, targeting symptoms and sequelae. Therapeutic regimens were thus highly individualised, reflecting the proclivities of the practitioner and social position of the patient. For working class or poor patients with limited means or no insurance, symptomatic remedies, whether

134 West, ‘An Address on Influenza’, 1049. 135 Lori Loeb, ‘Beating the Flu: Orthodox and Commercial Responses to Influenza in

Britain, 1889–1919’, Social History of Medicine, 18.2 (2006), 203–224. 136 ‘Influenza’, Lancet (21 December 1889), 1293. 137 Loeb, ‘Beating the Flu’, 208.

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prescribed by general practitioners or sold commercially, were an alternative to leaving work or entering the poor law infirmary.138 Middle class and patrician patients represented a lucrative market for prescription and patent medicines. Able to afford to follow a regime of rest and nourishment, they could also afford the many therapies available to manage the disease. Alcohol was a popular if disputed remedy, with wine and brandy prescribed for their alleged nutritional and analgesic properties. Antipyretics were widely promoted to reduce fever. Quinine, a synthesised version of which had been used since the 1820s, was popular as an antipyretic treatment and prophylactic, as were salicin, antipyrin, and antifebrin.139 Opium was also prescribed to relieve fever and pain.140 While the medical profession officially sanctioned only a limited number of treatments, commercial manufacturers filled the gap with patent medicines for almost every symptom associated with influenza. Lozenges, pastilles, syrups, vapors and embrocations were marketed as remedies for influenza-related coughs, congestion, sore throats, fevers, and more serious respiratory problems such as bronchitis. Symptomrelief medicines were often advertised as both preventives and curatives, offering properties that covered the entire course of the disease. Substances that strengthened the body were widely promoted, with wellestablished brands such as Bovril and Lemco marketing their extracts as offering defense against influenza and its symptoms. Manufacturers also seized on the new idea that influenza was a contagious disease to market various disinfectants, particularly carbolics, for use in the home and workplace.141 Even before a specific germ was identified as the cause of influenza, makers of carbolics and other preventives used the language of bacteriology to promote their products for preventing or treating the disease.142 138 Loeb, ‘Beating the Flu’, 208. 139 See, for example, Peter Eade, ‘Influenza’, Medical Annual (1893), 295–298;

W. Broadbent, ‘Note on the Therapeutics and Prophylaxis of Influenza by Quinine’, Practitioner, 78.1 (January 1907), 13. 140 Thomas Horder, ‘General Principles in the Treatment of Influenza’, Lancet (28 December 1918), 871. Horder reviewed the state of treatment as it had developed from the 1890s. 141 Loeb, ‘Beating the Flu’, 211–216. 142 One product, marketed by the Carbolic Smoke Ball Company, gave rise to one of

the most important cases in contract law, which remains a key legal precedent. See, A.W.B.

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The state of treatments reflected the uncertain state of medical knowledge, particularly the difficulty in determining what counted as influenza. With no specific sign and a variable symptomatology, physicians often relied on its epidemiological characteristics to direct their clinical observations. In the second edition of his Principles and Practice of Medicine, the renowned English-Canadian physician William Osler noted that, ‘when [influenza] occurs in epidemic form’ it could be easily identified by its ‘sudden onset, short duration, acute fever, great prostration, more or less severe catarrh, neuralgic pains, or gastrointestinal disturbance and the disease’s tendency towards severe respiratory complications.’143 Yet he warned against making hasty diagnoses outside of recognised epidemics, when influenza could be easily conflated with other respiratory ailments. Because of the threat of complications, Osler insisted that ‘in every case the disease should be regarded as serious, and the patient should be confined in bed until the fever has completely disappeared.’144 But he could offer little else.

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The Influenza Germ

Part of the clinical challenge related to practitioners’ inability to identify influenza’s cause. The BMJ summed up the practical constraints: ‘A rational systematic mode of treatment is of course impossible, so long as the aetiology remains obscure, and hence we have at present to rely upon the main symptoms for indications.’145 An apparent solution emerged from the laboratory of the Berlin bacteriologist, Richard Pfeiffer, in January 1892, when he identified a new bacillus as the cause of influenza. Many hoped that Pfeiffer’s discovery would lead to new causebased approaches to treating and preventing the disease. Certainly, the incorporation of the bacillus into the discourses and practices of clinical

Simpson, ‘Quackery and Contract Law: The Case of the Carbolic Smoke Ball’, The Journal of Legal Studies, 14.2 (1985), 345–389; Janice Dickin McGinnis, ‘Carill v. Carbolic Smoke Ball Company: Influenza, Quackery, and the Unilateral Contact’, Canadian Bulletin for the History of Medicine, 5 (1988), 121–141. 143 William Osler, The Principles and Practices of Medicine (London: Young & Pentland, 1895), 92–93. 144 Osler, The Principles and Practices of Medicine, 94. 145 ‘Concerning Influenza’, BMJ (23 January 1892), 184.

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and public health medicine established the laboratory as a new site in the negotiation of influenza’s medical identity. Historians treat Pfeiffer’s bacillus as the wrong aetiological agent around which an entire generation organised its knowledge. Retrospective assessments point to flaws in the methods and reasoning used to establish its role. ‘No organism,’ wrote the London pathologist, Robert Donaldson, in an authoritative review of the bacteriology of influenza in 1922, ‘has had such wide acceptance on grounds so insufficient as Pfeiffer’s so-called Bacillus influenzae.’146 The historian of influenza Alfred Crosby described Pfeiffer’s bacillus as ‘an authoritative road sign pointing in the wrong direction.’147 It is worth remembering, however, that the bacillus was represented, investigated, mobilised, and disputed as the primary cause of influenza for nearly forty years, from the mid-1890s to the early 1930s. In medical, hygiene, and bacteriology textbooks it was viewed as key to defining influenza as a specific infectious disease.148 Rather than dismiss the bacillus as an erroneous object, we need to understand how it gained legitimacy as influenza’s causative agent and how it was employed in laboratory, clinical and public health medicine. While it turned out that the bacillus was not the primary cause, work on it played a vital role in redefining influenza as an infectious disease. Crosby attributes the widespread acceptance of the bacillus to Pfeiffer’s position as director of the Berlin Institute of Infectious Diseases, his connection to his famous father-in-law, Robert Koch, and his own eminence as a bacteriologist.149 Other accounts point to the medical world’s generally ‘receptive mood’ for bacteriology in the 1890s and 1900s.150 Another historian has argued that, ‘in the climate of triumphant

146 Robert Donaldson, ‘The Bacteriology of Influenza—With Special Reference to Pfeiffer’s Bacillus’, in F.G. Crookshank (Ed.), Influenza: Essays by Several Authors (London: William Heinemann, 1922), 153. 147 Alfred W. Crosby, America’s Forgotten Pandemic—The Influenza of 1918 (Cambridge: Cambridge University Press, 1989), 269. 148 See James F. Goodhart, ‘Influenza’, in Thomas Clifford Albutt (Ed.), A System

of Medicine, vol. 1 (London: Macmillan and Co., 1896), 679–700; Abel Heywood, Influenza: Its Causes, Cure and Prevention (Manchester: Abel Heywood & Son, 1902); Fredrick T. Lord, ‘Influenza’, in William Osler (Ed.), A System of Medicine (London: Henry Frode, 1915), 534–549. 149 Crosby, America’s Forgotten Pandemic, 269. 150 Donaldson, ‘The Bacteriology of Influenza’, 153.

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bacteriology few … doubted the German scientist’s discovery.’151 Yet these explanations are too general. For one, the reception of bacteriology varied considerably and depended on local contexts.152 In London medicine, elite physicians greeted bacteriological innovations with a mixture of cautious acceptance and occasional scepticism.153 MOHs adapted them to particular medical problems and existing professional interests. Pathologists, who functioned as the conduits for the new science, employed competing bacteriological ways of knowing. No discovery in Berlin was guaranteed ready acceptance in London. The fate of Pfeiffer’s bacillus in Britain was intimately linked to the emerging role of laboratory-based bacteriology in public health medicine and the work of the LGB’s Medical Department. Edward Klein had slowly incorporated Louis Pasteur’s and Koch’s practices into the Department’s scientific investigations and organised them on the core principle of specific aetiology. One of the foundations of bacteriology, this principle rested on a series of procedures to establish the identity of a specific agent with a specific disease. Formalised in the 1880s as ‘Koch’s postulates’, the procedures required that: (i) a living microorganism must be shown to be constantly present in all cases of the disease; (ii) the microorganism must be isolated from diseased tissue and correlate with and explain the disease phenomena; (iii) the microorganism must be grown and isolated in pure culture; and (iv) the pure culture must then produce the same disease when inoculated into healthy test animals.154 These procedures depended on combining techniques of pure culture, staining, microphotography, and animal experimentation. The postulates were not hard paradigmatic rules, but rather acted as a standard of proof and as the basic technical, methodological, and disciplinary framework for laboratory-based investigations of infectious disease. Although Edward Klein was noted for his initial resistance to Koch’s procedures, preferring Pasteur’s methods, by

151 Tognotti, ‘Scientific Triumphalism’, 103. 152 For the mixed reception of Koch’s bacteriology in Germany, see Christoph Grad-

mann, Laboratory Disease: Robert Koch’s Medical Bacteriology, trans. Elborg Forster (Baltimore: Johns Hopkins University Press, 2009). 153 For patterns of reception in Britain, see Worboys, Spreading Germs and Wall, Bacteria in Britain. 154 Friedrich Löeffler first set out the procedures in 1883. See, Kodell C. Carter, ‘Koch’s Postulates in Relation to the Work of Jacob Henle and Edwin Klebs’, Medical History, 29 (1985), 353–373.

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1892 he and his colleagues had successfully applied them in studies of a range of major diseases.155 Between 1892 and 1893 Klein worked to confirm Pfeiffer’s aetiological claims according to Koch’s postulates and, in so doing, also legitimised the key role for the laboratory in defining influenza. During the 1889–1890 epidemic, eminent researchers in Berlin, Vienna, Paris, and other European cities rushed to find the specific cause of the epidemic and proposed a number of agents as the ‘influenza bacillus’. No fewer than eight different microbes made headlines.156 Pfeiffer’s bacillus was not among them. All were known germs, but none could be found in all cases. In Britain, the BMJ and the Lancet cautioned against accepting any as the cause of influenza but supported further bacteriological investigations. As critical gatekeepers for the profession, both journals played a significant role in shaping the reception of Pfeiffer’s bacillus two years later. Pfeiffer announced his discovery in Berlin on 4 January 1892, and it was widely heralded as a breakthrough. Otto Leichtenstern declared that Pfeiffer’s discovery was a triumph for bacteriology: ‘The leading discipline in the aetiology of acute infectious diseases, bacteriology has solved…the difficult problem of finding the specific causative agent [of influenza] after long and futile attempts.’ He predicted that, ‘if the “Bacillus influenza” that Pfeiffer discovered…proves to be the sole pathogen of influenza in the future, as we all expect it to be, then this discovery will be the most important triumph of our contemporary influenza period.’157 The medical press in Britain was equally enthusiastic. The Lancet proclaimed that the discovery would ‘advance … knowledge of this mysterious plague.’158 The BMJ translated Pfeiffer’s preliminary report and a supporting paper from his colleague, Shibashuro Kitasato. 155 See Worboys, Spreading Germs for extensive discussion of Klein’s career and different schools of British bacteriology; Michael Worboys, ‘Klein, Edward Emanuel (1844–1925)’, in Oxford Dictionary of National Biography (Oxford University Press, 2004) [online edn, Jan 2008 http://www.oxforddnb.com/view/article/57359]; William Bulloch, ‘Emanuel Klein’, Journal of Pathology and Bacteriology, 28 (1925), 684–699. 156 Donaldson, ‘The Bacteriology of Influenza’, 141–143. 157 Op. cit. Wilfried Witte, ‘The Plague That Was Not Allowed to Happen: German

Medicine and the Influenza Pandemic of 1918–19 in Baden’, in Howard Phillips and David Killingray (Eds.), The Spanish Influenza Pandemic of 1918–19: New Perspectives (London: Routledge, 2003), 53. 158 ‘Influenza’, Lancet (9 January 1892), 99.

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A week later, it printed ‘Some Remarks on the Influenza Bacillus,’ by Klein, who described how he had isolated and visualised a bacillus from the sputum of patients that ‘completely coincides with and confirms what is described by Pfeiffer and Kitasato.’159 The following week, the BMJ commented that the Berlin bacteriologists’ reports, along with Klein’s confirmatory study, supported ‘the assertion that the problem as to the microorganism of influenza has at last been solved.’160 In response to Pfeiffer’s reports, in early January 1892 the Royal College of Physicians and the LGB’s Medical Department discussed obtaining a Royal Commission to investigate the pathology of influenza, with a focus on Pfeiffer’s bacillus. In lieu of the commission, the Medical Department organised a second large-scale investigation in February 1892.161 In addition to new epidemiological work by Henry Parsons, it aimed at developing ‘more authentic modes of identifying influenza proper’ and gaining ‘better insight into the character, habits, and conditions of multiplication of the material of influenza.’162 Headed by Klein, it was the first state-based bacteriological study of influenza in Britain. Since bacteriology was still on the periphery of metropolitan medicine, a tacit goal of Klein’s inquiry was to further establish its medical relevance. More than just a means to isolate disease germs from sick bodies, bacteriological practices were constituted as necessary for the elucidation of the pathological properties of the influenza bacillus and in turn its clinical and epidemiological presentation.163 Explaining pathological processes through the proliferation and distribution of bacteria inside and outside the body was a prerequisite of bacteriological thinking.164 By identifying 159 Edward E. Klein, ‘Some Remarks on the Influenza Bacillus’, BMJ (23 January 1892), 171; ‘Concerning Influenza’, BMJ (23 January 1892), 184. 160 ‘The Influenza Bacillus’, BMJ (30 January 1892), 235. 161 ‘Royal Commission on Influenza’, BMJ (30 January 1892), 247; ‘The Official

Influenza Inquiry’, BMJ (6 February 1892), 299. 162 Local Government Board, Further Report and Papers on Epidemic Influenza, 1889– 92 (Local Government Board London: HMSO, 1893), x. 163 See Worboys, Spreading Germs, 211–212. 164 Andrew Mendelsohn and Christoph Gradmann respectively have developed this

argument. J. Andrew Mendelsohn, ‘Cultures of Bacteriology: Formation and Transformation of a Science in France and Germany, 1870–1914’, Unpublished Ph.D. Dissertation (Princeton, 1996); Christoph Gradmann, ‘A Harmony of Illusions: Clinical and Experimental Testing of Robert Koch’s Tuberculin, 1890–1900’, Studies in History and Philosophy of Biological and Biomedical Sciences, 35.3 (2004), 465–481.

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such properties, Klein linked Pfeiffer’s bacillus to the disease observed by clinicians and medical officers. Typical of the institutional position of bacteriology in late Victorian London, Klein’s laboratory was comprised of a series of pathology and histology rooms spread between the Brown Animal Sanatory Institution, the College of State Medicine, and Barts, where he had two small workrooms in the Department of Pathology.165 These institutional constraints affected the scale of his inquiry. Whereas Pfeiffer allegedly had access to hundreds of cases, Klein acquired clinical material from fifty-six patients. Most came from the Kensington Infirmary in south-west London, while a few samples were collected at the outpatient’s clinic at Barts and the boys’ orphanage, Dr Barnardo’s Home.166 The laboratory work was all done at Barts, where Klein recruited former pathology students, including Frederick W. Andrewes, to aid him. As it turned out, Klein himself suffered a bad case of influenzal pneumonia and passed the work to Andrewes, whose experiences in the 1890s would prove crucial to his later reassessment of the role of Pfeiffer’s bacillus. The Department’s inquiry was modelled on the Berlin workers’ preliminary publications, which Klein had presumably read in the original German.167 Pfeiffer reported first identifying the bacillus in November 1891 on cover-glass preparations of purulent sputum taken from the mouths and throats of influenza patients. When dried and stained the bacilli appeared under light microscope as ‘very tiny rodlets’, often strung together in chains of three or four.168 Kitasato isolated the bacilli in pure cultures on sloping surfaces of glycerine-agar, where they appeared as minute, translucent colonies that looked like little water droplets.169 Cultured bacilli were alleged to be readily distinguished

165 Fredrick W. Andrewes, ‘The Work and Needs of the Pathological Department’, St. Bartholomew’s Hospital Journal, 11 (1904), 105–109; idem., ‘The Beginnings of Bacteriology at Barts’, St Bartholomew’s Hospital Journal, 35 (1928), 100–104, 116–117. 166 Edward E. Klein, ‘Report on Influenza in Its Clinical and Pathological Aspects’, in Further Report and Papers on Epidemic Influenza, 1889–92 (London: HMSO, 1893), 85. 167 Richard Pfeiffer and M. Beck, ‘Weitere Mittheilungen über den Influenza-Erreger’, Deutsche Medicinische Wochnenschrift, 18 (1892), 465. 168 Richard Pfeiffer, ‘Preliminary Communication on the Exciting Causes of Influenza’, BMJ (16 January 1892), 128. 169 Shibashuro Kitasato, ‘On the Influenza Bacillus and the Mode of Cultivating It’, BMJ (16 January 1892), 128.

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from other microorganisms. Since Pfeiffer was unable to isolate them in other respiratory conditions, he surmised that they were specific to influenza. But Pfeiffer and Kitasato also ran into difficulties. Although establishing cultures was relatively straightforward, they had trouble keeping them alive. Even more vexing, they were unable to reproduce the disease in an experimental animal. Pfeiffer and Kitasato rather ingeniously accounted for these problems. Pfeiffer argued that the lack of a research animal indicated that, like cholera, influenza was specific to humans. This argument ran against considerable anecdotal evidence suggesting that influenza affected numerous non-human animals. At the same time, Kitasato suggested that the distinctive culture characteristics of the bacillus could be used as important markers for its identification. Initially overlooked, these culture problems later became important in debates over the aetiological status of Pfeiffer’s bacillus. As the third epidemic in London began to wane in early February 1892, Klein and Andrewes tested Pfeiffer and Kitasato’s findings, along with those of the Berlin physician Paul Canon, whose report of an identical bacillus in the blood of his patients had been translated and republished in the BMJ alongside Pfeiffer’s and Kitasato’s reports. It is likely that the BMJ took this decision because Canon’s findings had been confirmed by Koch as support for the idea, shared by other bacteriologists, that influenza’s varied constitutional symptoms were the result of a blood-borne microbe.170 Although challenged by Pfeiffer, these findings could not be ignored. So, through February, Klein and Andrewes tested Canon’s claims using blood from forty patients and Pfeiffer’s and Kitasato’s claims using bronchial samples from twenty patients, and one lung sample from a young victim of influenzal pneumonia.171 Their blood work contradicted Canon. Whereas he claimed to have consistently isolated the bacillus, they isolated it from only six cases and in each it was dead. This finding corroborated Pfeiffer’s observations that Canon’s bacillus could not be constantly found in blood samples and was thus not identical to the one he had discovered. More importantly, Klein’s and Andrewes’ experiments confirmed Pfeiffer’s contention that

170 Koch’s view was reported in The Times, ‘The Influenza Bacillus’ (8 January 1892),

3. 171 ‘Epitome of Current Literature’, BMJ (25 June 1892), 104; Klein ‘Report on Influenza’, 93.

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the respiratory tract was the primary locus of infection.172 Using coverglass preparations of stained bronchial sputa they identified his bacillus in all their samples. In many cases, it was visible in clusters and twisted chains among ‘crowds of other bacteria’ including streptococci and diplococci.173 Over half of the preparations contained an abundance of bacilli, often in almost pure culture. The same held true for the lung material. From both types of specimen, Andrewes produced broth and glycerineagar cultures, in which he isolated the bacillus in colonies identical to those described by Pfeiffer and Kitasato. Like the Berlin workers, he was unable to reproduce the disease in experimental animals; however, he was able to sub-culture the bacillus in broth tubes for numerous generations.174 Andrewes’ experimental work confirmed the identity of Pfeiffer’s bacillus and its presence in the sputa and respiratory tract of influenza patients. Yet this only fulfilled one aim of the study; the key task was to determine whether the bacillus provided a better means of identifying influenza in cases. The problem figured centrally in Klein’s official report. Published in September 1893 as part of the Medical Department’s second Report, it correlated three kinds of evidence: case notes of patients from whom clinical material was taken; laboratory studies that rendered the bacillus visible in this material and determined its properties; and photomicrographs of the bacillus in preparations from different body parts at different stages of the disease. By connecting the clinical picture to the properties of the bacillus Klein produced what he described as ‘the aetiology of influenza.’175 Correlating bacterial and clinical pictures involved using exemplary cases, such as that of Walter Hall.176 An eighteen-year-old butcher’s assistant, Hall was admitted to Kensington Infirmary on January 28, 1892, where the attending physician took his clinical history. Nine days earlier, he had come down with sudden and intense head pains, followed by shivers, which forced him to miss five days of work. He then had

172 Richard Pfeiffer, ‘Die Aetiologie der Influenza’, Zeitschrift für Hygiene, 12 (1893), 357–386. 173 Klein, ‘Report on Influenza’, 119. 174 Klein ‘Report on Influenza’, 266–270. 175 Klein, ‘Report on Influenza’, 150. 176 Klein, ‘Report on Influenza’, 120–121.

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a severe relapse after going back and ended up at the Infirmary. The relapse reached its height on February 3, when his fever spiked and his doctor reported signs of respiratory complications. A day earlier, Klein made cover-glass preparations and cultures of Hall’s bronchial sputum. He observed ‘an almost pure culture of the specific bacillus’ when he examined the microscope preparations, while on agar-culture he isolated and produced the characteristic chains of the bacilli. Photomicrographs demonstrated the results of both techniques and helped to identify and trace the pathogenesis of the disease (Fig. 8). Klein associated the presence of influenza symptoms with the presence of an abundance of bacilli in the patients’ sputum as the disease peaked. As influenza developed, characteristics of the bacilli changed. When Hall started to convalesce, they showed signs of dying and disappearing from the respiratory tract. Thus, by 6 February, with ‘the patient being much improved’, Klein noted that while he could identify ‘numerous bacteria of different species’ in Hall’s sputum, ‘it was difficult to find with certainty any but isolated Pfeiffer bacilli.’ This demonstrated the pathological connection between the bacillus and the disease: before a patient passed through the height of influenza, the number of bacilli present in bronchial sputum was ‘very great’; and as the disease abated and the patient got better, ‘the number of the bacilli also rapidly diminished.’ As the bacillus disappeared, so too did influenza.177 Klein also linked influenza’s epidemiology to the life cycle and ecology of the bacillus. It was ‘a matter of no small practical importance,’ he noted, ‘that in cases with bronchial expectoration, the fluids of the mouth contained an abundance of influenza bacilli.’178 Bacteriological examinations constituted the mouth, nose, and bronchial passageways as the loci and media of infection. Klein’s report highlighted the apparent congruence between Pfeiffer’s bacillus and influenza’s clinical and epidemiological identity. The supporting laboratory evidence was the strongest yet. The bacillus met aetiological criteria that no other candidate had: it was new; it was not associated with other respiratory diseases; it had a definite identity; it had unique culture requirements; its properties seemed to correspond to the clinical and epidemiological picture; and it

177 Klein, ‘Report on Influenza’, 121. 178 Klein, ‘Report on Influenza’, 121.

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Fig. 8 ‘Aetiology of Influenza’. Walter Hall’s Pfeiffer Bacillus. Cover-glass specimen of Hall’s sputum taken on 2 February, 1892, showing ‘an almost pure culture of the specific bacillus.’ The sputum was permeated by different forms of the bacilli, ‘singly’ in ‘dumbbells’ and ‘in larger and smaller groups’ (Source E.E. Klein, ‘Report on Influenza in Its Clinical and Pathological Aspects’, in Local Government Board, Further Report and Papers on Epidemic Influenza, 1889–92 [London: HMSO, 1893], 120)

appeared to be present in all recognisable cases.179 The Department sanctioned Klein’s evidence, as did the medical press. The Lancet profiled the bacillus’ characteristics, alleged role, and importance for understanding

179 These criteria were summed up in Klein’s 1893 report.

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pathogenesis and prevention.180 By late 1893, Pfeiffer’s bacillus was being referred to as the ‘influenza bacillus’ in the medical and popular press.

4

A New Influenza

The status of the new bacillus depended on how it conformed to the understandings of influenza in clinical and public health medicine.181 In clinical medicine, its reception was predictably mixed. Physicians debated its ‘diagnostic worth’ and evaluated its ‘clinical value’.182 The laboratory characterisation of the bacillus was attractive because it fit the clinical characterisation of influenza. Bacteriological work supported the notion that influenza was primarily a respiratory disease. But the most vexing problem was how to connect its clinical forms into one entity. If the bacillus was aetiologically linked to one form, as many physicians acknowledged, did it also play a causative role in the other forms, or were other agents at work?183 Pfeiffer offered a solution to this problem. Drawing on emerging notions of the role of toxins in bacterial infections such as tetanus and diphtheria, he attributed influenza’s forms to a toxin emitted by the bacillus during infection; its diffusion through the body produced different constitutional symptoms.184 The theory made Pfeiffer’s bacillus the ‘one and only origin’ of influenza.185 Although the alleged ‘influenza toxin’ had not been—and never was—identified, it was promoted on the promise that it simplified influenza’s clinical picture and provided the profession with an manageable entity. Yet in practice, quite the opposite happened. Basing influenza’s clinical identity on the bacillus and its toxin generated classificatory frameworks which were just as complicated as their predecessors and far more

180 ‘The Etiology of Influenza’, Lancet (8 April 1893), 810. 181 This echoes Worboys’ argument that a key factor in British doctors’ reception of

Koch’s tubercle bacillus was ‘the congruence between the reported properties of the bacillus and their clinical experience of the disease syndrome, Spreading Germs, 211–212. 182 ‘The Bacillus of Influenza’, Lancet (20 May 1899), 1378–1379. 183 ‘The Influenza Epidemic—Report of the Medical Department of the Local

Government Board’, BMJ (26 August 1893), 488. 184 Richard Pfeiffer, ‘Die Aetiologie der Influenza’, 357–386. 185 ‘Endemic Influenza’, Lancet, 12 February (1898), 449.

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esoteric.186 Numerous observers questioned the value of using bacteriological criteria to delineate influenza in the absence of laboratory evidence of the role of the toxin or the bacillus in different forms of the disease. Some critics doubted whether a single bacillus could be responsible for every manifestation of influenza. Others speculated that the initial respiratory infection involving Pfeiffer’s bacillus paved the way for other germs that crucially factored into the disease process. While most practitioners attributed an important role to the bacillus, rather than transform clinical frameworks it was subsumed under them.187 The bacillus attracted attention as the diagnostic marker physicians so dearly wanted. Distinguishing ‘epidemic influenza’ from the various catarrhs and ‘influenza colds’ was an on-going problem.188 Spurred by reports from Germany that microscopic analyses of patients’ sputa could be used to redress this problem, by the late 1890s the Lancet and the BMJ advocated including bacteriological examinations in the diagnosis of influenza, as was already becoming the case for tuberculosis and diphtheria. In a review of the clinical value of influenza bacteriology in January 1899, the Lancet asked: ‘Can the diagnosis of influenza be based on the microscopical finding alone of the influenza bacilli?’189 It maintained that in certain instances identification of the microbe in the sputum was sufficient. Yet, how and when to use bacteriological tests were open to question. Since clinical identification of influenza during epidemics was relatively straightforward, most physicians reckoned that there was little need for laboratory corroboration of their diagnoses. Where bacteriological examinations were thought to be most valuable was in diagnosing uncertain cases, especially during local epidemics and inter-epidemic periods, when physicians tended to confuse influenza with other diseases. For proponents, bacteriological tests represented a way to ‘prevent the indiscriminate diagnoses … occasionally made according to particular

186 Leichtenstern, ‘Influenza’, 591–592. 187 Thomas Clifford Allbutt, ‘Influenza’, The Practitioner, LXXVII (1907), 1–10;

William Gray, Influenza, with Special Reference to Some Peculiar Symptoms (London: H.K. Lewis, 1897). 188 ‘Influenza’, Lancet (18 March 1899), 778. 189 ‘Influenza’, Lancet (14 January 1899), 103.

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physicians’ own ideas of influenza rather than by the recognition of a disease having definite characteristics.’190 But the idea of bacteriology as an arbiter of clinical diagnoses was still novel and not easily digested.191 Using a bacteriological examination presupposed learning and adapting to a new kind of practice. Performing the delicate work needed to render the bacillus visible demanded time, skill, and the financial means to acquire equipment.192 Proponents argued that such obstacles were easily overcome, since the basic identification of the bacillus required only minimal experience and expense: ‘after the observer has become familiar with the appearance of the Pfeiffer bacillus under the microscope it may be readily identified in the sputum of a patient suffering from influenza by direct examination without awaiting the result of cultivation.’193 However, fitting bacteriological examinations into clinical practice was more than just a technical problem. Since the bacillus appeared to be only pathognomonic for respiratory influenza, physicians still had to rely on their observational skills when diagnosing other forms of the disease. Interpreting and classifying influenza’s symptoms continued to dominate everyday diagnostic practices. Thus, while physicians incorporated the bacillus into explanations of influenza, its laboratory identification was not readily used as a diagnostic aid. The bacillus did, however, produce noticeable changes in the professional perceptions and practices of preventive medicine. Pfeiffer’s descriptions of the bacillus provided new grounds for controlling influenza. In a series of studies in 1893, he determined that while the bacillus could survive in a patient’s sputum for up to two weeks, in samples of dried sputum it survived only for two days and in cultures exposed to water or air it died within a few hours.194 Three important conclusions were drawn from these laboratory facts. First, the bacillus was not capable of multiplication outside the human body, either in water or in the earth. Second,

190 ‘Influenza’, Lancet (14 January 1899), 103. 191 L. Stephen Jacyna, ‘The Laboratory and the Clinic: The Impact of Pathology on

Surgical Diagnosis in the Glasgow Western Infirmary, 1875–1910’, Bulletin of the History of Medicine, 62 (1988), 384–406. 192 Anne Digby, The Evolution of British General Practice, 1850–1948 (Oxford: Oxford University Press, 1999), 53ff. 193 ‘Influenza’, Lancet (18 March 1899), 778. 194 Pfeiffer, ‘Die Aetiologie der Influenza’, 357–386.

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the spread of influenza by dry sputum was rare. And third, moist secretions from the air passages as a rule produced infection. These properties not only put to rest any miasma theory, they also constituted ‘the moist secretions of the air passages’ as a specific target for preventive measures. Sir Richard Thorne Thorne, who succeeded George Buchanan as Medical Officer to the LGB, summed up the implications of this work in late 1893: The sputa of the sick are, especially in the acute stages of the disease, invariably charged with the microorganism which is pathognomonic of Influenza, and it may be hoped therefore that when these sputa come to be recognised as infectious and are dealt with, as is held necessary in the case of discharges from the throat, mouth and nostrils of scarlatine (sic) and diphtheria patients, the spread of Influenza from person to person may be to a corresponding extent controlled.195

Influenza prevention became modelled on frameworks established for tuberculosis, diphtheria, and other respiratory infections. Contagionminded epidemiologists outlined ‘human intercourse’ and the ‘assemblage of large numbers of people’ as the main pathways for spreading influenza.196 Bacteriologists identified the spreading agent and used laboratory knowledge of its properties to identify sneezing, coughing, spitting, and talking as the principal vehicles of infection. Focus on the bacillus made it possible to monitor influenza through the minute corporeal exchanges of urban life. Public health authorities and medical officers acquired a rationale for intervening in everyday behaviours and social interactions.197 Influenza was now linked to the enduring idea that ‘coughs and sneezes spread diseases.’ Official prevention approaches targeted the routes and places through which influenza bacillus spread.198 Control of the disease was based on 195 Local Government Board, Further Report and Papers on Epidemic Influenza, ix. 196 Provisional Memorandum Upon Precautions Advisable at Times When Epidemic

Influenza Threatens or Is Prevalent, Local Government Board (London: HMSO, 1892), xi. 197 For this process in relation to diphtheria, see Claire Hooker and Alison Bashford, ‘Diphtheria and Australian Public Health: Bacteriology and Its Complex Applications, c.1890–1930’, Medical History, 46 (2002), 41–64. 198 Provisional Memorandum Upon Precautions Advisable at Times When Epidemic Influenza Threatens or Is Prevalent, Local Government Board (London: HMSO, 1892), xi.

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three measures: prohibition of ‘unnecessary assemblages’ whenever an epidemic threatened; separation of the sick from the healthy; and disinfection of infected people and places.199 Given how quickly influenza spread, and the corresponding challenges of social-distancing and isolation, disinfection was the key instrument. A sick person’s nasal and bronchial passageways and expectorations were washed with germ-killing solutions.200 Disinfection was soon proposed for groups deemed ‘susceptible’ to infection. By the turn-of-the-century, the Medical Department and most local health authorities recommended that police officers, transit and railways workers, nurses and physicians, and school children gargle with disinfectants whenever an epidemic threatened.201 Similar measures were proposed for military personnel. Patent medicines and disinfectants promising to halt the bacillus took this message to the public.202 Although variable in effectiveness, these practices consolidated ‘influenza bacillus’ as an object of prevention and popular knowledge and underscored the collective experience of influenza as a democratic disease.

5 Re-aligning Clinical, Public Health and Laboratory Medicine Little laboratory work was done on Pfeiffer’s bacillus before 1900. But by the turn of the century, as bacteriology became increasingly institutionalised in British medicine and public health, and bacteriological education created professionals trained in bacteriological methods, laboratory work on the bacillus multiplied.203 Rather than secure the bacillus’ relation to influenza, increased laboratory scrutiny in the 1900s and 1910s problematised its aetiological status. Questions about its role first surfaced in 1899, when, during the largest epidemic since 1890, workers in Germany, France, and the United States, including Pfeiffer himself, failed to identify it in most clinical cases. The epidemic raised two issues that would loom 199 Provisional Memorandum, xi. 200 Provisional Memorandum, xi. 201 ‘Local Government Board’, Lancet (20 January 1906), 180–182. 202 Loeb, ‘Beating the Flu’, 213–222. 203 The bacillus first appeared in British bacteriology textbooks in 1896. See, Edward E. Klein, Microorganisms and Disease: An Introduction into the Study of Specific Microorganisms (London: Macmillan and Co, 1896); Edgar M. Crookshank, A Textbook of Bacteriology (London: HK Lewis, 1896).

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large in the new century. The first concerned the identity of the bacillus itself. Pfeiffer had characterised its reliance on blood to grow in culture as a defining property, leading to its classification as a Haemophilus bacillus (Fig. 9a and b).204 While the name was meant to set it apart from other agents, a number of researchers identified haemophilic bacilli that were indistinguishable from Pfeiffer’s bacillus but did not cause influenza.205 Found in other diseases, these ‘influenza-like’ bacilli complicated straightforward bacteriological diagnosis of influenza. This work gave rise to a second and related problem concerning the specificity of Pfeiffer’s bacillus. Researchers had started to find it in other diseases, including scarlet fever, measles, and pneumonia, as well as in healthy people. At the same time, other agents appeared to play a pathogenic role in influenza. The Cambridge University pathologist P.N. Panton summed up the difficulties: ‘While there is no doubt that [Pfeiffer’s] bacillus … is the causative agent of some influenzal epidemics, it must not be expected to recognise it in all cases of so-called influenza.’206 Bacteriologists developed two contending approaches to this problem. The first, proposed by Pfeiffer, insisted that influenza be regarded as a specific disease, solely caused by his bacillus and to be called ‘true influenza’, while clinically identical diseases caused by other organisms, would be called ‘pseudo-influenza.’207 The second suggested that influenza was not a single disease, but a group of diseases ‘probably… caused by different microbes.’208 Laboratory evidence existed to substantiate this argument. A host of other germs appeared to play an important role. One in particular, Micrococcus catarrhalis, attracted much attention (Fig. 10).209 Linked to numerous respiratory conditions, from mild catarrh to severe broncho-pneumonia, it was the most frequently isolated germ from influenza outbreaks in the early 1900s. Studies during an

204 Edward R. Stitt, Practical Bacteriology, Blood Work and Animal Parasitology: Including Bacteriological Keys, Zoological Tables and Explanatory Clinical Notes (London: H.K. Lewis, 1909), 79; Albert Besson, Practical Bacteriology, Microbiology and Serum Therapy (Medical and Veterinary): A Text Book for Laboratory Use, trans. H.J. Hutchens (London: Longmans, Green and co., 1913), 510. 205 Besson, Practical Bacteriology, 510–511; Edwin Oakes Jordan, A Text-book of General Bacteriology (London: W.B. Saunders, 1908), 301–302. 206 P.N. Panton, Clinical Pathology (London: J&A Churchill, 1913), 133. 207 W. D’Este Emery, ‘The Micro-organisms of Influenza’, The Practitioner, LXXVII

(1907), 109–117. 208 ‘Discussion on Influenza’, BMJ (13 May 1905), 1044–1045. 209 For Micrococcus catarrhalis; see, Besson, Practical Bacteriology, 504.

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Fig. 9 a and b Standard culture preparations of Pfeiffer’s bacillus. Left: B. influenzae in blood agar, indicated by small pocks. Right: photomicrograph of B. influenzae in pure culture (Source Richard Pfeiffer, ‘Influenza und die Gruppe der häemoglobinphilen Bakterien’, in E. Friedberger and R. Pfeiffer (Eds.), Lehrbuch der Mikrobiologie (Jena: Verlag Von Gustav Fischer, 1919 [originally published in 1893], 743. Photograph by Wellcome Library)

epidemic in 1905 prompted some to suggest that M. catarrhalis was the new ‘influenza bacillus’. William Bulloch, an avowed disciple of Pasteur, who had just been appointed as pathologist to the London Hospital, and Mervyn H. Gordon, a young pathologist at Barts’ Department of Pathology, were among a number of investigators who suggested that M. catarrhalis had replaced Pfeiffer’s bacillus as the primary causative agent.210 In a discussion at the Hunterian Society, Bulloch claimed that, ‘whereas in the early Nineties Pfeiffer’s bacillus was frequently met with, it had in recent years become much rarer, although epidemics of catarrh – described as influenza – were still very prevalent.’211 Pfeiffer and his supporters responded by insisting that what had been identified in 1905 was not ‘true influenza’ but ‘pseudo-influenza.’212 Nonetheless, the idea that influenza could be caused by different agents had been thrown into the mix.

210 ‘Discussion on Influenza’, BMJ (13 May 1905), 1044–1045. 211 “Discussion on Influenza’, BMJ (13 May 1905), 1044–1045. 212 Emery, ‘The Micro-organisms of Influenza’, 115.

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Fig. 10 A new influenza bacillus? Micrococcus Catarrhalis isolated and identified by Mervyn H. Gordon as the cause of clinical cases of “influenza” in Hertford, January 1905 (Source R.A. Dunn and M.H. Gordon, ‘Remarks on Clinical and Bacteriological Aspects of an Epidemic Simulating Influenza Which Recently Occurred in East Herts District’, British Medical Journal [26 August 1905], 425)

The combination of mounting laboratory evidence against Pfeiffer’s bacillus, and concerns over the implications of a shift in influenza’s bacteriology for medical and public health approaches, prompted moves to reframe approaches to the aetiology of influenza. Clifford Allbutt, Regius Professor of Physic at Cambridge, described ‘the bacteriological position’ as ‘rather exasperating’, but concluded that, ‘the responsible microbes seem to be several.’213 The practical and professional consequences of this kind of explanation worried bacteriologists interested in making bacteriology indispensable to medicine. W. D’Este Emery, a clinical pathologist at King’s College Hospital, summed up the dilemma. On the one hand, drawing a distinction between ‘true’ and ‘pseudo’ influenza was of little 213 Allbutt, ‘Influenza’, 2.

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use to practitioners: ‘the physician would hardly thank us if we told him that a patient in whom he diagnosed influenza was not suffering from that disease because Pfeiffer’s bacillus was absent, but was really ill of a disease identical in symptoms, course, event, sequelae, and treatment.’214 On the other hand, the idea that influenza was a multiple infection added problems to making a bacteriological diagnosis and explaining its pathogenesis. It also ran against the principle of specific aetiology. Although bacteriologists explored the notion that influenza was a ‘mixed infection’, most were unwilling to abandon this principle. Emery proposed a popular solution. Bacteriologists had to confront the possibility that they had not found the culpable pathogen. With unintended prescience, he came to the following conclusion: The only possible solution that is entirely satisfactory is absolutely hypothetical and unsupported by any evidence. It is that influenza is a specific disease, due to a definite single cause, but that this cause is undiscovered, and perhaps unsuspected; it may be an ‘invisible’ microbe, a protozoan, or some depressing ‘influence’ acting directly on the human constitution, and of a nature as little known as were bacteria when influenza received its name.215

While ‘invisible’ microbes had yet to fully emerge as laboratory objects, the idea that influenza might be caused by such an agent reflected the difficulties in using Pfeiffer’s bacillus to establish consensus on influenza’s identity. At this point one might attribute these difficulties to the fact that medical professionals were dealing with the wrong microbe. But such a retrospective judgement would only serve to efface all those who believed that it was the right one and all the labour they put into making it so. Crucially, we would overlook its importance in establishing new ways of understanding influenza. Work on the bacillus drove the development of the bacteriology of influenza. The spread of Pfeiffer’s investigations shaped and was shaped by clinical and epidemiological knowledge and provided medical professionals with a cause-based definition, which supplemented and, some hoped, would supplant symptom-based definitions of influenza. In clinical medicine, the bacillus was a resource for 214 Emery ‘The Micro-organisms of Influenza’, 114–115. 215 Emery, ‘The Micro-organisms of Influenza’, 116–117.

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explaining the pathogenesis of the disease; in public health medicine, it was used to make visible and to target its routes of transmission. Pfeiffer’s bacillus thus played a critical role in re-aligning epidemiological, clinical, and bacteriological knowledge around a new definition of influenza. Between 1890 and the outbreak of the First World War influenza’s medical identity had been transformed. The disease was incorporated into the disciplinary contexts of modern public health, clinical medicine, and bacteriology, where new knowledge was constructed of its epidemiology, symptomatology, aetiology, and pathogenesis. Together, these understandings established influenza as an important disease of modern life. ‘[W]e must…assume,’ argued Arthur Newsholme, MOH for Brighton and future Chief Medical Officer of the LGB, ‘that conditions since 1890 have become more favourable than in earlier years for the continuous prevalence of influenza endemically on a considerable scale.’216 For Newsholme and his contemporaries, these conditions were primarily epidemiological and had been first revealed by the Medical Department’s studies of the early 1890s as a combination of the growing population density of cities and their connection by networks of steam-driven rail and shipping, which at once eased and sped-up the transmission of influenza from one person and one place to another, thereby making constantly available fresh ‘soil’ for the disease. Modern influenza was thus intimately bound to the revolution in communications that re-shaped the Victorian world, its demography and urban geography. Yet, it was also bound to new ways of seeing, identifying, and tracking the disease within and between bodies that had been made possible by the incorporation of bacteriology into epidemiological and clinical knowledge and practices. This knowledge-making process did not simply proceed from laboratory to the clinic to the field, but involved considerable exchange and negotiation, with each providing the other with conceptual and material resources that, when drawn together, generated a new definition of influenza as an infectious disease. Defining modern influenza was not easy. As the challenges encountered in each of these contexts demonstrate, the disease resisted classification or control by any one approach. According to Clifford Allbutt, the outpouring of epidemiological, clinical and laboratory work from the 1890s onwards underscored the essential fact that influenza was ‘of 216 A. Newsholme, ‘Influenza from a Public Health Standpoint’, The Practitioner, 78 (1907), 119.

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protean diseases the most protean.’217 While it had been drawn into the frameworks of modern medicine, its protean nature reflected and reinforced differences in epidemiological, clinical, and pathological knowledge. Rather than resolve the problem of its identity, this transformation highlighted a crucial problem in modern medicine: how to align its different and often competing ways of knowing into working understandings of a disease. Establishing agreement on influenza’s medical identity would remain a key challenge through the first half of the twentieth century. New definitions and approaches that had been built since the 1890s would be put to the test above all in 1918, when Britain and the rest of the world were engulfed in a devastating global pandemic.

217 Allbutt, ‘Influenza’, 1.

CHAPTER 4

Fighting Flu: Military Pathology and the 1918–1919 Pandemic

On 13 November 1918, two days after armistice, Sir Arthur Newsholme, Chief Medical Officer of the Local Government Board, organised an emergency meeting of medical authorities at the Royal Society of Medicine. Like every major city in Europe, and most inhabited places around the world, London was in the grip of a devastating influenza epidemic. Over one million, nearly a quarter of the population, had been sick in the preceding month. Thousands of workers, from bankers to dockers, were laid up in bed or in hospital. Public services suffered massive staff shortages and the transport system had ground to a near standstill. Hospitals, dispensaries, infirmaries, and doctor’s offices were overrun with the ill. Physicians and nurses, their numbers already depleted by the war, struggled to cope. Many medical men and women were themselves stricken and many had already died on their own wards. All around London, military camps constructed to house troops on their way to the front were filled with returning soldiers who had survived the war but now battled a disease so virulent and with such perplexing symptoms that many medical observers first doubted that it was influenza. When Newsholme opened the ‘Discussion on Influenza’ at the Royal Society of Medicine the pandemic’s identity was at the forefront of his agenda: ‘Is it

© The Editor(s) (if applicable) and The Author(s), under exclusive licence to Springer Nature Limited 2023 M. Bresalier, Modern Flu, Medicine and Biomedical Sciences in Modern History, https://doi.org/10.1057/978-1-137-33954-6_4

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one disease, or a group of diseases? And is the disease now prevailing the disease which prevailed in the spring, and still more in July, of this year?1 In hindsight, historical epidemiologists have delineated the 1918–1919 pandemic into three consecutive waves.2 A relatively mild epidemic beginning in early summer 1918 was quickly followed by a lethal epidemic in autumn after which developed a somewhat less virulent epidemic in spring 1919. While each wave presented its own clinical and epidemiological characteristics, retrospective accounts have nonetheless linked them together into a single cataclysmic pandemic. Newsholme and his contemporaries had no such luxury. At the time, the relationship between the summer and autumn epidemics baffled medical experts. The summer epidemic shared characteristics with previous epidemics, with doctors describing extreme body aches, prostration, fever, sore throat, dry cough, nausea, and general lassitude in the vast majority of patients they saw. Yet important aspects did not fit the established picture. Experts and officials were unable to agree that it was ‘influenza’ until August 1918. By then, the early signs of a second epidemic had already started to be reported in military garrisons in France and Flanders, but little about it correlated with what had been seen in the spring. Indeed, it was so stunningly virulent that many medical experts thought they were encountering an entirely new disease. A dreadful array of secondary infections, rarely seen in previous epidemics, led to severe and often deadly pneumonic complications. By mid-November, the numbers of dead in London alone had already crept towards 16,000.3 Other major cities around the world fared much worse, 1 Arthur Newsholme, ‘Discussion on Influenza’, Proceedings of the Royal Society of Medicine, 12 (1918–1919), 1. 2 Edwin Oakes Jordan, Epidemic Influenza: A Survey (Chicago: American Medical Association, 1927); John S. Oxford, ‘Influenza A Pandemics of the 20th Century with Special Reference to 1918, Virology, Pathology, and Epidemiology’, Reviews in Medical Virology, 10 (2000), 119–133; Niall P.A.S. Johnson and J. Mueller, ‘Updating the Accounts: Global Mortality of the 1918–1920 “Spanish: Influenza Epidemic’, Bulletin of the History of Medicine, 76 (2002), 105–115. 3 Original estimates by the Registrar-General put the number of deaths from influenza in London between October and December 1918 at close to 12,000. Registrar-General, Report on the Mortality from Influenza in England and Wales during the Epidemic of 1918–19, Supplement to the Eighty-First Annual Report of the Registrar-General (London: HMSO, 1920). William Hamer revised the figure to close to 16,000. William H. Hamer, Report on Influenza by the County Medical Officer of Health (London: County Hall, 1919), 20. Recent estimates support this figure. Johnson and Mueller, ‘Updating

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with reports in the press of tens of thousands of people dying in places as far apart as Bombay, Boston, and Freetown. The total killed in England and Wales has been estimated to be 220,000.4 The global death toll was incalculable; current estimates put the minimum at 50 million.5 Not only did the epidemic display a new kind of virulence, who it killed also changed. A generation of textbooks taught that influenza-related deaths occurred among the very young, aged, and infirm. Epidemiologists who had plotted the age-distribution of influenza’s mortality since the 1890s typically traced a ‘U’ mortality curve. Yet in autumn 1918 the U turned into a ‘W’: the disease now killed a disproportionate number of men and women in the prime of life.6 The disjuncture between the summer and autumn epidemics made determining influenza’s identity crucial. Newsholme had invited leading military and civilian personnel to the Royal Society of Medicine to plan a way forward. As Britain’s Chief Medical Officer, Newsholme believed that to approach prevention rationally medical professionals had to know what they were fighting. ‘The first difficulty, he insisted, ‘is to define influenza.’ Before the disease could be ‘brought within the scope of prevention’, he argued, doctors needed ‘further knowledge – epidemiological, pathological, and bacteriological.’7 The autumn epidemic gave new urgency to address uncertainties about influenza that medical professionals had largely ignored or brushed aside. But from where was new knowledge

the Accounts’, 105–115; Christopher Langford, ‘The Age Pattern of Mortality in the 1918–19 Influenza Pandemic: An Attempted Explanation Based on Data for England and Wales’, Medical History, 46 (2002), 1–20. 4 The first estimates by the Registrar General put the toll at 151,446; when Scotland was included the figure was rounded up to 198,000. Registrar-General, Report on the Mortality from Influenza in England and Wales during the Epidemic of 1918–19, 3. More recent estimates have put the figure closer to 220,000. See Johnson, Britain and the 1918 Influenza Epidemic; Niall Johnson ‘1918–1919 Influenza Pandemic Mortality in England and Wales’ [computer file]. Colchester, Essex: UK Data Archive [distributor], July 2001a. SN: 4350. http://www.data-archive.ac.uk/ (Accessed 10 January 2018). 5 Karl G. Nicholson, Robert G. Webster and Alan J. Hay (Eds.), Textbook of influenza

(Oxford, Blackwell, 1998), 11. A more recent estimate suggests the number could range between 50 and 100 million; see Johnson and Mueller ‘Updating the Accounts’, 15. 6 Major Greenwood, ‘The epidemiology of influenza’, BMJ (23 November 1919), 563– 566. 7 Newsholme, ‘Discussion on Influenza’, 1; Arthur Newsholme, ‘Epidemic Catarrhs and Influenza’, Lancet (2 November 1918), 599.

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to come, and from which authorities were official strategies to be elaborated? The answers were clear enough to Newsholme and those attending the November meeting. They had to come from the system of military medicine that had been organised for the war effort and which by 1918 had determined the direction and imperatives of Britain’s corresponding war against disease. The pandemic was encountered by a militarised nation in which medicine itself had become crucial to the war machine.8 A new system of military medicine had been created in the early years of the war, which placed pathological laboratories at the centre of the diagnosis, treatment, and control of war diseases. Organised to collect, isolate, and identify pathogens from the battlefield and to facilitate production of vaccines and antisera, this system delivered therapeutic and preventive measures against a range of conditions, and its planners trusted that it could do the same with influenza. British approaches to the pandemic were governed by a military logic in which the pathological laboratory provided key solutions to understanding and managing the disease. This logic dictated two interrelated strategies: the identification of the primary causative agent—the germ—and the rapid production of preventive vaccines against it. During the war, these strategies were key to the military management of infectious disease. While not adhered to blindly, during the pandemic they acted as important reference points from which medical practices were developed and organised. The machinery of war thus generated a highly militarised form of medicine that played a decisive role in the development of official knowledge and strategies against the pandemic in Britain. Recognising this dynamic changes how we conceptualise the relationship between the war and the pandemic. Much historical interest has concentrated on how war conditions created novel ecological conditions for the rapid spread and increased virulence of influenza.9 I take 8 Mark Harrison, The Medical War: British Military Medicine in the First World War (Oxford: Oxford University Press, 2010), 1–15. 9 Mark Osborne Humphries, ‘Paths of Infection: The First World War and the Origins of the 1918 Influenza Pandemic’, War in History, 21.1 (January 2014), 55–81; John S. Oxford et al., ‘World War I May Have Allowed the Emergence of “Spanish” Influenza’, The Lancet Infectious Diseases Journal, 2.2 (February 2002), 111–114; Robert J. Brown ‘The Great War and the Great Flu pandemic of 1918’, Wellcome History, 24, 5–7; John S. Oxford, 2001, ‘The So-called Great Spanish Influenza Pandemic of 1918 May Have Originated in France in 1916’, Philosophical Transactions of the Royal Society of London, B, 336 (2001), 1857–1859; Andrea Tanner ‘The Spanish Lady Comes to London: The

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a different approach, which highlights how the wartime organisation of British medicine directly shaped responses to influenza. This approach makes sense of the nature, direction, and scale of medical mobilisation against the pandemic, and the authority accorded to specific medical bodies for elaborating and coordinating strategies.10 This chapter traces how pathology was organised for war and the concomitant fight against influenza. It reconstructs the ways in which medical officials mobilised military pathology to generate ways of fighting influenza that fit the demands of a nation in total war. Despite having worked well for other war-related diseases, influenza challenged this logic and the ability of scientific medicine to protect the nation against the pandemic.

1

The War and the Pandemic

The relationship between the war and influenza was a preoccupation during the pandemic and has remained so over the last century. Medical and lay observers in 1918 associated the pandemic with the war.11 Yet their explanations for this link varied considerably. Some sensational press stories claimed the pandemic arose from putrefying corpses on the Western Front, from which it spread like a miasma.12 Others blamed it Influenza Pandemic 1918–1919’, London Journal, 27 (2002), 51–76; Carol R. Byerly Fever of War: The Influenza Epidemic in the U.S. Army during World War I (New York: New York University Press, 2005). 10 The relationship between the militarisation of medicine and the pandemic has started

to receive some attention. Carol Byerly has examined how the organisation of military medicine within the U.S. Army affected its approaches to the pandemic. See, Carol R. Byerly, Fever of War: The Influenza Epidemic in the U.S. Army during World War I (New York: New York University Press, 2005); Carol R. Byerly, ‘The U.S. Military and the Influenza Pandemic of 1918–19’, Public Health Reports, 125, Suppl. 3 (2010), 82– 91. John Barry has elucidated the efforts (and failures) of laboratory pathologists enlisted in the American war machine to identify and control the influenza germ. See, John M. Barry, The Great Influenza: The Epic Story of the Deadliest Plague in History (London: Penguin Books, 2004). My argument has benefitted most from Anne Rasmussen, who has argued that in France ‘the management of influenza took place within the military health organization’. Anne Rasmussen, ‘Prevent or Heal, Laissez-Faire or Coerce? The Public Health Politics of Influenza in France, 1918–1919’, in Tamara Giles-Vernick and Susan Craddock (Eds.), Influenza and Public Health: Learning from Past Pandemics (London: Earthscan, 2010), 73. 11 Sandra M. Tomkins, ‘Britain and the Influenza Epidemic’, Ph.D. Thesis. Department of History, University of Cambridge (1989), 238. 12 Tomkins ‘Britain and the Influenza Epidemic’, 239.

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on gas warfare, citing similarities in the pathological reports on lungs of victims of gas attacks and of influenza.13 A popular notion directly attributed its severity to wartime privations. Although most medical observers did not believe that war conditions specifically caused the pandemic, they did believe that they enhanced influenza’s virulence. ‘The people’, suggested a Lancet editorial, were ‘suffering from an unusual strain, both mental and physical’; overwork, poor nutrition, and the loss of loved ones had ‘led to lowered vitality and weakened resistance to disease.’14 The strains of war had, according to many, induced general ‘war weariness’, a neurasthenic condition characterised by a state of nervous exhaustion, which, when combined with wartime privations prepared the ‘soil’ for the pandemic, the ‘seeds’ of which acted with impunity on weakened bodies.15 Privation theories had wide appeal, but were challenged by, among others, the BMJ and the War Office. Both had vested interests in upholding positive perceptions of the nation’s health: the BMJ was the journal of the British Medical Association, which was responsible for supplying the Royal Army Medical Corps with physicians, while the War Office orchestrated the war effort. The BMJ argued that any notion that ‘the war and privations caused by it are in some way responsible for the severity of the pandemic will not hold water’ for the simple reason that in countries with greater food restrictions, as in Germany, it had been no more severe, whereas in countries with limited restrictions, as in South Africa or the United States, it had claimed many more lives.16 Taking a similar line, the War Office argued that ‘there seems no reason whatever to suppose that the power of resistance in the troops is lowered; on the contrary, the general health of the army is probably as good now as it ever was.’17 The Ministry of Munitions’ epidemiologist and statistician, 13 Herbert French noted similarities in the gross pathology of the two conditions. Herbert French, ‘Influenza’, Guy’s Hospital Gazette, no. XXXIII (1919), 118–127. 14 ‘The Influenza Epidemic’, Lancet (2 November 1918), 595. 15 ‘The Spanish Influenza: a sufferers’ symptoms’, The Times (25 June 1918), 9; ‘The

Mystery of Influenza’, Times (28 October 1918), 7. For metaphors of ‘seed’ and ‘soil’, see Worboys Spreading Germs, 283–285. 16 ‘The Etiology of Influenza’, BMJ (2 November 1918), 494. 17 Influenza Committee of the Advisory Board to the D.G.A.M.S., ‘A Report on the

Influenza Epidemic in the British Armies in France, 1918’ BMJ (9 November 1918), 505.

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Major Greenwood, who later coordinated the Ministry of Health’s 1920 Report on the Pandemic of Influenza, supported this position: ‘When one remembers that the incidence of influenza has been equally severe upon our well-fed troops, their equally well-fed Allies, and the civilian population, we are entitled to conclude that rationing has had nothing to do with this epidemic.’18 Greenwood and medical officials proposed another connection. Rather than rationing or privations, the ‘special’ factors that had altered influenza’s virulence included troop movements, the concentration of soldiers in ships, camps and trenches, overcrowding on civilian transportation services, housing shortages and the massing of labourers in munitions factories and other war industries.19 Newsholme, though no ally of Greenwood’s, shared this view: ‘[a]lthough no satisfactory explanation is known of the causes exciting either the minor or major influenza epidemics, there can be no doubt that the movements of the recent war have been responsible on a large scale for its increased virulence.’20 This kind of explanation connected the changed virulence of the autumn epidemic to the mass mobilisation of troops and their movements between countries and continents; these movements facilitated the rapid diffusion of the influenza bacillus through military and civilian populations.21 The causal relationship between the war and the pandemic has remained a fixture of historical writing since the 1920s. Historians have supported theories associating the spread and severity of the pandemic with troop movements, while expanding refutations of privation theories. In his pioneering study, Alfred Crosby argued that little correlation existed between the degree of privation and who got sick and who died, or which nations were most seriously affected. Crosby noted that

18 Major Greenwood, ‘Discussion on Influenza’, Proceedings of the Royal Society of Medicine, 12 (1918), 23. 19 Greenwood ‘Discussion on Influenza’, 23–24; Major Greenwood, Epidemics and Crowd Diseases: An Introduction to the Study of Epidemiology (London: Williams and Norgate, 1935). 20 Newsholme ‘Discussion on Influenza’, 1. 21 Olga Amsterdamska, ‘Standardizing Epidemics: Infection, Inheritance and Environ-

ment in Prewar Experimental Epidemiology’, in Jean-Paul Gaudillière and Ilana Löwy (Eds.), Heredity and Infection: Historical Essays on Disease Transmission in the Twentieth Century (London: Routledge, 2001), 135–180.

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influenza was often more deadly in countries that had not suffered serious war deprivations than in those that had.22 A more rigorous critique of privation theories has come from Jay Winter, who has argued that changes in diet, nutrition, and social conditions in Britain played no significant role in the epidemiology of the autumn epidemic.23 Winter drew support from statistical analyses prepared in 1920 by the British Registrar General, T.H.C. Stevenson, whose report on the pandemic and subsequent study in 1922 of the incidence of influenza-related mortality in London and Paris showed that socio-economic status had little bearing on either the development or distribution of the autumn epidemic.24 Catherine Rollet’s comparative study of influenza in London, Paris and Berlin has substantiated this claim. She argues that the ‘the incidence of the greatest killer of all in the war decade was entirely fortuitous’ and completely ‘egalitarian’, claiming that socio-economic inequalities had little bearing on the severity or course of the pandemic.25 Not all historians have embraced this view. Revised analyses of how war economies influenced influenza-related mortality suggests that the demographic toll of the pandemic was far from egalitarian. In France, for instance, Patrick Zylberman has argued the ‘unequal distribution of material resources on the home and battle fronts affected the population’s ability to survive associated bacterial infections which were the immediate cause of the largest numbers of deaths.’26 Studies of British India, where the death toll is estimated to have reached 18.5 million, have challenged the notion that influenza was a democratic killer. Indian mortality was strictly ‘class orientated’ and inextricably linked to manmade famine. Ian Mills has argued that ‘famine and pandemic … formed

22 Crosby, America’s Forgotten Pandemic, 217. 23 Jay Winter, The Great War and the British People (London: Macmillan, 1985), 104;

114–117; 120–132. 24 Thomas H.C. Stevenson, ‘The Incidence of Mortality Upon the Rich and Poor Districts of Paris and London’, Journal of the Royal Statistical Society (1921), 1–30. 25 Catherine Rollet, ‘The ‘Other War’ II: Setbacks in Public Health’, in Capital Cities at War: Paris, London, and Berlin 1914–1919, Jay Winter and J-L. Robert (Cambridge: Cambridge University Press, 1997), 480, 482. 26 Patrick Zylberman, ‘A Holocaust in a Holocaust: The Great War and the 1918 ‘Spanish’ Influenza Epidemic in France’, in Howard Phillips and David Killingray (Eds.), The Spanish Influenza Pandemic of 1918–19: New Perspectives (London: Routledge, 2003), 191.

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a set of mutually exacerbating catastrophes.’27 A similar observation has been made for the experience in the Bombay Presidency, where malnutrition was a contributing factor.28 Correlations between social class and the pandemic’s lethality also have been demonstrated for various industrial nations. A study of Sydney, Australia concluded that, ‘working-class and blue-collar workers experienced the heaviest death rates,’ especially in the inner city, and where unemployment was an important predictor of mortality.29 Similar conclusions have been made in studies of the epidemic in Canadian cities.30 Far from being an equal opportunity disease, poverty and malnutrition, whether the direct or indirect product of war, were, as Mike Davis argues, ‘powerful determinants of the precise tax that the 1918 influenza exacted from different populations.’31 While the relationship between the pandemic’s severity and the political economy of war has divided historians, the ecological role of the war has remained undisputed. Virologists and evolutionary biologists have suggested that war conditions fostered the emergence of a new and deadly influenza virus. The Australian virologist and immunologist, F.M. Burnet, was an early proponent of the idea that the war facilitated the spread and increased the virulence of a new strain of the virus, which he and Ellen Clark ‘ascribed to the unprecedented opportunity afforded for the spread of infection in large bodies of men from various parts of the world … in Europe.’32 Others have built on his observations. The evolutionary biologist Paul Ewald has suggested that virulence changed as the virus moved person-to-person and that the ecology of the war allowed it to come into contact with new hosts—young, healthy soldiers—through 27 Ian D. Mills, ‘The 1918–1919 Influenza Pandemic—The Indian experience’, Indian Economic and Social History Review, 23.1 (1985), 35. For revised estimates of Indian mortality, see Johnson and Mueller, ‘Updating the Accounts’, 111–112. 28 Mridula Ramanna, ‘Coping with the Influenza Pandemic: The Bombay Experience’, in The Spanish Influenza Pandemic of 1918–1919, 95. 29 Kevin McCraken and Peter Curson, ‘Flu Down Under: A Demographic and Geographic Analysis of the 1919 Epidemic in Sydney, Australia’, in The Spanish Influenza Pandemic of 1918–19, 130–131. 30 Esllyt Jones, Influenza 1918: Disease, Death and Struggle in Winnipeg (Toronto: University of Toronto Press, 2007); Mark Humphries, The Last Plague: Spanish Influenza and the Politics of Public Health in Canada (Toronto: University of Toronto Press, 2013). 31 Mike Davis, The Monster at Our Door: The Global Threat of Avian Flu (London: New Press, 2005), 30. 32 Burnet and Clark, Influenza: A Survey of the Last 50 Years, 98.

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which it rapidly reproduced and evolved to take advantage of the crowded conditions and movement of people to and from the front. Troop transportation and trench warfare created the ideal conditions for an especially aggressive and deadly virus to gain unprecedented strength through a combination of random mutation and natural selection.33 More recent studies of the genetics and phylogeny of 1918 strains reconstructed from human lung tissue have associated its stunning virulence with the fact that it was a novel avian influenza virus that had crossed into humans from animals, becoming highly pathogenic in the process.34 Virological hypotheses have been important for historians seeking to understand the intimate relationship between the war and the pandemic. Carol Byerly has argued that ‘the war created the influenza epidemic by producing an ecological environment in the trenches in which influenza virus could thrive and mutate to unprecedented virulence…. War and disease together thus produced a human disaster of global proportions.’35 Similarly, Andrea Tanner has noted that ‘the British experience of the pandemic was inextricably linked to the war, not least through the transmission of the infection to the civilian population by military personnel.’36 Such arguments remind us that the pandemic was contingent on a specific conjunction of historical, social, and biological factors associated with the war. But they also demonstrate the degree to which historical studies of the relationship between the war and the pandemic have been dominated by retrospective virological explanations.37 By privileging modern disease concepts, and taking this relationship as self-evident, they exclude from historical analysis how it was understood and used by contemporary actors, particularly those involved in generating medical knowledge. The key point here is that questions about this relationship have a history that goes right back to the pandemic itself.38 33 Paul Ewald, Evolution of Infectious Disease (Oxford: Oxford University Press, 1994), 109–118. 34 Jeffery Taubenberger, ‘The Origins and Virulence of the 1918 “Spanish” Influenza’, Proceedings of the American Philosophical Society, 150 (2006), 86–112. 35 Byerly, Fever of War, 8. 36 Andrea Tanner, ‘The Spanish Lady Comes to London: The Influenza Pandemic

1918–1919’, London Journal, 27 (2002), 54. 37 See Roger Cooter, ‘Of War and Epidemics: Unnatural Couplings, Problematic Conceptions’, Social History of Medicine, 16 (2003), 283–302. 38 An exception is Tomkins, ‘Britain and the Influenza Epidemic’, 238ff.

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Indeed, the epidemic-war couplet was itself constructed through medical practices and their wartime organisation during and after the pandemic. In Britain, the mobilisation of military medicine against the pandemic bound the disease to the war, creating a common context through which strategies were conceptualised and put into action. Especially crucial was military pathology.

2

War Pathology

That the pandemic and official responses to it in Britain should be defined through military medicine is readily apparent when one considers the extent to which medicine had been organised on military lines.39 By 1918 over fifty per cent of the profession—nearly 14,000 physicians—had been recruited or conscripted into the RAMC.40 The problems they worked on were primarily military and required ways of seeing and managing diseases acquired on battlefields and in military hospitals.41 Military and civilian medicine converged around the maintenance and management of military manpower, including civilians who were the reserve labour pool for the military and the war industries. Medical authorities such as Sir Alfred Keogh, Director-General of the Army Medical Services until 1916, convinced military planners that the health of the troops and the nation were inextricably linked to winning the war. Working with the RAMC and the War Office, the British Expeditionary Force sanctioned the expansion of the AMS into a complex medical system. The joint medicalisation of the military and militarisation of medicine bound the organisation, production, and application of medical knowledge to the war.42 The wartime medical system combined medical institutions for the treatment, care, and management of personnel at 39 Harrison, The Medical War, 1–15. 40 Winter, The Great War, 186. According to Anne Hardy by 1918, the RAMC

consisted of 13,000 officers and 154,000 other ranks. See, Anne Hardy, ‘Lives, Laboratories and the Translations of War: British Medical Scientists, 1914 and Beyond’, Social History of Medicine, 30.2 (2017), 348; see also, www.ams-museum.org.uk/museum/his tory/ramc-history (Accessed 15 January 2018). 41 Ian R. Whitehead, ‘The British Medical Officer on the Western Front: The Training of Doctors for War’, in Roger Cooter, Mark Harrison and Steve Sturdy (Eds.), Medicine and Modern Warfare (Amsterdam: Rodopi, 1992), 163–184. 42 Roger Cooter, ‘War and Modern Medicine’, in William F. Bynum and Roy Porter (Eds.), Companion Encyclopedia of the History of Medicine (London: Routledge, 1993),

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the front with medical institutions at home.43 Highly-rationalised, it depended on triage, teamwork, specialisation, and large-scale communication, linking Casualty Clearing Stations at the front to field and base hospitals attached to each army division.44 Field hospitals were supported by territorial hospitals in mainland England, which were connected to major London and provincial teaching hospitals and run by consultants who were given temporary ranks in the RAMC and paid part-time salaries.45 At the core of this system was a network of pathological laboratories that supported every level of medical practice and institution. Pathology laboratories were an organisational innovation in British military medicine spurred by the growth and successes of bacteriology in civilian medicine and public health. Training in pathology and bacteriology was established as part of the curriculum of the RAMC in 1903.46 But the pathological laboratory was made a fundamental unit of military medicine only during the war.47 The organisation of pathological laboratories involved close collaboration between the War Office and the Medical Research Committee (MRC). Created in 1913, with limited responsibilities as a committee under the National Health Insurance Commission, the MRC established its authority in the coordination of medical science for the war effort.48 In his first annual report, the MRC Secretary, Walter Morley

1536–1573; Roy Cooter and Steve Sturdy, ‘Of War, Medicine and Modernity: Introduction’, in Roger Cooter, Mark Harrison and Steve Sturdy (Eds.), War, Medicine and Modernity (London: Sutton, 1998), 1–21; Mark Harrison, ‘Medicine and the Management of Modern Warfare’, History of Science, 34 (1996), 379–410. 43 For a detailed description and analysis, see Harrison, The Medical War, 16–122. 44 Christopher Lawrence, ‘Continuity in Crisis: Medicine, 1914–1945’, in The Western

Medical Tradition: 1800 to 2000 (Cambridge: Cambridge University Press, 2006), 257; Ian Whitehead, Doctors in the Great War (London: Leo Cooper, 1999), 210. 45 Roger Cooter, Surgery and Society in Peace and War: Orthopaedics and the Organisation of Modern Medicine, 1880–1948 (London: Macmillan, 1993), 111. 46 Cay-Rüdiger Prüll, ‘Pathology at War 1914–1918: Germany and Britain in Comparison’, in Medicine and Modern Warfare, 131–162. 47 William B. Leishman, ‘Organization of the Pathological Service’, in History of the Great War Based on Official Documents. Medical Services. Pathology, 1–31. 48 Joan Austoker, ‘Walter Morley Fletcher and the Origins of a Basic Biomedical research policy’, in Joan Austoker and Linda Bryder (Eds.), Historical Perspectives on the Role of the MRC: Essays in the History of the MRC of the United Kingdom and its Predecessor, the Medical Research Committee, 1913–1953 (Oxford: Oxford University Press,

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Fletcher, justified its role in terms of the value of medical research for the ‘efficiency of the fighting forces’ and for its future applications in peacetime (Fig. 1). The ‘conditions of war’, he argued, offered ‘special opportunities … for disciplined study and for repeated observation’.49 Every aspect of the war, Fletcher insisted, demanded ‘the application of the scientific method’—from the management of manpower and hospitals to medical diagnoses and treatments. Coordinated laboratory work in pathology was crucial to this goal.50 Sir William Boog Leishman, a career military pathologist, specialist in tropical medicine, and founding member of the MRC, spearheaded the integration of pathology into the medical service. A former student of the renowned pathologist and bacteriologist, Sir Almroth Wright, Leishman had been instrumental in the practical development of the military’s antityphoid vaccine at the Royal Army Medical College (RAMC) at Millbank (formerly at Netley) and the large-scale inoculation of troops at the outbreak of the war.51 In October 1914 he became Advisor in Pathology to the Director-General of the AMS (DGAMS) and was detailed to establish pathological laboratories in France and Flanders. Leishman and a small cadre of advisors defined the role of pathology laboratories along lines that fostered opportunities for ‘better cooperation between clinicians and pathologists.’52 He promoted pathological knowledge and practices as necessary for ‘the maintenance of the health of the troops and for the effective treatment of the sick and the wounded.’53 He took from Wright the notion that laboratory work be targeted ‘at the therapeutic application of certain ideas to the living soldier’ rather than at post mortem.54 British military pathological laboratories were initially organised to provide military doctors and surgeons with bacteriological services for the routine 1989), 22–33; Robert E. Kohler, ‘Walter Fletcher, F.G. Hopkins, and the Dunn Institute of Biochemistry: A Case Study in the Patronage of Science’, Isis, 69 (1978), 331–355. 49 Medical Research Committee, First Report of the Medical Research Committee, 1914– 15 (London: HMSO, 1916), 1–2. 50 Austoker, ‘Walter Morley Fletcher’, 23–24. 51 Leishman had been one of ‘Wright’s Men’. See Michael Worboys, ‘Almroth Wright

at Netley: Modern Medicine and the Military in Britain, 1892–1902’, in Medicine and Modern Warfare, 77–97. 52 Prüll, ‘Pathology at War, 1914–1918’, 144. 53 Leishman, ‘Organization of the Pathological Service’, 5–6. 54 Prüll, ‘Pathology at War 1914–1918’, 143.

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Fig. 1 (Sir) Walter Morley Fletcher, F.R.S., (1873–1933) (Source: Obituary Notices of Fellows of The Royal Society, Vol. 1 No. 2 [December] 1933)

diagnosis and treatment of infectious diseases.55 The high incidence of tetanus, gas gangrene, venereal diseases and blood poisoning in the early months of the war, along with the emergence of new infectious diseases 55 Prüll argues that this was a defining feature of British clinical pathology.

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such as trench foot, sand-fly fever, and cerebro-spinal fever served as an important rationale for expanding their role in military medicine.56 Beginning in 1914 Leishman oversaw the deployment of ninety-seven pathologists at eighty-five hospital laboratories in France and Flanders, the development of a fleet of twenty-five mobile laboratories to provide bacteriological services at the front, and the creation of a central research laboratory at Boulogne (Fig. 2).57 The routine work of the laboratories involved testing and monitoring patients, performing autopsies, analysing specimens, preparing and administering vaccines and serum therapies, and wiring important or unusual findings to appropriate agencies back home. The correlation of clinical examinations of known—and new—diseases with bacteriological tests became standard practice.58 Hospital and mobile laboratories were equipped with materials and tools for making media on which to culture and identify a considerable range of bacteria.59 The pathological department at the RAMC was the system’s institutional hub. It trained pathologists, and collected, analysed, and classified pathological material from military laboratories abroad and at home, and aided pathologists in the confirmation of difficult-to-diagnose diseases. College staff maintained close relations with pathologists at various London research institutions and medical schools, with their well-equipped laboratories and trained staff, many of whom were given temporary commissions in the RAMC.60 The most important role of the College’s pathology department was the production and supply of vaccines and serum therapies. The large-scale manufacture and inoculation of anti-typhoid vaccine at its Vaccine Department was a model for the successful application of laboratory methods to pathological problems, and shaped military medicine’s parallel war on disease.61 Antityphoid vaccination dramatically reduced 56 For a comprehensive account of this system, see Harrison, The Medical War, 65–122. 57 Leishman, ‘Organization of the Pathological Service’, 6. 58 Prüll ‘Pathology at War 1914–1918’, 131–162. 59 Leishman ‘Organization of the Pathological Service’, 29–30. 60 Leishman, ‘Organization of the Pathological Service’, 23–24. 61 Paul J. Weindling, ‘Between Bacteriology and Virology: The Development of Typhus Vaccines Between the First and Second World Wars’, History and Philosophy of the Life Sciences, 17 (1995), 81–90; Worboys, ‘Almroth Wright at Netley’. Anti-typhoid vaccine was also manufactured at the Lister Institute and Almorth Wright’s Inoculation Department of St. Mary’s Hospital.

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Fig. 2 Motor Laboratory—interior, circa 1917 (Source: Medical Research Committee, Bacteriological Studies in the Pathology and Preventive Control of Cerebro-Spinal Fever Among the Forces During 1915 and 1916 [London: HMSO, 1917], 100)

the disease’s incidence and spurred the production and widespread use of vaccines for cholera, plague, and dysentery. Although serum therapies against tetanus and diphtheria had been proven in peacetime, their efficacy during the war, along with new serum therapies against gas gangrene,

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trench fever and other diseases, further underscored the military relevance of laboratory medicine. Vaccines and serum therapies represented an efficient means of managing the health of military populations. For every disease that cropped up during the war the AMS turned to pathology for solutions. The MRC played a key role in the mobilisation of pathology. Although it maintained relations with the Royal Navy and, later, the Royal Air Force, it mostly assisted the Army Medical Services, and mostly in pathology.62 Crucially, it linked together civilian and military medical expertise. It encouraged pathologists working in hospitals, universities, and research institutions to take on war-related responsibilities. Most needed little convincing, and many were commissioned by the RAMC. Leishman used his advisory role to foster an ‘always very intimate’ relationship between the MRC and AMS.63 The MRC put researchers from its Department of Bacteriology at the service of the AMS. Its leading pathologist, Almroth Wright, ran the AMS’s central pathology laboratory at Boulogne, where he worked with young assistants, Alexander Fleming and Leonard Colebrook, on wound infections and antiseptics.64 The MRC also commissioned Captain S.R. Douglas, who oversaw production of anti-typhoid and other vaccines at Wright’s Inoculation Department at St. Mary’s Hospital.65 Civilian pathologists at St. Mary’s played an important role in military pathology, particularly in efforts to type bacteria and manufacture therapeutic agents. More generally, through a system of grants, the MRC ensured that military laboratories were supplied with trained staff, materials, and equipment.66 Leading pathologists were seconded on temporary commissions and pathological research at universities and hospitals was coordinated 62 Leishman, ‘Organization of the Pathological Service’, 20. 63 Leishman, ‘Organization of the Pathological Service’, 18. 64 Joan Austoker and Linda Bryder, ‘The National Institute for Medical Research and

Related Activities of the MRC’, in Perspectives on the Role of the MRC, 39. 65 Austoker and Bryder, ‘The National Institute for Medical Research’, 39. 66 For the MRC’s organisational activities, see: Medical Research Committee Annual

Report of the Medical Research Committee, 1916–17 (London: HMSO, 1918); Medical Research Council, Report of the Medical Research Council for the Year 1918–1919 (London: HMSO, 1920); Walter Morley Fletcher, ‘The National Organisation of Medical Research in Peace after War’, in William E. Welch et al. (Eds.), Contributions to Medical and Biological Research, Dedicated to Sir William Osler (New York: Paul B. Hoeber, 1919), 461–470.

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with research in military institutions.67 The MRC organised special research committees to combat specific illnesses, which fostered the organisational notion of ‘team work’ between military and non-military researchers and between clinicians and pathologists.68 The circulation of medical information was vital to making the system work. The MRC’s statistician, John Brownlee, joined the War Office to compile statistics on the sick and wounded in the forces, developing a novel system of card indices for rapidly transferring information from hospital records to a central database. It published leaflets and pamphlets on special areas of research, and the Medical Supplement, a compendium and analysis of foreign medical publications distributed to military hospitals and laboratories as well as to government departments and American and French medical services.69 The MRC also drove efforts to standardise methods, equipment, and materials across pathological laboratories.70 Most notable was the largescale preparation of uniform culture media for pathology units, to ensure accuracy in routine diagnostic work.71 When this was institutionalised, the MRC turned its attention to supporting research on war-related problems. Small teams of physicians and pathologists did most of the wartime pathological research.72 Rather than draw a line between specialist and 67 Steve Sturdy, ‘War as Experiment: Physiology, Innovation and Administration in Britain, 1914–1918: The Case of Chemical Warfare’, in War, Medicine and Modernity, 65–84. 68 Roger Cooter, ‘Keywords in the History of Medicine: “Teamwork”’, Lancet, 363.9416 (2004), 1245; Andrew Hull, ‘Teamwork, Clinical Research, and the Development of Scientific Medicines in Interwar Britain: The “Glasgow School” Revisited’, Bulletin of the History of Medicine, 81 (2007), 569–593; Sturdy and Cooter, ‘Science, Scientific Management, and the Transformation of Medicine in Britain’, 421–466; A. Landsbury Thomson, Half a Century of Medical Research. Origins and Policy of the Medical Research Council (UK), Vol. 1 (London: HMSO, 1973), 95–99. 69 Medical Research Committee, Interim Report on the Work in Connection with the War at Present undertaken by the Medical Research Committee (London: HMSO, 1915), 3. 70 Medical Research Committee, Interim Report, pp. 3–6; First Report of the Medical

Research Committee, 31–48. 71 Austoker and Bryder ‘The National Institute for Medical Research’, 53. 72 For the relationship between the war and the professionalisation of pathology, see:

William D. Foster, Pathology as Profession in Great Britain and the Early History of the Royal College of Pathologists (London: E&S Livingstone, 1965), 19–20; for the scale of pathological research, see Prüll, ‘Pathology at War 1914–1918’, 142–143.

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routine pathology, Fletcher recognised that ‘routine work in proper hands may be expected to suggest and give an opportunity for research … [and] might provide … valuable gains in knowledge and in methods of treatment.’73 Military pathology made it possible to mobilise laboratory research on an unprecedented scale. Moreover, it appeared to work. Fewer soldiers died of infections than in any previous war.74 Antityphoid vaccination symbolised this success. Leishman had organised efforts to redress problems in the preparation and testing of an antityphoid vaccine developed by Wright before the war, and by 1916 technical improvements and the imperatives of the manpower economy transformed it into a model for military approaches to infectious disease prevention.75 So when an epidemic that appeared to be influenza broke out among troops in spring 1918, the War Office, AMS, and MRC trusted that if the suspected influenza germ could be identified, a preventive vaccine could be developed to protect soldiers and military interests.76

3

A New Disease?

Influenza was hardly new to the British military in 1918. The disease had broken out for three consecutive years between 1915 and 1917. On AMS estimates, over 36,000 cases were admitted to its hospitals in France in 1916 and nearly 30,000 in 1917.77 Medical officials considered this ‘normal’, but a constant drag on manpower.78 Although treatment was, as it had been in peacetime, largely symptomatic, with anti-pyretics, hydration and, wartime conditions permitting, bed rest, this depended on a reasonably accurate diagnosis. Diagnosing influenza during non-epidemic periods remained notoriously difficult, since it lacked a pathognomic sign and its symptoms were easily confused with other diseases. By the outbreak of the war, however, some progress

73 Medical Research Committee, Interim Report, 32. 74 Harrison, Medical War, 292–295. 75 Anne Hardy, ‘”Straight Back to Barbarism”: Antityphoid Inoculation and the Great War, 1914’, Bulletin for the History of Medicine, 74 (2000), 265–290. 76 Leishman, ‘Organization’. 77 French ‘Influenza’, 174. 78 French ‘Influenza’, 174.

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had been made as diagnosis increasingly was confirmed by the bacteriological identification of B. influenzae. Some of the difficulty in cultivating the bacillus had been alleviated, though not completely solved, by modifications to Pfeiffer’s blood-agar medium and his technique of sowing samples on an agar slope smeared with a few drops of blood. These techniques had been slowly incorporated into British bacteriological practice and the bacillus had gained provisional standing as the ‘germ of influenza’. Both became part of the general organization of pathology for war. Most military pathologists were familiar with cultivating and identifying B. influenzae from sputa, nasal discharges and post-mortem samples of sick or dead soldiers.79 From as early as 1915, its isolation was used to distinguish the various atypical respiratory conditions encountered on the battlefield and local outbreaks of influenza in France and Belgium.80 The bacillus first came to the attention of medical military personnel in late December 1916 when it was isolated from an epidemic of ‘purulent bronchitis’ at Étaples.81 A team of investigators reported that during February and March 1917 in more than 45 per cent of all pulmonary autopsies performed in the hospital, purulent bronchitis was the ‘primary condition’.82 Most soldiers died of ‘lung block’, resulting from the accumulation of fluid and pus in the lungs. The bronchi and lungs of soldiers filled with pus, causing emphysema and cyanosis and some observers estimated a mortality rate of 50 per cent.83 What struck the investigators was that in smears and cultures of sputa and lung samples from 20 cases they tested, B. influenzae appeared to be the primary agent, even though the disease bore little clinical or pathological resemblance to influenza

79 John George Adami, ‘Influenza’, in History of the Great War Based on Official Documents. Medical Services. Pathology, 413–466. 80 Adolphe Abrahams, Norman F. Hollows, John W.H. Eyre and Herbert French, ‘Purulent Bronchitis: Its Influenza and Pneumococcal Bacteriology’, Lancet (8 September 1917), 377–380; Aldolph Abrahams, ‘Epidemic at Aldershot: Discussion’, Transactions of Royal Society of Medicine, 12 (1917), 97; John Matthews, ‘Influenza or Epidemic Catarrh’, Lancet (2 April 1915), 727. 81 J.A.B.Hammond, W. Rolland, & T.H.G. Shore, ‘Purulent Bronchitis: A Study of Cases Occurring Among the British Troops at a Base in France’, Lancet (14 July 1917), 41–46. 82 Hammond, Rolland, and Shore, ‘Purulent Bronchitis’, 43. 83 Adami ‘Influenza’, 417.

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or influenzal pneumonia. Observations by another team of investigators at Connaught Hospital at Aldershot Command in September 1917 supported this observation.84 The Aldershot team identified B. influenzae as the primary agent in the eight cases they tested and other well-known respiratory germs—particularly pneumococci, Micrococcus catarrhalis and streptococci—as secondary infections. Like their counterparts at Étaples, the Aldershot group concluded that the isolation of B. influenzae from the majority of cases of purulent bronchitis indicated a ‘serious form of influenzal infection.’85 This was further supported by pathologists and physicians working at the No. 3 Canadian General Hospital at Boulogne, who carried out a ‘full clinical, pathological and bacteriological study’ of purulent bronchitis. From all but one of the nine cases they were able to grow B. influenzae in pure culture, which they interpreted as a key indicator that the bacillus caused the disease.86 Pathologists used the identification of B. influenzae to frame purulent bronchitis as a type of ‘influenzal infection’. But the outbreaks were so local that they were treated as one of the many anomalous respiratory infections encountered in the war. It was only when an almost identical condition appeared in large numbers of soldiers in August 1918, and in civilians in October, that the same pathologists started to connect purulent bronchitis to the autumn influenza epidemic. When the official military history of the 1918–1919 pandemic was written in the early 1920s, the severe outbreaks of purulent bronchitis that began in December 1916, and the milder outbreaks of influenza in the intervening years, were characterised as the ‘first phase’.87 The isolation of B. influenzae was essential to drawing this link: ‘It was evident, in light of these careful studies, that the frequent presence of the B. influenzae, noted by the earliest of observers was of no little significance, and further, that influenza existed among the troops prior to the onset of the pandemic, sporadically … and not of sufficient frequency to cause alarm, but there, nevertheless.’88

84 Abrahams, Hollows, Eyre and French, ‘Purulent Bronchitis’, 377–380. 85 Abrahams, Hollows, Eyre and French, ‘Purulent Bronchitis’, 379. 86 Adami, ‘Influenza’, 419. 87 Adami, ‘Influenza’, 423. 88 Adami, ‘Influenza’, 420.

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Studies on purulent bronchitis underscored the extent to which pathological perceptions of influenza were directed by its presumed aetiological link with B. influenzae. Bacteriological diagnosis rested on the assumption that ‘true influenza’ was present in only those cases from which B. influenzae alone was consistently isolated. Its presence, even in obscure or borderline conditions, was enough to establish a disease’s influenzal identity, while its absence cast doubt on it. Up until 1918, military pathology thus worked on the assumption that influenza was a bacterial disease caused by Pfeiffer’s bacillus. Trust vested in the bacillus accordingly shaped official strategies when a widespread epidemic broke out among troops in spring 1918. But important anomalies in the bacteriology also challenged this consensus. Signs of what was later identified as the first wave appeared in the British Expeditionary Force in France and Flanders in early April 1918. Physicians and pathologists attached to the First and Second Armies reported local outbreaks of a mild but rampant fever in troops in Rouen and Wimereux in the ill-famed Ypres salient, where ‘disease of all sorts seemed to flourish.’89 The fever raised concern because the British and American armies were bracing for a major German assault on the Western Front. By early May, it had affected thousands of soldiers in the Second Army and had started to appear in other parts of the military.90 Colonel A.B. Soltau of the AMS claimed that it had ‘important military bearings’ on the supply of manpower and the fighting fitness of the army: ‘Whole units were sometimes put out of action. One army brigade of artillery... had at one time two-thirds of its strength laid up, and was unable to go into action, though badly needed, for three weeks.’ By June, it had turned into an epidemic and admissions to military hospitals sky-rocketed. The Second Army’s CCS admitted over 1,900 cases in the first week of June and nearly 3,900 in the second.91 The Grand Fleet reported that an

89 A.B. Soltau, ‘Discussion on Influenza’, Proceedings of the Royal Society of Medicine,

12 (1918–1919), 27. 90 Influenza Committee ‘The Influenza Epidemic in British Armies in France, 1918’,

505. 91 Influenza Committee, ‘The Influenza Epidemic in British Armies in France, 1918’, 505; James McIntosh, Studies in the Aetiology of Epidemic Influenza, Medical Research Council Special Report Series, No. 63 (London: HMSO, 1922), 6–7.

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estimated 10 per cent of men had been struck.92 The Army reported a total of 226,615 cases with a further 93,670 soldiers incapacitated.93 By the end of the month, the epidemic reached Britain’s civilian population, most likely transmitted by military personnel.94 The identity of the epidemic perplexed army doctors and pathologists. While it shared characteristics with influenza, important aspects did not fit the established picture. It occurred in summer instead of autumn. Rather than the usual susceptible groups—the very young, aged, and infirm—it affected young, healthy soldiers.95 Few of the typical symptoms associated with influenza’s complications or sequelae were evident in cases admitted to hospitals; morbid anatomists in the First and Second armies noted that in the relatively small number of fatal cases, death appeared to be caused by a strange pneumonic and hemorrhagic condition that produced a suffocating cyanosis.96 But most of the confusion stemmed from uncertainties about its specific cause. Suspecting the epidemic was influenza, through spring and summer 1918 AMS pathologists tried to isolate B. influenzae from sick soldiers’ sputum, nasal passages, and blood, and from the lesions of the few cases that ended up on the autopsy table. Yet so seldom were their efforts successful that many concluded that it was at best associated with, but not essential to, the epidemic. Its absence led some to question whether the epidemic was influenza. Names reflected these uncertainties.97 The spring fever was first classified as ‘Pyrexia of Unknown Origin’ (P.U.O.), a category that had been introduced in 1915 for infectious diseases, like ‘trench fever’, for which neither specific causal agents nor pathognomonic signs could be determined.98 When the fever became epidemic in troops 92 David Thomson and Robert Thomson, ‘Influenza (Part I)’, Annals of the PickettThomson Research Laboratory (London: Bailliere, Tindall and Cox, 1933), 8. 93 McIntosh, Studies in the Aetiology of Epidemic Influenza, 6–7. 94 Tanner, ‘The Spanish Lady Comes to London’, 54. 95 Tanner, ‘The Spanish Lady Comes to London’, 54. 96 Aldophe Abrahams, Norman F. Hollows, and Herbert French, ‘A Further Investi-

gation into Influenzo-Pneumococcal and Influenzo-Streptococcal Septicaemia: Epidemic Influenzal “Pneumonia” of Highly Fatal Type and its Relation to Purulent Bronchitis’, Lancet (4 January 1919), 1–11. 97 Tanner, ‘The Spanish Lady Comes to London’, 54. 98 John Burnford, ‘A Note on Epidemics’, BMJ (20 July, 1918), 50–51; S.W. Patterson,

‘The Pathology of Influenza in France’, Medical Journal of Australia, 1 (1920), 207–210.

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in June 1918, P.U.O. was replaced by a new term, ‘three-day fever’, which reflected its typical clinical course: ‘three days’ incubation, three days’ fever, and three days’ convalescence.’99 It was only when the epidemic reached the civilian population in late June 1918 that it started to be called ‘influenza’, first in the lay press, where it was erroneously labelled ‘Spanish Influenza’, and then in the medical press, where, beginning in mid-July, it was used cautiously and the notion of the epidemic’s Spanish origins was immediately challenged. The Lancet was hesitant to describe it as ‘influenza’ because of the term’s use by the media, public and many practitioners to denote all sorts of mild respiratory conditions. Its editors often put the term in scare quotes. These uncertainties affected official responses. Notably, the DGAMS did not officially recognise the disease as ‘influenza’ until the first week of August, when the summer epidemic had all but smoldered out. Historians have noted that military officials wanted to conceal the disease and that censorship not only delayed reports of the epidemic but also contributed to the popular notion that it was of Spanish origin and hence the use of the misnomers, ‘Spanish ‘Flu’ or ‘Spanish Influenza’.100 However, the main reason for the delay was that military experts and officials were genuinely confused about its identity. Arthur Newsholme, who, on similar grounds, decided not to issue an official LGB memorandum to civil authorities in summer 1918, shared the DGAMS’s confusion. Newsholme’s decision would later be the focus of scathing criticism of the LGB’s failure to respond to the epidemic.101 Yet at the time, no one was certain about the disease. The key constraint for medical experts and officials was that the bacteriological evidence did not sufficiently support classifying the epidemic as ‘influenza’. A contradictory bacteriological picture emerged in summer 1918. The medical and general press printed accounts from German

99 Soltau, ‘Discussion on Influenza’, 27. According to French, the First Army’s report of 18 June called the disease ‘three-days fever’. French, ‘Influenza’, 187. 100 Crosby, America’s Forgotten Pandemic, 26. 101 Newsholme, ‘Discussion on Influenza’, 13.

For contemporary criticisms of Newsholme, see: John M. Eyler, Sir Arthur Newsholme and State Medicine, 1885– 1935 (Cambridge: Cambridge University Press, 1997), 270–73; Sandra M. Tomkins, ‘The Failure of Expertise: Public Health Policy in Britain during the 1918–19 Influenza Epidemic’, Social History of Medicine, 5 (1992), 440.

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bacteriologists who claimed they too had failed to find the bacillus.102 Pfeiffer himself was reported as remaining silent on the issue, while the German medical community was sharply divided on the role of his bacillus in the pandemic.103 At the same time, anecdotal reports from British pathologists in France suggested that the bacillus was occasionally found and in some cases was being characterised as the predominant organism in the epidemic.104 The BMJ argued that, ‘the general consensus of opinion seems to indicate Pfeiffer’s Bacillus Influenzae as the infecting agent.’105 This contradicted not only the editorial views of the Lancet, which doubted whether the epidemic was influenza, but also reports in the BMJ ’s own pages. Studies published in both journals between July and September 1918 revealed conflict rather than consensus in pathologists’ ranks: four reports noted the almost complete absence of the bacillus; three claimed its constant presence. Worried about ‘the loose application of the term “influenza” to a febrile infection in which Pfeiffer’s bacillus cannot be demonstrated,’ the Lancet counselled using the generic term ‘catarrhal fever’ until the bacteriology of the disease was sorted out.106 Through summer 1918, two loosely defined camps of pathologists clashed over the causal agent and identity of the epidemic: the ‘Pfeiffer school’ defended the so-called ‘orthodox concept’ of influenza and argued that failures to isolate Pfeiffer’s bacillus stemmed from technical failures; the ‘anti-Pfeiffer school’ argued that its absence indicated either that the epidemic was not influenza or that influenza was caused by another organism.107 Questions about the causative agent were inevitably questions about professional competence, skills and interests. They also 102 ‘Influenza’, Medical Supplement (1 October 1918), 353. 103 For debates within German medicine and bacteriology, see Wilfried Witte, ‘The

Plague That Was Not Allowed to Happen: German Medicine and the Influenza Pandemic of 1918–19 in Baden’ in Phillips and Killingray (Eds.), The Spanish Influenza Pandemic of 1918–19 (2003), 49–57. 104 Edward B. Krumbhaar, ‘The Bacteriology of the Prevailing Epidemic’, Lancet (27 July 1918), 123. 105 ‘The Pandemic of Influenza, BMJ (27 July 1918), 91–92. 106 ‘The Prevailing Epidemic’, Lancet (13 July 1918), 51. 107 Ludwik Rajchman, editor of the MRC’s Medical Supplement, used the term ‘Pfeiffer

school’ to describe adherents to the orthodox notion that ‘true influenza epidemics’ were caused only by B. influenzae. ‘Influenza’, Medical Supplement, 1 October 1918, 354. Fildes and McIntosh used the term ‘anti-Pfeiffer school’ to describe critics of Pfeiffer’s

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had profound implications for understanding the clinical pathology of the disease and its prevention. Uncertainties and disputes about the aetiology of the first wave would have important bearing on the elaboration of official strategies during the second wave.

4

Disputed Germs

Contrary to the BMJ ’s claim, through summer 1918 most observers agreed that bacteriological evidence and opinion weighed against Pfeiffer’s bacillus.108 Its absence was explained in various ways. Many pathologists followed the assumption that without B. influenzae there could be no influenza. In the first published bacteriological report on the pandemic in Britain, which appeared in the Lancet on 13 July 1918, three Canadian Army Medical Corps pathologists took this reasoning to its logical conclusion.109 Working from their mobile laboratory on the Western Front, T.R. Little, C.J. Garofalo and P.A. Williams dealt with nearly 1,000 cases of the summer fever. Suspecting influenza, they ran bacterial tests on nasal and sputa samples from twenty soldiers. But they reported being unable to isolate B. influenzae. They instead found a small diplococcus in great abundance and often in pure cultures. Based on this evidence, they concluded that the epidemic was not influenza and that their diplococcus was likely ‘the causative organism.’110 While the Canadians would be hard pressed to find supporters for their diplococcus, many pathologists employed similar reasoning. Paul Fildes and James McIntosh, former colleagues at the London Hospital’s Department of Bacteriology, typified those who stood by Pfeiffer’s bacillus. Both men were experienced and respected researchers.111 They had worked on a number of war-related conditions, including wound

bacillus. Paul Fildes and James McIntosh, ‘The Aetiology of Influenza’, British Journal of Experimental Pathology, II (1920), 159–174. 108 See reviews by Fildes and McIntosh, ‘Aetiology of Influenza’, 159–174; McIntosh, Studies in the Aetiology of Epidemic Influenza. 109 T.R. Little, C.J. Garofalo, and P.A. Williams, ‘Absence of the Bacillus Influenzae in the Exudate from the Upper Air-Passages in the Present Epidemic’, Lancet (13 July 1918), 34. 110 Little, Garofalo, and Williams ‘Absence of the Bacillus Influenzae’, 34. 111 C.P. Gladstone, C.J.G. Knight and Graham Wilson, ‘Paul Gordon Fildes, 1882–

1971’, Biographical Memoirs of Fellows of the Royal Society, 19 (1973), 317–374.

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infections, for which they had created an ‘anaerobic jar’ for growing the spores of gangrene.112 McIntosh remained in civilian service at the London, while Fildes served as pathologist to the Royal Naval Hospital at Haslar in Plymouth. Here, with the support of the MRC and the Admiralty, he ran a pathology laboratory that gave him unobstructed access to sick servicemen at Haslar, including those who started flooding into the wards with the so-called ‘Spanish influenza’.113 As in other naval bases, the disease had been endemic in Portsmouth since early spring 1918, and Fildes and his colleagues made it the ‘subject of considerable inquiry and study.’114 At first Fildes was not convinced it was influenza: ‘The question of influenza as a factor in the disease was discussed and studied,’ he noted in a report published in November 1918, ‘but owing to the complete absence of bacteriological support the causative importance of this bacillus was discredited.’115 He attributed the epidemic to one of a number of ‘respiratory’ organisms— haemolytic streptococci, pneumococci, or streptococcus pyogenes —which, he thought, ‘had taken on increased virulence, owing to the somewhat unsatisfactory weather and presence of large numbers of young “new entries” in the barracks,’ among whom the epidemic was largely confined.116 McIntosh shared Fildes’ scepticism. A taciturn Scotsman who came to the London Hospital in 1908 after spending two years in Paris on Elie Metchnikoff’s bacteriological course at the Pasteur Institute, McIntosh was well established in London pathological circles.117 Like many civilian pathologists, he had started investigating influenza in early summer 1918. With clinical material taken from a few cases and post-mortem examinations, he tested for B. influenzae using ordinary blood agar and found no trace. As he later admitted, he concluded, ‘perhaps rather rashly,’ that the bacillus ‘did not play an important part in the causation of the epidemic’ 112 Paul Fildes and James McIntosh, ‘A New Apparatus for the Isolation and Cultivation of Anaerobic Micro-Organisms’, Lancet (8 April 1916), 768–770. 113 NA FD1/530 Medical Research Committee, Influenza Research by Dr. Fildes. 114 Paul Fildes, S.L. Baker, and W.R. Thompson, ‘Provisional Notes on the Pathology

of the Present Epidemic’, Lancet (23 November 1918), 695–700. 115 Fildes, Baker, and Thompson, ‘Provisional Notes’, 697. 116 Fildes, Baker, and Thompson, ‘Provisional Notes’, 697. 117 Paul Fildes, ‘James McIntosh 1882–1948’, Journal of Pathology and Bacteriology,

61 (1949), 285–299.

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and ceased to pursue this line of investigation.118 While Fildes was able to suggest other possible candidates, McIntosh failed to find ‘a single type of bacterium … with any constancy.’119 Despite this difference, both men’s approaches to the epidemic reflected the grip that Pfeiffer’s bacillus had on pathologists’ perceptions and practices. When they failed to find the bacillus, the natural conclusion was that the epidemic was not influenza. But if this was not influenza, what was the epidemic and what was its cause? A host of prospective diseases and agents emerged from pathological laboratories and medical minds. Researchers probing the respiratory tracts of the sick were supplied with an abundance of well-known microorganisms, many of which caused disease and could even be epidemic under the right circumstances. Yet no one could agree on the main culprit. A week after the Canadian pathologists’ publication, two pathologists at the Central Royal Air Force Hospital in Hampstead, Oliver Gotch and Harold Whittingham, identified M. catarrhalis as the ‘predominating organism’ in fifty cases, and suggested that it was ‘probably the specific organism’ of the epidemic, acting alone or, more likely, as a mixed infection in conjunction with B. influenzae (which they had isolated from a small number of patients).120 Still other candidates were proposed from the various types of familiar respiratory germs, including meningococci, pneumococci, pneumo-bacilli, streptococci, and staphylococci. A brief consensus emerged shortly after the summer epidemic subsided when reviews of laboratory work in Britain, Germany, France, and the United States noted that one type of respiratory germ, the ‘diplostreptococci’, was almost ‘universally recorded’.121 Yet, no sooner had this agent been identified as a possible candidate than pathologists started to question its status. While some suggested that it was the specific cause of a new epidemic disease, others argued that it was part of a unique compound infection involving various agents, and still others insisted that it was

118 James McIntosh, ‘The Incidence of Bacillis Influenzae (Pfeiffer) in the Present Influenza Epidemic’, Lancet (23 November 1918), 696. 119 McIntosh, ‘The Incidence of Bacillis Influenza’, 696. 120 Oscar H. Gotch and Harold E. Whittingham, ‘A Report on the “Influenza”

Epidemic of 1918’, BMJ (27 July 1918), 82. 121 ‘Influenza, Medical Supplement (1 October 1918), 358.

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nothing more than a secondary infection, with the primary agent still unknown.122 These skirmishes illuminate the challenge pathologists faced when abandoning or challenging a familiar disease category. Those sceptical about whether the epidemic was influenza encountered the daunting prospect of not just characterising the agents and identity of yet another influenza-like disease, but also of forging a consensus about them. Proponents of Pfeiffer’s bacillus did not need to traverse this bacteriological minefield. Accepting that the summer epidemic was influenza, they argued that the problem was to deploy the right techniques in the right manner to isolate the bacillus—an argument that implicitly cast doubt on the technical competence of those opposed to the Pfeiffer school. Many defended the role of Pfeiffer’s bacillus, but in Britain none was more vocal or more assiduous than John Matthews. A member of Wright’s Inoculation Department, Matthews worked on various aspects of vaccine production, including making stock ‘Anti-catarrh’ vaccines from Pfeiffer’s bacillus, which were marketed and sold through the Parke, Davis and Company and supplied to the Army.123 During an epidemic in London in March 1915, he successfully isolated and made what he claimed to be an effective vaccine from it. At the time he insisted that only the rigorous use of established culture technique could produce successful results: ‘nothing short of the employment of an agar plate, rich in fresh blood, gives one any confidence in giving an opinion. This, I imagine, is the experience of every competent bacteriologist.’124 In summer 1918, he wielded this view against those who questioned the causative role of Pfeiffer’s bacillus. He took aim at the Canadian pathologists. Within a week of their report, he accused them of a fundamental error. Their culture medium was ‘devoid of blood’, a remarkable oversight given the known growth requirements of the bacillus, and one that undermined their experiments. While Matthews criticised the Canadians—and other pathologists—for their technical incompetence, he could not level the

122 ‘Influenza’, Medical Supplement (1 October 1918), 358. 123 For the Inoculation Department’s vaccines, see Wei Chen, ‘The Laboratory as Busi-

ness: Sir Almorth Wright’s Vaccine Programme and the Construction of Penicillin’, in Andrew Cunningham and Perry Williams (Eds.), The Laboratory Revolution in Medicine (Cambridge: Cambridge University Press, 1992), 245–292. 124 John Matthews, ‘Influenza or Epidemic Catarrh’, Lancet (3 April 1915), 727.

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same argument against more established peers, like Fildes and McIntosh, who had followed standard procedures. Their experiences raised a different kind of problem, which had to do with the standard of established media and culture techniques. Blood-agar medium was finicky and, as most pathologists knew, getting its composition right was especially important to making the bacillus visible. Variations in media also produced variations in results. Accordingly, Matthews argued that the lack of good quality media was the primary reason pathologists had failed to find the bacillus. Between June and October 1918, he devoted much effort to drawing attention to and resolving these issues. In July, Matthews reported that he had devised a new medium on which pathologists could more accurately and consistently visualise Pfeiffer’s bacillus. Based on a technique developed for making diagnostic blood cultures by his colleagues at the Inoculation Department, S.R. Douglas and Leonard Colebrook, Matthews’ method involved mixing a small portion of blood with the commercially manufactured pancreatic secretion, trypsin, and some broth, before combining it with agar. The process created a product that produced ‘profuse growth’; and moreover, it was highly ‘selective for this organism.’125 Trypsinized blood appeared to inhibit the growth of other organisms in plate culture—a notorious problem in cultivating B. influenzae—that enabled the free growth of the bacillus. The medium gave Matthews exceptional results during the summer epidemic. He recovered the bacillus from a dozen cases at St. Mary’s Hospital, ‘frequently in profuse and practically pure cultures.’ Confident that he had found a solution to the culture problem, he claimed that ‘if this medium be used, Pfeiffer’s bacillus will be found universally associated with the epidemic.’126 He started campaigning to get the medium into the hands of other pathologists and to standardise its manufacture. Matthews’ medium appeared to live up to its billing. When a severe and far more deadly epidemic appeared in troops in August, pathologists who had at first failed to isolate Pfeiffer’s bacillus reported regularly finding it, and many attributed their success to the medium. Fildes and McIntosh were spurred to re-investigate the role of Pfeiffer’s bacillus in influenza.

125 John Matthews, ‘On a Method for Preparing Medium for the Culture of Pfeiffer’s Influenza Bacillus’, Lancet (27 July 1918), 104. 126 Matthews, ‘On a Method for Preparing Medium’, 104.

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Fildes used Matthew’s medium to isolate the bacillus from new cases at Haslar in August and devised his own medium, ‘K’, which employed the peptic digest of sheep’s blood.127 McIntosh reported ‘successful results with a version of Matthews’ trypsinised blood medium.’128 Recanting his earlier doubts, he testified that, ‘the Bacillus influenza belongs to the delicate group of haemophilic bacteria which require special media for their isolation. Up to the present it was generally supposed that ordinary laboratory media to which some blood had been added were sufficient.’129 Matthews had apparently proved this assumption wrong. Using variants of his medium, pathologists who had initially questioned the summer epidemic’s identity became convinced that, provided sufficient care was given to isolation methods, Pfeiffer’s bacillus could be found in every case (Fig. 3). Innovations of media were not new and the support for Matthews’ media did not assuage critics’ doubts about the role of the bacillus in the summer epidemic. The most damning criticism came in the MRC’s Medical Supplement. Its editor, Ludwik Rajchman, a Polish émigré bacteriologist who had come to King’s College in 1910 as an assistant to William Bulloch, worked with Fildes at the London Hospital, and was made head of London’s Central Laboratory on Dysentery in 1914, highlighted the contradictory nature of laboratory evidence. In a lengthy review of bacteriological work, Rajchman concluded that there was ‘sufficient material to shake the orthodox conception out of its high altar.’130 Rajchman argued that the mere presence of B. influenzae did not prove its causal role in influenza. Any one of the abundant organisms found during the epidemic could meet this criterion. Moreover, reports on the morbid anatomy of the summer epidemic failed to directly connect the bacillus to the pathological lesions of the disease—particularly lobar pneumonia and haemorrhages in the respiratory tract. He insisted that, ‘the cold logic of the post-mortem room in the dispassionate home surroundings does not leave any doubt that when present [B. influenzae] did

127 Fildes and McIntosh, ‘The Aetiology of Influenza’, 159–174. 128 McIntosh, ‘The Incidence of Bacillis Influenza’, 696. 129 McIntosh, ‘The Incidence of Bacillis Influenza’, 696. 130 Marta Alexandra Balinska, ‘Ludwik Rajchman: Pioneer of International Health’,

International Health History Newsletter, 1 (1995), 8–9.

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Fig. 3 McIntosh and Fildes’ Influenza Bacillus. Diagrammed section of human bronchus of a fatal case of influenza. Scores of B. influenzae are drawn as minute black dots at the surface of the section. Following standard practice of the ‘Pfeiffer School’, McIntosh and Fildes used histopathological images to demonstrate the association between the bacillus and influenza (Source Plate from James McIntosh, Studies in the Aetiology of Epidemic Influenza, Medical Research Council Special Report Series, no. 63 [London: HMSO, 1922])

not play any more important part [in the epidemic] than the ubiquitous diplostreptococci.’131 Rajchman’s view was representative of a small but influential group of pathologists who claimed that while the summer epidemic was influenza, its cause was not Pfeiffer’s bacillus. Rajchman’s mentor, William Bulloch, known for challenging reductive aetiological models, and Mervyn Gordon, who led the MRC’s wartime investigations into 131 ‘Influenza’, Medical Supplement (1 October 1918), 359.

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cerebro-spinal fever, had taken a similar position during the 1905 influenza epidemic. The difference now was that not only did numerous pathological reports seem to support such a claim, but the stakes in deciding the matter were considerably higher. Powerful as a media arm of the MRC, the Medical Supplement ’s role as a conduit of militarily relevant medical information shaped professional opinions and agendas. Its reviews were regularly summarized in the medical and general press and taken as definitive. With this backing, Rajchman’s report made an impact. The Lancet commented that it could ‘recall no more masterly a review in our language of this or, indeed, any other “war disease” during the last four years … that we should take it as a basis’ for understanding the bacteriology of the epidemic.132 Exploration of alternatives to Pfeiffer’s bacillus was now officially sanctioned. If this bacillus was the culprit, proof of its identity needed to be better established. If some other entity was the agent, then pathologists had better find it fast. Rajchman not only illuminated existing divisions among pathologists, he also raised the key question of what laboratory expertise should form the basis of official pandemic strategies. What might have appeared as little more than intra-professional rivalry in summer 1918 was, by the time of Rajchman’s review in early October 1918, of grave medical and military importance. Divisions among pathologists, and variations in their laboratory practices, had consequences for approaches to the far more catastrophic autumn epidemic. Ideally, wartime medical officials wanted a uniform strategy based on the rapid identification of the disease and its pathogen, followed by the equally rapid production and distribution of an effective prophylaxis. In reality, official strategies in autumn 1918 reflected divisions and uncertainties amongst laboratory and medical experts. Although the summer epidemic was mild and received only passing attention from civilian medical and public health authorities, many military pathologists and officials worried that it would be followed by a more virulent recrudescence.133 Records of the 1889–1894 pandemic 132 ‘Lessons of a Great Epidemic: the pathology of influenza’, Lancet (5 July 1919),

25. 133 NA FD1/535 Influenza Committee: correspondence with Local Government Board and War Office. Richard Reece (War Office) to Fletcher, 3 November 1918; Fletcher to Reece, 6 November 1918; FD5/186 Memorandum on a scheme of inquiry concerning influenza.

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supported this expectation: they showed how two deadly epidemics succeeded a mild one. The MRC put credence in this precedent and became the first government body to draw attention to possible ‘secondary waves of the infection.’134 Assuming that the summer epidemic was influenza, but undecided about its specific cause, Fletcher and his colleagues believed that it was not a matter of whether there would be a recrudescence, but when. No one could predict how quickly it would come or how severe it would be. But planning was imperative.135 On 5 August 1918 Fletcher sent a memorandum to the BMJ and the Lancet calling on pathologists and practitioners to prepare for a second epidemic.136 He asked for the results of any work on influenza’s bacteriology to be sent directly to the Committee. The memorandum was the first part of an evolving plan to coordinate influenza research.137 The MRC wanted to ensure that laboratory and clinical work was well organised and, as far as possible, centrally administered. Changes in influenza’s virulence provided the rationale. For when the MRC issued its memorandum, evidence was already emerging that a second wave had been identified in troops in France and at bases at home. As the summer epidemic abated among civilians in late July, a new form of the disease appeared among troops in late August. The second wave likely gained a foothold in Britain at naval ports in Portsmouth, Southampton, and Liverpool.138 Reports indicated that the early outbreaks were highly virulent and far more deadly than anything seen during the summer. While resembling influenza, what was singularly outstanding, according to observers, was how rapidly it turned into a lethal respiratory condition.139 For thousands of soldiers, a dreadful 134 ‘Bacteriology of the Influenza Pandemic’, BMJ (10 August 1918), 139–140. 135 NA FD1/535 Influenza Committee: correspondence with Local Government Board

and War Office. 136 Medical Research Committee (1918b). ‘Memorandum’, Lancet (5 August 1918), 717; ‘Bacteriology of the Influenza Pandemic’, BMJ (10 August 1918), 139–140. 137 NA FD1/533 MRC—General Scheme of Influenza Investigations, 11 November

1918. 138 For the spread of the epidemic in Britain, see Niall P.A.S. Johnson, ‘Aspects of the Historical Geography of the 1918–19 Influenza Pandemic in Britain’, Ph.D. Thesis, Department of History, University of Cambridge (2001), 325–327; Niall Johnson, Britain and the 1918 Influenza Epidemic, 55–56. 139 Abrahams, Hollows and French, ‘A Further Investigation into InfluenzoPneumococcal and Influenzo-Streptococcal Septicaemia’, 1–11; Thomas S. Horder, ‘Some

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array of secondary infections, rarely seen in previous epidemics, led to severe and often deadly pneumonic complications.140 By November, it had engulfed the nation.141 At Portsmouth, Fildes and his colleagues were struck by the ‘acute alteration’ in the disease’s characteristics. Young naval recruits were the most severely affected. By the end of August, cases among them became ‘more and more numerous and the clinical aspect more and more acute.’142 Fildes later reckoned that Portsmouth was an epicentre from which the epidemic radiated out to the rest of the nation.143 What he and his colleagues observed on their wards and in their morgues foreshadowed what would happen once the disease spread into civilians. Large numbers of young men with acute pneumonia were admitted to hospital, and among these the death rate was very high. Post-mortems showed that rather than dying from what seemed to be a general infection, ‘patients appeared to be drowned’ by a massive accumulation of pus, fluid and blood in their lungs, bronchial tree, and upper respiratory tract. In a typical case, significant parts of the lungs of a ‘well developed muscular young man, aged eighteen’ were ‘airless’ and full of blood and mucous, a condition that induced marked cyanosis. As he slowly suffocated, his fingers and lips turned blue and his complexion a pallid grey.144 This shocking pathological picture soon became the norm. Herbert French, Adolphe Abrahams, Norman F. Nallows, and John W.H. Eyre, consulting pathologists at Aldershot Hospital, who had described cases of purulent bronchitis in 1916, produced the standard descriptions of soldiers dying from the strange heliotrope cyanosis. In the weeks and months that followed, physicians and pathologists describing thousands of similar cases would recognise cyanosis as a sign of imminent death

Observations on the More Severe Cases of Influenza Occurring During the Present Epidemic’, Lancet (28 December 1918), 871–873. 140 Mark Harrison notes that ‘influenza was rife throughout Mesopotamia, and it was the main cause of admissions to hospital among British troops in the last months of the war and after armistice,’ Medical War, 284. 141 William Hamer, Chief Medical Officer of the London County Council estimated the number of deaths between October and December 1918 to be close to sixteen thousand. Hamer, Report on Influenza, 20. 142 Fildes, Baker and Thompson, ‘Provisional Notes’, 698. 143 Fildes, Baker and Thompson, ‘Provisional Notes’, 697. 144 Fildes, Baker and Thompson, ‘Provisional Notes’, 697.

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and the cyanotic patient, suffering acute respiratory damage, became the iconic symbol of the epidemic (Fig. 4).145 The early signs of a new epidemic prompted the MRC to expand its plans for ‘an organized scheme’ of pathological and medical work. In a series of ‘emergency arrangements’ in September, Fletcher asked MRC pathologists at various universities and institutes to put aside their current research to work on influenza.146 He hoped their work would be coordinated with research pathologists in the army and navy, who were also asked to concentrate their efforts.147 While military officials were hesitant to prioritise studies of the epidemic, Fletcher argued that such ‘research was necessary from a service point of view.’148 By early September, the MRC had started working with the War Office and AMS to organise investigations into the primary cause and to determine possible methods of prevention and treatment.149 The second wave forced the DGAMS to act. Through the summer, official military policy had been to ‘carry on’ in the face of the epidemic.150 But with forewarnings from the MRC, the threat of yet another epidemic jeopardising military operations, and new laboratory evidence from military pathologists that the disease appeared to be caused by Pfeiffer’s bacillus, on 6 August 1918 the DGAMS issued orders to return the epidemic as ‘influenza’.151 Soon after, its Advisory Board created a special ‘Influenza Committee’ to oversee the work of its medical and pathological services on the pandemic.152 The Committee included representatives from the Army, Admiralty, War Office, LGB, and MRC. For direction, it relied on Fletcher and Leishman, who had taken up his 145 Abrahams, Hallows and French, ‘A Further Investigation into InfluenzoPneumococcal and Influenzo-Streptococcal Septicaemia’, 1–11. 146 NA FD1/534 MRC Influenza Committee (1918), 72. 147 Medical Research Committee, Annual Report of the Medical Research Committee,

1917–18 (London: HMSO, 1919), 72–73. 148 NA FD1/530 Medical Research Committee, Influenza Research by Dr. Fildes. Fletcher to Sir W… 12 November (1918). 149 Medical Research Committee, Annual Report of the Medical Research Committee, 1917–18, 73. 150 The phrase was attributed to Newsholme, but it reflected official opinion. Arthur S. Newsholme, ‘Epidemic Catarrhs and Influenza’, Lancet (2 November 1918), 599–603. 151 French, ‘Influenza’, 176. 152 NA FD1/535 Influenza Committee.

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Fig. 4 Heliotrope Cyanosis. ‘It is impossible for a heliotrope cyanosis patient to recover’ (Source A. Abrahams, N. Hallows, and H. French, ‘A further investigation into influenzo-pneumococcal and influenzo-streptococcal septicaemia: Epidemic influenzal “pneumonia” of highly fatal type and its relation to “purulent bronchitis”’, Lancet [4 January 1919], 1–11 [Illustrator: W. Thornton Shiells; Originally published as a grayscale])

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new post as Advisor on Pathology to the War Office. From August to early October, the Committee mapped out a rudimentary response plan. The plan involved two interrelated strategies. The first concentrated on the development of a vaccine; the second on improving bacteriological methods for vaccine manufacture. Influenza’s bacteriology posed a host of practical problems for vaccine production. With the primary cause still unknown, the micro-organisms to make up a vaccine had to be selected, typed, and cultivated. While Leishman and Fletcher were under no illusion about the challenge of manufacturing an effective vaccine, they also understood its importance for consolidating the role of pathology in controlling the pandemic. A successful vaccine was a way to resolve influenza’s aetiology. If it prevented cases, then this could be taken as evidence of the causative role of the agent(s) used. Much was at stake in attempting to produce an effective vaccine.

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Mixed Vaccines

Influenza vaccines had been developed in the decades before the war but remained unproven.153 Most were either so-called anti-catarrhal vaccines produced using different microorganisms associated with catarrhal infections or streptococcus and pneumococcus vaccines targeted at secondary infections. Because of its identified role in the disease, Pfeiffer’s bacillus was regularly included in these mixtures. Various anti-catarrhal vaccines were bought and marketed by pharmaceutical companies. Parke, Davis and Company’s ‘Anti-Catarrhal Vaccine’, made at Wright’s Inoculation Department using Matthews’ medium, was advertised as a preventive and a remedy for colds, catarrhs, and influenza.154 Laboratories typically produced two kinds of vaccine: one prophylactic, to prevent infection or reduce complications from it; and the other therapeutic, administered after infection as a form of treatment aimed at boosting the patient’s immunity by inducing the production of immune substances called ‘opsonins’. This widely-followed two-pronged approach was Wright’s 153 For USA, see John Eyler, ‘The Fog of Research: Influenza Vaccine Trials During the 1918–19 Pandemic’, Journal of the History of Medicine and Allied Sciences, 64 (2009), 401–428; John Eyler, ‘The State of Science, Microbiology, and Vaccines Circa 1918’, Public Health Reports, Suppl. 3., 125 (2010), 27–36. 154 John Matthews, ‘Influenza and Preventive Inoculation’, Lancet (2 November 1918),

602.

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creation; he had characterised opsonins and developed an opsonin index in 1902 and established this to produce therapeutic and prophylactic vaccines.155 On this model, the efficacy of a vaccine was judged in terms of either curative or preventive qualities. The therapeutic use of catarrhal vaccines had gained popularity in civilian practice. While some were reportedly highly effective, in the decade before the war there was little to suggest that they much reduced the incidence of influenza. Some evidence indicated that these, as well as pneumococcus vaccines, prevented respiratory complications, and some practitioners reported good results when vaccines were used as treatments.156 But nothing approaching a systematic evaluation of the kind applied to typhoid vaccines had been carried out earlier in the decade.157 During the summer epidemic, military pathologists tested the efficacy of ‘mixed’ catarrhal vaccines. Targeting secondary complications, their composition varied considerably. J.W.H. Eyre, who had helped characterise ‘purulent bronchitis’ at Aldershot in 1917, worked with the pathologists at the New Zealand Expeditionary Force’s (NZEF) General Hospital at Walton-on-Thames on the first large-scale investigation of a prophylactic ‘mixed catarrhal vaccine’ (M.C.V.).158 Developed at Eyre’s Bacteriology Department at Guy’s Hospital, the vaccine was made from seven different heat-treated organisms isolated from soldiers and prepared for use in two dosage strengths, delivered ten days apart. Between March and August 1918, Eyre and his NZEF colleagues inoculated 16,104 new recruits and used another 5,700 as uninoculated controls. Comparing the average of all respiratory complications among the inoculated and uninoculated, the study showed that M.C.V. reduced complications.159 Promising as this was, it did not prevent infection. Some pathologists argued that while targeting secondary complications was necessary, the primary goal should be prophylaxis. ‘[I]f the influenza can be prevented,’

155 Chen, ‘The Laboratory as Business’; Worboys, ‘Almroth Wright at Netley’. 156 John W.H. Eyre and C.E. Lowe, ‘Prophylactic Vaccinations against Catarrhal Affec-

tions of the Respiratory Tract’, Lancet (12 October 1918), 484–487; W.H. Wynn, ‘The Use of Vaccines in Acute Influenza’, Lancet (28 December 1918), 874–876. 157 John Eyler, has examined this problem in American efforts to manufacture influenza vaccines. Eyler, ‘The Fog of Research’, 401–428. 158 Eyre and Lowe, ‘Prophylactic Vaccinations against Catarrhal Affections, 484–487. 159 Eyre and Lowe, ‘Prophylactic Vaccinations against Catarrhal Affections, 487.

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argued Fildes, ‘complications will not arise.’160 This goal raised the contentious problem of what organism or organisms should form the basis of a specific vaccine. So-called ‘Pfeiffer’ vaccines, made from pure cultures of B. influenzae, had been tested in the United States and proven to be prophylactics.161 While variation in the composition of anti-catarrhal vaccines was acceptable, introducing such variation into the composition of influenza vaccines relegated Pfeiffer’s bacillus to the status of a secondary invader, which its proponents were loath to do.162 Despite their uneven record, using vaccines to combat the autumn epidemic appealed to medical officials as the most efficient approach.163 There were few other options since, as the Royal College of Physicians declared, ‘[n]o drugs have yet been proved to have any specific influence as a preventive of influenza.’164 Standard public health measures of isolation, disinfection and notification were of little effect, although some local authorities introduced one or a combination of them.165 A vaccine could potentially reduce the incidence of the disease, mitigate more severe complications, and also alleviate some of the burden on medical services. It could also be used therapeutically on the worst cases. Since maintaining manpower was the most crucial concern for military planners as they lurched towards victory in autumn 1918, a vaccine that kept or got soldiers out of hospital had obvious attractions over the provision of precious resources for convalescence and nursing. This logic also appealed to the LGB and other civilian medical authorities, whose ranks and thus capacity to respond to a pandemic had been seriously diminished by military demands.166 On 14 October 1918, Leishman organised a conference at the War Office to decide on an official approach to ‘preventive vaccination’. A group of London pathologists closely allied to the War Office and

160 Fildes, Baker, and Thompson, ‘Provisional Notes’, 700. 161 Eyler, ‘The Fog of Research’, 404. 162 Fildes, Baker, and Thompson, ‘Provisional Notes’, 700. 163 Medical Research Committee, Studies of Influenza in Hospitals of the British Armies

in France, 1918 (London: HMSO, 1919). 164 ‘Memorandum by the Royal College of Physicians’, BMJ (16 November 1918),

546. 165 Johnson, Britain and the 1918–19 Influenza Pandemic, 98–140. 166 Eyler, Sir Arthur Newsholme and State Medicine, 272–273.

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MRC were entrusted with its elaboration. Along with Eyre, whose mixed catarrhal vaccine was being distributed throughout the AMS, Leishman invited fellow MRC member, and now Barts Professor of Pathology, F.W. Andrewes, who had worked with E.E. Klein in first isolating Pfeiffer’s bacillus in 1892, and S.R. Douglas, who had been developing methods for typing ‘races’ of bacteria, which was essential to vaccine development. They were joined by two military officials who would be responsible for vaccine production: Lieutenant-Colonel D. Harvey, officer in charge of the RAMC’s Vaccine Department, and the Deputy-Surgeon General, P.W. Bassett-Smith, who oversaw the vaccine department at the Royal Naval College. The committee aimed to establish a vaccine formula to be used throughout the military services, with the hope that it would control the ‘incidence and severity of the epidemic.’167 Vaccines developed with the known causative agents of a disease were regarded as most promising. Yet when the committee reviewed the bacteriology of the summer and early autumn epidemics, they ‘agreed that there was considerable doubt as to the primary etiological significance of the Bacillus Influenzae.’168 Rather than risk developing a ‘Pfeiffer’ vaccine, they advocated a ‘mixed’ vaccine. Determining the composition involved selecting which organisms to include and in what quantities. Both decisions would be controversial. Concentrating on those agents known to play the most significant role in influenza’s complications, they decided that B. influenzae should form its basis, with two other organisms—streptococcus and pneumococcus— selected because of their role in grave secondary infections.169 The host of other organisms isolated from the epidemic were excluded. Two weeks after the conference, the War Office published its recommendations for the manufacture and administration of the vaccine in the Lancet. Different strains of each organism were to be used; each had to be isolated from cases during the epidemic and submitted to strict tests for their ‘race and type.’170 The committee made no recommendations for the best methods of cultivating the organisms but did define the ‘relative proportions’ of the different organisms and the dosage size. The

167 ‘The utilisation of vaccine for the prevention and treatment of influenza,’ Lancet (26 October 1918), 565. 168 ‘Utilisation of vaccine’, 565. 169 ‘Utilisation of vaccine’, 565. 170 ‘Utilisation of vaccine’, 565.

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vaccine would be administered in two doses, spread ten days apart, with the second dose doubling the dosage of the first. Since its primary role was preventive, inoculations were to be given before exposure to infection. But because it also targeted secondary infections, the committee saw no reason to withhold its use on influenza cases. Finally, following the approach established for testing antityphoid vaccine, the War Office asked that steps be taken to secure exact statistical records on reactions and the incidence and complications of the disease following inoculations in all clinical settings.171 Large-scale manufacture for the Army and Navy was centralised at the vaccine departments of the RAMC and RNC, where production began soon after the War Office conference. The organisms used were first screened, typed, and selected by Douglas, who was assisted by the MRC in preparing the vaccine and classifying the types of B. influenzae isolated at different centres.172 Other laboratories were left to produce and test the vaccine voluntarily, and no coordinated effort was made to mass-produce the vaccine for civilians. The War Office formula embodied the limitations of existing pathological knowledge of influenza. Many experts and observers noted that it was little more than a mixed ‘Pfeiffer’ vaccine of the kind manufactured before the war.173 Those with experience in making such vaccines questioned the composition, dosages, and practicalities of mass production. Many wondered why important pathogens, such as M. catarrhalis, were excluded and criticised the quantity of organisms in the vaccine itself. Compared to other mixed vaccines, the dosages of the formula were significantly smaller. Whereas a ‘mixed catarrhal vaccine’ made at St. Mary’s contained 300 million influenza bacilli, the War Office formula recommended only 30 and 60 million influenza bacilli.174 W.H. Wynn, an expert on prophylactic and therapeutic vaccines at Birmingham General Hospital, argued that the dosage recommendations were ‘inadequate and

171 ‘Utilisation of vaccine’, 565. 172 Medical Research Committee, Annual Report of the Medical Research Committee,

1918–19, 72. 173 Thomas S. Horder, ‘Influenza and Preventive Inoculation’, Lancet (9 November 1918), 642. 174 Matthews, ‘Influenza and Preventive Inoculation’, 602.

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likely to imperil the value of the vaccine.’175 Successful vaccines, including those for typhoid and pneumonia, contained huge numbers of organisms (a minimum of 1,000 million) because, claimed Wynn, their makers understood that ‘the period of immunity [was] probably proportionate to the size of dose used.’176 The War Office’s dosage cast doubt on the committee’s expertise. Setting the tone of criticism, John Matthews argued that in the absence of experimental work on influenza vaccines, the question of dosages—and any other aspect of its manufacture—could not be ‘a question of pure science’ but was rather ‘a question of practice’ and reliable expertise.177 He challenged the recommendations of a committee that did not include any practitioners and relied on the ‘experience of … a minority’ of pathologists. Not surprisingly, he believed that the limitations of this approach were most glaring with respect to B. influenzae By not outlining a suitable culture method the committee had demonstrated its ignorance of established techniques, and in particular the relevance of his own medium. Older culture methods could not be relied upon to make the quantity and quality of bacillus needed for mass vaccination. ‘[I]t is almost inconceivable,’ he argued, ‘that under old conditions a vaccine … could have been provided in a reasonable time for large bodies of troops. This aspect has been entirely changed by my method.’178 Matthews insisted that his method was indispensable. It had already been used for two years at St. Mary’s for mixed catarrhal vaccines, which were being supplied to military authorities.179 While Matthews wanted a wider representation of expert opinion in formulating the vaccine, others challenged the assumptions on which the formula was based. In a scathing analysis, the eminent Barts physician, Thomas Horder, argued that the committee had failed to acknowledge two fundamental problems. First, they had ignored the constraints posed by the lack of knowledge and consensus on the aetiological agent. ‘Bricks cannot be made without straw,’ he argued, ‘and dogmatic advice on the

175 W.H. Wynn, ‘The Use of Vaccines in Acute Influenza’, Lancet (28 December 1918), 874. 176 Wynn, ‘Influenza and Preventive Inoculation’, 643. 177 Matthews, ‘Influenza and Preventive Inoculation’, 602. 178 Matthews, ‘Influenza and Preventive Inoculation’, 602. 179 Matthews, ‘Influenza and Preventive Inoculation’, 602.

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prevention and cure of a disease cannot be given in the absence of accurate data on its causation.’180 The committee had dismissed the primary role of B. influenzae and then based a vaccine upon it. The claim that such a vaccine could control influenza was without foundation. Second, even if the formula was workable, Horder argued that the committee had failed to acknowledge the time it would take to produce. While every committee member knew that typing strains was a ‘highly expert and lengthy technique’, they had proceeded ‘as though all this work … had already been done!’ By skirting over the contentious matter of how best to cultivate Pfeiffer’s bacillus, they also had failed to confront a crucial obstacle to vaccine production. These oversights suggested to Horder that the War Office had ‘very little faith in its nostrum, at least as a preventive for the present epidemic.’181 Not about to abandon its plans, the War Office addressed some criticisms, but ignored others. With the help of the MRC, it acted quickly to establish the best culture methods for the selection and mass production of B. influenzae.182 Matthews’ medium was recognised as a prime candidate, but so too was a German formulation developed by Walter Levinthal, which Fildes and other pathologists had successfully employed. In early November the MRC asked pathologists to compare the two methods. Most found that Levinthal’s medium produced better growth, with Matthews’ medium better suited for isolation and strain selection.183 While the War Office incorporated advice on the medium it resisted changing its vaccine formula and made the vaccine as originally planned. Between November 1918 and July 1919, the Royal Army Vaccine Department alone made 1,806,325 doses, while the Royal Navy Vaccine Department produced 144,000, enough to inoculate the Grand Fleet.184 Mass inoculations in the Army began on 1 November 1918,

180 Horder, ‘Influenza and Preventive Inoculation’, 642. 181 Horder, ‘Influenza and Preventive Inoculation’, 642. 182 NA FD1/533 MRC, Influenza General research in UK, 1918 ‘Circular sent to

District Laboratories,’ 1 November 1918. 183 See Fletcher’s correspondence with pathologists, NA FD1/534 Medical Research Committee. 184 Leishman, ‘Organization’ 30; ‘The vaccines and serums supplied to the Royal Navy’, Lancet (25 January 1919), 545. One dose = 1c.cc.

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along with voluntary trials at numerous bases in England and France.185 Leishman hoped the War Office formula would be adopted across the armed forces. To an extent, he got his wish. The leading manufacturers of medical therapies for Canadian and Australian forces—Connaught Laboratories in Toronto and the Commonwealth Serum Laboratories in Melbourne—began mass producing the War Office vaccine almost immediately on release of the formula.186 American forces were also supplied with a vaccine based on a similar formula. However, reception of the vaccine outside military circles was more mixed. Pathologists who remained unconvinced by the formula continued to work independently.187 Numerous unofficial preventive vaccines were made and issued. Most commonly, these included organisms excluded from the official vaccine; the proportions of organisms were altered; and, most tellingly, the dosage sizes were usually significantly increased. A number of pathologists, including Wynn, also employed aggressive therapeutic vaccines for cases with acute or chronic respiratory complications.188 Not only were these different vaccines a challenge to the official formula but their circulation made it difficult for the War Office to assess accurately its own vaccine. Trials of the official vaccine lacked the systematic organisation that had been developed for typhus vaccine years earlier. As with other forms of vaccination, influenza inoculation was voluntary, which limited the number of available experimental subjects. The War Office relied on the judgements of physicians and pathologists to determine the effectiveness of the vaccine. The MRC helped the Advisor in Pathology to the DGAMS in France, S.L. Cummins, coordinate trials at Boulogne in November 185 William B. Leishman, ‘The Results of Protective Inoculation Against Influenza in

the Army at Home, 1918–1919’, Lancet (24 January 1920), 214–215. 186 J.J. Heagerty, ‘Influenza and Vaccination’, Canadian Medical Association Journal, 9 (1919), 226–28; Patrick George Hodgson, ‘Flu, Society and the State: The political, social and economic implications of the 1918–1920 influenza pandemic in Queensland’, PhD Thesis, James Cook University (2017), 67–69. The official history of Commonwealth Serum Laboratories claims that the company produced 3 millions doses of the vaccine: ‘A History of CSL’ at www.toxinology.com/fusebox.cfm?staticaction=generic_static_files/ avp-csl-01.html (accessed on 20 April 2018). 187 For different vaccine preparations, see Harold E. Whittingham and C. Sims, ‘Some Observations on the Bacteriology and Pathology of Influenza’, Lancet (28 December 1918), 865–871; ‘Prophylatic Inoculation in Influenza’, Lancet (5 April 1919), 572–573. 188 Wynn, ‘The Use of Vaccines in Acute Influenza’, 874–876.

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and December 1918, in which over two thousand soldiers were inoculated.189 The most thorough evaluation came from inoculation records supplied to Leishman from camps in the home commands, where over eleven thousand soldiers had received one or two doses in November 1918, and another five thousand had been inoculated between December 1918 and April 1919.190 While Leishman admitted that these results were not conclusive or even free from ‘large fallacies’, he believed that they demonstrated an ‘encouraging’ general trend. Inoculation appeared to provide a moderate degree of protection against infection and had ‘decidedly beneficial effects’ in reducing the frequency and severity of complications. Among the inoculated, Leishman reported an infection rate of 14.1 per 1000; among the uninoculated the rate was 47.3 per 1000. Rates of pneumonia in inoculated soldiers were 1.6 per 1000, in contrast to 13.13 per 1000 among the uninoculated, while deaths were 0.12 per 1000 among the former and 2.25 per 1000 among the latter.191 For Leishman, the results vindicated the vaccine: ‘they confirm and even strengthen our original anticipations.’192 Leishman’s assessment appeased only those who trusted the vaccine. For others, it was built on false premises. There were questions about the identity of the disease against which it was to protect; the primary agent against which the vaccine was targeted was still unknown; and, once vaccination proceeded, many doubted that it was possible to collect accurate statistical evidence of its effectiveness. Pathological investigations during the second wave illuminated the first two problems. Describing a stunningly complex disease entity, investigators struggled to produce consistent pictures of the processes of infection they encountered post-mortem and were divided over which organisms contributed to which pathological changes in victims’ bodies.193 Herbert French, who produced some of the most detailed reports on the clinical pathology, 189 NA FD1/529 MRC, Influenza Research by Colonel Cummins with British Forces in France, ‘Prophylactic Anti-influenza Vaccination’, 21 December 1918. 190 Leishman, ‘The Results of Protective Inoculation Against Influenza’, 214–215. 191 These figures were reported in G. Dansey-Browning, ‘A Study of the Prevention of

influenza’, JRAMC, 57 (1 September 1931), 188. Dansey-Browning the reported total number of “non-inoculated” observed as 43,520 and the number of inoculated observed as 15,624. 192 Leishman, ‘The Results of Protective Inoculation Against Influenza’, 215. 193 Adami, ‘Influenza’, 413–466.

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argued that a primary infection, which he believed was B. influenza, setup the most severe complications.194 This view gained renewed support in autumn 1918, as pathologists began to find the bacillus with increasing frequency. Fildes and McIntosh defended its primary role and emerged as staunch proponents of the ‘Pfeiffer School.’ The decisive evidence for them was the remarkable increase in the incidence of the bacillus. They attributed this change to improvements in culture media and methods, and not to an epidemiological factor. They claimed that the bacillus had been present throughout the summer and autumn but had eluded bacteriologists who lacked adequate techniques or expertise to make it visible. ‘[T]he epidemic can be divided into two stages,’ argued McIntosh, ‘a first in which B. influenzae was seldom demonstrated, and a second, in which this bacillus was demonstrated with great regularity. This fact is not attributable to any alteration in the epidemic itself, but to the application of new methods for the demonstration of the bacillus of influenza.’195 For Fildes and McIntosh, the innovation of selective media, which improved the cultivation of B. influenzae and controlled the overgrowth of cultures by other microorganisms, put bacteriologists in a position to establish its primary role. The technique enabled researchers to do three things necessary to meet Koch’s postulates. First, they could regularly identify the bacillus from large numbers of cases; second, they could identify or isolate it in broncho-pneumonia lesions clinically associated with the disease; and finally, they could use pure cultures for inoculation of animals and humans. Fildes and McIntosh declared: We have a characteristic living organism which is present in the lesions of influenza and has a pathogenic action for man. Pure cultures of this bacillus are capable of producing in animals a condition which has important points in common with influenza in man, and it is only the indefinite nature of the essential lesions of influenza which causes hesitation in accepting the experimental disease in animals as the same as the natural disease in man. If this relationship is accepted, then the criteria by which a bacterium should be judged the cause of a disease are fulfilled.196

194 Herbert French, ‘The Clinical Features of the Influenza Epidemic of 1918–1919’, in Report on the Pandemic of Influenza, 1918–1919, 66–78. 195 McIntosh, ‘Studies in the Aetiology of Epidemic Influenza’, 33. 196 Fildes and McIntosh, ‘The Aetiology of Influenza’, 172.

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The evidence generated with selective media was, according to Fildes and McIntosh, enough to counter the ‘great revolt against the view... that B. influenzae... was the cause of the disease.’197 Many refused to accept the causal relationship and criteria they proposed. H.B. Maitland and Gordon Cameron, two British pathologists at the University of Toronto who closely scrutinised such claims, argued that the body of evidence from experiments on Pfeiffer’s bacillus did not support Fildes’ and McIntosh’s conclusions. They noted that rather than demonstrate a causal relationship, inoculation experiments with B. influenzae had generally failed to produce a characteristic lesion in laboratory animals; and while the bacillus was frequently associated with lesions found in post-mortem studies of humans, the failure of animal experiments favoured ‘the opinion that B. influenzae is a secondary invader.’198 Critics of the War Office vaccine made much of these discrepancies. They noted that the problems surrounding prevention during the pandemic had changed little since influenza’s bacteriology first started to be explored in the 1890s. In a review on the prospects of prevention in January 1919, W. D’este Emery felt no need to change the views he had expressed twelve years earlier. Evidence from the pandemic had only confirmed that pathologists ‘do not know the cause of influenza. It is hardly necessary to point out,’ he noted, ‘that if the influenza bacillus is not the cause of the disease, we can scarcely hope to get good. results from the use of a vaccine made from this organism as a prophylactic measure.’199 Emery’s observations set the tone for debates among bacteriologists over the prospects of an effective influenza vaccine. The primary issue remained the status of the aetiological agent. Supporters of Pfeiffer’s bacillus hoped that an effective vaccine would indirectly secure its specific role in influenza. But the War Office decision to produce a mixed vaccine rather than a Pfeiffer vaccine only added to the doubts about its aetiological status. When Leishman and his colleagues formulated the vaccine they were aware of the mounting evidence against B. influenzae, and understood that the mixed vaccine was an unsatisfactory solution. But 197 Fildes and McIntosh, ‘The Aetiology of Influenza’, 119. 198 H.B. Maitland and Gordon Cameron, ‘The Aetiology of Epidemic Influenza: A

Critical Review’, Canadian Medical Association Journal, 6 (1920), 492. 199 W. D’este Emery, ‘Influenza and the Use of Vaccines’, Practitioner, LXXXIV (Ferbuary 1919), 73.

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they had few options. One was to organize research into other possible causative agents.200 At the time, Fletcher argued that, ‘on the hypothesis that B. influenzae, no less than pneumococci and streptococci, are secondary [infections],’ new research was needed on ‘some as yet undiscovered virus.’201 As we shall see, in November 1918 he set in train the first investigations into the possible role of a so-called filter-passing agent. But this was a long-term solution to an immediate problem. In the short term, a key issue concerned the evidence available to support using the official vaccine. As part of his efforts to rehabilitate the antityphoid vaccine, Leishman had made control trials and systematically collected clinical information necessary to the evaluation process.202 But implementing similar procedures to test influenza vaccine proved challenging. Leishman noted that, while ‘clear statistical evidence... should have been easy to collect through the workings of official machinery,’ the strains of the epidemic on medical personnel, combined with demobilisation, made it very difficult to organize field trials and to accurately collect and record results.203 In the data he did receive, nearly half of those inoculated had been given only one of two proposed doses, and there was limited information on the interval between inoculation and subsequent immunity or attacks of the disease. Medical statisticians who had scrutinized the antityphoid vaccine studies and had used them to develop new criteria for designing valid vaccine trials, were hardly impressed.204 The statistician and epidemiologist, Major Greenwood, who was a leading advocate of biometrical approaches in medicine, challenged Leishman’s claims. In his 1920 Report on the Pandemic of Influenza for the newly established Ministry of Health, Greenwood noted that the War Office trials were organised under extreme conditions, which ‘combined to diminish any hopes of a dramatic success in the use of anti-influenza vaccines such as [had] crowned the anti-typhoid campaign.’205 Lessons

200 NA FD1/530 Walter Fletcher to Paul Fildes, 22, 28 October 1918; NA FD1/533 MRC Influenza General Research, 1918, 1 November 1918. 201 NA FD1/533, Walter Fletcher to Paul Fildes, 28 October 1918, 171. 202 Hardy Anne Hardy, ‘“Straight Back to Barbarism”’, 278–279. 203 Leishman, ‘Results of Protective Inoculation’, 367. 204 For these criteria, see Eyler, ‘Fog of Research’, 24–26. 205 Major Greenwood, ‘The Prophylaxsis of Influenza’, in Report on the Pandemic of Influenza, 1918–1919, 175.

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about effective trial design were not applied in the War Office trials: vaccinated and control groups were not matched; and since the vaccine was administered during the epidemic, the exposure periods of the vaccinated and unvaccinated groups were not identical. But the greatest shortcoming was the poverty of organised clinical records: ‘the returns were so incomplete,’ noted Greenwood, ‘evidence of true comparability in the few instances in which a large measure of protection seemed to have been conferred upon the inoculated, so slight and untrustworthy, that we are unable to say that the arguments in favour of prophylactic inoculation as a general measure have been at all strengthened by our experience of the 1918–19 pandemic.’206 Questions about the composition of the War Office vaccine and results from field trials took on new meaning as official priorities slowly shifted from military to civilian needs after the end of the war. Despite doubts about the efficacy of the vaccine, the LGB wanted it made available to civilian medical services. As early as October 1918, Newsholme discussed with Fletcher how to provide ‘a large supply of vaccine’ for the general population.207 At the time, however, the LGB’s own laboratory lacked manpower and facilities for large-scale production, and the War Office’s efforts were devoted to the troops. Small amounts were commercially manufactured by Burroughs Wellcome Company and for Parke, Davis and Company at St. Mary’s, but could not meet the LGB’s objective of supplying vaccines to practitioners on demand.208 Through autumn 1918, an emergency ‘Influenza Committee’, setup by the MRC, explored ways to shift military vaccine production to meet civilian needs once demobilisation started. Fletcher was especially keen to facilitate this transfer and worked to expedite the release of skilled pathologists.209 By the end of December, with assistance from the War Office, the LGB was able to distribute ‘considerable amounts of prophylactic vaccine’ and the MRC coordinated the first official trials in the civilian population.210 The 206 Greenwood, ‘The Prophylaxsis of Influenza’, 175–176. 207 NA FD1/535 Walter Fletcher to Arthur Newsholme, 23 October 1918. 208 NA/FD1/535 Walter Fletcher to Arthur Newsholme, 23 October 1918; Parke

Davis & Co., ‘Influenza Prophylaxis Vaccines’, Lancet (4 October 1919), 616. 209 NA FD1/530, MRC, Walter Fletcher to Paul Fildes, 22 October 1918;, NA FD1/ 535 Walter Fletcher to George Buchanan, 4 March 1919;, NA FD1/537 Schools Reports on Cases and Treatment of Influenza, 1919. 210 NA FD1/535 Arthur Newsholme to Walter Fletcher, 3 January 1919.

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transfer of the vaccine from military to civilian application was not without challenges. The LGB’s Medical Department demanded that the proportions of B. influenzae in the official formula be increased, in line with suggestions made by critics. The War Office finally relented, and in April 1919 a vaccine, with significantly more B. influenzae was prepared for the LGB by the RAMC and supplied to all practitioners, free-of-charge, by the Government Lymph Establishment in London.211 But it was too late: the pandemic had almost subsided.

6

Reckoning and Reconstruction

The transfer of the War Office vaccine into civilian medicine underscored the crucial role of military pathology in shaping general strategies against the pandemic. Unlike the epidemics of the early 1890s, against which British medicine and public health had to construct new approaches grounded in bacteriological ideas and practices, in 1918 authorities were able to mobilise an integrated system of military medicine, with laboratory pathology at its core. For the first time, large numbers of trained pathologists were able to investigate influenza’s aetiology and pathogenesis, and to test methods, criteria, and established concepts of the disease and its control. Their studies were crucial to framing the summer epidemic and shaping strategies against the deadly autumn wave. Yet, the military logic of the medical system that had worked effectively for much of the war faced significant challenges when encountering the pandemic. While the strategy of identifying the pandemic agent or agents and then producing a vaccine might have been generally accepted, official guidelines for doing so were not. Laboratory pathology, which the War Office, MRC, and RAMC vested with considerable authority in guiding official strategies, was a source of conflicting evidence and claims rather than scientific consensus. This magnified rather than resolved fundamental problems in existing knowledge and approaches. Difficulties in identifying and agreeing on the specific cause vexed the War Office’s efforts to produce a general vaccine, and its value as a preventative instrument

211 ‘The Prevention of Influenza’, Lancet (3 January 1920), 41; ‘Preparations for an Influenza Epidemic’, Lancet (31 January 1920), 271.

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would remain in question. Some critics took these conflicts as indication of the failure of laboratory pathology and its reductive approaches to disease aetiology and called for reappraisals of prevention strategies.212 Historians have arrived at similar conclusions, arguing that scientific medicine proved defenceless against the pandemic and that its presumed power was fundamentally challenged.213 Yet this is too simplistic a judgement. It is important to recall the exigencies under which pandemic plans were elaborated in Britain and elsewhere in autumn 1918: the summer epidemic was novel and unclear in epidemiological terms, and bacteriological evidence seemed to confirm this. Officials had only weeks to organize their responses to the deadly second wave, and their plans had to navigate wartime priorities and increasingly contested knowledge and methods. Despite these challenges, the War Office and the MRC were widely lauded for their efforts. Mobilisation against the pandemic tested the authority of laboratory pathology, but it did not undermine it. For those promoting its advancement, the pandemic represented new opportunities. This was certainly the case with vaccines. Rather than deter researchers and manufacturers, questions and doubts about their effectiveness spurred efforts to develop better products. The leading maker of commercial vaccines, Wright’s laboratory at St. Mary’s, expanded its work on combined ‘anti-influenza’ vaccines, with particular emphasis on improving methods for growing and purifying B. influenzae. Demand for better vaccines had grown as result of the pandemic and, recognising their increased commercial value, the laboratory’s commercial partner, Parke, Davis and Company was keen to bring new products to an expanding market (Fig. 5).214 For those involved in post-war reconstruction, the pandemic afforded different opportunities. Fletcher argued that the rapid organisation of coordinated strategies in 1918–1919 was testimony to the merits of laboratory-based military pathology. He attributed the challenges in

212 For example, William Hamer, ‘The Relationship Between Influenza, Cerebrospinal Fever, and Poliomyelitis’, Appendix to the Report of the County Medical Officer of Health and School Medical Officer for the Year 1918 (London: County Hall, 1919); William Hamer, ‘The Influenzal Constitution’, Proceedings of the Royal Society of Medicine, 20 (1927), 1349–1368. 213 See, for example, Johnson, The Overshadowed Killer: Influenza in Britain in 1918– 19,152–154; Tognotti, ‘Scientific Triumphalism and Learning from Facts’, 97–110. 214 Chen, ‘The Laboratory as Business’, 253–259.

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Fig. 5 Anti-catarrh vaccine, prepared by Almorth Wright’s Inoculation Department and marketed and distributed by Parke, Davis and Company. The advertisement refers readers to the Department’s Mixed Anti-Influenza Vaccine, which had been in production since 1915 (Source: Journal of Laryngology and Otology, 37.9 [1922], vi)

managing the pandemic to the general lack of resources for basic pathological research during wartime. While war conditions may have contributed to the severity of the pandemic, British mortality, in both the services and amongst civilians, was still lower than in other countries.215 With better funds and institutional supports, Fletcher argued that the organisational successes of military pathology could be improved and translated into more effective approaches in peacetime. He began pursuing this agenda almost immediately after the pandemic and was able to generate agreement in government that modernising medicine and science, with pathology as a focal point, could best solve the problems 215 Johnson and Mueller, ‘Updating the Accounts’, 113.

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encountered in controlling influenza and other modern maladies. Historians have shown how the MRC built credibility for its aims and authority during the war.216 The pandemic was also enrolled in this mission and would be used to justify the modernisation of medical science in interwar Britain. The system of military pathology that had been mobilised against the pandemic became a key resource for reconstructing scientific medicine in peacetime. Forged in the time of total war, and challenged by a devastating pandemic, laboratory pathology would emerge as a model for modern medical scientific organisation.

216 Sturdy, ‘War as Experiment’, 82–83.

CHAPTER 5

Mobilising Flu: The Medical Research Council and the Genesis of British Virus Research

On 3 May 1922, Walter Morley Fletcher organised a secret meeting of leading British pathologists to outline a new scheme of research on ‘diseases probably caused by filter-passing organisms.’1 Having used the war to apply laboratory science to military medicine, in peacetime the MRC was seeking new challenges and the still relatively unknown filter-passing viruses offered just such opportunities for improving medical science and the health of the nation. An immediate reason for the MRC’s interest was the recent pandemic. In his Annual Report for 1921–1922, Fletcher stressed that investigations into the purported connection between a ‘filter-passer’ and influenza were a key motivation for the new scheme: There could hardly be a set of problems whose solution has more potential importance for the community than this. Influenza kills regularly, though its slaughter is chiefly effected during epidemics. In a few months in 1918– 1919 it killed more persons in India than died from the plague there during the previous twenty years….2

1 NA FD1/1279 Research into Diseases Probably Caused by Filterable Viruses, 3 May 1922 (Hereafter, ‘Virus research’). 2 Medical Research Council, Report of the Medical Research Council for the Year 1921– 1922 Report of the Medical Research Council (London: HMSO, 1923), 12.

© The Editor(s) (if applicable) and The Author(s), under exclusive licence to Springer Nature Limited 2023 M. Bresalier, Modern Flu, Medicine and Biomedical Sciences in Modern History, https://doi.org/10.1057/978-1-137-33954-6_5

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The pandemic had ignited interest in the possible role of a filterable virus and the general nature of such agents, yet the way forward was unclear. As Fletcher observed: ‘The chief problem which the investigator of [filterable viruses] meets is the difficulty of proceeding by sound experimental methods.’3 The suspected influenza virus was one of a group of pathogens that could not be seen or studied by standard cultivation or light microscopy techniques, and only could be investigated indirectly through pathological changes in experimental animals and through serological tests. The MRC’s scheme was to build on these methods to transform viruses into workable laboratory objects and to develop new methods for their control. In the decade after 1918, the pandemic and virus research became inextricably linked in MRC plans to reconstruct medical science in Britain. To effectively investigate questions about influenza’s virus identity and more general questions about viruses and virus diseases, new researchers and institutions would have to be created. The 1922 scheme became a trademark of the MRC approach to interwar research organisation.4 The MRC’s flagship laboratory, the National Institute for Medical Research (NIMR), which was to be home to work on vitamins, hormones, nutrition, cancer and pharmacology, was designated the hub of a research network dedicated to developing scientific expertise for studying and controlling ‘virus diseases’. The Institute and the virus scheme operated on the principles of collectivising the production of medical scientific knowledge and fostering a research culture based on the exchange of ideas, materials, and practices.5 The exchanges facilitated by the virus scheme slowly consolidated a new scientific field in the 1920s, which together lead to the institutionalisation of virus research in British pathology and medicine. Work on influenza was pivotal.

3 Ibid., 12. 4 Robert E. Kohler, From Medical Chemistry to Biochemistry: The Making of a

Biomedical Discipline (Cambridge: Cambridge University Press, 1983), 71–93. 5 Andrew Hull, ‘Teamwork, Clinical Research, and the Development of Scientific

Medicines in Interwar Britain: The “Glasgow School” Revisited’, Bulletin of the History of Medicine, 81 (2007), 569–593; Robert E. Kohler, ‘Walter Fletcher, F.G. Hopkins, and the Dunn Institute of Biochemistry: A Case Study in the Patronage of Science’, ISIS, 69 (1978), 331–355; Sturdy and Cooter, ‘Science, Scientific Management, and the Transformation of Medicine in Britain c. 1870–1950’, 421–466.

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British medical science had played an important role in the battle against the pandemic. But it was also importantly shaped by it. Donald Fisher has argued that the pandemic represented a ‘central turning point’ in efforts to modernise British medicine: ‘the death of millions of persons as a result of influenza made the advancement of medical knowledge and practice urgent.’6 The pandemic was an important catalyst in prompting the British state to take a new role in medical scientific administration and education, primarily through the MRC.7 The MRC’s collaboration with the Rockefeller Foundation to reform British medical education was an important legacy of the pandemic. But the legacy reached further, into the very organisation and content of medical scientific research. The MRC’s virus scheme clearly demonstrates this point. Fletcher regularly invoked the possible link between a filterable virus and the greatest pandemic since the Black Death to bolster support for MRC plans to scientifically modernise British pathology.8 Experience during the war and the pandemic convinced Fletcher and his colleagues that pathology needed to be founded on experimental principles, and located above all in university science departments and research institutions.9 Experimental pathology was to become one of the foundations of medical knowledge and advance, and crucial to the health and stability of the nation and the empire.10 The NIMR emerged as one of its key institutional supports, with virus research closely allied to its development. While the MRC’s virus scheme generally aimed to create a new science of disease, it was specifically fashioned as a response to problems crystallised by the pandemic, the most crucial of which was determining the specific cause of influenza and ways to control it. Across the world, these problems attracted governments, medical institutions and philanthropies,

6 Donald Fisher, ‘The Rockefeller Foundation and the Development of Scientific Medicine in Britain’, Minerva, 16 (1978), 26. 7 Peter Alter, The Reluctant Patron: Science and the State in Britain 1850–1920 (Oxford: Berg, 1987), 127ff. 8 A. Landsborough Thomson, Half a Century of Medical Research. The Programme of

the Medical Research Council (UK), Vol. 2, (London: HMSO, 1975), 114. 9 Christopher Lawrence, Rockefeller Money, the Laboratory, and Medicine in Edinburgh, 1919–1930: New Science in an Old Country (Rochester: University of Rochester Press, 2006), 11–23. 10 For the role of scientific experts in interwar Britain, see David Edgerton, Warfare State: Britain, 1920–1970 (Cambridge: Cambridge University Press, 2005), 15–58.

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led by the Rockefeller Foundation, and gave rise to a massive outpouring of studies through the early 1920s, but with little resolution.11 In Britain, approaches to the influenza problem were marked by disputes among medical scientists and epidemiologists and between the MRC and the new Ministry of Health, both of which developed competing visions for how best to tackle influenza and related infectious diseases. Until 1924, when the two bodies were forced by government to agree to a concordat that defined their respective spheres of responsibility, they vied for control over research on infectious diseases.12 The MRC virus scheme was an important instrument to demarcate the MRC’s authority in this area and to draw the scientific study of influenza under its control. The pandemic served as both a symbolic and a material resource in the construction of the virus scheme. Rather than generating general opposition to or abandonment of scientific medicine, failure to master the pandemic spurred governmental, medical, and public backing for its improvement and expansion. The virus scheme was testament to the widely perceived value of medical science in tackling the most challenging diseases. From a historical perspective, the scheme also shows that the pandemic was neither ignored nor forgotten in the domains of medical science.13 Indeed, virus research became one of the lasting legacies of the pandemic, a cornerstone of a new medical scientific system that became an emblem of modernity in interwar Britain. Work on virus diseases either directly linked to influenza or seen as possible models for understanding viruses more generally garnered strong public support, patronage, and engagement. This support, along with the MRC’s ability to mobilise the

11 For a measure the output, close to three-quarters of the 4,000 publications collected by the London pathologists, David and Robert Thomson, in their comprehensive twovolume annals of influenza research, had been published between 1918 and 1923, mostly on the bacteriological and pathological aspects of the disease. David Thomson and Robert Thomson R. ‘Influenza’, Annals of the Pickett-Thomson Research Laboratory, Parts I & 2 (London: Bailliere, Tindall and Cox, 1933, 1934), v. 12 NA MH 123/498 Relations between the Ministry of Health and the Medical Research Council, 12 February 1924. 13 For recent challenges to the idea that the pandemic was ‘forgotten’ see Samuel K.

Cohn Jr. Epidemics: Hate and Compassion from the Plague of Athens to AIDS (Oxford: Oxford University Press, 2018), 408–424; Elsytt W. Jones, ‘Recollecting Influenza: Form, remembrance, and interpretation in Canada’s pandemic’, In M. Bresalier (Ed.), One Hundred Years of Influenza: Afterlives of the 1918–19 Pandemic (London: Routledge, Forthcoming).

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pandemic in its arguments for building virus research, suggests the existence of a broader social consensus about the dangers posed by influenza and the need to bolster medical science to manage such threats to modern life. In what follows, I trace how the MRC sharpened this rationale in its clashes with the Ministry of Health and used the pandemic as a key justification for the creation of its virus scheme. The next chapter explores the specific style of virus research developed and formalised under the scheme.

1

Competing Visions

In the aftermath of the pandemic, Britain’s reconstruction government looked to the two medical bodies it created in 1919 to produce new approaches to managing influenza. Government hoped that the MRC, which had been designated as an independent research Council, and the new Ministry of Health, would collaborate on major health problems. While they tried to work together, more often conflict characterised their relationship. Sir George Newman, who took the reins of the Ministry, and Fletcher, who retained his position as Secretary of the MRC, shared a common interest in remaking British medicine as a modern, statemanaged institution.14 But they differed fundamentally on the nature and goals of medical reconstruction. In particular, they were guided by different ideologies of science, which divided them on the key question of the place of laboratory-based knowledge and practices in clinical and public health medicine. Newman’s vision was built on epidemiological notions of diseases and epidemics as complex phenomena, in which laboratory investigations were one part of an integrated system determined by public health priorities.15 In contrast, Fletcher organised the MRC around the view that experimental research should structure the practical 14 Joan Austoker, ‘Walter Morley Fletcher and the Origins of a Basic Biomedical Research Policy’, In J. Austoker, & L. Bryder (Eds.), Historical Perspectives on the Role of the MRC: Essays in the History of the MRC of the United Kingdom and its Predecessor, the Medical Research Committee, 1913–1953 (Oxford: Oxford University Press, 1989), 24; Linda Bryder, ‘Public Health Research and the MRC’, In Historical Perspectives on the Role of the MRC, 59–81. 15 For Newman, see Steve Sturdy, ‘From Hippocrates to State Medicine: George Newman on the early Policy of the Ministry of Health’, In George Weisz and Christopher Lawrence (Eds.), Greater than the Parts: Holism in Inter-war Medicine (Oxford: Oxford University Press, 1998), 112–134. For Newman’s conflicts with the MRC, see

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and conceptual foundations of clinical and public health medicine. In this vision, the laboratory and the principle of specific aetiology—that every disease had a definable and singular cause—were the bedrock of a modern medical system.16 The Ministry and MRC clashed on almost every major issue concerning the future direction of British medicine. Influenza was no different. The devastation of the pandemic put the disease at the forefront of their agendas. Yet even before it had smouldered out, they vied to stake out their authority over its management. One of Newman’s first initiatives was an official Report on the Pandemic of Influenza.17 Tracing the clinical, epidemiological, and bacteriological dimensions of the pandemic in Britain and across the empire, the Report took stock of the state of medical knowledge and highlighted key questions it had raised about influenza’s nature, identity, and prevention. Highly influential in its day, and a document of lasting historical import, it also carried an agenda that closely mirrored Newman’s view of the future organisation of medicine.18 Newman’s decision to appoint Major Greenwood as editor of the Report reveals some of the assumptions behind this agenda. A disciple of Karl Pearson, with socialist leanings, Greenwood was a leading proponent of a new population-based epidemiology.19 Rooted in Pearson’s biometrics, it relied on probabilistic models to identify the complex factors at play in the development of epidemics. Greenwood’s epidemiology was avowedly multifactorial and anti-reductionist, and he used it to critique bacteriological models of specific aetiology that had

Linda Bryder, ‘Public Health Research and the MRC’, In Historical Perspectives on the Role of the MRC, 59–81. 16 Lawrence, Rockefeller Money, 11–62; D. Cox-Maksimov, ‘The Making of the Clinical Trial in Britain, 1910–1945: Expertise, the State and the Public’, Ph.D. Thesis. Department of History and Philosophy of Science, University of Cambridge, 1998. 17 Ministry of Health, Report on the Pandemic of Influenza, 1918–19 Reports on Public Health and Medical Subjects, No. 4, (London: HMSO, 1920). 18 Sturdy, ‘From Hippocrates to State Medicine’, 115. 19 For Greenwood, see Olga Amsterdamska, ‘Standardizing Epidemics: Infection, Inher-

itance and Environment in Prewar Experimental Epidemiology’, In Jean-Paul Gaudillière and Ilana Löwy (Eds.), Heredity and Infection: Historical Essays on Disease Transmission in the Twentieth Century (London: Routledge, 2001), 138; and John R. Matthews, Quantification and the Quest for Medical Certainty (Princeton: Princeton University Press, 1995).

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come to dominate traditional epidemiology and public health.20 He privileged predisposition over infection, and ‘soil’ over ‘seed’ in explanations of the origins of epidemics. Despite also working for the MRC and being a friend of Fletcher’s, Greenwood’s approach was at odds with the Council’s abiding ethos of reductionism, which aimed to breakdown physiological or pathological processes to single determinant causes. His approach was part of a more general push to position epidemiology as distinct from the dominant aetiological focus of bacteriology, concentrating on the complex factors and mass (or population) aspects of epidemics or disease prevalence.21 Multifactorial ideas had important proponents from across the spectrum of British medicine. Like Greenwood, they saw the pandemic as vindication of more inclusive and holistic explanatory frameworks of disease causation. A key ally was William Bulloch, one of several microbiologists who was revising Pasteur’s conception of the variable virulence of microbes to explain the rise and fall of epidemics in terms of the interaction of germ, host, and environment.22 Another was Clifford Allchin Gill, who had worked as a medical officer for the Indian Medical Service and authored The Genesis of Epidemics, in which he advocated a naturalhistorical approach that drew upon a wide range of analytical methods to create a holistic understanding of the development of influenza and other epidemic diseases.23 The most ardent proponent, however, was William Hamer, Medical Officer of Health for the London County Council. He and the Oxford-trained physician, F.G. Crookshank, made the pandemic the focal point for an attack on reductive scientific approaches and used it to revive a Hippocratic theory of epidemics as products of particular ‘constitutions’.24 Hamer organised his report on the pandemic for 20 J. Andrew Mendelsohn, ‘From Eradication to Equilbrium: How Epidemics Became Complex after World War I’, In Greater than the Parts, 303–331; J. Andrew Mendelsohn, ‘Medicine and the Making of Bodily Inequality in Twentieth Century Europe’, In Heredity and Infection, 21–80. 21 Olga Amsterdamska, ‘Demarcating Epidemiology’, Science, Technology, & Human Values, 1 (2005), 17–51. 22 For Bulloch’s association, see Mendelsohn, ‘From Eradication to Equilibrium’, 309–

310. 23 Clifford Allchin Gill, The Genesis of Epidemics and Natural History of Disease (London: Bailliere, Tindall and Cox, 1928). 24 For holism in British medicine, see Christopher Lawrence, ‘Edward Jenner’s Jockey Boots and the Great Tradition in English Medicine, 1918–1939’, In Christopher Lawrence

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the London County Council around these principles, while Crookshank edited a widely cited volume on Influenza in 1922, in which Hamer had a chapter, that pushed their neo-Hippocratian philosophy.25 While harkening Sydenham’s idea of an ‘epidemic constitution’, the revamped notion of the 1920s was, as Andrew Mendelsohn has argued, ridded of reference to ‘atmospheric influences’ and now emphasised the role of hereditary and environmental factors to explain variations in the susceptibility, incidence and severity of infectious diseases and of the microbes involved in these processes.26 Although Greenwood resisted neo-Hippocratic impulses, he shared the view of epidemics as complex phenomena, and his Report on the Pandemic of Influenza clearly bore its marks.The Report was notably broad and balanced, but its conclusions emphasised the epidemiological complexity of the pandemic. Greenwood challenged the bacteriological idea that the pandemic was the result of an invasion of a germ or germs from a specific breeding ground. He attributed it to a conjunction of factors in individual nations that conspired to produce the right conditions from which epidemic influenza could emerge and spread, and he used this to explain variations in mortality across the globe. ‘Epidemic influenza,’ he concluded, was ‘largely an internal problem of each nation; there is no question of shutting the wolf out of the sheepfold, he has been regularly lying down with the lamb for years.’27 Only with right conditions could influenza attack on a mass scale. Understanding these conditions and their interaction was the foundation for prevention. Newman translated this view into a plan to protect Britain against future epidemics. He attributed the pandemic to a ‘sum of etiological factors’ linked to adverse social conditions, which weakened the population, and to epidemiological conditions, in which the seeds of the and Anna K. Mayer (Eds.), Regenerating England: Science, Medicine and Culture in Inter-War Britain (Amsterdam: Rodopi, 2000), 45–66. 25 Crookshank, Influenza: Essays by Several Authors; William H. Hamer, The Relationship between Influenza, Cerebrospinal Fever, and Poliomyelitis. Appendix to the Report of the County Medical Officer of Health and School Medical Officer for the Year 1918 (London: County Hall, 1922); William H. Hamer, Report on Influenza by the County Medical Officer of Health (London: County Hall, 1919); W.H. Hamer, ‘The Influenzal Constitution’, Proceedings of the Royal Society of Medicine, 20, (1927), 1349–1368. 26 Mendelsohn, ‘From Eradication to Equilibrium’; 311–313; and Mendelsohn, ‘Medicine and the Making of Bodily Inequality in Twentieth Century Europe’, 21–80. 27 Ministry of Health, Report on the Pandemic of Influenza, 1918–19, 29.

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pandemic were sown before 1918 with outbreaks of cerebro-spinal fever, poliomyelitis, and purulent bronchitis—diseases he and others assumed to be directly related to influenza. ‘It seems impossible,’ Newman claimed, ‘to escape the conclusion that these various conditions bore a fundamental relationship to each other and to the pandemic of influenza.’28 Following this reasoning, he stressed the importance of improving population health and social conditions: ‘One thing is certain … the fundamental requirement to make us masters of our fate is a universal improvement in the standard of health and the conditions of life. No technical device, no narrow or specific remedy for pestilence, can ultimately triumph apart from a sanitary environment for the community and the sound nutrition of the individual.’29 Challenging the logic that had defined official approaches to influenza during the pandemic, Newman’s preventive system prioritised general ideals of sanitary and social medicine, with laboratory science construed as but one among many instruments for realising them. Newman’s plans for tackling influenza relied on a combination of public education, epidemiological intelligence, and medical research. Sandra Tomkins has suggested that, from late 1919, the Ministry sought to balance bacteriologically-based measures of disinfection and vaccination with interventions aimed at helping local authorities and medical practitioners cope with large numbers suffering from influenza.30 Exclusive preventive measures, focused on germ control, were deemed to be only partially effective, not least because the specific disease agent had not been determined. Nursing support was recognised to have played an important role in reducing mortality during the third wave in early 1919. Other countries, notably New Zealand, had taken this approach with some success, but it is unclear if Newman and his colleagues were following these examples.31 Though the particular roots of this change

28 Ministry of Health, Report on the Pandemic of Influenza, xvii. 29 Ministry of Health, Report on the Pandemic of Influenza, xxi. 30 Tomkins, ‘Britain and the Influenza Epidemic’, 105. 31 A number of historical studies have shown that governments and local authorities

which prioritised nursing care reduced mortality rates among their populations. See Nancy Bristow, American Pandemic: The Lost Worlds of the 1918 Influenza Epidemic (Oxford: Oxford University Press, 2012), 122–151; Sandra Opdycke, ‘A Caregiver’s Nightmare: Trying to Treat Influenza’, In idem., The Influenza Epidemic of 1918: America’s Experience in a Global Health Crisis (London: Routledge 2014), 63–85; A. Keeling, ‘“Alert to

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in approach are uncertain, for the first time British public health circulars emphasised methods of caring for influenza sufferers in addition to methods of prevention.32 As part of this new focus, the capacity of London hospitals to take in early pneumonia cases was assessed. Particular stress was put on providing community nursing and home-help for stricken households.33 Yet, it would be wrong to conclude that all policy under Newman came to be organised around nursing or palliative measures. The Ministry of Health also actively sought to reframe influenza prevention as a combined problem of surveillance, research, and vaccination. Its first memorandum on influenza after the pandemic emphasised the role of vaccines in general prevention strategies.34 A modified version of the War Office vaccine continued to be manufactured and the Ministry distributed it freely to general practitioners and medical officers of health on request.35 Drawing on experiences of the pandemic, vaccination was recommended as a prophylactic against secondary infections, but not as specific protection against influenza. In contrast to the approach taken in 1918–1919, the use of the vaccine was meant to be based on the systematic monitoring of the prevalence of influenza. In early 1920, Newman put in place the building blocks of a system for collecting medical information on the incidence of influenza and influenzal pneumonia from medical officers in Britain, the empire, and armed forces.36 The system was to enable medical and public health authorities to predict and prepare for future epidemics, and thus when best to use vaccines. A standing Influenza Committee of medical heads from the Ministry, MRC, and armed forces was to meet the Necessities of the Emergency”: U.S. Nursing During the 1918 Influenza Pandemic’. Public Health Reports, Suppl 3.125 (2010), 105–12. G. Rice and L. Bryder, Black November: The 1918 influenza Epidemic in New Zealand (Wellington, N.Z.: Allen & Unwin, 1988). 32 NA FD1/546 Summary of Influenza Measures, 9 January 1920. Ministry of Health, Influenza: Hints and Precautions (London: HMSO, 1920). 33 Ministry of Health, Influenza: Hints and Precautions (London: HMSO, 1920). 34 Ministry of Health, Influenza: Hints and Precautions (London: HMSO, 1920). 35 Ministry of Health, Influenza Vaccine: Instructions to Medical Officers of Health,

Signed by George Newman (London: HMSO, 1919); ‘Prevention of Influenza’, Lancet, (3 January 1920), 41; ‘Preparations for an Influenza Epidemic’ Lancet, (31 January 1920), 270–271. 36 Ministry of Health, Report on the Pandemic of Influenza, xxi; NA FD1/546 Summary of Influenza Measures, 9 January 1920.

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weekly at Whitehall to discuss the intelligence, plan national responses, and coordinate local inquiries.37 The proposed system was also to participate in a new international epidemiological intelligence service being formulated by the Epidemic Commission of the League of Nations’ Health Organization.38 As part of these plans, epidemiological surveillance was to be linked to clinical, bacteriological, and pathological investigations. Laboratory work was given an important role in improving or producing preventive tools, including bacteriological tests and vaccines, and in developing knowledge of the cause and spread of influenza. The limited preventive value of the official vaccine was one reason for Ministry of Health support for new lines of scientific research. Newman acknowledged that uncertainty about the specific causative agent meant that ‘we are ignorant of the basic element for such a vaccine’ and stressed the need ‘to apply researchers anew to search and research the causes of [the] primary and secondary infections [of influenza]….’39 To this end, Newman sought the support of Fletcher, and in January 1920 the Ministry joined the MRC on an Emergency Research Committee to consider ways to better organise ‘coordinated research and investigation’. The Committee saw as urgent the need to link university-based bacteriologists with medical officers, general practitioners, and clinicians to generate new bacteriological and clinical knowledge of influenza.40 Despite the appearance of a joint effort, the Committee and its plans reflected MRC interests. Fletcher and his colleagues argued that effective surveillance and prevention had to be based on the laboratory identification of the disease agent (or agents). This meant expanding basic pathological and bacteriological research that had been organised during

37 NA FD1/535 Influenza Committee Agenda, 3 February 1920. 38 NA MH 113 51 Reports by the Delegate of Great Britain on the Sessions of

the Committee of the Office International d’Hygiène Publique, Paris and of the Health Committee of the League of Nations (Reports 1–12), 1920. 39 Ministry of Health Report on the Pandemic of Influenza, xx. 40 NA FD1/545 Cooperation between ‘field’ and laboratory, Letters sent to researchers,

physicians and Ministry of Health Officials, 31 January 1920; NA FD1/546 Influenza epidemic: reports and correspondence; Medical Research Council, Annual Report of the Medical Research Council, 1919–1920 (London: HMSO, 1920), 49.

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the pandemic.41 Between 1920 and 1922, the Committee concentrated on two objectives. One involved developing joint bacteriological and clinical studies to better define the role of different pathogens in the aetiology and pathogenesis of influenza. Another aimed to establish a network of bacteriologists dedicated to tracking the incidence of B. influenzae in healthy populations, with a view to better understanding its role in epidemics.42 Both initiatives depended on forging links between different medical constituencies. This was difficult because joint laboratory-clinical investigations were marred by inter-professional rivalries. William Bulloch, who participated on the Research Committee, noted ‘the great difficulty in getting thorough co-operation between clinicians and pathologists’ in London.43 Pathologists and bacteriologists working on the plan reported similar difficulties in other cities.44 In response, Fletcher decided to shift the majority of investigations to selected public schools where he had close ties and where medical officers of health and school physicians were less entrenched in professional commitments. Little in the way of practical results came out of the Committee. Fletcher primarily used it as one of a number of vehicles for establishing MRC authority over medical science.45 As he and his colleagues navigated their troubled relationship with Newman and the Ministry, they also began mapping out a separate research strategy, which concentrated on determining the specific role of filterable viruses in influenza and other infectious diseases. Building expertise in this direction soon became a priority. Specialising in virus research was justified as a vital strategy for equipping the nation against future epidemics. But it was also an important part of MRC efforts to take control of the planning and direction of medical scientific research.

41 NA FD1/545 Notes of an informal conference on the requirements of research workers in the event of an influenza epidemic, 6 February 1920. In attendance were: Fletcher, Leishman (Chair), William Bulloch (University of London), Thomas Carnwath (Ministry of Health), S.L. Cummins (RAMC), Douglas (MRC/NIMR), Fildes (London Hospital), Alexander Fleming (St. Mary’s Hospital), F. Griffiths (Ministry of Health), McIntosh (Middlesex Hospital), Twort (Brown Institution). 42 NA FD1/545 Cooperation between ‘field’ and 43 NA FD1/545 Cooperation between ‘field’ and 44 NA FD1/545 Cooperation between ‘field’ and 45 Linda Bryder, ‘Public Health Research and the

laboratory. laboratory. laboratory. MRC’, 68.

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New Agents, Old Problems

Viruses and virus diseases existed on the borderlands of medicine and pathology in the first decades of the twentieth century. Medical and veterinary bacteriology had provided investigators with ways of working on and defining these entities. Louis Pasteur had first proposed the existence of ‘infinitely small’ pathogens, invisible to light microscopes, to explain his inability to isolate the specific cause of rabies.46 A generic Latin term originally meaning ‘poison’, the virus concept slowly gained specificity when investigators started to associate it with particular disease-causing agents that eluded capture by existing microbiological methods of filtration, cultivation, and light microscopy.47 The first evidence for such an agent appeared in 1892 from the laboratory of the Russian plant pathologist, Dmitri Ivanovski. But in Britain and elsewhere, interest in viruses was sparked by discovery claims that linked them to important animal and human diseases.48 The watershed first opened in 1898, when two colleagues of Robert Koch, Friedrich Loeffler and Paul Frosch, identified the cause of footand-mouth disease as a filterable agent that multiplied in infected animals, but was invisible under the light microscope and could not be cultivated in artificial media.49 Similar discovery claims were soon made for bovine pleuro-pneumonia, myxomatosis, and African horse sickness.50 The first human virus disease had only been identified in 1900, when the American tropical pathologists, Walter Reed and James Carroll, characterised the mosquito-borne agent that caused yellow fever as a filterable virus.51 Medical interest started to be galvanised when the Vienna-based pathologists Karl Landsteiner and Constanin Levaditi identified a filterable

46 Lise Wilkinson, ‘The Development of the Virus Concept as Reflected in Corpora of

Studies on Individual Pathogens. 4. Rabies—Two Millennia of Ideas and Conjecture on the Aetiology of a Virus Disease’, Medical History, 21 (1977), 22–24. 47 Sally Smith-Hughes, The Virus: A History of a Concept (London: Heineman, 1977) 48 Lise Wilkinson, ‘Animal Viruses, Veterinary Pathology, and the Formulation of Ideas

Concerning Filterable Viruses’, Historia Medicinae Veterinariae, 3 (1978), 1–15. 49 Wilkinson, ‘The Development of the Virus Concept, 4—Rabies’, 30. 50 A. Waterson and L. Wilkinson, An Introduction to the History of Virology

(Cambridge: Cambridge University Press, 1978), 30–33. 51 Ilana Löwy, Virus, Moustiques et Modernite: La Fievre Jaune au Brasail entre Science et Politique (Paris: Editions des archives contemporaines, 2001).

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virus in monkeys as the cause of poliomyelitis in 1909.52 The association of a filterable agent with this high profile and lethal childhood disease propelled researchers to search for poliovirus and to explore the nature and role of similar agents in other human diseases. In 1910, Simon Flexner, who had worked extensively on polio, established the first research programme dedicated to virus diseases at the Rockefeller Institute for Medical Research (RIMR) in New York, which would serve as a general model for the MRC in creating its own virus programme and a crucial place for British and other researchers to gain training in virus work.53 Bacteriological principles and practices guided most medical and veterinary virus research through the interwar years. Bacteriology provided an ontological approach to understanding these pathogens as specific entities.54 Reliance on techniques of bacterial filtration, cultivation, and microscopy to identify viruses and to determine their role in disease causation supported a concept of viruses as living microorganisms, which many argued could be studied and explained in a manner similar to bacteria. Characterised in this way, filterable agents were especially attractive because they could be used to explain the cause of important infectious diseases for which bacteria could not be readily found.55 Yet viruses also vexed bacteriology. While their presence could be indirectly determined by their infectivity for host organisms or by serological tests, the vast majority could not be grown in pure culture in artificial media, made visible by available methods of light microscopy, or retained

52 Anne Hardy, ‘Poliomyelitis and the Neurologists: The View from England, 1896– 1966’, Bulletin of the History of Medicine, 71 (1997), 249–272; Waterson and Wilkinson, An Introduction to the History of Virology, 50–51. 53 G.W. Corner, The Rockefeller Institute: Origins and Growth, 1901–1953, New York: Rockefeller Institute Press; Ilana Löwy and Patrick Zylberman, ‘Medicine as a Social Instrument: Rockefeller Foundation, 1913–45’, Studies in History and Philosophy of the Biological and Biomedical Sciences, 31 (2000), 365–379. 54 Ton van Helvoort, ‘History of Virus Research in the Twentieth Century: The Problem of Conceptual Continuity’, History of Science, XXXII (1994), 185–235. 55 John McFaydean, ‘The Ultravisible Viruses’, Journal of Comparative Pathology and Therapeutics, XXI (1908), 66.

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by standard bacterial filters.56 These negative properties were acknowledged in the prefixes researchers used when naming these agents, which included ‘filter-passer’—popular in Britain—as well as ‘filterable’, ‘ultramicroscopic’, and ‘invisible’.57 Rarely did the term ‘virus’ stand alone. A pathogen was characterised as ‘filterable’ when clinical material passed through the smallest of available filters still induced disease in a healthy host or experimental animal.58 While negative operational criteria gave some insight into certain properties of viruses—or at least, what they were not—these criteria were judged to be an insufficient basis for classification. Researchers who sought to explore the basic nature and role of viruses in disease not only confronted limitations in scientific technique and knowledge but also in the general lack of institutional support for such work. By the outbreak of the war, only the Pasteur Institute in Paris, the Koch Institute in Berlin and the RIMR in New York supported nascent programmes of virus research. Before the MRC initiated its scheme in 1922, research on virus diseases in Britain was spread unevenly over a patchwork of pathological and bacteriological laboratories that had been incorporated into medical and veterinary institutions from the 1890s. Most were in London. Pathologists worked independently on a diseaseby-disease basis. Typical of this pattern was John McFadyean, Principal of the Royal Veterinary College in London and founder of the Journal of Comparative Pathology and Therapeutics .59 McFadyean almost singlehandedly pioneered British virus research at the College’s tiny pathology laboratory in St. Pancras. After spending some time confirming European research on the role of filter-passers in a number of animal diseases, in 1900 he made his own contribution with the identification of a filterable

56 F.W. Twort, ‘The Ultramicroscopic Viruses’, The Journal of State Medicine, 31 (1923), 351–366; T.M. Rivers, ‘Filterable Viruses: A Critical Review’, Journal of Bacteriology, 14 (1927), 217–258; T.M. Rivers, ‘Some General Aspects of Filterable Viruses’, In T.M. Rivers Filterable Viruses (London: Bailliere, Tindall & Cox, 1928), 3–52; T.M. Rivers, ‘Filterable Viruses’, In E.O. Jordan and I.S. Falk (Eds.), The New Knowledge of Bacteriology and Immunology, (Chicago: University of Chicago Press, 1928). 57 For the use of these prefixes, see Ton van Helvoort, ‘History of Virus research in the Twentieth Century: The Problem of Conceptual Continuity’, History of Science, XXXII, (1994), 185–235. 58 Rivers, Filterable Viruses, 6 59 Iain Pattison, John McFadyean, Founder of Modern Veterinary Research (London: JA

Allen, 1981).

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agent as the cause of African horse-sickness.60 Eight years later, in 1908, he published ‘Ultravisible Viruses’, one of the earliest surveys of the new field, in which he characterised the primary role of these agents in fifteen animal and human diseases, as well as one plant disease.61 McFadyean took a strongly comparative pathological approach, which was the norm in most medical and veterinary virus research.62 To understand the nature and role of filterable agents, medical and veterinary pathologists needed to work across diseases and species. Since most filterable agents appeared to resist cultivation in artificial media, the only available route for research was through either naturally occurring or experimentally-induced infections. While using humans as experimental subjects was common enough—as studies of influenza in 1918 showed— viruses were primarily investigated as diseases manufactured in living animals. Already an established part of bacteriology and physiology, this way of working required the researcher to move between animal and human, and between different animals.63 Though a generally accepted experimental principle, comparative pathology was difficult to put into practice. A key obstacle for workers in Britain was the lack of access to dedicated research animals. Animal experimentation was regulated under the 1876 Cruelty to Animals Act, which restricted the numbers and

60 John McFadyean, ‘African Horse Sickness’, Journal of Comparative Pathology and Therapeutics, XIII (1900), 1–20. 61 John McFadyean, ‘The Ultravisible Viruses’, Journal of Comparative Pathology and Therapeutics, XXI (1908), 58–68, 168–175, 232–242. 62 Lise Wilkinson, Animals and Disease: An Introduction to the History of Comparative Medicine (Cambridge: Cambridge University Press, 1992); Rachel Mason Dentinger and Abigail Woods. ‘Introduction to Working Across Species.’ History and Philosophy of the Life Sciences 40.2 (2018), 30–41. 63 William F. Bynum, ‘“C’est une Malade!” Animal Models and Concepts of Human Diseases’ Journal of the History of Medicine and Allied Sciences 45 (1990), 397–413; Cheryl Logan, ‘Before there Were Standards: The Role of Test Animals in the Production of Empirical Generality in Physiology’, Journal of the History of Biology 35 (2002), 329– 363; Michael Worboys. ‘Germ Theories of Disease and British Veterinary Medicine, 1860– 1890’, Medical History 35 (1991): 308–327; Christoph Gradmann. ‘Robert Koch and the Invention of the Carrier State: Tropical Medicine, Veterinary Infections and Epidemiology around 1900’, Studies in History and Philosophy of Biological and Biomedical Sciences 41 (2010): 232–240.

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kinds of animals used in laboratory work.64 Only licensed researchers or institutions could perform experimental studies. Crucially, as Robert Kirk has shown, the supply of research animals was dependent upon and constrained by the vagaries of a commercial small animal market, which could not keep up with growing demand for good quality animals. Standardised animal breeding for medical scientific research would only start to be addressed in the 1920s and only became a norm after the Second World War.65 Professional and institutional constraints also presented obstacles. In the absence of university departments or institutions dedicated to bacteriological research, in many cases those interested in virus diseases had to balance their studies with the demands of the running of hospital, public health, or veterinary diagnostic services. Before the war, the LGB’s Medical Department financed investigations on the role of filterable agents in infectious diseases such as polio, mumps, and smallpox for which bacterial causes had not been determined. Generally, however, little opportunity existed to carry out what would later be characterised as ‘basic’ or ‘pure’ research on suspected virus diseases. University pathology departments had yet to be established. The Lister Institute did not start virus research until after the war.66 An exception was the Brown Animal Sanatory Institution, which provided laboratory facilities for the LGB and became the base for Frederick W. Twort’s ground-breaking work on the ‘bacteriophage’.67 Twort had started studying filterable agents associated with vaccinia (cowpox) 64 R.D. French, Antivivisection and Medical Science in Victorian Society (Princeton, NJ and London: Princeton University Press, 1975); Paul Elliot, ‘Vivisection and the Emergence Of Experimental Physiology in Nineteenth-century France’, In N. Rupke (Ed.), Vivisection in Historical Perspective (London, Croom Helm, 1987), 48–77; M.A. Finn and J.F. Stark, ‘Medical Science and the Cruelty to Animals Act 1876: A Re-examination of Anti-vivisectionism in Provincial Britain’, Studies in History and Philosophy of Biological & Biomedical Sciences 49 (2015), 12–23. 65 Robert G.W. Kirk, ‘Wanted—Standard Guinea Pigs’: Standardisation and the Experimental Animal Market in Britain ca. 1919–1947, Studies in History and Philosophy of Biological and Biomedical Sciences 39.3 (2008), 280–291. 66 Harriet Chick, M. Hume and M. MacFarlane, War on Disease: A History of the Lister Institute (London: A. Deutsch, 1971), 187ff; 212ff. 67 Paul Fildes, ‘Frederick William Twort, 1877–1950’, Obituary Notices of Fellows of The Royal Society, 7 (1951), 507–517; Ton van Helvoort, ‘The Construction of Bacteriophage as Bacterial Virus: Linking Endogenous and Exogenous Thought Styles’, Journal of the History of Biology, 27 (1994), 91–139.

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and variola (smallpox) as possible keys to understanding bacterial adaptation and mutation. He established his mark in 1915 with the identification of the phenomena of bacterial lysogeny in colonies of cocci that had contaminated cultures of vaccine lymph from which he had been trying to isolate the purported vaccinia virus. Undecided about the nature of the ‘lytic principle’, he attributed it to either an ‘ultramicroscopic virus’ or a transmissible enzyme secreted by the cocci.68 His speculations presaged a vociferous dispute over the nature of the ‘bacteriophage’, the term introduced by the French-Canadian microbiologist Felix d’Herelle in 1917 to denote the agent he associated with a specific filterable virus of bacteria.69 Against d’Herelle, Twort supported the notion that the bacteriophage was a ferment secreted by certain bacteria rather than an exogenous agent. But his main dispute with d’Herelle was over the priority in the discovery of the bacteriophage.70 This dispute, and an obsession with the theoretical notion that viruses were the key to the origins of life, isolated Twort from other researchers.71 While contributing important knowledge of viruses, and advising the MRC, he devoted little attention to building the Brown Animal Sanatory Institution into a centre of virus work. By the outbreak of the war, a cluster of pathological researchers and institutions in London had made viruses and virus diseases medically and scientifically important entities. Virus research had gained a profile in medical journals, with discovery claims reported in the Lancet and the BMJ , as well as the Journal of Pathology and Bacteriology and McFadyean’s Journal of Comparative Pathology and Therapeutics . These foundations made it possible for laboratory pathologists to entertain and investigate the possible role of a filterable agent as the cause of influenza in 1918. Yet, the place of virus work in pathology, public health, and clinical medicine was tenuous. The landscape changed fundamentally after the 68 F.W. Twort, ‘An Investigation of the Nature of Ultramicroscopic Viruses’, Lancet, (4 December 1915), 1241–1243. 69 Ton van Helvoort, ‘Bacteriology and Physiological Research Styles in the Early Controversy on the Nature of the Bacteriophage Phenomenon’, Medical History, 36 (1992), 243–270; William C. Summers, Felix d’Herelle and the Origins of Molecular Biology (New Haven; London: Yale University Press, 1999). 70 A. Twort, In Focus, Out of Step: A Biography of Frederick William Twort F.R.S., 1877–1950 (Dover, NH: A. Sutton, 1993). 71 Scott H. Podolsky, ‘The Role of the Virus in Origin-of-Life Theorizing’, Journal of the History of Biology, 29 (1996) 87; Lise Wilkinson, ‘Review: In Focus, Out of Step: A Biography of Frederick William Twort, F.R.S.’ Medical History, 38 (1994), 340–341.

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war. London emerged as a world-leading centre of medical virus work, and medical and public interest in viruses and virus diseases grew considerably. A key reason for this development lies with the MRC. The scheme it assembled in 1922 facilitated the institutionalisation of virus research in pathology and medicine. Linked to the MRC’s broader program of scientifically modernising British medicine, the 1918–1919 pandemic was a crucial impetus and rationale. So too was American money and knowhow. Fletcher and his colleagues were fully aware of the Rockefeller Foundation’s support for virus research.72 Rockefeller funding and collaboration would play a crucial role in the development of the MRC virus research scheme in the 1920s and 1930s. MRC interest in filterable viruses was initially galvanised by experience in organising studies to determine the possible role of a filterable agent as the cause of influenza in autumn 1918. This backdrop was crucial to the MRC’s move into virus research and in shaping the particular research problems it would set out to tackle under its scheme. Failure to confirm the primary role of Pfeiffer’s bacillus or any other bacterial agent had prompted Fletcher and Leishman to call for new lines of laboratory work as they prepared for the second wave of the pandemic. ‘On the hypothesis that B. influenzae, no less than pneumococci and streptococci are secondary [infections],’ argued Fletcher in October 1918, ‘official strategy would be better served by exploring the possible role of a so-called “filter-passing virus”.’ Soon after, the MRC and the War Office put in train the first British efforts to ‘search for an unrecognized virus.’73 A virus theory of influenza had been first proposed in 1914 by the German bacteriologist, Wilhelm Kruse, in studies of the common cold.74 Interest in the theory grew in summer 1918 as a possible explanation for bacteriological failures. The first experimental claims about the role

72 For a brief overview of these connections, see Barbara C. Canavan, ‘Collaboration Across the Pond: Influenza Virus Research’, Rockefeller Archive Center Research Reports Online, 2014. Accessed 15 October 2019. http://rockarch.org/publications/resrep/can avan.pdf. 73 NA FD1/533 Fletcher to Fildes, 28 October 1918. Medical Research Committee, Studies of Influenza in Hospitals of the British Armies in France, 1918 (London: HMSO, 1919). 74 Wilhelm Kruse, ‘Die Erreger v. Husten und Schnupfen’, Münchener medizinische Wochenschrift, 65 (1914), 1228.

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of a filterable agent in the pandemic came from researchers at the Pasteur Institutes in Paris and Tunis.75 In early 1918, Charles Nicolle and Charles Lebailly announced that they had discovered a filter-passer in nose and throat samples taken from influenza cases in Tunis.76 As proof, they reported reproducing the disease in healthy men and monkeys by serial inoculation of filtered bronchial secretions from infected cases.77 Nicole and Lebailly’s study provided a benchmark for British investigations. Between October and December 1918, the MRC assisted S.L. Cummins, Advisor in Pathology to the Army Medical Services, in organising filterpasser studies at military field laboratories in Abbeville, Flanders, and Étaples, France.78 Major Howard Graeme Gibson led the Abbeville team.79 With Major F.B. Bowman and Captain J.I. Connor, Gibson’s team first attempted to repeat Nicole and Lebailly’s experiments. Relying on the MRC for technical expertise and materials, including macaque monkeys and baboons shipped to Abbeville from the London Zoo, within weeks Gibson reported to Fletcher that his team had isolated a filterable agent and produced an experimental disease.80 In December 1918, they described how they had reproduced a characteristic lung haemorrhage

75 Rene Dujarric de la Riviere, ‘La grippe est-elle une maladie a virus filtrant?’ Comptes

Rendus de l’Academie des Sciences. Paris, 167 (1918), 606–607; Charles Nicolle and Charles Lebailly, ‘Quelques notions experimentales sur le virus de la grippe’, Comptes Rendus de l’Academie des Sciences Paris, 167 (1918), 607–610. For a brief discussion of de la Riviere’s work, see Ilana Löwy, ‘Influenza and Historians: A Difficult Past’ In T. Giles-Vernick and S. Craddock (Eds.), Influenza and Public Health: Learning from Past Pandemics (London and Washington: Earthscan, 2010), 92. 76 C. Nicolle and C. Lebailly, ‘Quelques notions experimentales sur le virus de la grippe’, Comptes Rendus de l’Academie des Sciences Paris, 167 (1918), 607–610. 77 Op.cit., D. Thomson and R. Thomson, ‘Influenza (Part I)’, Annals of the Pickett-

Thomson Research Laboratory, (London: Bailliere, Tindall and Cox, 1933), 607. 78 H.G. Gibson, F.B. Bowman and J.I. Connor, ‘The Etiology of Influenza: A Filterable Virus as the Cause’. In Medical Research Committee, Studies of Influenza in Hospitals of the British Armies in France, 1918 (London: HMSO, 1919), 19–36. 79 S.L. Cummins, ‘Major H.G. Gibson’, British Medical Journal, 8 March (1919), 294– 295. Gibson had joined the RAMC in 1907, trained in bacteriology and developed an anti dysenteric serum-vaccine at the College’s Vaccine Department in 1917, after which he joined the AMS an assistant advisor in pathology. 80 NA FD1/529 MRC, Influenza Research by Colonel Cummins with British Forces in France. S.L. Cummins, Studies of Influenza in Hospitals of the British Armies in France, Medical Research Committee, Special Report Series No. 36 (London: HMSO, 1919); Gibson, Bowman and Connor, ‘The Etiology of Influenza’, 645–646.

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in two monkeys, similar to that seen in clinical cases, and isolated and cultured minute ‘coccoid bodies’ from the tissue. Since the agent passed through filters and produced ‘experimental influenzal’ lesions, they reckoned that it was a ‘filterable virus’ and ‘in all probability the cause of influenza’81 (Fig. 1). Tragically, Gibson died from a severe attack of influenza, leaving the team’s work unfinished. But this was not before the team at Étaples, headed by Major-General John Rose Bradford and Captain James Wilson, reported isolating similar bodies (Fig. 2). Like their counterparts at Abbeville, they too claimed that these were similar to the agent identified by Nicole and Lebailly and the possible causative agent of the pandemic (Fig. 3). Although preliminary, these studies won support from the Lancet and the BMJ . Cummins argued that the ‘two series of observations, carried out independently, should confirm each other, [and] greatly strengthen the case for the new organism.’82 F.W. Andrewes, now Director of Pathology at St. Bart’s, pointed to Gibson’s ‘experiments at Abbeville’ as providing the best evidence for the primary role of a filterable virus.83 These endorsements did not allay sharp criticisms of the work. In August 1919, Joseph A. Arkwright, a respected bacteriologist at the Lister Institute and member of the War Office committee on trench fever, levelled a devastating analysis of the Étaples research.84 Arkwright demonstrated that the coccoid bodies were identical to those found in uninoculated tubes and that the cultures were contaminated with ordinary bacteria. In effect, the bodies were not filterable pathogens, but either benign globoids or bacteria. Arkwright’s analysis forced Rose Bradford and Wilson to reconsider their research, and, in a stunning move,

81 Gibson, Bowman and Connor, ‘The Etiology of Influenza’, 646. 82 Gibson, Bowman and Connor, ‘The Etiology of Influenza’, 24. 83 F.W. Andrewes, ‘The Bacteriology of Influenza’, In Report on the Pandemic of

Influenza, 1918–1919, 110–125. 84 J.A. Arkwright, ‘A Criticism of Certain Recent Claims to Have Discovered and Cultivated the Filter-passing Virus of Trench Fever and of Influenza’, BMJ (23 August 1919), 233–235; W.J. Bishop, ‘Arkwright, Sir Joseph Arthur (1864–1944)’, Oxford Dictionary of National Biography. Retrieved 10 December 2019, www.oxforddnb.com/view/10.1093/ ref:odnb/9780198614128.001.0001/odnb-9780198614128-e-30442.

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Fig. 1 Abbeville Filter-passer. Photomicrograph taken for Gibson and his colleagues by the MRC microscopist, J.E. Barnard in February 1919. Gibson’s co-worker, F.B. Bowman, sent it to W.M. Fletcher on 11 February: ‘I am enclosing a photo of our “bug” which we have isolated from filtered material. It is practically identical with John R[ose] B[radford]’s’ (Source NA FD1/ 529, Bowman to Fletcher, Medical Research Committee, Influenza Research by Colonel Cummings with British Forces in France, 11 February 1919. Used with permission from the National Archives)

they publicly retracted their claims.85 ‘[I]t has to be stated’, Wilson acknowledged, ‘that it has not been proved that a filter-passing organism 85 John Rose Bradford ‘Notes on Dr. Arkwright’s Article’, BMJ (23 August 1919), 236–237.

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Fig. 2 Étaples Filter-passer. Étaples workers’ virus in Noguchi cultures at (1) 3 days’ growth, (2) 5 days’ growth, (3) 7 days’ growth. Filtrates of the culture material were inoculated into guinea-pigs and monkeys (Source John R. Bradford, E.F. Bashford and J.A. Wilson, ‘The Filter-passing Virus of Influenza’, Quarterly Journal of Medicine, no. 12 [1919], 307)

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Fig. 3 Étaples Filter-passer Films. Prepared from cultures, in films the organism had ‘the appearance of a minute, rounded, or slightly oval, undifferentiated coccus-like body, arranged in colonies of twenty to sixty elements’ (Source Bradford, Bashford, Wilson [1919], 308)

has been grown in pure culture….’86 Shortly after, the Abbeville virus was subjected to similar criticism. Building on Arkwright’s analysis, Paul Fildes, who had returned to his position at the London Hospital, and James McIntosh argued that all filter-passing work was ‘unconvincing.’87 86 J.A. Wilson, ‘Notes on Dr. Arkwright’s Article’, BMJ (23 August 1919), 237. 87 Fildes and McIntosh, ‘The Aetiology of Influenza’, 159–174.

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Gibson’s research was symptomatic of its shortcomings. Neither the identity of the virus nor its relationship to influenza had been demonstrated.88 Fildes and McIntosh insisted that the alleged pathogenic bodies were similar to those found in normal albuminous mixtures. It was unclear what if any role they had in the production of the experimental lesions; indeed, such lesions were known to occur spontaneously in monkeys held in captivity. Moreover, inoculation experiments on humans—of the kind used by Nicolle and Lebailly—were easily discredited because, as other observers noted, researchers either failed to isolate subjects from previous infections or simply produced a different illness.89 The alleged filter-passer thus failed to meet any of Koch’s postulates. Most damningly, Fildes and McIntosh reckoned that researchers used the filter-passer as an alibi: ‘the invisible virus concept absolves the discoverers from the necessity of producing evidence of a characteristic microbe.’90 These challenges to the virus theory were part of an effort to rehabilitate B. influenzae and the bacterial theory of influenza. Though the status of the bacillus had been put into question during the pandemic, Fildes and McIntosh were among a number of bacteriologists who continued to advocate its primary role. Pfeiffer himself argued in a 1922 review that the bacillus satisfied Koch’s postulates and no other agent came close to meeting the necessary criteria.91 J.G. Adami, a respected pathologist, who had been assistant director of the Canadian Army Medical Services and was now Chair of the MRC’s Committee on Bacteriological Procedures, took a similar stance in his account of the pandemic for the official history of the war: ‘One agent, and 1 only, was primarily responsible for the cases of the pandemic; … this agent was the influenza bacillus….’92 These claims were bolstered by fresh evidence generated by two American researchers, Francis G. Blake and Russell L. Cecil, as part of a larger study of pneumonia for the Surgeon General of the United States. In 1920 they 88 Fildes and McIntosh, ‘The Aetiology of Influenza’, 164. 89 H.B. Maitland, M.L. Cowan and H.K. Detweiler, The Aetiology of Epidemic

Influenza: Experiments in Search of a Filter-passing Virus (Toronto: The University Library [Toronto], 1921). 90 Fildes and McIntosh, ‘The Aetiology of Influenza’, 159. 91 R. Pfeiffer, ‘Das Influenzaproblem’ [The influenza problem] Ergebnisse der Hygiene,

Bakteriologie, Immunitätsforschung und experimentellen Therapie 5 (1922), 1–18. 92 ‘The Pathology of Influenza’, Lancet, (31 March 1923), 665–666; J.G. Adami ‘Influenza’, 413–466.

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reported a method of inoculating B. influenzae into the nose and mouth of twelve Cebus and Macaque monkeys to produce an influenza-like respiratory disease, reviving the hope that these primates could be used for new experimental studies on the role of the bacillus.93 By this point, however, the pandemic had significantly altered views on the bacteriology of influenza. Scientists and public health authorities were no longer ready to cast their lot with Pfeiffer’s bacillus. Studies in the early 1920s generated more contradictory evidence and uncertainty. In clinically defined outbreaks of influenza investigators often found the bacillus in abundance in one locale but not in another. ‘Clinical influenza,’ noted J.W. Edington in an investigation of influenza in Canterbury, Dover, Shorncliffe, and Hythe in 1920, ‘may be due to more than 1 variety of infecting organism.’94 Even when the bacillus was isolated from large numbers of sufferers, investigators hesitated to conclude that it was the primary cause. During a widespread epidemic in January 1922, William M. Scott, a leading Ministry of Health bacteriologist, found the bacillus in sixty-five per cent of cases of influenza and influenza pneumonia, but cautioned that ‘the presence of influenza bacilli, even in large numbers, in the discharges or local lesions of respiratory disease is not a sufficient argument on which to establish their primary pathogenic activity, since this correlation may represent a secondary invasion, the consequence of their prevalence in the normal respiratory mucosa.’95 Many simply failed to isolate the bacillus, noting instead the abundance of familiar agents such as pneumococcus, M. catarrhalis and streptococci.96 With the wide availability of effective culture media, such failures could no longer be chalked up to technical incompetence.

93 Francis G. Blake and Russell L. Cecil, ‘Studies in Experimental Pneumonia. IX. Production in Monkeys of an Acute Respiratory Disease Resembling Influenza by Inoculation with Bacillus Influenzae’ Journal of Experimental Medicine 32.6 (1920), 691–717; ibid., ‘Studies in Experimental Pneumonia. X. Pathology of Experimental Influenza and of the Bacillus Influenzae Pneumonia in Monkeys’, Journal of Experimental Medicine 32.6 (1920), 719–744. 94 J.W. Edington, ‘An Investigation into the Causal Organism of Influenza’, Lancet, (14 August 1920), 340. 95 W.M. Scott, ‘Observations on the Distribution and Serological Characters of Influenza Bacilli’, Ministry of Health Reports on Public Health and Medical Subjects, No. 13 (London: HSMO 1922), 76. 96 C.F.T. East, ‘Pneumococcal Influenza’, BMJ , 2 (1922), 1117.

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In some quarters, doubts were raised about whether the cause of influenza could ever be found. In an authoritative review, Robert Donaldson, Director of Pathology at St. George’s Hospital in London, observed that there were no good empirical grounds to support either a filterable virus or Pfeiffer’s bacillus.97 He agreed with criticisms of the filterable virus, but found little to support Pfeiffer’s bacillus. While frequently identified in post-mortem studies, most inoculation experiments failed to produce a characteristic lesion in laboratory animals.98 This strongly suggested that it was a secondary infection. Donaldson challenged the idea that a causal inference could be drawn from its apparently high incidence during the 1918 autumn wave. ‘We are not at liberty to claim, that because an organism is always present, it is therefore necessarily the cause.’99 Proponents of Pfeiffer’s bacillus had mistaken an association for a cause.100 These uncertainties were soon reflected in official public health policy. When the Ministry of Health issued its first memorandum on influenza since the pandemic, it conceded that ‘no conspicuous advance has been made recently in our knowledge of the bacteriology of influenza’, and that ‘the claims for Pfeiffer’s bacillus are now put forward in a somewhat temperate fashion, with the admission that they are not fully substantiated.’101 Having lost its privileged position as the specific cause of influenza, B. influenzae was recast as a ‘secondary invader’. William Scott was among a number of bacteriologists who argued that it played a significant role in the most serious respiratory complications, a view that gained traction in the 1920s.102 Surveys of its prevalence confirmed its

97 R. Donaldson, ‘The Bacteriology of Influenza—With Special Reference to Pfeiffer’s Bacillus’, In Influenza: Essays by Several Authors, 139–213. 98 H.B. Maitland and G.C. Cameron, ‘The Aetiology of Epidemic Influenza: A Critical Review’, Canadian Medical Association Journal, XI, (1921), 492. 99 Donaldson, ’The Bacteriology of Influenza’, 158. 100 For a discussion of Donaldson’s analysis of Pfeiffer’s bacillus, see Tan von Helvoort,

‘A Bacteriological Paradigm in Influenza Research in the First Half of the Twentieth Century’, History and Philosophy of the Life Sciences, 15 (1993), 8–10. 101 NA MH/55 57 Memorandum on Influenza (Revised Edition), 1927; MH/55 57 Influenza and Common Colds, 1920. 102 W.M. Scott, ‘The Influenza Group of Bacteria’, In P. Fildes, P. & J.C.G. Ledingham (Eds.), A System of Bacteriology in Relation to Medicine (London: HSMO, 1929), 326– 394.

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wide distribution in both the sick and healthy, and in a range of other conditions, including tuberculosis, bronchitis, measles, and whooping cough.103 Its ubiquity in the respiratory tract of the healthy suggested that it also could exist in a carrier state, which explained why it seemed to crop up almost everywhere and how it could become an opportunistic infection. Reframing B. influenzae as a secondary infection meant that it remained an important focus of influenza research and prevention. Another important reason for continuing interest was the use of the bacillus as a crucial element in vaccines and therapies. Despite the limited evidence for their effectiveness in preventing influenza, demand for prophylactics remained high among medical professionals and the public. The Ministry of Health’s Pathological Laboratory continued to produce mixed influenza vaccines aimed at reducing secondary infections, with B. influenzae a key constituent, along with pneumococcus and streptococcus. The bacillus was included in Ministry vaccines because of its presumed ‘association with influenza, and of its being a factor of primary importance in the production of fatal sequelae.’104 Based on this thinking, mixed bacterial vaccines were supplied to local authorities and schools while the vaccine departments of the Army, Navy and Air Force did the same for military populations. Alongside government suppliers a large market for commercial influenza vaccines also developed. Lucrative and highly competitive, through the 1920s it was dominated by Almroth Wright’s Inoculation Department at St. Mary’s Hospital in London. As it had before the pandemic, Wright’s Department mass-produced preventive ‘mixed’ influenza and anti-catarrh vaccines for Parke Davis and Company, which had exclusive purchasing arrangements with the London County Council, local authorities and, when extra supplies were needed, the armed forces. To take advantage of increased public demand, the Department prioritised improving vaccine manufacture, particularly methods of cultivating and purifying B. influenzae. Alexander Fleming, who had first started working on the bacillus during the pandemic, led these efforts.105 Fleming had returned to the subject when he and 103 Scott, ‘The Influenza Group of Bacteria’ and Scott, ‘Observations on the Distribution and Serological Characters of Influenza Bacilli’, 76–89. 104 Ministry of Health, Memorandum on Influenza, 1927 (revised 1929). 105 A. Fleming, ‘On Some Simply Prepared Culture Media for B. Influenzae, with a

note regarding the agglutination reaction of sera from patients suffering from influenza to this bacillus’, Lancet (25 January 1919), 138–39; A. Fleming and F.J. Clemenger,

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Leonard Colebrook began developing new influenza vaccines after the war. Treating B. influenzae as a secondary infection, they concentrated on improving ways of isolating and purifying it for a mixed ‘Anti-Influenza Vaccine.’106 It was from this research that Fleming chanced upon a mould growing in a staphylococcus culture, which he later identified as Penicillium notatum. Fleming and his colleagues attempted to isolate and purify the mould, but not so much for its potential uses as an ‘antibiotic’ but for controlling bacterial growth in cultures, and particularly to better isolate B. influenzae.107 The mould made it easier to grow large quantities of the bacillus for mixed vaccines. Fleming also promoted penicillin as useful for the identification and surveillance of the bacillus in suspected influenza outbreaks. As Wei Chen has argued, framing penicillin in this way reflected the practical orientation of Wright’s laboratory enterprise and the importance placed on influenza vaccines as commercial products.108 If the pandemic had increased demand for these products, then Parke Davis and Company ensured that the ‘Spanish Influenza’ figured centrally in its advertising campaigns for Wright’s mixed vaccines as both a prophylaxis against and treatment for seasonal and epidemic influenza. Whatever the limitations of these vaccines, scientific and commercial commitments to their continued development ensured that B. influenzae and the recent pandemic remained a prominent part of medical research and approaches to influenza.

3

Experimentalising Pathology

While the MRC supported ongoing work on the bacillus, its commitments lay with developing virus research to resolve questions about the specific cause and potential control of influenza. The scheme it began to assemble in 1922 coupled together the goal of determining the role of

‘An Experimental Research into the Specificity of the Agglutinins Produced by Pfeiffer’s bacillus.” Lancet (15 November 1919), 869–871. 106 Wei Chen, ‘The Laboratory as Business: Sir Almorth Wright’s Vaccine Programme

and the Construction of Penicillin’, In A. Cunningham and P. Williams (Eds.), The Laboratory Revolution in Medicine (Cambridge: Cambridge University Press, 1992), 277. 107 A. Fleming, ‘On the Antibacterial Action of Cultures of a Penicillum, with special Reference to Their Use in the Isolation of B. influenzae’, British Journal of Experimental Pathology, X (1929), 226–234; W. Chen, ‘The Laboratory as Business’, 287–292. 108 W. Chen, ‘The Laboratory as Business’, 245–292.

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viruses in major diseases with the goal of transforming the organisation and role of basic sciences in medical training, practice, and research.109 For Fletcher, the pandemic underscored the particular need to modernise pathology.110 In his first annual report after the war, he characterised British pathology as an anathema to experimental science.111 Unlike physiology, which had generated researchers, discoveries, and university departments of international importance, pathology lacked an experimental orientation and a place in universities. In hospitals, medical schools, and public health, its practitioners played a service role, generating income but little new research and few trained researchers.112 Modern Britain, Fletcher insisted, needed a pathology based on experimental principles and located in dedicated laboratories, funded by the state, and coordinated by experts.113 Immediately after the war, Fletcher pressed universities and medical schools to free pathology from clinical and commercial demands and to establish it as an academic discipline. The campaign bore mixed results. Largely for reasons of economic necessity, provincial universities and medical schools maintained the service orientation of pathology laboratories, with experimental work more often pursued in conjunction with routine work.114 Despite these obstacles, Fletcher did succeed in creating new pathology departments at Oxford and Cambridge, with aid of large benefactions from the Dunn Trustees and Rockefeller Foundation respectively.115 But the most important site for realising the MRC’s vision was the NIMR. 109 Austoker, ‘Walter Morley Fletcher and the Origins of a Basic Biomedical Research Policy’, 22–33. 110 Medical Research Council, Report of the Medical Research Council for the Year 1922–1923 (London: HMSO, 1924), 14–22. 111 Medical Research Council, Report of the Medical Research Council for the Year 1919–1920 (London: HMSO, 1921), 1–12. 112 R.E. Kohler, ‘Bacterial Physiology: The Medical Context’, Bulletin of the History of Medicine, 59 (1985), 55–56. 113 Alter, The Reluctant Patron, pp. 127ff. 114 Steve Sturdy, ‘The Political Economy of Scientific Medicine: Science, Education

and the Transformation of Medical Practice in Sheffield, 1890–1922’, Medical History, 36 (1992), 125–159. 115 Medical Research Council, Report of the Medical Research Council for the Year 1922– 1923, 16; Mark Weatherall, Gentlemen, Scientists, and Doctors: Medicine at Cambridge, 1800–1940 (Rochester, NY: Boydell Press 2000), 169–172.

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The idea of the Institute was born with the creation of the MRC, but only after the war was it established as the flagship for British medical science (Fig. 4). Occupying Mount Vernon Hospital in leafy Hampstead in North London, built between 1880 and 1900 and purchased by the MRC in 1914, originally the Institute was to be directly modelled on the RIMR in New York.116 The MRC had incorporated important aspects of the Rockefeller approach into its plans—particularly the positioning of experimental sciences as foundational to medical education and to the production of medical knowledge and therapeutics—and it depended on Rockefeller Foundation patronage.117 Yet the MRC research system and NIMR itself was also adapted to the British context, where the state and clinical medicine played important roles in shaping policy.118 As in Germany, which had been an important model for modernisers like Fletcher before the war, the MRC made government an active agent of change and used its own authority and institutions to pursue its agendas. The NIMR was crucial to the MRC mission. Early on it was decided that it would have no formal affiliation with hospitals nor a clinical wing of its own (as the RIMR had) but would rather serve as an independent government research institution. Its primary function was to foster scientific medicine based on principles of teamwork, which prioritised research that straddled disciplinary boundaries.119 ‘It is a chief characteristic of the work [at the NIMR]’, Fletcher noted in his 1922 Annual Report, 116 Austoker and Bryder, ‘The National Institute for Medical Research’, 39–52; C.H. Harrington, ‘The Work of the National Institute for Medical Research’, Proceedings of the Royal Society of London, 136 (1950), 333–349. Thomson, Half a Century of Medical Research, Vol. 2, 110–11. 117 Austoker, ‘Walter Morley Fletcher and the Origins of a Basic Biomedical Research Policy’, 27; Fisher, ‘The Rockefeller Foundation and the Development of Scientific Medicine in Britain’; L. Wilkinson, ‘Burgeoning Visions of Global Public Health: The Rockefeller Foundation, the London School of Hygiene and Tropical Medicine, and the ‘Hookworm Connection’, Studies in History and Philosophy of Biological and Biomedical Sciences, 31 (2000), 397–407. 118 Alter, The Reluctant Patron, p. 127. 119 For teamwork as an organisational principle in interwar British medicine, see Andrew

Hull, ‘Teamwork, Clinical Research, and the Development of Scientific Medicines in Interwar Britain: The “Glasgow School” Revisited’, Bulletin of the History of Medicine, 81 (2007), 569–593; Roger Cooter, ‘Keywords in the History of Medicine: “Teamwork”’, Lancet, 363 (2004), 1245; Steve Sturdy, ‘Scientific Method for Medical Practitioners: The Case Method of Teaching Pathology in Early Twentieth-Century Edinburgh’, Bulletin of the History of Medicine, 81 (2007), 760–792.

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Fig. 4 National Institute for Medical Research—Hampstead (Front View) (Source Wellcome Library)

‘that its division under nominal departments is made only for administrative and technical reasons, and does not impede the ready association of men of varied scientific equipment in joint investigation or in organised team work.’120 Experimental pathology was one of its cornerstones.121 The task of building this area of research initially came under the remit of the Department of Bacteriology, one of four departments dedicated to applying laboratory science to medical and biological problems. In its first years, the Department searched for a programme to mark out its identity. Until 1922, it stuck closely to serological work on bacterial infection and immunity pioneered by Wright at St. Mary’s. Wright had directed the MRC’s bacteriological research during the war and had been

120 Medical Research Council, Report of the Medical Research Council for the Year 1921–1922 (London: HMSO, 1923), 23. 121 Austoker and Bryder, ‘The National Institute for Medical Research’, 35–38; Thomson, Half a Century of Medical Research, Vol. 1. 108–109.

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poised to become director of the Institute in peacetime, but the offer was never formalised.122 Nonetheless, two of Wright’s men—Leonard Colebrook and S. R. Douglas became permanent NIMR staff and initially stuck closely to his serological programme, collaborating on the development of methods for preparing bacterial culture media to type races of bacteria and to isolate, produce, and test bacterial toxins and antitoxins.123 A serological approach also characterised the work of the two other original members of the Department, the protozoologist, Clifford Dobell, and the chemical pathologist, William Ewart Gye. Dobell had led the War Office Committee on Dysentery and was recruited to develop his research on intestinal protozoa. Gye was brought from the Imperial Cancer Research Fund, where he had started working on chemical problems of cancer but had turned to the serology and chemical bacteriology of anaerobic infections during the war.124 Developing expertise in serology was necessary for establishing the NIMR as the nation’s standard-setting institution for therapeutic substances.125 But while an important practical and investigative resource, serology was never envisioned as the primary focus of the Department’s research. The MRC wanted it to innovate in experimental pathology. By 1921, Fletcher, Douglas, and Henry Hallett Dale, who was appointed as the Institute’s acting director, decided that experimental pathology should be primarily constructed around filterable viruses.126 Part of the rationale for this decision was that filterable viruses represented a unique opportunity to establish British authority in a new area of medical research—an opportunity that most thought had been missed at the end 122 It is likely that Wright’s clashes with the War Office and MRC over the treatment of war wounds, and his own commercial interests, lead to a mutual agreement to withdraw the offer. A.L. Thomson Half a Century of Medical Research, Vol. 1. Origins and policy of the Medical Research Council (UK) (London: MRC, 1973) 112, 115–116. 123 See, Worboys, ‘Almroth Wright at Netley’. Douglas worked closely with Wright at Netley in the development of vaccine therapy and was Assistant Director at the Inoculation Department until 1914. P.P. Laidlaw, ‘Stewart Rankin Douglas, 1871–1936’, Obituary Notices of Fellows of The Royal Society, 2, (1936), 175–182. 124 Christopher H. Andrewes, ‘William Ewart Gye, 1884–1952’ Obituary Notices of Fellows of the Royal Society 8 (1952), 418–430; Joan Austoker, A History of the Imperial Cancer Research Fund, 1902–1986 (Oxford: Oxford University Press, 1988), 16, 62–63. 125 P.M.H. Mazumdar, ‘“In the Silence of the Laboratory”: The League of Nations Standardizes Syphilis Tests’, Social History of Medicine, 16 (2003), 437–459. 126 Dale became the NIMR’s first director in 1928.

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of the nineteenth century in the development of bacteriology. Unlike bacteria, which now could be observed, studied, and managed in a variety of non-specialist settings, filterable viruses were still exclusively experimental entities, which only could be made visible and intelligible under specialised conditions.127 The challenges they posed demonstrated the need for laboratory-based knowledge in general and for an experimental approach to pathology in particular. The Division of Applied Optics, established within the Department of Bacteriology in 1920, would play a key role. Headed by the west-end hatter and microscopist, Joseph E. Barnard, the scheme tasked the Division to develop new microscopic instruments and techniques that researchers at the Institute, across London, and throughout the country could use to make suspected viruses visible. Filterable viruses were seen as ideal agents for building a cuttingedge research programme at the NIMR dedicated to transforming the experimental and technical foundations of pathology. This vision for virus research gained considerable support from the new British Journal of Experimental Pathology.128 Established in 1920 by researchers closely allied to the MRC, the journal emphasised the special nature of experimental pathology and its role as a foundation for medical knowledge and practice.129 The editorial committee, led by Paul Fildes, described the BJEP ’s mission as providing an alternative to observational research based in the morbid anatomy, clinical pathology and epidemiology of infectious disease. Fashioned on the Rockefeller-funded Journal of Experimental Medicine, it aimed to publish ‘original communications describing the techniques and results of experimental research into the causation, diagnosis, and cure of disease in man.’130 No one discipline defined this approach. Experimental pathology was to join together ‘bacteriological, biochemical, pharmacological, physiological, serological and other subjects’ in the production of new pathological knowledge.131 127 For the transformation of bacteriology into a ‘popular science’ in Britain, see Rosemary Wall, Bacteria in Britain, 1880–1930 (London: Pickering & Chatto, 2013). 128 R.M. Hicks, ‘Journal of Experimental Pathology: The Journal Comes of Age’, British Journal of Experimental Pathology, 71 (1990), i–iv. The BJEP ran from 1920–1990, after which it was renamed the Journal of Experimental Pathology. 129 The first editorial board included Fildes, McIntosh, J.A. Murray, and W.E. Gye. 130 Paul Fildes, ‘Unititled Editorial’, British Journal of Experimental Pathology, I

(1920), i. 131 Ibid., i.

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Multidisciplinary in character, it was bound together by the core principle of specific aetiology—that every disease had a specific cause that could be determined by means of laboratory investigation. The BJEP played a crucial role in allying virus research with experimental pathology. Most of what the journal published on the subject in the 1920s took it as paradigmatic that studying viruses depended on experimental pathological analysis of virus diseases in laboratory animals. The histological lesion produced by virus infection in specific cells constituted the virus worker’s primary research object: when experimentally induced, the lesion signified the presence of the agent; it was a source of virus material for microscopic examinations and serial passage experiments; it was the basis for serological tests, for quantifying virus, and for evaluating the potency of virus antiserums and vaccines; and it served as a model of the disease under study. This approach was strongly comparative, in three important senses: first, it involved using laboratory animals as proxies for humans, on the assumption that disease processes in both followed similar laws; second, it involved reasoning analogically between the experimental (animal) and clinical (human) disease, with the aim of establishing an identity between the two; and finally, it involved studying pathological lesions and processes in a wide range of non-human animals to establish the best analogue. The American virus researcher, Thomas Rivers, characterised this approach as being based on composing and decomposing ‘pathological pictures’ of viruses in animal and human bodies. Human and animal virus research supported a particular kind of perception in which the material definition of a virus was intimately connected to the disease it produced.132 A crucial part of a virus worker’s training and research thus involved learning to produce, see, judge, and manipulate experimentally-induced lesions in the living tissue of research animals. As it became evident that viruses could not be straightforwardly isolated with bacteriological methods and that their pathophysiology and biology were entangled with the living tissue of the lesion, virus workers increasingly identified themselves as ‘experimental pathologists’ rather than as bacteriologists.

132 Thomas M. Rivers, ‘Some General Aspects of Filterable Viruses’, In T.M. Rivers (Ed.), Filterable viruses, (London: Bailliere, Tindall & Cox, 1928), 3–52.

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4

The Virus Scheme

Fresh attempts to study the suspected influenza virus underscored the pressing need for the MRC virus scheme. Two years before the inception of the scheme, the MRC had started funding new influenza work by Mervyn H. Gordon at the Department of Pathology at St. Bart’s Hospital. An enthusiastic researcher, Gordon had worked in the Department since 1908. Early on, he was drawn to testing the idea that filterable agents might be the causes of high-profile infectious diseases for which bacterial agents could not be found. In 1912, with support from the LGB, he confirmed the claim made by the Viennese pathologists Karl Landsteiner and Erwin Popper that a filter-passer played a primary role in poliomyelitis.133 In 1914, he announced that he had successfully isolated a filter-passer from cases of mumps.134 When he returned to filter-passer work after the war, he and his director, F.W. Andrewes, decided to focus on influenza. Andrewes was by now an influential figure in London medical research circles, including the MRC, with a career reaching back to the 1880s. Having assisted Edward Klein in the LGB’s first bacteriological studies of Pfeiffer’s bacillus in 1891, he had a longstanding interest in influenza. Crucially, however, during the 1918-19 pandemic he became convinced that a filterable virus rather than the bacillus held the keys to influenza’s aetiology, a view he presented in his chapter on the bacteriology of influenza in the 1920 Ministry of Health Report on the Pandemic of Influenza, and which he pressed in his role as an advisor to the MRC.135 An important impetus for Gordon’s research was a widely reported discovery by two Rockefeller pathologists, Peter K. Olitsky and Frederick L. Gates, of an alleged ‘new’ filter-passing agent from cases of

133 Mervyn H. Gordon, ‘Notes on Acute Poliomyelitis with Reference to its Etiology, Histology, and as to Immunity’, Reports of Local Government Board, Medical Officer (London: Local Government Board, 1911–12), 115–121. 134 Mervyn H. Gordon, ‘On Experimental Investigations in Relation to Mumps or Epidemic Parotitis, Reports of Local Government Board, Public Health, New Series, 96 (London: Local Government Board, 1914). 135 Fredrick W. Andrewes, ‘The Bacteriology of Influenza’, in Report on the Pandemic of Influenza, 1918–19, Ministry of Health, Reports on Public Health and Medical Subjects, No. 4 (London: HMSO, 1920), 110–115.

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influenza.136 Working at the RIMR, Olitsky and Gates first identified the agent during the pandemic. In May 1920 they reported a new technique that enabled them to produce and serially transmit a ‘definite and characteristic’ infection in rabbits. Like human influenza, the experimental infection was localized in rabbits’ lungs, from where they isolated an agent. To establish its filterability, they passed solutions of ground lung material through grades of Berkefeld filters, and then used the filtrate to reproduce the infection in healthy rabbits. They also employed a special method for cultivating the agent, developed in 1911 by their colleague, the Japanese-born bacteriologist, Hideyo Noguchi. The socalled ‘Noguchi’ medium was composed of fresh rabbit liver tissue, set in narrow glass tubes, sealed with wax and vaseline.137 Rockefeller researchers had used the medium in studies of the common cold, as had British researchers at Étaples in their influenza work. According to Olitsky and Gates, the medium enabled them to make pure cultures of the agent, to photograph it, and to study its properties. A testament to their belief that they had found the specific cause of influenza, in a further fourteen papers published between 1920 and 1923, they detailed its morphological, pathogenic, and serological characteristics. They concluded that it was a minute organism, with particular affinity for the lungs, and accordingly named it, Bacterium pneumosintes —‘a bacterium that injures the lung’.138 The American researchers’ animal experiments and culture system appeared to solve the two fundamental methodological problems that had hampered filter-passer studies in 1918: they had an experimental animal—the rabbit—and a culture system for growing the agent in vitro. Yet, the reception of their research among supporters of the filter-passer theory was cautious. Gordon, for one, believed they had simply identified an agent like that identified by British workers in 1918, and had

136 P. Olitsky and F.L. Gates, ‘Experimental Study of the Nasopharyngeal Secretions from Influenza patients: Preliminary Report’, Journal of the American Medical Association, 74 (1920), 1497–1499. 137 Hideyo Noguchi, ‘A Method for the Pure Cultivation of Pathogenic Treponema Pallidum (Spirochata Pallida)’, Journal of Experimental Medicine, 14 (August 1911), 99– 108. 138 Peter Olitsky and F.L. Gates, ‘Methods for the Isolation of Filter-passing Anaerobic Organisms: From Nasopharyngeal Secretions’, Journal of the American Medical Association, 78 (April 1922), 1020–1022.

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only ‘added precision’ to these original studies.139 He tested their claims during an influenza epidemic in late December 1921. Using the Noguchi method, he ran bacteriological tests on nasal and throat washings of staff at St Bart’s and the Ministry of Health.140 In early January he reported to Landsborough Thomson, Assistant Secretary to the MRC, that ‘something very like [Olitsky and Gates’] filter passer is coming up in my cultures.’ The agent also looked like the one identified by British workers in late 1918.141 But Gordon admitted that ‘rendering the filterable organism was difficult’, because its presence was only indicated by a rather vague ‘cloudiness near the piece of kidney at the foot of the [Noguchi] tube.’ It became visible when Gordon made films of material that had been fixed, stained, and chemically differentiated. These procedures yielded ‘swarms of minute round bodies’, but they were so small that they could be ‘very easily missed unless especially looked for’ and might be dismissed ‘by an inexperienced observer’.142 Unlike Olitsky and Gates, Gordon was unable to induce an experimental disease in rabbits or any other animal. He was, however, able to see the pathogen. Gordon had Barnard’s Division of Optics at the NIMR produce photomicrographs of the culture and slide preparations to compare their morphology with those described by the British and Americans (Fig. 5). The images did little to resolve his uncertainties. It was unclear if the agent was a ‘coccoid’ or a ‘baccilloid’. Moreover, when he consulted existing literature on filter-passers, he was struck by their morphological similarity with bodies found in other diseases. These problems raised rather than settled questions about the filterpasser’s identity. The most vexing centred on its nature and classification. Gordon and his American counterparts reckoned that it was a filterable organism. Its ‘prodigious multiplication’ convinced them that it was living and not, as earlier critics had claimed, a protein.143 This aligned it with the dominant view of filterable viruses in medical and veterinary 139 Mervyn H. Gordon, ‘The Filter Passer of Influenza’, Journal of the Royal Army Medical Corps, 39 (1 July 1922), 6. 140 Gordon, ‘The Filter Passer of Influenza’, 7, 10. 141 NA, FD1/1297 Gordon to Thomson, 11 January 1922; Gordon to Fletcher, 3

February 1922. 142 Gordon, ‘The Filter Passer of Influenza’, 9. 143 M.H. Gordon, ‘The Filter Passer of Influenza’, Journal of the Royal Army Medical

Corps, 39, (1922), 400.

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Fig. 5 ‘To Illustrate “The Filter Passer of Influenza”’. Photomicrograph taken for M.H. Gordon by J.E. Barnard at the NIMR in early 1922, of a film of Gordon’s filter-passer grown ‘in pure culture’ in Noguchi medium, which had been inoculated with filtrates of diluted nasal secretions from a nurse at Barts suffering from flu. After a fortnight, material from the base of the culture was examined for bacteria, diluted, spread on a coverslip and dried. The film was fixed and stained, before being photographed (Source M.H. Gordon, ‘The Filter Passer of Influenza’, Journal of the Royal Army Medical Corps , 39 [1922], 11)

pathology: the ability of these agents to multiply, demonstrated by the ability to produce disease, was evidence of their basic biological nature. In effect, filterable viruses were akin to and thus could be treated as a unique type of bacteria. This biological theory was not the only one available for explaining filterable viruses. An important alternative approached them as chemicals, and thus differentiated them from living pathogens.144 This theory had various roots, but in British pathology it was most influenced by Twort’s characterisation of the bacteriophage as a chemically-induced lytic

144 Creager, Life of a Virus, 19, 32–38.

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phenomenon.145 H.M. Woodcock, head of the Department of Protozoology at the Lister Institute, enlisted Twort’s concept to challenge Gordon.146 Woodcock accepted the existence of a pathogenic ‘virus’, but not that it was living. He argued that those who viewed influenza virus as a micro-organism had no direct method for distinguishing it from protein particles. Gordon’s photomicrographs did not support this conclusion. Quite the contrary, on their staining properties and physical appearance in photomicrographs, they looked more like typical ‘protein enzymes’, the result of the breakdown of cell material by a ferment.147 If these bodies were indeed the cause of influenza, Woodcock argued, they were not exogenous organisms but by-products of an endogenous chemical process occurring within human cells. These arguments spilled into a general debate about viruses and virus diseases, and the experimental methods used to elucidate them. Through the early 1920s, the MRC organised several discussions on the state of virus research. The many research challenges were brought to the fore in July 1922 at a special panel on the ‘Bacteriology of Influenza’ at the annual meeting of the British Medical Association in Glasgow. Concentrating on Gordon’s work, discussants probed his filter-passer. James McIntosh recapitulated the view that all studies had failed to establish its pathogenic identity. Sympathetic researchers observed that neither adequate methods nor criteria were available for determining its nature. Charles Ledingham, head of bacteriology and of a new virus program at the Lister Institute, argued that the greatest difficulty remained ‘the lack of any animal, other than man, [that] was readily susceptible to the causal agent.’ Poor filtration methods were identified as another obstacle. J.H. Dible, junior lecturer in pathology at Manchester University, noted that filtration was ‘extremely crude’; bacterial filters were ‘not reliable’ and the criteria for deeming an agent ‘filterable’ depended on an inexact calculation of the relationship between the largest hole in the filter and the smallest bit of protoplasm being filtered; much of the process was left

145 F.W. Twort, ‘An Investigation of the Nature of Ultramicroscopic Viruses’, Lancet, (4 December 1915), 1241–1243. 146 H. Chick, M. Hume & M. MacFarlane, War on Disease, 74. 147 Creager Life of a Virus, 32–33.

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to chance. F.W. Twort stressed the need for standard methods of filtration. Leishman, who chaired the meeting, concluded that, the status of the filter-passer remained a ‘big unsolved problem’.148 The BMA meeting made one thing clear: too little was known about the general category of viruses to determine the identity of one. ‘[The] search for the primary infective agent in influenza,’ agreed Gordon, ‘has led us into the realm of filter-passers’, a realm rife with new problems.149 Supporters of the filter-passer theory viewed these problems as features of an emerging field of experimental research, the boundaries of which urgently needed to be defined. As Fletcher noted, ‘for new progress in this field, every effort must be made to enlist new weapons in the shape of new technical methods of investigation.’150 This was precisely the task of the MRC virus scheme. Meetings through spring and summer 1922 were taken up with practical questions concerning the organisation of the scheme. The NIMR was established as its institutional hub and charged with, among its primary goals, developing a programme on human and animal virus diseases that linked virus workers to medical and veterinary institutions in London and across Britain.151 At the NIMR, researchers trained in pathology, bacteriology, biochemistry, physics, and microscopy were to be responsible for generating new disease models, skills, instruments, and expertise for the general study of viruses and virus diseases, while associated workers such as Gordon were to draw upon and contribute to this resource by developing and applying virus research to diseases of specific medical

148 ‘Meeting of the British Medical Association—Bacteriology of Influenza’, Lancet (2

September 1922), 516–518. Dible worked under H.R. Dean, who had been appointed to the chair of pathology at the University of Manchester in 1915 and was part of the network of pathologists the MRC organised to coordinate clinical-pathological studies in the event of influenza epidemics. J. Mills, ‘James Henry Dible 29 October 1889–1 July 1971’, Journal of Pathology and Bacteriology, 111 (1973), 65–76. 149 Gordon, ’The Filter Passer of Influenza’, 11. 150 Medical Research Council, Report of the Medical Research Council for the Year

1922–1923, 11 151 A.L. Thomson, Half a Century of Medical Research. Origins and Policy of the Medical Research Council (UK), Vol. 1, (London: HMSO, 1973), 120–123; A.L. Thomson, Half a Century of Medical Research. The Programme of the Medical Research Council (UK), Vol. 2, (London: HMSO, 1975), 114–129.

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interest.152 Fletcher stressed the importance of working on virus diseases of recognised medical value: ‘The choice for investigation of one or more of the acute infectious fevers of man, reputed to be due to filter-passing organisms, would have the advantage of direct practical application to human medicine.’153 From the outset, emphasis was placed on the translation of laboratory research into clinical and public health knowledge and practice. A key priority was to recruit a highly skilled and inventive experimentalist to oversee the complex demands of virus work at the NIMR. Dale later recalled that they wanted someone ‘with good experience in infective pathology, but especially one who had also the breadth of scientific discipline, the versatile ingenuity and the quickness of imagination, which might all be needed to advance into a new territory by methods yet to be discovered.’154 Dale recruited Patrick Laidlaw for the job (Fig. 6). A respected Cambridge-trained biochemist and pathologist, who qualified in medicine at Guy’s Hospital, Laidlaw had collaborated with Dale at the Wellcome Physiological Laboratories in the early 1900s on studies of the actions of histamine, before being appointed to the William Dunn lectureship in pathology at Guy’s in 1913. Preferring the bench to the office desk, he embraced the opportunity.155 Along with developing the Institute’s program, Laidlaw was tasked with positioning it as the centre for virus research for the nation. Under the scheme it was agreed that Gordon would continue working on influenza at Barts, while Twort would concentrate on vaccinia at the Brown Animal Sanatory Institution, with ongoing support from the NIMR. Close connections were maintained with Ledingham’s bacteriology department at the Lister Institute, which was developing a program on vaccinia and variola, as well as on foot-and-mouth virus.156 The focus on virus diseases of practical medical value drove efforts to develop links 152 NA FD1/1279 Virus research; Medical Research Council, Report of the Medical Research Council for the Year 1921–1922, 11–13. 153 NA FD1/1279 ‘Virus research’, 3 May 1922. 154 H.H. Dale, ‘Patrick Playfair Laidlaw’, Obituary Notices of Fellows of The Royal

Society, 3 (1941), 430. 155 H.C. Cameron, ‘Patrick Playfair Laidlaw’, Guy’s Hospital Reports, 90 (140–41)

1–14. 156 Abigail Woods, A Manufactured Plague? The history of foot and mouth disease in Britain (London: Earthscan, 2004).

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Fig. 6 Patrick Playfair Laidlaw, F.R.C.P., F.R.S. (1881–1940), Obituary Notices of Fellows of the Royal Society, 3.9 (1941), 427–447

with the Metropolitan Asylums Board, which controlled London’s isolation hospitals.157 The MAB was not under the control of the Ministry of Health, so collaboration represented a way to circumvent Newman’s interests. The MAB offered the MRC use of its various hospital facilities for research.158 Since the NIMR had no affiliated hospital, this was an

157 Brand, Doctors and the State, 75–84. 158 Bryder, ‘Public Health Research and the MRC’, 60, 75; ‘Pathological Research

Under the Metropolitan Asylums Board’, BMJ (14 May 1927), 882–883.

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opportunity to bring together virus researchers, pathologists, and physicians, and to gain access to patients suffering with suspected virus diseases ‘for the supply of [infective] material necessary for experimental investigation.’159 In return, the NIMR accommodated a MAB pathologist who coordinated joint studies on measles, scarlet fever, and the role of herpes virus in encephalitis lethargica. For Fletcher, collaboration lay at the heart of the scheme, both inside and outside the NIMR’s walls: ‘[The Council] hope that … [new technical methods] may result from co-operation in their National Institute and outside it between biochemists, physicists and pathologists who have been selected for the work, and that these studies may be brought into increasingly effective union with work which has been arranged at fever hospitals under the Metropolitan Asylums Board and elsewhere.’160 Signalling the new direction at the NIMR, the Department of Bacteriology was renamed the Department of Bacteriology and Experimental Pathology, with emphasis on the latter and priority given to producing basic knowledge of viruses and virus diseases.161 Along with its central role in developing medical virus research in Britain, the Department also developed a close working relationship with the RIMR, sending researchers to New York to be trained, exchange materials, tools, and ideas. Dale reckoned the virus program would put the NIMR at the cutting-edge of pathological science, making it one of only a handful in the world specialising in this nascent field.162

5

Uses of the Pandemic

The 1918–19 pandemic was a crucial factor behind the development and organisation of British medical virus research. It transformed influenza’s social and medical identity. Before the pandemic, influenza had been seen as a familiar and inescapable malady. Capable of affecting upwards of twenty-five per cent of an urban population, it was nonetheless deadly for only a small proportion of the aged, infirm, and very young. But after 1918, it also became viewed as a major threat to modern life. The Proteus

159 NA FD1/1297 Virus research, 3 May 1922. 160 Medical Research Council (1923), p. 12. 161 NA FD1/1297, 17 June 1922. 162 NA FD1/1297 Virus research, 17 June 1922.

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had become Janus-faced: influenza could appear as a mild annual malady that almost everyone could catch; but, without warning, it also could become a deadly global epidemic. Medical and public health authorities had no means to predict which face influenza would present in a given year and they had no effective preventive tools. Approaches still relied on models constructed a quarter-century earlier. Measures aimed to control transmission through vaccination, disinfection, and limited restrictions on gathering in public or in institutions, but in the absence of a known cause, these proved inadequate. Concerns about the recurrence of another pandemic spurred the Ministry of Health and the MRC to search for new approaches. Whereas the Ministry prioritised public health strategies based on a combination of epidemiological and bacteriological knowledge and practices, the MRC prioritised laboratory-based strategies based on determining and controlling the specific cause(s) of influenza. While the two government bodies found ways to collaborate, early on the MRC decided to forge a separate path, directed towards viruses and their possible role in the pandemic. By late 1922, it had set in place the key pieces for building virus research into a new experimental science for combatting disease and modernising pathology. Its formation was a crucial part of MRC efforts to wrest authority for medical scientific research from the Ministry of Health. These efforts proved successful. When Fletcher and Newman signed a ‘concordat’ in 1924, the MRC assumed formal responsibility for the planning and direction of all biomedical research, while the Ministry was to concern itself with epidemiological and clinical problems relevant to public health.163 An important effect of this arrangement was that the Ministry increasingly relied on the scientific advice of the MRC in developing its approaches, including those for influenza.164 The MRC’s ability to rally support for its virus research scheme was importantly tied to how it mobilised the experience of the 1918-19 pandemic. The genesis of the scheme can be traced to the battlefields of the First World War, to military pathology, and to debates over influenza’s aetiology during and after the pandemic. The scheme shows that the experiences and memories of the pandemic played key roles in efforts 163 NA MH 123/498 Relations between the Ministry of Health and the Medical Research Council, 12 February 1924. 164 Helen Valier and Carsten Timmermann, ‘Clinical Trials and the Reorganization of Medical Research in post-Second World War Britain’, Medical History, 52 (2008), 497.

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to transform medical research in Britain. Failure to master influenza in 1918-19 spurred the MRC to improve and expand laboratory-based medical science. Fletcher made strategic use of the pandemic to justify a new focus on viruses as potential causes of a host of major diseases. The MRC valued these entities for the multiple roles they could play in modernising pathology. From a research perspective they were especially attractive because of their novelty and esoteric status. As disputes over influenza’s aetiology demonstrate, the basic nature of filterable viruses and the disease processes they produced represented both fundamental and highly practical problems that could only be tackled by developing more effective laboratory knowledge. Fletcher never hesitated to point out that without such knowledge medicine would be helpless against a class of diseases that threatened the nation and all humanity. As complex problems, viruses and virus diseases demanded an approach that involved transforming pathology into an experimental science and linking it to the needs of clinical and public health medicine. Under the MRC programme, this approach came to be defined as ‘experimental pathology’.165 Medical virus research grew out of a bacteriological paradigm, organised around the concept of viruses as pathogenic microorganisms. But it also broke with the practical and conceptual constraints of this paradigm. As several historians have shown, interwar virus work depended on the exchange of chemical, bacteriological, biological, and pathological practices, and supported a range of virus concepts.166 In Britain, experimental pathology served as an umbrella for linking together these heterogenous practices and concepts. Virus workers identified themselves as ‘experimental pathologists’ rather than as bacteriologists. This distinction took on important meaning as it became evident that viruses resisted key bacteriological methods because they differed in their basic nature from bacteria. In turn, virus researchers were forced to develop specific skills and knowledge appropriate to studying these agents.167 Work on viruses

165 For the term’s history, see Bynum ‘“C’est un malade”: Animal Models and Concepts of Human Diseases”. 166 Creager, Life of a Virus, 33. 167 P.P. Laidlaw, Virus Diseases and Viruses, The Rede Lecture (Cambridge: Cambridge

University Press, 1938); T.M. Rivers (1928a). ‘Filterable Viruses’, In E.O. Jordan & I.S. Falk (Eds.), The New Knowledge of Bacteriology and Immunology (Chicago: University of Chicago Press, 1928); T.M. Rivers, ‘Some General Aspects of Filterable Viruses’, In Rivers, T.M. (Ed.), Filterable viruses (London: Bailliere, Tindall & Cox, 1928), 3–52;

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and virus diseases depended on combining pathological, immunological, biochemical, and physical methods and instruments, which was itself crucial to the scientific identity of medical virus research.168 But these combinations alone were not sufficient to establish virus research as a new medical scientific field. The production of knowledge of viruses and determining their role in human diseases also involved linking together the expertise, skills, and interests of practitioners inside and outside of medicine. How this new approach took form and was put into practice is the subject of the next chapter.

Scott H. Podolsky, ‘The Role of the Virus in Origin-of-Life Theorizing’, Journal of the History of Biology, 29 (1996), 79–126. 168 Creager and Gaudillière, ‘Experimental Arrangements and Technologies of Visualisation’; Daniel J. Kevles and Gerald L. Geison, ‘The Experimental Life Sciences in the Twentieth Century’, Osiris, 10 (1995), 108–120.

CHAPTER 6

Modelling Flu: Dog Distemper and the Promise of Virus Research

In the last chapter we saw how the possible role of a ‘filter-passer’ in the 1918–1919 pandemic spurred the creation of a research programme on diseases caused by filterable viruses at the NIMR. Calculated to raise the status of British experimental pathology at home and abroad, the MRC’s commitment to this programme reflected its broader ambition to position Britain at the leading edge of medical science. While filterable viruses had attracted the attention of medical, veterinary, and biological researchers around the world, at the time only the RIMR in New York had made them a specific focus.1 Even then, there was little consensus about their identity and nature or the best ways to study them. Recognising the potential opportunities of venturing into this domain, Fletcher and his colleagues plotted a strategic course. In what became a pattern across MRC research schemes, an important part of the strategy was to build close working relationships with Rockefeller researchers.2 Drawing on Rockefeller resources and expertise, and working on similar problems, facilitated exchange and collaboration, which the MRC believed was key to generating results and reputation. This strategy was especially important to the development of the MRC virus research scheme. Close working partnerships were viewed as the best 1 Creager, Life of a Virus, 38–42. 2 Lawrence, Rockefeller Money, 11–23.

© The Editor(s) (if applicable) and The Author(s), under exclusive licence to Springer Nature Limited 2023 M. Bresalier, Modern Flu, Medicine and Biomedical Sciences in Modern History, https://doi.org/10.1057/978-1-137-33954-6_6

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way to tackle the many problems these agents posed to laboratory investigation. While the nature of viruses remained in question, by the early 1920s there was growing agreement on the major experimental obstacles in virus research. The most vexing were the resistance of viruses to standard methods of cultivation, light microscopy, and filtration, all of which relied on instruments designed for studying bacteria. One consequence of these obstacles was that workers had no means to directly investigate the basic properties of filterable agents, including their status as forms of life.3 Viruses were initially defined by their negative properties in relation to established criteria for defining bacteria. Historians of virology have argued that medical scientists initially tackled these problems from within a ‘bacteriological paradigm’.4 Tan von Helvoort has shown that those working from bacteriological principles started from the assumption that viruses were pathogenic microorganisms that were typically smaller but not fundamentally different from bacteria.5 Priority was given to developing ways to solve problems of cultivation, visualisation, and filtration in order to determine their role in specific diseases and to produce methods of control and treatment. The prevention of virus diseases was a primary concern. In this framework, questions about the fundamental nature of viruses were addressed through research aimed at translating laboratory results into medical or public health practice. As we have seen with early work on influenza, efforts to make human and animal viruses into workable laboratory objects ran up against the limitations of established bacteriological techniques and concepts. By the early 1920s it had become increasingly evident that the bacteriological paradigm could not provide effective solutions to the most fundamental problems of virus work. This spurred technical innovations and methods that gave rise to new ways of knowing the agents.6 Most important was the conceptualization of viruses as obligate parasites —entities dependent

3 Creager, Life of a Virus, pp. 18–19, 30–31. 4 Tan von Helvoort, ‘A Bacteriological Paradigm in Influenza Research in the First

Half of the Twentieth Century’, History and Philosophy of the Life Sciences, 15 (1993), 3– 21. For similar observations, see: Sally Smith-Hughes, The Virus: A History of a Concept (London: Heineman, 1977); A.P. Waterson and L. Wilkinson, An Introduction to the History of Virology (Cambridge: Cambridge University Press, 1978). 5 Von Helvoort, ‘A Bacteriological Paradigm’, 16–17. 6 For an important analysis, see William Summers, ‘Inventing viruses’, Annual Review

of Virology, 1 (2014), 25–35, esp. 26–27. For virology as a discipline, see Pierre-Olivier

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on living tissue for their multiplication (and, ultimately, for replication). While this concept had been proposed as early as 1900, as more and more researchers ran up against the limitations of bacteriological techniques and developed ways of working with viruses in vivo, it grew into a basic framework that came to be used to demarcate the disciplinary boundaries of virus research.7 Many researchers and institutions contributed to this reconceptualisation of viruses, but the NIMR programme played a leading role. In tackling practical challenges posed by viruses, NIMR workers framed viruses and virus diseases as complex problems that required multidisciplinary collaboration. They generated approaches that drew from disciplines as varied as serology, immunology, chemistry, and physics. They were not alone in taking this multidisciplinary approach. As Angela Creager and Jean-Paul Gaudillière have shown, rather than being bound to a single discipline, interwar virus work was characterised by the integration of a range of scientific practices from various disciplines.8 This characteristic resulted in variations between research programmes and, as we shall see in the next chapter, made aligning technical or methodological differences both a key challenge and an important dynamic in creating virological knowledge and the new biomedical field. The NIMR programme was built around two basic lines of research, both of which were housed in the Department of Bacteriology and Experimental Pathology. The first, over which Patrick Laidlaw took charge,

Méthot, ‘Writing the History of Virology in the Twentieth Century: Discovery, Disciplines, and Conceptual Change’, Studies in History and Philosophy of Biological and Biomedical Sciences, 59 (2016), 145–153. 7 For classic statements, see, John McFaydean, ‘The Ultravisible Viruses’, Journal of

Comparative Pathology and Therapeutics, XXI (1908), 58–68, 168–175, 232–242; Thomas M. Rivers, ‘Some General Aspects of Filterable Viruses’, In T.M. Rivers (Ed.), Filterable Viruses (London: Bailliere, Tindall & Cox, 1928), 3–52. For later conceptualizations of viruses as organisms, see, P.P. Laidlaw, Virus Diseases and Viruses, The Rede Lecture (Cambridge: Cambridge University Press, 1938) and F. Macfarlane Burnet, Virus as Organism: Evolutionary and Ecological Aspects of Some Human Virus Diseases (Cambridge, MA.: Harvard University Press, 1946). 8 Creager, Life of a Virus, 33; Angela Creager and Jean-Paul Gaudillière, ‘Experimental Arrangements and Technologies of Visualisation: Cancer as a Viral Epidemic, 1930–1960’, In J-P. Gaudillière and I. Löwy, (Eds.), Heredity and Infection: Historical Essays on Disease Transmission in the Twentieth Century (London: Routledge, 2001), 203–242.

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aimed to create pathological and ‘immunological devices’ for the identification, investigation, and control of virus diseases.9 Laboratory animals were the material basis for growing and isolating viruses, for serological assays, and for the development of therapeutic sera and vaccines, all of which aimed to translate laboratory research into applied medicine. The second line aimed to use physical and biochemical methods to create instruments and techniques for exploring the basic properties of viruses. The main locus for this work was the Division of Applied Optics, where Joseph Barnard would build the first ultra-violet microscope in Britain, which became a key instrument in all the virus work done at the Institute. Working closely with William Gye on tumour viruses, Barnard concentrated on the physical problems associated with rendering viruses visible and with filtration methods for purifying them and determining their size.10 Both lines of research were developed through the study of specific diseases that were selected according to particular criteria: a filterable virus had to be implicated; a research animal had to be available; and the disease had to be of great enough importance to medicine and public health to warrant investment. These criteria were given broad interpretation and, most importantly, included the possibility of using animal diseases as proxies for human diseases. The MRC considered including influenza when the virus programme was conceived in 1922. Mervyn Gordon had already tested the most recent research on the potential role of a filterable agent. Memory of the 1918–1919 pandemic and subsequent smaller epidemics ensured that the public and medical profile of influenza remained high. But the disease was deemed unsuitable because of the seeming inability to cultivate the suspected virus and thus to study its nature and role in influenza. The lack of a viable experimental animal meant that uncertainties remained about the identity of the causative agent. Many researchers still held that it was a bacillus and not a virus. So the decision was made to approach influenza through the study of an analogous disease. When plans were settled in June 1922, the three candidates chosen for the programme

9 Medical Research Council, Report of the Medical Research Council for the Year 1928– 1929 (London: HMSO, 1930), 15. 10 Joan Austoker A History of the Imperial Cancer Research Fund, 1902–1986 (Oxford: Oxford University Press, 1988), 93–98.

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were measles, chicken sarcoma, and canine (dog) distemper.11 Measles was a widespread and deadly childhood disease, regularly encountered in MAB hospitals, where clinical and laboratory research could be carried out in relation to large numbers of patients.12 A filterable agent had been identified as early as 1905 and in 1921 the RIMR researchers Francis G. Blake and J.D. Trask reported new methods to transmit and isolate the virus in monkeys, opening the possibility of developing a vaccine.13 While measles represented a means to maintain the MRC’s relationship with the MAB, the two animal diseases became the principle research objects at the NIMR. Both were approached comparatively and as proxies for human diseases. Chicken sarcoma was used to study the role of viruses in cancer and to develop new techniques and instruments for investigating the physical properties of a variety of agents.14 Dog distemper was chosen for its potential use in unravelling influenza and related respiratory infections. According to Fletcher, its apparent similarities with influenza made it ‘peculiarly suitable for working out methods by which human diseases of this class might be subsequently investigated.’15 Work on sarcoma and dog distemper contributed to the emerging style of virus research at the NIMR in the 1920s, but they followed different trajectories. The search for cancer viruses through chicken sarcoma would end in failure, while the work on dog distemper would win the Institute national and international renown. Though crucial elements of the distemper research would become a model for future influenza work, the story would be incomplete without considering how cancer work led to new techniques that became crucial for all aspects of virus research at the Institute.

11 NA FD1/1297, ‘Virus Research’, 3 May 1922; NA FD1/1297 ‘Virus Research’, 17 June 1922. 12 For the social and epidemiological history of measles in Britain, see Anne Hardy, Epidemic Streets, 30–56. 13 L. Hektoen, ‘Experimental Measles’, Journal of Infectious Disease, 2 (1905), 238;

F.G. Blake and J.D. Trask Jr., ‘Studies on Measles: I. Susceptibility of Monkeys to the Virus of Measles, Journal of Experimental Medicine, 33 (1921), 385; F.G. Blake, and J.D. Trask, J. D., Jr.: Studies on Measles: II. Symptomatology and Pathology in Monkeys Experimentally Infected, Journal of Experimental Medicine, 33 (1921), 413. 14 NA FD1/1297 ‘Virus Research’, 17 June 1922. 15 NA FD1/1297, ‘Virus Research’, 3 May 1922.

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1

Making Virus Instruments

Cancer virus research was the beacon of the NIMR programme in its first years. The MRC held it in especially high esteem.16 Fletcher sang its praises and it attracted wide interest. It drew new researchers who were introduced to pathological, biochemical, and microscopic analyses of filterable viruses in animal tumours. The possible role of viruses as cancer-causing agents had been proposed by the RIMR researcher, Peyton Rous, and had already attracted considerable attention as a challenge to orthodox theories of cancer.17 As the primary focus for work on the possible virus aetiology of cancer, chicken sarcoma served as an important vehicle for developing new techniques and ideas.18 Its characteristics, especially the pronounced appearance of skin lesions, made it popular for the study of neoplasms—abnormal or excessive growths of tissue.19 In 1910, Rous established chicken sarcoma as a general model for studying the role of filterable viruses in cancer tumours, an association that at the time was widely dismissed.20 A decade later, the MRC joined with the Imperial Cancer Research Fund to resurrect Rous’ research with a view to improving his pathological, chemical, and physical methods.21 William Gye took the lead on this work, developing methods for isolating

16 Austoker A History of the Imperial Cancer Research Fund, 93–98. 17 Robin Wolfe Scheffler, Contagious Cause: The American Hunt for Cancer Viruses

and the Rise of Molecular Biology (Chicago: University of Chicago Press, 2019), 41–60. 18 For the uses of chicken sarcoma in cancer virus research, see Scheffler, Contagious Cause, 41–60; Ton van Helvoort, ‘Start of a Cancer Research Tradition; Ilana Löwy, ‘Variances in Meaning in Discovery Accounts: The Case of Contemporary Biology’, Historical Studies in the Physicial and Biological Sciences, 21 (1990), 87–121; H-J. Rheinberger, ‘From Microsomes to Ribosomes: ‘Strategies’ of ‘Representation’’, Journal of the History of Biology, 28 (1995), 49–89. 19 Creager and Gaudillière, ‘Experimental Arrangements and Technologies of Visualization: Cancer as a Viral Epidemic’, 206–208. 20 P. Rous, ‘A Transmissible Avian Neoplasm (Sarcoma of the Common Fowl)’, Journal of Experimental Medicine, 12 (1910), 697–7055; P. Rous, ‘Transmission of a malignant new growth by means of a cell-free filtrate’, Journal of the American Medical Association, 56 (1911), 198; P. Rous, and J.B. Murphy, ‘On the Causation by Filterable Agents of Three Distinct Chicken Tumours’, Journal of Experimental Medicine, 19 (1914), 52– 68. For the reception of Rous’ work see, Eva Becsei-Kilborn, ‘Scientific Discovery and Scientific Reputation: The Reception of Peyton Rous’ Discovery of the Chicken Sarcoma Virus’, Journal of the History of Biology, 43.1 (2010), 111–157. 21 Austoker, A History of the Imperial Cancer Research Fund, 95.

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the filterable agent and for determining the process and nature of cancerinducing virus infection. He worked closely with Barnard, who was responsible for developing techniques for making the suspected virus particles visible. In a short time, Gye confirmed Rous’s earlier observations and reported that he had determined the virus aetiology of malignant tumours.22 Starting with material supplied by Rous in 1922, he grew experimental tumours by injecting cell-free filtrates of pre-existing tumours into healthy chickens and various other fowl. From these he identified two separate factors involved in the production of neoplasms. One was an extrinsic agent, the other a cell-specific adjuvant. He showed that agent had the properties associated with filterable viruses: it could be serially propagated in animals (chickens), inducing tumours in each; it was filterable; and it was highly cyto-specific, meaning that it would only grow in specific fowl tissue. In 1925, he announced in the Lancet the discovery of these two factors, which he claimed acted together in the formation of cancerous growths. Important evidence for the filterable virus came from images produced by Barnard using a powerful new technique of ultraviolet light microphotography, which he had developed for making visible the smallest biological entities.23 His photomicrographs yielded what appeared as inclusion bodies in tumour cells, which Gye then interpreted as virus particles. Gye pursued his work on the role of filterable viruses in fowl tumours through the 1920s, culminating in The Cause of Cancer, published in 1931 with his long-time collaborator, W.J. Purdy. The problem for Gye, however, was that attempts to replicate the research in other laboratories produced inconsistent results. Just as quickly as his claims gained notoriety, they ran into practical challenges and scepticism among pathologists about the role of viruses in cancer.24 By the early 1930s, the first cycle of work on cancer-causing viruses had ended. 22 W.E. Gye, ‘The Aetiology of Malignant New Growths’, Lancet (18 July 1925), 109– 117; W.E. Gye, ‘Contribution to a Discussion On: Filter-passing Viruses and Cancer’, BMJ (1 August 1925), 189–192. 23 J.E. Barnard, ‘The Microscopical Examination of Filterable Viruses’, Lancet (18 July 1925), 117–123. 24 Austoker and Bryder, ‘The National Institute for Medical Research and Related Activities of the MRC’, 42. The MRC stopped funding Gye’s cancer virus work in 1930, and in 1935 he left the NIMR to become Director of the Imperial Cancer Reserch Fund. C.H. Andrewes ‘William Ewart Gye, 1884–1952’, Obituary Notices of Fellows of the Royal Society, 8.22 (November 1953), 418–430, 422–425.

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Barnard’s physical techniques proved more durable. His ultraviolet microscope modified one developed by the German microscopist, August Köhler, a specialist in illumination techniques at the Zeiss Optical Works in Jena. In 1904, Köhler and a colleague, Moritz von Rohr, designed the first ultraviolet microscope.25 The apparatus used ultra-violet radiation from a cadmium spark to increase the resolution of the light microscope. Light emitted by the spark was resolved by a system of quartz prisms, which directed the ultra-violet wavelengths into a glass condenser, where the light was focused onto the object of study. The illuminated object was then projected onto a fluorescent screen and recorded by a photographic method.26 Barnard added greater precision to Köhler’s apparatus.27 Along with his expertise in microscopy and optics, its modification depended on contributions from two assistants, John Smiles, a member of the Royal Microscopical Society whose knowledge of optical measurement and dark ground microscopy was key to the new illumination techniques, and Frank V. Welch, with whom Barnard wrote a manual and who specialised in specimen preparation. No less important were the Institute’s machinists and Barnard’s close relationship with the London microscope manufacturers, R&J Beck, who made and supplied specially designed lenses and condensers. In 1925 Beck built a prototype for sale to other laboratories.28 To improve illumination and focus, Bernard and his colleagues replaced Köhler’s glass condenser and fluorescent screen, which failed to produce sufficiently sharp images, with a dual-purpose condenser, comprising an outer dark-ground illuminator mounted over a quartz condenser. The illuminator was used in preliminary focusing and examination of the object with visible light, while the condenser was used for ultra-violet illumination. A specially designed microscope enabled fine focal adjustments to be made in the transfer of the invisible light waves onto the object. 25 Anon. ‘Pioneers in Optics’, http://micro.magnet.fsu.edu/optics/timeline/people/ Kohler.html. 26 W.J. Elford, ‘Ultraviolet Light Photography’, in R. Doerr and C. Hallauer (Eds.), Handbuch der Virusforschung (Vienna: Verlag von Julius Springer, 1938), 181–190. 27 My description is drawn from Barnard, ‘The Microscopical Examination of Filterable Viruses’, 117–123. Also see, Elford, ‘Ultraviolet Light Photography’, 181–190. 28 Report of the Medical Research Council for the Year 1922–1923 (London: HMSO, 1924), 37–38.

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For the photographic system, a camera with interchangeable eyepieces and ultra-violet sensitive photographic plates was designed to fit onto the microscope. Finally, to control for vibrations that could alter image quality the apparatus was mounted on a rigid steel bench (Fig. 1). Ultraviolet microscopy and its images were incorporated into all facets of the Institute’s virus research.29 The general workability of the instrument was first established with studies on large filterable agents— bovine pleuro-pneumonia, foot-and-mouth, and infectious ectromelia.

Fig. 1 Barnard’s Ultraviolet microscope (Note A1 and A2 are screws for course and fine adjustment. O1 carries the objective, while O2 carries the ocular. O3 is the combined dark-ground and ultraviolet illuminator, moved by a screw controlled by a large graduate head, A3. A4 are milled heads to control movements of the object on the stage. M1 is a mercury-vapor lamp mounted on an optical bench. At M3, a reflecting prism is mounted on a swing to enable the beam of light from the mercury vapor-lamp to be projected into the microscope. The spark S1 is projected by a quartz lens S2 through a quartz prism S3 into the central part of the microscope condenser. Source J.E. Barnard ‘The Microscopical Examination of Filterable Viruses’, Lancet [18 July 1925], 121)

29 P. Collard, The Development of Microbiology (Cambridge: Cambridge University Press, 1976), 23. This work was recorded in the MRC’s Annual Reports between 1923 and 1926.

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Researchers across London sent Barnard slides and samples of suspected virus material to be micro-photographed. This was how M.H. Gordon produced images of his suspected ‘filter-passer’ of influenza in 1922. But the early development of Barnard’s instrument was most closely tied to Gye’s cancer work.30 The images Barnard produced of inclusion bodies in chicken sarcoma tumour cells were important research objects, through which he and Gye studied the suspected virus. They served as key forms of evidence in Gye’s efforts to establish the identity and aetiological role of the virus. Barnard’s sarcoma work also highlighted a number of technical problems with the instrument. Ultraviolet microscopy was a more complex system of visualisation than standard light microscopy and, until a prototype became available, it was hard to reconstruct the instrument in other settings. Even when UV microscopes did become available, they proved difficult to use. A significant problem was the photographic process. Since ultraviolet light is invisible, its use to extend the limit of resolution meant that direct visual observation of the object had to be replaced by a photographic image. Much hinged on the quality of the image. The biggest challenge was the preparation of objects for visualisation.31 It was known that long exposure to ultraviolet light killed cells, bacteria, and viruses. Special attention thus had to be given to the selection of media to preserve the specimen. The quality of the specimen was also crucial. Because filterable viruses could not be obtained in pure culture, microscopical work had to be done with infected tissue and tissue extracts purified through filtration. Disputes over the nature of viruses in the 1920s often stemmed from challenges in studying them in tissue material, where it was difficult to distinguish virus particles, cell-products, inclusion bodies, and disintegrated substances. Barnard’s UV microscope did little to resolve these difficulties.32 Until the late-1930s, when ultra-centrifugation came into general use, filtration was the primary method of purification. Yet standard filtration 30 Barnard, ‘The Microscopical Examination of Filterable Viruses’; Gye, ‘The Aetiology

of Malignant New Growths’. 31 Elford, ‘Ultraviolet Light Photography’, 187–188. 32 They would only start to be settled with the introduction and wider use of ultra-

centrifugation and electronmicroscopy. For the history of the electron microscope, see Nicolas Rasmussen, Picture Control: The Electron Microscope and the Transformation of Biology in America, 1940–1960 (Stanford: Stanford University Press, 1997).

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techniques, which relied on Chamberland earthenware candles or Berkefeld diatomaceous earth filters that had been developed for bacteriological work in the 1890s, did not yield sufficiently pure filtrates for the purposes of ultraviolet microscopy. Their porosity was difficult to calibrate, and they were prone to contamination. Since ultraviolet microscopy illuminated objects by the refraction or diffraction of invisible light waves, impure specimens introduced potential artefacts into the image, which threatened the ability to identify and interpret the virus particle. Precisely because of these issues, filtration became a focal point for Barnard’s Division. Filtration was one of the most technically challenging areas of virus work.33 In 1925, in the wake of the announcements on the discovery of cancer viruses, the NIMR recruited the University of Bristol chemist and physicist, William J. Elford, to work on developing new methods of virus filtration.34 Elford concentrated on adapting the colloid membranes introduced into biological and medical research by the Frankfurt biochemist, Heinrich Bechhold. In 1907, Bechold described a method of ‘ultrafiltration’, which used colloid membranes with specifically graded porosities to estimate and control the particle size of suspensions.35 Size determination had become an important criterion for virus identification and classification, and filtration was the method.36 During his first years, Elford devised an elegant system for making thin, stable, and durable collodion films. Using mixtures of cellulose dissolved in different solvents he was able to control their formation and permeability. He created a series of membranes with precisely graded pore sizes, which eventually enabled him and his colleagues to exactly measure the particle sizes of viruses. By the late 1920s, Elford’s membranes had become the basis for a new size-based classification of viruses. The membranes also provided more precise methods for preparing virus filtrates.37 Elford 33 For discussion of the general problem of filtration in virus work, see Ton van Helvoort, ‘History of Virus Research in the Twentieth Century’, 190–194. 34 C.H. Andrewes, ‘William Joseph Elford’, Obituary Notices of Fellows of The Royal Society, 8 (1952–1953), 149–158. 35 A.P. Waterson and L. Wilkinson, An Introduction to the History of Virology (Cambridge: Cambridge University Press, 1978), 17–18. 36 Andrewes, ‘William Joseph Elford’, 150. 37 W.J. Elford, ‘A New series of Graded Collodion Membranes Suitable for General

Bacteriological Use, Especially in Filterable Virus Studies’, Journal of Pathology and Bacteriology, 34 (1931), 505.

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named and patented them as ‘gradocol’ membranes, tailored to meet the specific needs of virus work.38 Barnard’s ultraviolet microphotography and Elford’s gradocol membranes became key equipment used by NIMR virus researchers. They formed an essential part of work on the size and structure of viruses—important physical properties for their classification—and for establishing their legitimacy.39 While Elford’s membranes eventually came into wide use, Barnard’s microscope would be superseded by the electron microscope in the early 1940s. Yet, the gradocol membranes and UV microscope shaped and were shaped by the NIMR’s research culture through the 1930s. Their immediate value derived from their application to understanding the cause and nature of the diseases chosen for virus research. They contributed to a style of research specifically adapted to the demands of human and animal viruses. As we have seen, the NIMR’s research style involved working between species, using animal diseases to produce new knowledge and techniques relevant to understanding human diseases.40 As a form of comparative experimental pathology, the underlying assumption was that pathological and immunological reactions induced by filterable viruses could be used and investigated analogically. While this way of working was already entrenched in bacteriology and pathology, recognition of the obligate nature of viruses—that their reproduction depended on living

38 W.J. Elford and J.D. Ferry, ‘The Calibration of Graded Collodion Membranes’, British Journal of Experimental Pathology, XVI (1935), 1–14. 39 Van Helvoort has discussed the importance of virus particle size to debates over the nature of viruses in the 1920s and 1930s. Ton van Helvoort, ‘History of Virus Research in the Twentieth Century’, 190–194. 40 For examples of comparative medicine, see Abigail Woods, ‘Animals in the history of human and veterinary medicine’, In Hilda Kean and Philip Howell (Eds.), The Routledge Companion to Animal-Human History (London: Routledge, 2018), 147–170; Abigail Woods, ‘Between Human and Veterinary Medicine: The History of Animals and Surgery’, In Thomas Schlich (Ed.), Palgrave Handbook of the History of Surgery (Basingstoke: Palgrave Macmillan, 2017), 115–132; Lise Wilkinson, Animals and Disease: An Introduction to the History of Comparative Medicine. Cambridge: Cambridge University Press, 1992; Anita Guerrini, Experimenting with Humans and Animals: From Galen to Animal Rights (Baltimore: John Hopkins University Press, 2003); Ilana Lowy, ‘The Experimental Body’, in Roger Cooter and John Pickstone (Eds.), Companion Encyclopedia of Medicine in the Twentieth Century (London: Routledge, 2003), 435–449.

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cells—meant that all research had to be carried out on living organisms.41 In medical and veterinary virus research, the default organisms were animals susceptible to virus infection. Thus, medical and veterinary virus work was directly tied to the study of naturally occurring or experimentally induced diseases. The virus particles Barnard and Elford investigated by methods of ultraviolet microscopy and filtration were derived from infections produced in chicken and mice. Material was usually extracted post-mortem, but tumours could also be taken from living animals. Inferences about the nature and pathogenicity of viruses relied upon pathological and serological evidence extracted from lesions, while healthy animals were used as controls. Photomicrographs of virus particles in lesions were then used to establish and legitimise the identity of a virus disease. In this investigative cycle, pathological, physical, and biochemical work (including serology) was aligned in a general comparative approach to viruses and virus diseases. Important for gaining insight into the fundamental nature of both, this approach was also seen as crucial to translating experimental research into applied medicine. Efforts to make laboratory findings directly relevant to clinical medicine were evident in the early promotion of Gye’s cancer research. But while chicken sarcoma research contributed to the creation of new physical instruments, it was canine distemper that became the model for making experimental virus work directly applicable to the control of virus diseases.

2

A Proxy Disease

The MRC selected distemper for study because it addressed a broad range of interests within and beyond virus research. As Fletcher highlighted in his Annual Report for 1921–1922, its relevance as a potential analogue for influenza was most important: There is good reason to think that [dog distemper] offers a close parallel to human influenza. It seems probable that the infective agent is a filterable virus, and that here also the severity of the resulting disease depends largely

41 For the role of animals in comparative medicine See Abigail Woods, ‘Animals and Disease’, In Mark Jackson (Ed.), Routledge History of Disease (London: Routledge, 2016), 147–164; Anne Hardy, ‘Animals, Disease and Man: Making Connections’, Perspectives in Biology and Medicine, 46 (2003), 200–215.

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upon secondary infections, facilitated by the primary infection. There is ground for hope that the study of dog’s distemper under strict experimental conditions may throw important light upon analogous problems of human disease, and at least suggest new clues for investigation or new technical methods for the investigator. It is with the primary object of gaining knowledge of human disease that the Council decided to support further study of distemper in dogs. On that ground alone they find complete justification of the expenditure of part of their funds in this direction.42

The need to justify research on dog distemper stemmed from a concern that critics would see this choice as being at odds with the NIMR’s mandate to work on human diseases. Fletcher noted to Charles J. Martin, Professor of Pathology and Director of the Lister Institute, that ‘it is, I think, quite easy to justify [dog distemper] though we may have some possible political difficulty justifying the expenditure of the Medical Research Fund upon the study of an animal disease.’43 Framing dog distemper as a means to tackle influenza and other suspected human diseases was one way to address this potential difficulty. For Laidlaw and fellow NIMR researchers, parallels between the two diseases made distemper a good proxy for studying influenza and general problems associated with virus infection and immunity. Like influenza, it was a clinically protean disease that lacked a clearly indicative sign or symptom. Its aetiology was disputed, with some researchers supporting a filterable virus and others supporting different bacterial agents. But there was one crucial difference: unlike influenza, distemper could be explored through a research animal—the dog—that was already in use at Dale’s Department of Biochemistry and Pharmacology and for the NIMR’s work on the standardisation of insulin.44 Dog distemper also appealed as a research problem in its own right because of its broad social and cultural significance. Unknown in Britain before the 1790s, by the early twentieth century it had become a disease

42 Medical Research Council, Report of the Medical Research Council for the Year 1921– 1922 Report of the Medical Research Council (London: HMSO, 1923), 13. Italics mine. 43 NA FD1/1275 Fletcher to C.J. Martin, 13 October 1922. 44 E.M. Tansey, ‘Protection Against Dog Distemper and Dogs Protection Bills: The

Medical Research Council and Anti-vivisectionist Protest, 1911–1933’, Medical History, 38 (1994), 11.

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of national importance and focal point for many different groups.45 Through the nineteenth century it had developed alongside new country ways of life fashioned around hunting and rural sporting pursuits.46 The disease attracted special concern from landed patricians because it threatened two key symbols of this way of life—the foxhound and the fox hunt. It was also a menace to dog shows, which became popular from the midnineteenth century, and to dog breeders and pet owners, both of whom had established the dog as a ‘companion animal’ and symbol of Britishness. The dangers of distemper and how it spread were regularly discussed in the pages of sporting journals, such as The Field, in the pedigree breeders’ newspapers, such as the Fancier’s Chronicle and Breeders’ Gazette, and in dog fancy magazines, such as the Dog’s Own Annual. Veterinarians took particular interest in the disease. As the profession made the transition from concentrating on large animals, especially the horse, to small animals, among which pedigree and purpose-breed dogs were a crucial market, the threats posed by canine distemper took on greater importance.47 Veterinarians played a key role in developing ways of understanding its clinical and epidemiological features. By the 1870s, they had characterised distemper as an infectious disease with highly variable symptoms, which made it difficult to diagnose and treat. Infected dogs would first show a fever, vomiting and lethargy, and in a second phase would develop weeping eyes and nose, broncho-pneumonia, and diarrhoea, which could run into chorea and fits. A widely noted symptom was the hardening of the paws, but this was not a definitive clinical sign. Its variability in presentation was commonly attributed to

45 For an expanded analysis, on which this section is based, see Michael Bresalier and Michael Worboys, ‘“Saving the Lives of Our Dogs ”: The development of canine distemper vaccine in interwar Britain’, The British Journal for the History of Science, 47 (2014), 305–334. 46 Emma Griffin, Blood Sport: Hunting in Britain since 1066 (New Haven: Yale University Press, 2008). 47 J.R. Fisher, ‘Not quite a profession: the aspirations of veterinary surgeons in England in the mid- nineteenth century’, Historical Research, 66 (1993), 284–302; Abigail Woods and Stephen Matthews, ‘”Little, if at all, removed from the illiterate farrier or cowleech”: the English veterinary surgeon, c.1860–1885, and the campaign for veterinary reform’, Medical History, 54 (2010), 29–54; Anne Hardy, ‘Professional advantage and public health: British veterinarians and State Veterinary Services, 1865–1939’, Twentieth Century British History, 14 (2003), 1–23.

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the environmental conditions in which dogs lived and the constitutional susceptibilities of different breeds.48 From the 1870s, bacteriological studies introduced new aetiological conceptualisations of the disease. While there was hope that such studies would improve methods of identification and control, establishing the specific causative agent proved challenging and quickly generated controversy. Investigators from various specialisms in different parts of Europe identified a number of different distemper germs, and, likely inspired by Pasteur’s work on rabies, tried to develop a vaccine.49 British studies began in 1890 when Everett Millais, who was a dog breeder and part-time biomedical researcher at C.S. Sherrington’s laboratory at St Thomas’s Hospital, claimed to have isolated ‘the pathogenic microbe of distemper’ and to have made a protective vaccine.50 While the vaccine proved ineffective and discredited the role of Millais’s microbe, the announcement spurred other work. The first pathogen to be given widespread consideration in Britain was isolated by the pathologist and leading smallpox vaccine researcher Sidney Monckton Copeman in 1900.51 Convinced that a small bacillus he found in the mouths of dogs was the infecting agent, Copeman used it to produce an ‘experimental distemper’ and a vaccine. However, there were other candidate microbes. In 1901, two French microbiologists, J. Lignières and Charles Phisalix, identified Pasteurella canis as the primary cause and soon an apparently effective vaccine, made by the Pasteur Vaccine Company, was available in Britain.52 Controversy followed this new laboratory work. An acrimonious debate between two leading British canine veterinarians, Henry Gray and A.J. Sewell, over Phisalix’s vaccine prompted an investigation by a committee of prominent 48 Hamilton Kirk, Canine Distemper: Its Complications, Sequelae and Treatment (London: Baillière, Tindall & Cox, 1922). 49 On early distemper vaccines see Ian Tizard and Roland D. Schultz, ‘Grease, anthraxgate, and kennel cough: A revisionist history of early veterinary vaccines’, Advances in Veterinary Medicine, 41 (1999), 7–24. 50 Everett Millais, ‘The Pathogenic Microbe of Distemper in Dogs, and its Use for Protective Inoculation’, British Medical Journal, 1 (12 April 1890), 856–859. 51 Sidney Monckton Copeman, ‘The Micro-organism of Distemper in the Dog and the Production of a Distemper Vaccine’, Proceedings of the Royal Society of London, 67 (1900), 459–461. 52 Charles Phisalix, ‘Maladie des jeunes chiens: Statistique des vaccinations pratiquées du 15 mai au 15 août 1902’, Comptes rendus de l’Académie des sciences, 134 (1902), 1252. Lignières and Phisalix’s bacillus is discussed in Kirk Canine Distemper, 32–33.

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veterinarians in 1903. The committee’s investigations resolved little, with the majority deciding that neither Phisalix’s nor Copeman’s vaccine was an effective prophylactic, implicitly questioning the role of their respective microbes.53 In 1905, the French pathologist Henri Carré announced that a filterable agent was the primary cause of distemper.54 While he had succeeded in experimentally transmitting the agent to dogs, he failed to isolate it in artificial culture or to make it visible by light microscopy. Carré’s claim was challenged by American and British researchers, who aligned themselves behind another new agent, Bacillus bronchisepticus, identified in 1911.55 After the war, distemper emerged as a galvanising issue. The disease remained a major threat to dogs and prospects for controlling it were bleak. Disagreements about the aetiology of the disease remained, and neither preventive nor curative measures had altered high mortality rates. Leading veterinarians argued that new work on distemper’s cause was desperately needed, and they looked to laboratory science for solutions.56 So too did landed patricians, whose prized hunting dogs continued to be decimated by the disease. In autumn 1922 they came together when Sir Theodore Cook, editor of The Field, established the Field Distemper Fund (FDF). With the support of Sir Frederick Hobday, editor of the Veterinary Journal, and steered by a select group of aristocrats, the Fund sought to raise donations to underwrite an ambitious research programme. Cook approached Fletcher in October 1922 with a proposal for cooperation with the MRC on the ‘Distemper Question’.57 Cook and his colleagues were convinced that new research would be best served by a ‘centralising effort’, overseen by a single scientific body. In the absence of an agricultural research council, which would only be established in 53 ‘Report of a Committee formed to carry out experiments with the vaccine of Dr. Phisalix’, Journal of Comparative Pathology and Therapy, 17 (1904), 274; ‘Some Remarks on Distemper’, Veterinary Record, 18 (1906), 757. 54 Henri Carré, ‘Sur la maladie des jeunes chiens’, Comptes rendus de l’Académie des Sciences, CXL (29 Mai 1905), 689–690. 55 Newell S. Ferry, ‘Etiology of Canine Distemper’, Journal of Infectious Diseases, 4

(1911), 399–420; J.P. M’Gowan, ‘Some Observations on a Laboratory Epidemic, Principally Among Dogs and Cats, in Which the Animals Affected Presented Symptoms of the Disease called “Distemper”’, Journal of Pathology and Bacteriology, 15 (1911), 372 ff. 56 Kirk, Canine Distemper, ix; 58–81. 57 NA FD1/1274, Cook to Fletcher, meeting to discuss ‘The Distemper Question’, 21

October 1922.

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1930, the MRC had positioned itself as such an authority. Just as importantly, it had made experimental work with dogs central to its activities. The value of this focus was already being shown by investigations it coordinated into vitamins, hormones and, beginning in the same year as the distemper appeal, insulin. Crucially for the FDF, the MRC was deeply invested in the ideology of translating knowledge and tools produced in experimental animals into medically applicable knowledge and practice. Cook’s proposal was also attractive to the MRC on practical grounds. As part of its mandate, and due to strict restrictions on the amount of government funding it received, the MRC actively sought nongovernment sources of support. The FDF patronage made it possible to realise its plan to study distemper as part of the NIMR virus programme. Fletcher noted in a letter to Cook in November 1922 that, ‘even if there is no parallel in human beings to distemper in dogs, the investigation into the latter might well prove to give some valuable clues to guide in studying one or more of the numerous virus diseases in human beings.’58 Through the 1920s, a highly organised campaign against distemper brought MRC administrators and NIMR scientists together with landed elites and their social networks, veterinarians and their professional bodies, the dog-owning public and its organisations, as well as with scientists in commercial pharmaceutical laboratories. These collaborations would eventually yield effective tools for controlling distemper in Britain and beyond. Managing the different interests associated with the distemper campaign required novel forms of organisation. A Field Distemper Council (FDC) was created to oversee fund-raising and publicity, while a Distemper Research Committee (DRC) was established ‘to initiate and direct the scientific work.’59 Parallel research in the United States was organised by an American Distemper Committee, which had representatives on the British Field council.60 Landed patricians and those closely allied with their interests controlled the FDC, while leading figures from 58 NA FD1/1274, Fletcher to Cook, 14 November 1922. 59 NA FD/1275, The Cure and Causes of Distemper, The Field Distemper Council,

November 1924. 60 Susan D. Jones, Valuing Animals: Veterinarians and Their Patients in Modern America, (Baltimore: Johns Hopkins University Press, 2003), p. 132; A. Eichhorn, ‘Credit Where Credit is Due (Letter to the Editor)’, Journal of the American Veterinary Medical Association, 85 (1934), 823–824.

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British medical science controlled the DRC. Fletcher’s old colleague and MRC stalwart, William Leishmann, acted as provisional chair of the DRC, until Charles J. Martin assumed the position in 1923. Fletcher kept a foot in both camps. The DRC brought together representatives from both animal and human pathology with the express aim of creating ‘a constant and invaluable interchange of ideas and methods.’61 Unlike the MRC’s other patronage arrangements, which relied on single large donors such as the Rockefeller Foundation and Dunn Trust, the Fund was built through soliciting voluntary contributions directly from small organisations and individuals from across Britain and the empire, as well as from the United States. Cook made regular appeals through the pages of The Field and was helped considerably when the Daily Telegraph did the same. Noting the ‘futility of commencing research on any small or indefinite sum’, the Fund set a fundraising target of £25,000 (roughly equivalent to £1.54 million in 2020), which it exceeded.62 Over the entire course of the programme the Fund contributed £37,000—with £22,000 coming from voluntary donations from Britain and the empire and further £15,000 from the American Distemper Committee. The MRC’s grant-in-aid contributed £18,000.63 Between 1923 and 1932, £55,000 was spent on distemper research at the NIMR.64 The Fund was a major boon to the development of the virus research programme. From early 1923, Laidlaw made distemper his primary focus, 61 Medical Research Council, Report of the Medical Research Council for the Year 1921– 1922 (London: HMSO, 1923), 85. Along with Martin and Leishman, members of the Committee included the veterinary surgeon, Frederick Hobday and the canine surgeon to the King and Kennel Club, Professor A.J. Sewell. 62 Frederick Hobday, ‘Saving the lives of our dogs’, The Field, 4 February 1933. All conversions have been made from the Bank of England “Inflation Converter”, https:// www.bankofengland.co.uk/monetary-policy/inflation/inflation-calculator. 63 Figures based on reports issued by the Field Distemper Fund, NA FD 1/1274. Report for January 1927, ‘Details of Contributions to The Field Distemper Fund to the end of 1925’, pp. 12–18; ‘Details of Contributions to The Field Distemper Fund for 1926’, pp. 18–20. ‘Details of Contributions to The Field Distemper Fund for 1927 and to the 3rd of December, 1928’, in P.P. Laidlaw and F.W. Dunkin, ‘A Report Upon the Cause and Prevention of Dog Distemper’, Progress Report of the Distemper Research Committee, the Field Distemper Fund, 1928, 19–20. 64 NA FD1/1281 Letter to Lord Astor from Lord Mildmay, 1 December 1932, Field Distemper Council. Also see Hobday, ‘Saving the Lives’, p. iii. £55,000 was roughly equivalent to £4.05 million in 2020.

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working on all aspects of it with G.W. Dunkin, a Cambridge-trained veterinary pathologist and superintendent of the NIMR’s animal facilities.65 They started from the assumption that a key problem in previous experimental investigations had been the lack of a ‘standard’ animal guaranteed to be free from prior infection.66 The need for purpose-bred animals was recognised as a general requirement of all facets of research at the NIMR, and Fletcher and Dale had devised plans for a large-scale, centralised animal-breeding programme that was to be geographically separate from the Institute.67 Aided by monies from the Distemper Fund, the MRC purchased a forty-acre agricultural site at Rhodes Farm at Mill Hill.68 Completed in 1924, the ‘Farm Laboratories’ had provision for the breeding and housing of dogs and other research animals, a wellequipped laboratory, and an isolation compound for quarantining dogs with distemper (Figs. 2 and 3).69 The Farm Laboratories put Laidlaw and Dunkin in a unique position to carry out distemper studies under controlled conditions and to settle the dispute over the causative agent. Starting in summer 1923, Dunkin began establishing a stock of research dogs to be used to produce and study ‘experimental distemper’.70 Managed breeding allowed Laidlaw and Dunkin to control the susceptibility of the dogs to infection, which had hampered previous aetiological studies. Indeed, given how easily distemper was known to spread in close quarters, controlling accidental infection was integrated into every aspect of the experimental system. Healthy dogs were separated from sick dogs. Researchers and assistants handling animals wore rubberised gloves and outer garments, which were 65 Thomas Dalling, ‘George William Dunkin, 1886–1942’, Journal of Pathology and Bacteriology, 54 (1942), 401–402. 66 Laidlaw and Dunkin, ‘A Report Upon the Cause and Prevention of Dog Distemper’, pp. 5–6. See Robert G.W. Kirk, ‘“Wanted—Standard Guinea Pigs”: Standardization and the Experimental Animal Market in Britain ca.1919–1947’, 283–285. 67 Medical Research Council, Report of the Medical Research Council for the Year 1930– 1931 (London: HMSO, 1932), 27. 68 ‘Field Distemper Fund’, Fletcher to Cook, 24 January 1924, NA FD1/1275. 69 P.P. Laidlaw and F.W. Dunkin, ‘A Report Upon the Cause and Prevention of Dog

Distemper’, Progress Report of the Distemper Research Committee, the Field Distemper Fund, (1928), 19–20. 70 G.W. Dunkin and P.P. Laidlaw, ‘Studies in Dog-Distemper. II. Experimental Distemper in the Dog’, Journal of Comparative Pathology and Therapeutics, 39 (1926), 201–213.

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Fig. 2 Dog distemper isolation compound, Mill Hill ‘Farm’ Laboratories (Note The entrance and disinfection house are at the left corner. A kennel maid’s bungalow is in the foreground, behind the tree, with the kennels in the background. Source P.P. Laidlaw and G.W. Dunkin, ‘A Report Upon the Cause and Prevention of Dog Distemper’, In Field Distemper Fund, Progress Report of the Distemper Research Committee [1928], 12)

Fig. 3 Animal Hospital, Mill Hill ‘Farm’ Laboratories (Source Laidlaw and Dunkin, ‘A Report Upon the Cause and Prevention of Dog Distemper’, In Field Distemper Fund, Progress Report of the Distemper Research Committee [1928], 14)

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bathed in Lysol before entering and leaving a building. Care was taken to disinfect hands, tongs, syringes, thermometers, and other instruments to prevent inadvertent transfer of the disease. Under these precautions, Laidlaw and Dunkin began contact experiments by putting a healthy puppy with dogs they had infected with distemper. Once the puppy contracted the disease, they tried to transmit it to other healthy puppies through direct contact or by inoculating them with tissue extracted postmortem from previously infected dogs. While they were able to transmit the disease, they were unable to produce cultures of known bacilli associated with distemper from material that induced the experimental infection.71 Their conclusion was that this result ruled out a primary role for a bacterium, including B. bronchisepticus, and that the filterable virus identified by Carré was a more likely candidate. Carré’s methods had been difficult to replicate. Laidlaw and Dunkin chalked this up to two constraints: the highly variable symptoms and severity of distemper in dogs and the lack of a reliable source of pathogenic material for laboratory work. Their purpose-bred, infectionfree puppies removed both obstacles. Their strategy was to stabilise and standardise the disease in the dog, which would allow them to study and manipulate the virus in vivo. First, they generated and characterised a new disease entity—‘experimental dog-distemper’—with a typical clinical picture: it was an acute infection, with an incubation period of four days, followed by fever, discharge and severe gastro-intestinal symptoms. Experimental distemper rarely killed the dogs, but it was easy to transmit serially and, just as important, could be used to provide reliable pathogenic materials that were essential for developing serological tests and, eventually, for therapeutics and a vaccine. Laidlaw and Dunkin found that the best material came from the liver, spleen, and mesenteric glands extracted post-mortem.72 Preparing bacteria-free filtrates of these materials was important for countering a common criticism that Carré’s inoculums contained B. bronchisepticus.73 71 Laidlaw and Dunkin, ‘A Report Upon the Cause and Prevention of Dog Distemper’,

5. 72 P.P. Laidlaw and G.W. Dunkin, ‘Studies in Dog Distemper. V. The Immunisation of Dogs’, Journal of Comparative Pathology and Therapeutics, 41 (1928), 209–227. 73 G.W. Dunkin and P.P. Laidlaw, ‘Studies in Dog-Distemper. II. Experimental Distemper in the Dog’, Journal of Comparative Pathology and Therapeutics, 39 (1926), 213–221.

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Laidlaw and Dunkin turned to Elford’s new techniques for filtering, purifying, and measuring ‘ultramicroscopic’ agents from blood and tissue.74 By early 1926, they claimed that ‘the infecting agent of dog-distemper belongs to the class of filter-passing viruses’ on three counts: its filterability, its resistance to cultivation, and its dependence on living tissue such that it could not be grown ‘outside the [animal] body’.75 The results were in line with the emerging view that filterable viruses could be distinguished from bacteria on the basis of their unique dependence on living tissue. They named the new agent ‘Rhodes virus’ after the farm at Mill Hill, and it became their master strain. For the first year and a half of their research, Laidlaw and Dunkin worked solely with dogs, but they were not ideal subjects. The use of dogs at the NIMR was the focus of vociferous anti-vivisection agitation around the proposed Dogs’ Protection Bill.76 Dogs were also expensive to keep, did not breed rapidly, and were emotionally unsuited to strict isolation quarantines.77 As a solution to these difficulties, in 1924 Laidlaw and Dunkin turned to the ferret.78 At the suggestion of S.R. Douglas, director of the Department, and through their connections with the Field Distemper Council, they learnt that ferret handlers had long reported that the animal was highly susceptible to canine distemper.79 In Britain, ferrets were used for rat control and rabbit hunting, and in the

74 Medical Research Council, Report of the Medical Research Council for the Year 1924–1925 (London: HMSO, 1926); Medical Research Council, Report of the Medical Research Council for the Year 1925–1926 (London: HMSO, 1927). 75 P.P. Laidlaw, and G.W. Dunkin, ‘Studies in Dog-Distemper. III. The Nature of the Virus’, Journal of Comparative Pathology and Therapeutics, 39 (1926), 228. 76 E.M. Tansey, ‘Protection Against Dog Distemper and Dogs Protection Bills: the

Medical Research Council and Anti-vivisectionist Protest, 1911–1933’, Medical History, 38 (1994), 12–13. 77 Dunkin and Laidlaw, ‘Studies in Dog-Distemper. II’, 213. 78 NA FD1/1275. Third Report of the Distemper Research Committee – Ferrets, 7

October 1924, On ferrets, see Arthur R. Harding, Ferret Facts and Fancies: A Book of Practical Instructions on Breeding, Raising, Handling and Selling; Also Their Uses and Fur Value (Columbus: A.R. Harding, 1919). 79 NA FD1/1275. Third Report of the Distemper Research Committee – Ferrets, 7 October 1924. The veterinary surgeons, Henry Gray and A.J. Sewell, who had battled over distemper in the early 1900s, also informed Laidlaw and Dunkin that they had succeeded in infecting ferrets with distemper. Dunkin and Laidlaw, ‘Studies in Dog-Distemper. I.’ pp. 201–212.

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working-class ‘sport’ of ferret-legging. Domestication into the NIMR’s virus programme marked the first time the ferret was used as an experimental animal for medical research and the start of a long scientific career.80 All the ferrets were purpose-bred at Mill Hill in a special hut isolated from the rest of the facility, and they bred readily and quickly, producing up to three hundred kits (young) per year.81 Moreover, unlike the dog, they were known to thrive in small spaces, which made them well suited for confinement in laboratory cages. Contrary to their reputation as vicious predators, Laidlaw and Dunkin found ferrets easy to manage and they became invaluable partners in the research.82 The ferret quickly became Laidlaw and Dunkin’s preferred research animal, because distemper was easy to reproduce and to identify—it was invariably fatal (Fig. 4). Equally important, the virus tended to be concentrated in the spleen, which provided a ready source of experimental material. Laidlaw and Dunkin ran every important line of research on both the dog and the ferret, including the development of an experimental vaccine. Although they were confident they now had the ‘right’ pathogen, along with the right experimental animals, facilities and techniques for its manipulation, they found, as others had before them, that producing virus vaccines was difficult.83 The key obstacle was the lack of artificial culture media and techniques with which to purify the pathogen. The problem was repeatedly highlighted in MRC and DRC reports, 80 Alexander P. Thomson, ‘A History of the Ferret’, Journal of the History of Medicine, 6 (1951) 6, 471–480; C. Sweet, R.J. Fenton and G.E. Price, ‘The Ferret as an Animal Model of Influenza Virus Infection’, in Oto Zak and Merle A. Sande (Eds.), Handbook of Animal Models of Infection: Experimental Models in Antimicrobial Chemotherapy (London: Academic Press, 1999), 288–298. 81 Visit to Mill Hill Farm Laboratories’, Veterinary Record, 8 (1928), 1101. 82 Laidlaw and Dunkin, ‘A Report Upon the Cause and Prevention of Dog Distemper’,

10. 83 Dunkin and Laidlaw, ‘Studies in Dog-Distemper. I’, 209–210. The challenges in producing virus vaccines were widely explored in late 1920s and early 1930s, with considerable work being done at the NIMR. See, for example, S.P. Bedson, ‘Observations on the Mode of Action of a Viricidal Serum’, British Journal of Experimental Pathology, 9 (1928), 235–240; C.H. Andrewes, ‘Immunity in Virus Diseases’, Lancet, 2 (1931), 1046–1049; W.W.C. Topley, An Outline of Immunity (London: Edward Arnold & Co., 1933), 254–273. The problem was also explored at Burroughs Wellcome Company; see R.A. O’Brien, ‘Certain Practical Aspects of Immunity’, British Journal of Medicine, 2 (29 November 1927), 975–978.

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Fig. 4 Purpose-bred ferrets at Mill Hill. Date unknown (Source NA FD1/ 1284)

and in the veterinary and medical press.84 Virus vaccines had to be produced and standardised at the whole-animal or tissue level, as in the well-established vaccines used for smallpox and rabies.85 In the 1920s, researchers searched for improved methods for purifying viruses and

84 For example, ‘Distemper and Influenza’, The Lancet, 1 (26 February 1927), 445. 85 Lise Wilkinson, ‘The Development of the Virus Concept as Reflected in Corpora of

Studies on Individual Pathogens. 5. Smallpox and the Evolution of Ideas on Acute (Viral) Infections’, Medical History, 23 (1979), 1–28; Wilkinson, ‘The Development of the Virus Concept as Reflected in Corpora of Studies on Individual Pathogens. 4. Rabies: Two Millennia of Ideas and Conjecture on the Aetiology of a Virus Disease’, Medical History, 21 (1977), 15–31. In interwar Britain, purifying vaccinia virus for the Government Lymph Department was crucial issue tackled by C.H. Ledingham at the Lister Institute. See Harriett Chick, Margaret Hume and Marjorie MacFarlane, War on Disease: A History of the Lister Institute (London: A. Deutsch, 1971), 133–134.

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producing virus vaccines, and the NIMR’s work on dog distemper was at the forefront of this research programme in Britain and internationally. By the 1920s, the goal of vaccine development was to produce standard, high-quality antigens that, when inoculated, would induce artificial immunity by stimulating antibody production.86 An ideal antigen generated immunity without causing disease. There were two types of vaccine: ‘live’ and ‘killed’. The former, modelled after Pasteur’s rabies vaccine, involved using an attenuated (weakened) virus to produce a sub-clinical or mild infection, while the latter used dead virus particles with antigenic properties. Killed virus vaccines were made by either heating the virus or treating it with chemicals. Laidlaw and Dunkin chose a killed vaccine, treating their spleen extract with formalin, a method they borrowed from researchers working on a foot-and-mouth vaccine at the Lister Institute.87 After testing various protocols, Laidlaw and Dunkin found that the most effective was a two-step process.88 It involved, first, administering the formolised vaccine to stimulate antibody production, and then fourteen days later injecting a dose of the live virus to reinforce the immune response and to make it longer lasting. They refined their system in trials in ferrets that ran through 1927 and demonstrated that it was safe and effective in both laboratory and field conditions; for the latter, they worked with three ferret keepers from country estates.89 However, when the ferret vaccine was trialled with dogs, it provided only limited protection. Laidlaw and Dunkin soon determined that an effective dog vaccine required a ‘homologous’ antigen made from dogs.90 This meant developing methods to prepare a virus that was produced and extracted from dog tissue.91 While dogs were used as sources of the virus for vaccine

86 Pauline M.H. Mazumdar, ‘“In the Silence of the Laboratory”: The League of Nations Standardizes Syphilis Tests’, Social History of Medicine, 16 (2003), 437–459. 87 P.P. Laidlaw and G.W. Dunkin, ‘Studies in Dog Distemper. IV. The Immunisation of Ferrets Against Dog Distemper’, Journal of Comparative Pathology and Therapeutics, 41 (1927), 5. 88 Laidlaw and Dunkin, ‘Studies in Dog Distemper. IV’, 9–10. 89 Laidlaw and Dunkin, ‘Studies in Dog Distemper. IV’, 7–9. 90 Laidlaw and Dunkin, ‘A Report Upon the Cause and Prevention of Dog Distemper’,

11–12. 91 Laidlaw and Dunkin, ‘A Report Upon the Cause and Prevention of Dog Distemper’, 12; ‘Dr. Laidlaw and Mr. Dunkin on Their Distemper Investigations’, Veterinary Record, 8 (1928), 1104.

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production, ferrets continued to be used as the source of the live virus for the second inoculation. Vaccine development for dogs moved rapidly from the laboratory to the field. Trials began in 1928 and were coordinated through the FDC, whose membership was used to enrol masters of foxhounds, veterinary surgeons, and dog owners.92 Laidlaw and Dunkin oversaw the selection of participants and controlled the provision and testing of the vaccine. They insisted that only veterinary surgeons administer the vaccine and the virus, and only according to specific guidelines. The trials compared vaccinated with unvaccinated animals, using a rather ad hoc notion of control.93 The trial design relied on both groups of animals being ‘naturally’ exposed to distemper, which was thought to be especially rife in the countryside. Packs of foxhounds, as well as breeds from established kennels, were the main trial subjects. Leading hunts were keen to volunteer their dogs and to participate in the studies. Foxhounds were useful because of their breeding and maintenance, while other dogs were studied to determine the range of protection. In the first round, 340 foxhounds and a hundred other dogs were vaccinated, with only two deaths.94 The results were compelling, and the trial was extended so that by November 1928, two thousand dogs had been vaccinated.95 Only a small percentage of vaccinated dogs (an estimated 1 per cent) contracted distemper, compared to infection rates of between 50 and 75 per cent in unvaccinated dogs. These results, much more than the earlier laboratory demonstrations, confirmed for veterinarians, dog owners and many scientists that the distemper characterised by Laidlaw and Dunkin in the laboratory was truly a virus disease in the field.96

92 Laidlaw and Dunkin, ‘A Report Upon the Cause and Prevention of Dog Distemper’, 16–17. 93 For the concept of control in MRC clinical trials see Martin Edwards, Control and the Therapeutic Trial: Rhetoric and the Therapeutic Trial in Britain, 1918–1948 (Amsterdam: Rodopi, 2007). 94 MRC, Report of the Medical Research Council for the Year 1927–1928 (London: HMSO, 1929), 106. 95 Ibid., 106. 96 ‘The Inoculation for Distemper’, Veterinary Record, 9 (1929), 123–124. Reprinted

from ‘The “Field” Distemper Fund’, The Field (January 1929).

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3

Translating Viruses into Vaccines

On receiving Laidlaw and Dunkin’s report on the trials in November 1928, the FDC quickly released a summary to the veterinary and general newspaper press, generating a wave of interest and enthusiasm, assessments of the practical implications of the vaccine, and immediate demands for its general release.97 The success was celebrated in national and local newspapers. Laidlaw and Dunkin were front-page celebrities in The Daily Mirror, and the Manchester Guardian observed: ‘There should be a concerted wagging of tails throughout the world’s kennels at the good news for dogdom that has been announced.’98 The key role played by Sir Theodore Cook, who had died earlier the same year, and monies raised by the Distemper Fund, were also celebrated. The Veterinary Journal suggested that, there can be no doubt that had it not been for [Cook’s] practical encouragement and generous help … together with the clever propaganda appeals issued by the persevering Secretary of the Fund ... the money would not have been forthcoming, and this Research could not have been done.99

Veterinarians also played key roles, particularly for the crucial transition from the laboratory to the field. In the early stages of the research, when Laidlaw and Dunkin were constructing their ‘experimental distemper’, veterinarians validated the correspondence between the disease at the NIMR and that met with in dogs in their practices. Similarly, field trials of the vaccine depended on the ability of veterinarians to carry out inoculations, report results, identify cases of distemper, and suggest modifications to the procedure. The Veterinary Record took the moment ‘to emphasise the great advantages that must necessarily follow collaboration and discussion between the research workers and clinicians’ and that ‘open and free 97 ‘The Prevention of Distemper: Discovery of an Immunity Vaccine’, Veterinary Journal, 84 (1928), 595–596. 98 ‘Distemper Conquered—Fruit of 5 Years’ Work’, Daily Mirror (30 November 1928), 1; Manchester Guardian (30 November 1930), 20. Also see Daily Mirror (20 October 1928), 5A and (30 October 1928), 1, including front-page photographs of Laidlaw and Dunkin; The Times (23 December 1926), 12 ff.; (25 January 1927), 9D; (29 November 1928), 9a and Editorial. 15C; Editorial (20 December 1929), 8G. The Field (30 November 1929) and (21 December 1929). 99 Editorial, ‘Animal Immunity’, Veterinary Journal, 8 (1928), 591.

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discussion of the knotty problems as they occur … conduces towards that harmonious working which is absolutely essential to complete success.’100 Emboldened by the success of the distemper programme, the FDC pushed for commercial production of the vaccine by companies in Britain and the United States.101 The MRC and DRC were worried about the ‘marketing of inferior preparations’, so they attempted to control the selection of companies for commercialisation.102 In December 1928, arrangements were made with the Burroughs Wellcome Company for the vaccine to be produced for the British market at its Wellcome Physiological Research Laboratories (WPRL) in Kent, where Laidlaw had previously worked and which had good relations with the NIMR.103 The American Distemper Committee made similar arrangements with two firms, Lederle Laboratories and Mulford Laboratories, both of which sent representatives to the NIMR to learn the methods of preparation.104 Burroughs Wellcome quickly scaled-up commercial production and supply, but in late 1929 quality problems emerged, which were soon linked to inadequate measures against cross-infection in the animals being used.105 Production was temporarily halted, until Laidlaw and Dunkin developed appropriate precautions. This was the first of a number of issues involving the quality of the vaccine that the NIMR and Burroughs Wellcome scientists had to confront. For nearly two years, they worked closely to improve the preparation, stability, and standardisation of the different products used in the manufacturing process. In 1931, Burroughs Wellcome finally took over commercial production of distemper vaccine, as well as serum therapies 100 Editorial, ‘Distemper Research’, Veterinary Record, 8 (1928), 1095. 101 Laidlaw and Dunkin, ‘A Report Upon the Cause and Prevention of Dog

Distemper’, 11. 102 Ibid., 11. 103 NA FD1/1296 Geo. E. Pearson (deputy director, BWC) to E.S. Grew (secretary,

Field Distemper Council) on monopoly, production, distribution, naming of vaccine, 11 December 1928. Also see Church and Tansey, 349–350; H.J. Parish, ‘The Wellcome Research Laboratories and Immunisation: A Historical Survey and Personal Memoir– chronologies and biographical notes, mimeograph, c.1970’, Wellcome Library Archives, WF/M/H/08/19. 104 ‘Success of Vaccine Treatment’, Veterinary Record, 10 (1930), 38; Lederle Laboratories, ‘The Control of Canine Distemper’, 1952, p. 4, available at http://babel.hathit rust.org/cgi/pt?id=coo.31924000254262, accessed 10 May 2020. 105 Medical Research Council Report of the Medical Research Council for the Year 1930–1931 Report of the Medical Research Council (London: HMSO, 1932), 113–114.

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developed by Laidlaw and Dunkin, and in 1933 a special supplement of The Field celebrated the decade-long process to conquer the ‘scourge of dogdom’.106 For the MRC and NIMR, the distemper programme was a clear demonstration of the practical value of its virus scheme. Dale later described it as an exemplar of ‘a complete and systematic investigation of a virus disease’, and its culmination in the large-scale production of a vaccine symbolised the efficacy of the NIMR approach to virus research.107 Several aspects ensured that it had wide-reaching significance. It established a style of virus research that linked together fundamental and applied research in ways that broke down that distinction. The innovation and commercial manufacture of a vaccine demonstrated the practical relevance of virus research. The two-stage method of immunisation was incorporated into the development of vaccines against yellow fever in West Africa and rinderpest in South Africa; it was also recommended for poliomyelitis.108 From a professional standpoint, the campaign was crucial to legitimising virus research. When Laidlaw and his colleagues started their work in 1923, the challenges of rendering viruses by established bacteriological techniques of filtration, in vitro cultivation, and light microscopy remained significant obstacles. By 1931, effective ways of overcoming these obstacles had been established. Work at the NIMR became organised around the biological concept of viruses as obligate parasites and the experimental approach it demanded. Its crucial feature was the reliance on pathological and immunological tools fashioned through experimental animals. By the end of the 1920s this had become a general feature of medical and veterinary virus research. The innovation of virus vaccines and serological assays highlighted virus research’s unique dependence on immunology in the identification and control of virus diseases. The distemper research showed that this approach was

106 Frederick Hobday, ‘Saving the Lives of Our Dogs’, The Field (4 February 1933),

1. 107 H.C. Cameron, ‘Patrick Playfair Laidlaw’, Guy’s Hospital Reports, 90 (1940–1941),

9. 108 Medical Research Council, Report of the Medical Research Council for the Year 1930–1931 Report of the Medical Research Council (London: HMSO, 1933), 20; Daniel Gilfoyle, ‘Veterinary Immunology as Colonial Science: Method and Quantification in the Investigation of Horsesickness in South Africa, c. 1905–1945’, Journal of the History of Medicine and Allied Sciences, 61 (2005), 26–65.

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immensely productive of both expert knowledge and tools for tackling virus diseases. The distemper campaign became an organisational model for the kind of collaborative research the MRC wanted the NIMR to embody. Linking together researchers from different disciplines, it also linked the Institute, and virus research, to groups outside the laboratory who were necessary to every stage of the investigations. By the time Laidlaw and Dunkin handed over responsibility for their distemper vaccine to Burroughs Wellcome Company in 1931, virus research was becoming an established medical scientific field. Through distemper, NIMR workers fashioned their scientific identities as virus researchers and the authority of their Institute. Laidlaw was knighted for his distemper work in 1933. Virus research was now funded in universities and hospitals, and the Lister Institute had created its own programme. In 1929, the MRC devoted an entire volume of its System of Bacteriology in Relation to Medicine to ‘Viruses and Virus Diseases’, and Laidlaw contributed a chapter on distemper, which took its place alongside other recognised virus diseases including, smallpox, mumps, measles, yellow fever, and poliomyelitis, as well as a range of animal, plant, insect and bacterial virus diseases.109 The distemper programme played a key role in establishing virus diseases as a distinct category of infection. Unlike the work on cancer, the distemper research stood out because it was both a distinctively British contribution and profoundly important for the development of medical virus research. Fletcher had repeatedly justified the programme in terms of its potential implications for the field, and returned to the theme in 1931, just as the NIMR handed over vaccine production to Burroughs Wellcome Company: It is already clear that the usefulness of this work is not to be limited to the prevention and cure of canine distemper. In the field of medical research the work has at many points aided the development of technical methods for the study of viruses in general.110

The hope, of course, was that the success of this style of virus research could be applied to other suspected virus diseases. Many, including Fletcher, believed that the distemper programme would open the door for 109 P. Fildes P. and J.C.G. Ledingham, ‘Viruses and Virus Diseases’, in Fildes P. et al., (Eds.), A System of Bacteriology in Relation to Medicine (London: HMSO., 1930). 110 Medical Research Council Report… 1931–1932 (1933), 19.

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a new approach to influenza. This had been a stated goal from the outset: ‘The right weapons for attack upon influenza’, Fletcher noted in his 1925–1926 Annual Report, ‘are perhaps only forged in the easier experimental animal maladies nearest akin to it.’111 Such rhetoric, combined with the demonstrated success with distemper, raised expectations that the foundations had been laid at the NIMR to tackle influenza with the tools of virus research.

4

The ‘Flu Problem’

The distemper campaign became the measure against which strategies for tackling influenza were judged. By most appraisals, scientific success with distemper contrasted sharply with scientific failure with influenza. Through the 1920s, influenza continued to occupy a central place in the social experience of health and disease in Britain. Epidemics in 1922, 1924, 1927, and 1929, and minor epidemics in almost every other year, underscored its epidemiological presence and reinforced persistent worries about the possibility of another pandemic (Table 1). Medical and media representations dramatised influenza as a public health danger. Widespread interest marked a transformation in its social and medical identity that had been brought about by the pandemic a decade earlier. Whereas at the turn of the century influenza was characterised as an inevitable fact of modern life, it was now characterised as one of key the threats to modern society. Among infectious diseases, it remained a significant contributor to morbidity and mortality. Only diphtheria and scarlet fever accounted for Table 1 Annual Flu Morbidity Rates per 100,000 in England (and Wales), Germany and the United States, 1920–1929 Country

1920

1921

1922

1923

1924

1925

1926

1927

1928

1929

England Germany USA

28.2 96.0 70.9

23.7 27.2 11.4

56.3 64.2 31.2

22.0 38.8 44.3

49.0 23.5 19.4

32.7 22.4 29.7

22.9 25.8 40.8

56.7 46.3 22.6

19.6 19.4 45.3

73.4 57.5 55.5

Source Z. Deutschman, ‘Trends of Influenza Mortality During the Period 1920–1951’, Bulletin of the World Health Organization, 8(1953), 636

111 Medical Research Council Report… 1926–1927 (1927), 24.

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higher annual levels of sickness in the decade. Although influenza rarely killed on its own, complications continued to produce stunning levels of death. In the 1920s, ‘influenzal pneumonia’ accounted for the most annual deaths among infectious diseases, killing on average nearly ten times more people than diphtheria or measles (Table 2). The disease typically ranked highest amongst cases reported by general practitioners and amongst patients’ complaints.112 The North Riding physician, William Pickles, famous for his epidemiological studies in Wensleydale in the 1930s, described influenza as the ‘commonest and most important’ infectious disease in interwar Britain.113 Some medical observers wondered if the high numbers were an artefact of clinical custom or convention marked by the experience of the pandemic. Doctors readily used influenza as a catchall for various idiopathic respiratory, gastric, and nervous conditions. In popular discourse, the ‘flu referred to an array of ailments, from fevers and colds to dangerous pneumonias. Others, however, reckoned that, because influenza was not a notifiable disease, because it took many forms and because doctors did not always report cases, the numbers represented in statistical data were but a small fraction of the total.114 Regardless of the accuracy of such data, the apparent epidemiological burden of influenza took on new political and economic significance in the 1920s. For government and the captains of industry battling constant economic crises, its nebulousness mapped onto anxieties about efficiency, the loss of manpower, and national fitness.115 Despite the explosion of research during and immediately after the pandemic, measures against influenza remained as they had been before 1918. Public health and medical authorities had no effective ways of preventing the disease. The leading epidemiologist, Major Greenwood, who had edited the Ministry of Health’s Report on the Influenza Pandemic in 1920, admitted a decade later that the disease was far more challenging than any epidemiologist could have anticipated.116 112 Digby, The Evolution of British General Practice, 209, 213. 113 W.N. Pickles, Epidemiology in Country Practice (London: The Keynes Press, 1983),

29. 114 Watson Davis, ‘Unsolved by Science—The ‘Flu’, The Sphere (2 March 1929), 364. 115 For the corporate language ‘efficiency’ in British medicine, see Sturdy and Cooter,

‘Science, Scientific Management, and the Transformation of Medicine’. 116 Major Greenwood, Epidemics and Crowd Diseases: An Introduction to the Study of Epidemiology (London: Williams and Norgate, 1935), 20. See also, Major Greenwood,

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Table 2 1929

Deaths from the three leading notifiable infectious diseases, 1926–

Disease Influenzal Pneumonia Diphtheria Measles and German Measles

1926

1927

1928

1929

32,339 2994 3518

37,242 2732 3642

31,014 3191 4314

43,846 3446 3419

Source Adapted from the Eleventh Annual Report of the Ministry of Health, 1929–1930. London: HMSO, 1930, 30

Its scale and virulence had raised doubts about simple causal models and directed attention to multiple factors, including changes in the environment, susceptibility, the pathogen, or a combination of all three— as being responsible for epidemiological variations and the rise and fall of epidemics.117 Doctors and medical officers still had to contend with influenza’s complexity. While a general clinical picture of the disease was now well established, in the absence of a pathognomonic sign or specific agent from which to make a clear-cut diagnosis, medical practitioners were always negotiating symptoms. Uncertainty about the specific cause of influenza meant that laboratory-based definitions had little bearing on clinical practice. The pandemic and subsequent epidemics highlighted the elusiveness of influenza immunity. Doctors now knew that a bout provided limited protection and, as a result, individuals were susceptible to repeated attacks. Just how often a person could catch ‘flu and the factors involved were disputed. The idea that people of certain dispositions or poor constitutions were at greater risk of the disease might have lost favour after the pandemic swept away healthy young people, but, besides the aged and infirm, there was little agreement on who was most at risk. Concern over influenza had grown since 1918–1919; so too had frustration over the lack of effective measures against it. Large epidemics in Epidemiology, Historical and Experimental: The Herter Lectures for 1931 (Baltimore: Johns Hopkins Press, and London: Oxford University Press, 1932). 117 M. Greenwood, ‘The Periodicity of Influenza’, Journal of Hygiene, 29 (1929), 227–235. For debates on the nature of epidemics, see Olga Amsterdamska, ‘Achieving Disbelief: Thought Styles, Microbial Variation, and American and British Epidemiology, 1900–1940’, Studies in History and Philosophy of Biological and Biomedical Sciences, 35 (2004), 483–507; Mendelsohn, ‘From Eradication to Equilibrium’.

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1927 and again in 1929 summoned memories of the ‘Spanish ‘flu’ and underscored the apparent powerlessness of medicine. Reports on the toll of these epidemics were headline news: ‘Over 30,000 more people died in 1927 than 1928,’ noted a lead story in The Daily Mirror, ‘the principal cause being influenza.’118 A Times editorial in late December 1928 observed that: At more or less regular intervals, influenza breaks out and marches across the world, claiming millions of victims and causing grievous dislocation of human enterprise. Immense sums of money are spent on sickness benefits and on the care of the sick, and heavy losses are incurred by the majority of industrial undertakings; while numberless men and women lose their health permanently and become dependent on others.119

Medical science, the editorial noted, had made little headway in countering the costs of influenza: ‘Even the most important recent discoveries and achievements look insignificant when compared with the failure to control a disease which can compass the world in a few weeks and in the same period of time rob humanity of its normal powers of resistance to a large number of other diseases.’120 Significant scientific developments, especially in virus research, had failed to make any marked progress in controlling influenza since the great pandemic. ‘Unsolved by Science’, ran the title of a review of the state of research in the popular magazine, The Sphere, in March 1929. ‘Despite thousands of experiments, hours upon hours of tedious and faithful work, the volunteering of human subjects for tests that might mean death, experts sadly shook their heads and admitted frankly: “We know no more about influenza than we did in 1918”.’121 The 1929 epidemic spurred renewed demands for more concerted research. The MRC came under pressure from its patrons, politicians, the press, and the medical profession. Its strategy for addressing influenza indirectly through distemper had established important building blocks for virus work. But its strategy of supporting influenza research through

118 ‘Secrets of the Nation’s Health: Flu’s Death Toll’, The Daily Mirror (22 October, 1928), 3. 119 ‘The Control of Influenza’, The Times (28 December 1928), 13. 120 ‘The Control of Influenza’, The Times (28 December 1928), 13. 121 Watson Davis, ‘Unsolved by Science—The ‘Flu’, The Sphere (2 March 1929), 116.

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grants to individual researchers working on various aspects of its aetiology had paid few dividends. The research tended to be episodic, with flurries of activity coinciding with epidemics or outbreaks, which presented opportunities to collect and study pathological material from clinically defined cases of the disease. But these short bursts resulted in little progress on the aetiological question. Researchers remained divided. ‘[M]uch mystery still surrounds the nature of the causative organism of the disease,’ noted an editorial in The Times. ‘The bacillus influenzae still numbers staunch supporters among bacteriologists whose opinions are received with world-wide respect. But detractors are scarcely less numerous. They are divided into two groups—those who give their regard to one or other of the so-called filterable viruses, and those who look upon all reputed organisms as so many “pretenders”.’122 James McIntosh was among those who doggedly defended B. influenzae. Paul Fildes, his old research partner, abandoned work on the bacillus altogether for general investigations on bacterial physiology and nutrition. Alexander Fleming and his colleagues at St. Mary’s continued their work on methods of improving influenza vaccines, but they did so largely without questioning the assumption that B. influenzae was the primary cause.123 Meanwhile, Mervyn Gordon defended the virus theory. Many other workers explored the problem without resolving it.124 The recalcitrance of influenza to experimental work frustrated claims on either side.

5

Limits of Control

Gordon’s experience exemplifies the resistance of influenza to straightforward lines of attack and the challenges it posed to virus research. Despite his claim to have identified the ‘virus of influenza’ in 1922, within a 122 ‘Influenza’, The Times (13 January 1927), 13. 123 A. Fleming, ‘On the Antibacterial Action of Cultures of a Penicillum, with special

Reference to Their Use in the Isolation of B. influenzae’, British Journal of Experimental Pathology, X (1929), 226–234; A. Fleming and I.H. Maclean, ‘On the Occurence of Influenza Bacilli in the Mouths of Normal People’, British Journal of Experimental Pathology, XI (1930), 127–134. 124 For a full survey, D. Thomson and R. Thomson, ‘Influenza (Part I)’, Annals of the Pickett-Thomson Research Laboratory, (London: Bailliere, Tindall and Cox, 1933); ‘Influenza (Part II)’, Annals of the Pickett-Thomson Research Laboratory (London: Bailliere, Tindall and Cox, 1934).

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year he ran into the familiar technical obstacles that hindered such work. Unable to maintain the filter-passer in artificial cultures, and unable to establish it in a research animal, he was forced to halt his investigations. In 1923, he started studying vaccinia to develop his skills and as a potential analogue of influenza virus. This work resulted in a major report for the MRC but yielded few inroads into influenza.125 Gordon returned to his influenza studies during a large epidemic in 1927. Based on his vaccinia work, he tried but failed to establish the rabbit as an influenza model. He aided two junior colleagues, Lawrence P. Garrod and R.G. Canti, in attempts to isolate filter-passing agents, including B. pneuomosintes, from cases at Barts. Yet they were stymied by inadequate culture methods and the lack of research animals susceptible to the agents.126 Soon thereafter, Gordon completely abandoned influenza for more promising virus work on mumps. He was not alone. By the end of the 1920s, published work on the filter-passer and the bacteriology of influenza had slowed considerably. A Ministry of Health review of the state of research on influenza in 1927 concluded that, ‘recent reports on the isolation of a filter-passer, while not lacking conviction on the part of their authors, recognise that the work has not yet advanced to the stage which would entitle this theory to general acceptance.’127 The hope of resolving the aetiological problem with new scientific research, which had opened the 1920s, had turned to despair by the end of the decade. Influenza’s aetiology was mired in dispute and dead ends. A Ministry of Health ‘Memoranda on Influenza’, issued in response to the 1927 epidemic, concluded that: ‘No conspicuous advance has been made recently in our knowledge of the bacteriology of influenza. Opinion is still divided between adherents of Pfeiffer’s theory and those who believe that the true causal agent is some other organism—probably a filter-passer …

125 M.H. Gordon, Studies of the Viruses of Vaccinia and Variola, Medical Research Council Special report Series, 98 (London: HMSO, 1925). 126 L.P. Garrod, ‘Filter-passing Anaerobes in the Upper Respiratory Tract’, British Journal of Experimental Pathology, IX (1928), 155–160. 127 Ministry of Health, ‘Memorandum on Influenza (Revised Edition)’ (London: HMSO, 1927), 6.

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The present outlook as to the primary causation, therefore, is not particularly hopeful.’128 Two years later, in a review of influenza research for the MRC’s System of Bacteriology, the Ministry of Health bacteriologist, William M. Scott, came to a similar conclusion: ‘Discussion of this question has in the past been conducted with unnecessary passion on both sides, and even now detractors and defenders of Pfeiffer’s bacillus as the cause of epidemic influenza hold their positions more by faith than by reason. The truth is that a reasoned conviction is not yet possible; it has to be admitted, when the pros and cons are carefully considered, that the absolute affirmative or negative will have to be decided in the future.’129 Scott’s assessment was echoed by two of London’s leading experimental pathologists, W.W.C Topley and G.W.S. Wilson, in the first edition of their Principles of Bacteriology and Immunity, published in 1929: ‘The etiological problem presses for solution, for against epidemic influenza the public health administration is at the moment, entirely powerless.’130 Without a clear understanding of the specific cause of influenza, the general perception was that medicine and public health remained largely impotent against an epidemic. When the Ministry of Health issued a revised ‘Memorandum on Influenza’ during the 1929 epidemic, it highlighted the lack of progress. ‘The laboratory’, it noted, ‘has not yet given us a specific form of treatment for influenza or of protection against it.’131 All the Ministry could do was revise recommendations that had been made in 1920 of the limited measures available to health and local authorities in the event of an epidemic. These aimed to protect individuals and the wider community. Health authorities were advised to inform the public, through leaflets, posters, press notices, school lectures, and other media on how to ward off an attack, the precautions to be taken when infected, and how to mitigate the spread of the disease. Information covered a range of topics,

128 NA MH 55 57 Issue of Ministry of Health Memorandum on Influenza, 1927, to Local Authorities Circulars 761, 955; Revised Memorandum on Influenza, 1929. Ministry of Health ‘Memorandum on Influenza (Revised Edition)’, 6. 129 W.M. Scott, ‘The Influenza Group of Bacteria’, in P. Fildes, & J.C.G Ledingham (Eds.), A System of Bacteriology in Relation to Medicine (London: HSMO, 1929), 355. 130 W.W.C. Topley and G.S. Wilson, The Principles of Bacteriology and Immunity (London: Edward Arnold, 1929), 1008. 131 Ministry of Health ‘Memorandum on Influenza (Revised Edition 1929)’, 5.

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including how to be prudent about nutrition, avoidance of crowds, ventilating rooms and the home, personal hygiene and cleanliness, gargling to disinfect the nose and mouth, and other ways to maintain health and resistance to infection. Emphasis was placed on ‘the duty of the individual not only to do the best for himself in case of attack but … also to protect others.’132 While individual duty was a cornerstone of prevention, the state also had a key role to play. Along with providing information to the public, the Memorandum stressed that health authorities were bound to take practical steps to reduce the spread of infection, to assist in the treatment and nursing of individual cases, and to help alleviate hardships and risks to households stricken by the disease. The reality, however, was that health authorities had few practical measures at their disposal. Vaccination was an obvious means to protect the community. But because of the lingering uncertainty about the causal agent, bacterial vaccines were ruled out as effective preventive tools against infection. Instead, in the event of an epidemic, local authorities were advised to focus on controlling the spread of influenza through a combination of social distancing measures, school and cinema closures, isolation of the sick, and social hygiene, including guidance on spitting, coughing, and sneezing in public. All these measures had been recommended and used before, with mixed results. School closures were thought to be of some value in rural or small urban areas, ‘but of little utility in densely populated urban areas’, where children regularly came in contact with each other outside of school.133 A more effective measure was thought to be the exclusion from school of children with influenza symptoms. Schools were to notify health authorities of such cases and the child would only be re-admitted after careful medical examination of the heart and lungs to eliminate potential complications. No other public spaces were subject to such interdictions. Regulations enacted in late 1918 to close cinemas or to exclude school-age children from them had not been used since early 1919 and doubts remained about their efficacy. Overcrowding in public spaces and on public transportation was a recognised danger, but difficult to manage. Ongoing ventilation of cinemas, trains, and trams was advised and widely adopted, but routine disinfection of premises or of articles used by those suspected of having influenza was

132 Ministry of Health, ‘Memorandum on Influenza (Revised Edition 1929)’, 6. 133 Ministry of Health, ‘Memorandum on Influenza (Revised Edition 1929)’, 12.

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not recommended because there was little evidence to suggest it worked. General disinfection of public spaces was also deemed to be ‘of doubtful utility, and only tends to create a false sense of security.’134 All told, existing preventive measures only could be expected to slow the spread of influenza: ‘At present … the fact must be accepted that in a period of world-wide prevalence [of influenza] most members of the community who go about their ordinary avocations must expect to be exposed to infection and many to have the illness in some for or other….’135 Stopping an influenza epidemic was illusory. Faced with these realities, the Ministry of Health stressed the need for local authorities to be prepared for large numbers of sick, with a significant proportion at risk of or suffering from more serious secondary infections. Complications associated with bronchitis, influenzal pneumonia, and other respiratory conditions were noted as ‘the chief dangers of influenza’ and the main cause of death.136 The Ministry’s 1929 Memorandum reiterated an important lesson from the 1918–1919 pandemic: because prevention measures were limited, during an epidemic priority needed to be given to reducing complications and assisting the sick. Health authorities and medical professionals had some options at their disposal. Bacterial vaccines, including the Ministry’s own mixed Pfeiffer vaccine, had been shown, in some cases, to reduce the severity of secondary infections, especially B. influenzae, pneumococcus and streptococcus, which were associated with the development of life-threatening pneumonias and bronchitis. Such vaccines had been widely used in Britain and abroad since 1918 to mitigate the severity of influenza, but there was little evidence that they prevented complications.137 Specific treatments for pneumonia were limited. Anti-pneumococcal serum therapies had been in use for lobar pneumonia since 1910, but their production and quality were complicated by the existence of different types of pneumococci.138 There was widespread scepticism among British medical professionals about their therapeutic value: not only were they expensive

134 Ministry of Health, ‘Memorandum on Influenza 135 Ministry of Health, ‘Memorandum on Influenza 136 Ministry of Health, ‘Memorandum on Influenza 137 Ministry of Health, ‘Memorandum on Influenza

(Revised Edition1929)’, 13. (Revised Edition 1929)’, 6. (Revised Edition 1929)’, 9. (Revised Edition 1929)’, 10.

138 S.H. Podolsky, Pneumonia Before Antibiotics: Therapeutic Evolution and Evaluation

in Twentieth-Century America (Baltimore: Johns Hopkins University Press, 2006), 13–21.

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and tedious to administer, but clinical results were inconsistent.139 Patent medicines filled the therapeutic void. All kinds of therapies continued to be advertised as cure-alls for influenza and its complications. As part of mounting efforts against commercial treatments, the Ministry deemed such medicines to be roundly ineffective and ‘as likely to do more harm than good.’140 In the event of an epidemic health authorities would be stretched to provide medical, nursing, and ambulance services for the large numbers of sick. For those with typical symptoms, the home was designated as the primary site of care, with nurses, health visitors, and volunteers tasked with providing domiciliary support and advice, notifying medical officers of serious cases, arranging food for badly affected households, and organising creches for children whose parents were stricken with the disease. Emphasis was placed on bed rest, keeping warm, nutrition, and good ventilation. The focus on home care was a way to relieve pressure on hospitals and infirmaries, which, as past pandemics showed, threatened to be rapidly overrun by an influx of patients with a range of symptoms, from mild to severe. Hospital care was to be prioritised for the most serious cases, who were identified and selected for admission by medical practitioners. Precedence was given to those with severe pulmonary complications, who were to be isolated in separate wards where medical and nursing attendants observed strict precautions for treating an acute respiratory infection. These measures were proposed in the face of continued uncertainty about the identity of influenza. The very term—‘influenza’—remained as protean as the manifestations of the disease itself and could still be applied to a range of symptoms or conditions. ‘[I]nfluenza is so mysterious a disease, and is at present the subject of so many differences of opinion among those who have studied it closely,’ editorialised The Times, ‘that positive statements about the manner of its appearance, its 139 M. Worboys, ‘Treatments for pneumonia in Britain 1910–1940’, In Ilana Löwy and J.-P. Gaudillière (Eds.), Medicine and Change: Historical and Sociological Studies of Medical Innovation (Montrouge, France: John Libbey Eurotext, 1993), 317–336; Martin Edwards, Control and the Therapeutic Trial, 93–97. 140 Ministry of Health ‘Memorandum on Influenza (Revised Edition 1929)’, 13. The 1925 Therapeutic Substances Act marked the beginning of government regulation of commercial medicine in Britain. See, Jonathan Liebenau, ‘The MRC and the Pharmaceutical Industry: The Model of Insulin’, In J. Austoker and L. Bryder (Eds.), Historical Perspectives on the Role of the MRC (Oxford: Oxford University Press, 1989), 163–180.

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spread, its incidence, or its probable character in the immediate future are scarcely justified.’141 This was the main reason why the Ministry of Health decided, just as the LGB had decades before, to not make influenza a notifiable disease: No sure means are yet available for distinguishing the “common or influenzal cold” from true influenza, nor is it yet certain that they are distinct clinical entities. The autumn and winter outbreak of “influenzal catarrahs” are, except in severity, clinically indistinguishable either in themselves or in their complications, including pneumonia, from the disease which wrought such world-wide havoc during the pandemics of 1918 and 1890.142

When the Ministry’s 1927 Memorandum was re-issued in 1929, these lines—and all other recommendations—remained unchanged. Indeed, they harkened back to observations made during the 1889–90 pandemic and were a reminder of how little had changed in the intervening years. Most of all, they highlighted the marked lack of progress that medical science had made in providing public health and medical authorities with the specific cause of influenza that could be used to resolve these uncertainties and establish more effective ways to identify and control inevitable future epidemics. Against this backdrop of fear and failure, the success of the NIMR’s dog distemper work and the new possibilities it raised for virus research, attracted much attention. ‘[T]he sad state of unpreparedness in which the world finds itself ought to awaken determination to discover, if possible, some means of prevention,’ the editor of Times argued in December 1932. ‘An effective approach to the [influenza] problem,’ the editorial continued, had been demonstrated with dog distemper: ‘Is it too much to ask that work on similar lines be undertaken on the cause of influenza? The work on distemper has opened a way; general studies organised by the Medical Research Council on virus diseases have made parts, at any rate, of that way smooth. Has not the time arrived to launch a campaign and to come to grips with the enemy?’.143

141 ‘Influenza’, The Times (13 January 1927), 13. 142 Ministry of Health, ‘Memorandum on Influenza (Revised Edition 1929)’, 6. 143 Editor, ‘Influenza Again’, The Times (29 December 1932), 9.

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The MRC’s response to these demands reflected its trust in virus research, in the NIMR’s approach, and in the model developed around dog distemper. But simply replicating the distemper campaign was not possible. Influenza may have shared important characteristics with distemper, but it was evident that it was a different disease. A revised approach required building on the foundations of distemper research while also developing new knowledge, skills, tools, and organisation specific to influenza.

CHAPTER 7

Viralising Flu: Towards a New Medical Consensus

In December 1935, Patrick Laidlaw and two younger NIMR researchers, Wilson Smith and C.H. Andrewes, joined physicians and pathologists at hospitals and military establishments around London in a crucial series of studies on influenza.1 Two years earlier, Laidlaw, Smith, and Andrewes had developed a method using ferrets to isolate a filterable virus from influenza patients. The discovery in early 1933, noted the Institute’s director, Sir Henry Dale, had finally drawn influenza ‘within the realm of experiment’, making it possible to elucidate the primary role of a virus as the cause of the disease.2 Along with the ferret, the team had also fashioned a laboratory mouse for a serological test that enabled them to identify and measure antibodies associated with the virus, and thus to indirectly determine its presence in individual cases and communities. The test also opened the possibility of assessing the effectiveness of an experimental vaccine the team had developed. These breakthroughs went far towards making influenza into a new object of virus research. But establishing influenza’s identity as a virus disease required more than a working experimental system. As the NIMR researchers knew, such efforts hinged 1 The studies were published final report, C.H. Stuart-Harris, C.H. Andrewes, and Wilson Smith, A Study of Epidemic Influenza: With Special Reference to the 1936-Epidemic, Medical Research Council, Special Report Series, No. 228 (London: HMSO, 1938). 2 Report of the Medical Research Council for the Year 1932–1933 (London: HMSO, 1934), 39.

© The Editor(s) (if applicable) and The Author(s), under exclusive licence to Springer Nature Limited 2023 M. Bresalier, Modern Flu, Medicine and Biomedical Sciences in Modern History, https://doi.org/10.1057/978-1-137-33954-6_7

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on their ability to link the virus disease they produced in ferrets with the one that medical professionals and public health authorities knew in their patients and populations. The team thus had to confront the critical challenge of how to make a new laboratory entity—influenza virus—relevant to constituencies outside the laboratory walls. This was the point of the collaborations they had initiated in 1935: the aim was to correlate laboratory and clinical evidence to support a new definition and approach to influenza (Figs. 1 and 2). Since the NIMR was a freestanding institution with no formal hospital connections, the team recruited a young Barts physician and clinical researcher, Charles Herbert (C.H.) Stuart-Harris to develop and coordinate relations with hospital clinicians and pathologists. The team hoped that they could align the laboratory disease they had produced in ferrets and mice with a specific clinical entity in humans, and thereby solve the long-standing question of what constituted ‘influenza’.3 These collaborations would also be key to testing an experimental vaccine which, if shown to be effective, would further support their claims for the primary role of their virus. The construction of influenza’s virus identity would thus involve building new social relations and a new medical consensus around the disease.4 The challenges were many and took time to resolve. They stemmed in good part from the virus itself. Its biology would throw up a host of novel problems. Considerable work had to go into rendering the new agent, understanding its nature as a pathogen, and establishing it as the specific cause of influenza and its practical value for the different groups who already claimed expertise over the disease. This process depended on the NIMR’s innovations and findings being incorporated into and changing existing medical approaches to influenza. 3 C.H. Andrewes, P.P. Laidlaw, and Wilson Smith, ‘Influenza: Observations on the Recovery of Virus from Man and on the Antibody Content of Human Sera’, British Journal of Experimental Pathology, XVI (1935), 566; Stuart-Harris, Andrewes, and Smith, A Study of Epidemic Influenza, 8. 4 John Eyler, in an account of the making of flu virus in the United States that parallels mine, has argued that the metaphor of ‘construction’ too readily presupposes virus researchers’ following and realizing a master plan, regardless of nature’s constraints. John M. Eyler, ‘De Kruif’s Boast: Vaccine Trials and the Construction of a Virus’, Bulletin of the History of Medicine, 80 (2006), 437. I take the ‘problem of construction’ to be a social process in which ‘facts’ produced in and through local contexts become universalized or gain general application. Both nature and culture act as constraints on the construction and generalisation of medical scientific knowledge. See, Jan Golinski, Making Natural Knowledge, 98–100.

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Fig. 1 Wilson Smith M.B., F.R.S. (1897–1965) (Source Obituary Notices of Fellows of the Royal Society, 12 [1966], 478–487)

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Fig. 2 Christopher Howard Andrewes, M.B., F.R.S. (1896–1987) (Source MRC National Institute for Medical Research, https://commons.wikimedia. org/wiki/File:Christopher_Howard_Andrewes.jpg#filelinks)

Negotiating the different roles of both the virus and virus research was part of the process of viralising influenza.

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As we have seen, a generation of physicians, epidemiologists, public health professionals, and medical researchers knew influenza as remarkably protean and dangerous. Despite being classified as an infectious disease since the early 1890s, four decades of research had failed to settle questions about the causative agent and thus to put its diagnosis and control on more certain scientific foundations. Many British medical textbooks still accepted—albeit with qualifications—that Pfeiffer’s bacillus was the causative agent. While the possible role of a filterable virus had been acknowledged and explored since 1918, such research lacked convincing support, with the most significant problem being the absence of a readily susceptible laboratory animal in which investigators could reproduce and study the disease. The NIMR’s investigative tools raised new hopes for a solution to these vexing problems. The ferret was crucial. Its previous role in the success with dog distemper generated the tangible possibility that the virus aetiology of influenza could be settled, and effective methods of prevention could become a reality. The mouse was also crucial. The serological work that it made possible would prove vital for understanding immunity conferred by infection and vaccination, and the changing susceptibility and resistance to influenza viruses. Infected mice were also a source of virus material for the first influenza vaccines. By 1935, as the NIMR team prepared its collaborative studies, sorting out influenza’s highly variable clinical and epidemiological characteristics appeared within reach. In terms strikingly reminiscent of bacteriologists in the 1890s, StuartHarris suggested that he and his colleagues were in a position to delineate ‘true influenza’ from the ‘scrap-heap’ of conditions usually associated with the disease.5 Besides the diagnostic implications, linking the virus to a specific disease underpinned the testing of vaccines on accurately identified cases of influenza. The prospect of new methods for managing influenza won the NIMR researchers attention and praise in the medical and general press, but as new actors in influenza medicine and public health, they needed to build credibility for their research. Collaborative studies were part of the ongoing work of positioning virus research—and virus workers—as indispensable to the elucidation and control of a major infectious disease.

5 Stuart-Harris, Andrewes, Smith, A Study of Epidemic Influenza, 3.

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This positioning depended, to a large degree, on the ability of the NIMR researchers to move their work from the laboratory into the realms of hospitals and public health. The production of tools to bridge these realms was vital to this process.6 Not all the tools in interwar virus research could serve this function. For example, using ferrets and even mice to run diagnostic tests required expertise and materials most hospital or public health laboratories lacked at the time. The right tools had to be familiar enough to doctors, pathologists, and public health officers so that they could read and interpret results generated from them and to translate them into terms relevant to their understanding of influenza. One such tool—a virus neutralization test fashioned first with ferrets and then with mice—gained characteristics of a ‘boundary object’ that moved between and mediated the different social worlds through which influenza was framed and worked upon.7 Widely used, neutralization tests were serological assays first developed for bacteriological work but then adapted to virus work. The influenza virus neutralization test developed at the NIMR could be applied to laboratory, clinical, and public health problems and was crucial in shaping influenza’s virus identity. The multiple uses of this test for the serological identification of influenza virus, for tracking serum antibodies in human populations, and for evaluating the potency and efficacy of vaccines enabled the NIMR workers to align their research with the interests and practices of medical constituencies who already claimed ownership over influenza. Neutralization tests, though widely used in interwar medical virus work, were also bound to the contexts in which they were deployed. The NIMR’s influenza test embodied the research style that had been developed at the Institute in the 1920s. As shown in the work on dog distemper, this style was characterised by an immunological approach to viruses and virus diseases as problems best solved by the making and use 6 I take the concept of the ‘right tools for the job’ from Adele E. Clarke and Joan H. Fujimura, ‘What Tools, What Job? Why Right?’, in idem. (Eds.), The Right Tools for the Job: At Work in Twentieth-Century Life Sciences (Princeton: Princeton University Press, 1992), 3–45. 7 Sharon Leigh-Star and James R. Griesemer, ‘Institutional Ecology, Translation, and

Boundary Objects: Amateurs and Professionals in Berkeley’s Museum of Vertebrate Zoology, 1907–1939’, Social Studies of Science, 19 (1989), 387–420. My approach has greater affinities with Ilana Löwy, ‘The Strength of Loose Concepts—Boundary Concepts, Federative Experimental Strategies and Disciplinary Growth: The Case of Immunology’, History of Science, XXX (1992), 371–396.

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of what NIMR workers called ‘immunological devices’.8 Some historians have suggested that this orientation was largely the product of the technical constraints and limitations of interwar virus work, with its roots in bacteriology.9 It was, but it also needs to be set in relation to broader professional and institutional concerns with the practical applications of immunology to medicine that characterised medical research through the 1920s and 1930s.10 Interwar virus workers used serological assays to demonstrate how virus research could address the concrete problems of disease aetiology, epidemiology, treatment, and immunization. The need for such workable tools in clinical and public health medicine were an important factor in shaping the NIMR’s style of virus work. As the distemper campaign illustrated, and as work on influenza would show, this style manifested an ethos promoted by the MRC, which aimed to translate the products of laboratory science into medicine. Immunological devices were seen as particularly useful for realising these goals.

1

Virus Neutralization

A decade’s worth of frustration with failed efforts to control influenza came to a head in December 1932, when yet another epidemic struck. Although not as severe as in 1929, it nonetheless summoned lingering fears and memories of 1918. ‘A new epidemic of Spanish influenza seems to have swept through Anglo-Saxon countries,’ announced The China Press. ‘In Great Britain … the epidemic has struck hard, even crippling the postal service….’11 By mid-January, a reported 500,000 persons had been stricken, with an estimated 50,000 in London alone. London hospitals had to create special wards for sick doctors and nurses. Prince George III was reportedly ‘in bed with influenza’ and unable to carry out his royal duties. With cases and deaths rising, especially in the Midlands and mining

8 Report of the Medical Research Council for the Year 1928–1929, Report of the Medical Research Council (London: HMSO, 1930), 15. 9 Ton van Helvoort, ‘A Bacteriological Paradigm in Influenza Research in the First Half

of the Twentieth Century’, History and Philosophy of the Life Sciences, 15 (1993), 3–21. 10 Michael Worboys, ‘Vaccine Therapy and Laboratory Medicine in Edwardian Britain’, In John V. Pickstone (Ed.), Medical Innovations in Historical Perspective (London: Macmillan, 1992), 87. 11 ‘England and U.S. Suffer Epidemic of Spanish Influenza’, The China Press (31 December 1932), 1.

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districts in Northern England, the Ministry of Health issued thousands of pamphlets to every town on how to prevent against infection.12 Letters sent to the MRC, and published in The Lancet and BMJ , demanded to know what research initiatives the Council was taking.13 ‘We have been flooded with questions about what is being done in the way of research in influenza,’ reported the MRC’s Assistant Secretary, Landsborough Thomson, in January 1933.14 A number of eminent London scientists, physicians, and philanthropists challenged the piecemeal approach the MRC had taken over the preceding decade. ‘You will forgive me,’ Sir John Collie, Professor of Organic Chemistry at University College, wrote to Fletcher, ‘when I say that in view of the appalling mortality as the result of these annual epidemics of influenza, the time has come when the MRC or some other Public Body, must have at its disposal the [sic] numbers of those who are investigating the cause of influenza … Your investigations – admittedly small in number – have failed.’15 Sir Halley Stewart, vice-chairman of the London Brick Company and director of the Halley Stewart Trust, which made significant donations to British medical and scientific research, offered Fletcher the considerable sum of £2500 to launch an ‘Influenza Campaign’ modelled on dog distemper.16 Similar concerns were expressed in the general press. ‘[I]n view of the widespread nature of the epidemic,’ noted an editorial in The Observer, ‘many people are asking, as they have asked before, why the medical profession is not able to do something about it.’17 Typical was the view of Charles Russ, a controversial venereologist and medical populariser, who asked in his regular column in the Daily Express, ‘How…can the medical profession reply to the seemingly justified common gibe that doctors have not yet found a cure for influenza, and what are they going to do about it? Why is there no remedy for this devastating disease?’ Russ insisted that new investment was needed: the ‘Government should back us with, say, the

12 ‘Influenza in Britain Has Struck 500,000’, New York Times (15 January 1833), 18. 13 NA FD1/3356 Influenza, Thomson to A. Salisbury McNalty, 20 January 1933. 14 NA FD1/3356 Influenza, Thomson to A. Salisbury McNalty, 20 January 1933. 15 NA FD1/3356 Influenza, Sir John Collie to Fletcher, 1 February 1933. 16 NA FD1/3356 Influenza, Halley Stewart to Fletcher, 2 January 1933. Based on the

current Retail Price Index, the value of £2500 was worth approximately £140,053.44. 17 ‘The Epidemic of Influenza: Hints on Avoiding Infection’, The Observer (15 January 1933), 17.

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price of a submarine. Give us a chance of really waging war on influenza.’ Now was the time, he concluded, to ‘intensify research as to bring in sight the end of influenza epidemics, and of the wastage of life, health, time, and money which they inflict on the nation.’18 With public pressure mounting, Fletcher and Dale decided that the best strategy was to concentrate influenza research in the hands of experienced workers at the NIMR. Laidlaw, recently knighted for his dog distemper work, was put in charge; Andrewes and Smith joined him as co-workers.19 Enrolling the NIMR addressed both public demands for concrete action and the recognised need for a new approach. Linkage to dog distemper was symbolic and pragmatic. As we have seen, Laidlaw’s distemper work solidified his reputation as an outstanding virus researcher and this association leant credibility to the NIMR’s move into influenza. The distemper programme was widely and readily invoked in early 1933: ‘since research on distemper has successfully brought about a cure for this disorder it only requires the same necessary facilities to be claimed for influenza,’ was a typical observation.20 Based on the identification and control of viruses through the production of serological assays, therapeutic sera and, ultimately, vaccines, the programme was part of wider MRC efforts to adapt immunological techniques to the special demands of viruses and virus diseases. Along with being familiar to practitioners as a source of therapies and preventatives, such techniques were also crucial for tackling the practical challenges of virus research. The resistance of viruses to cultivation in artificial media and visualisation by standard light microscopy meant that virus workers had two ways to 18 Dr. Charles Russ, ‘Have You Seen the “Flu Germ?”’, Daily Express (27 January 1933), 8. 19 There are a number of accounts of the NIMR move into influenza: C.H. Andrewes, ‘Influenza Virus and the Beginnings of Its Study in the Laboratory’, The Medical Press (1951), 225; F.M. Burnet, Changing Patterns: An Atypical Autobiography (Melbourne: Heinemann, 1968), 121–130; W.I.B. Beveridge, ‘Unravelling the Ecology of Influenza a Virus’, History and Philosophy of the Life Sciences, 15 (1993), 23–32; F.M. Burnet, ‘A Portrait of Influenza’, Intervirology, 2 (1979), 201–214; Crosby, America’s Forgotten Pandemic (1989), 286–290; Edwin Kilbourne, ‘Pandora’s Box and the History of the Respiratory Viruses: A Case Study of Serendipity in Research’, History and Philosophy of the Life Sciences, 14 (1992), 299–308; David A.J. Tyrell, ‘Discovery of Influenza Viruses’, in K.G. Nicholson, R.G. Webster, and A.J. Hay (Eds.), Textbook of Influenza (Oxford: Blackwell, 1998), 19–26. 20 ‘PURSUIT OF HEALTH: A specialist symposium on Influenza PREVENTION & CURE’, South China Morning Post (7 March 1933), 1.

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demonstrate their presence: either by inducing an experimental disease in a susceptible animal or by tests for serum antibodies in convalescent animals or patients.21 In this way of working, serum antibodies were treated as crucial evidence in establishing the aetiological role of a virus. Immunological tests were thus essential to the elucidation of the identity of virus diseases. The prominent Rockefeller virus researcher, Thomas M. Rivers, described medical and veterinary virus work as uniquely dependent on ‘the science of immunology’, and argued for revamping Koch’s postulates to include serological evidence as part of the criteria for determining the causal relationship of a virus to a disease.22 Unlike bacteriologists, who had developed sophisticated serological assays with a variety of antibodies, virus workers relied heavily on a particular group of antibodies for their immunological evidence—so-called neutralizing antibodies.23 Acquired naturally through infection or artificially through vaccination, these antibodies specifically inhibited or ‘neutralised’ the pathogenic effects of a virus. Neutralization tests were used to indirectly identify a virus through the presence of specific antibodies to it, to measure antibody levels in healthy, sick or recovered bodies, and to assess the potency of anti-serum and vaccines. They defined approaches to what contemporaries called ‘virus immunity’ and shaped ways of knowing viruses and virus diseases. Neutralization was a concept and technique intimately linked with the origins of immunology. When the Berlin bacteriologists Emil von Behring and Shibashuro Kitasato discovered in 1892 that a serum substance—a so-called ‘antitoxin’—inhibited diphtheria toxin, they illuminated a key immune reaction that paved the way for the late nineteenth century explosion in serum therapy and the development of humoral theories

21 Ilana Löwy, Virus, Moustiques et Modernite: La Fievre Jaune au Brasail entre Science et Politique (Paris: Editions des archives contemporaines, 2001), 186. 22 Thomas Rivers, ‘Viruses and Koch’s Postulates’, Journal of Bacteriology, 33 (1937),

3. 23 For contemporary reviews of serological tests for viruses, see W.W.C. Topley and G.S. Wilson, The Principles of Bacteriology and Immunity (London: Edward Arnold, 1936), 959–962; F.M. Burnet, E.V. Keogh, and D. Lush, ‘The Immunological Reactions of Filterable Viruses’, Medical Journal of Australia, 15 (1937), 227–368; C.E. van Rooyen and A.J. Rhodes, Virus Diseases of Man (London: Oxford University Press, 1940), 70–96.

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of immunity.24 Embraced as a key property of immunity, the mechanism of neutralization emerged as a defining problem in bacteriology and serology. The American bacteriologist, George Sternberg, first used the term ‘neutralization’ in 1892 to describe how a soluble substance in the serum of immune cows inhibited the pathological effects of vaccinia.25 A chemical term that referred to the reaction between acids and alkaloids, Sternberg used neutralization to denote the ability of a serum substance (antitoxins or antibodies) ‘to destroy the specific virulence of [a] virus, when it contacts it.’26 Paul Ehrlich, working on the standardisation of diphtheria anti-toxin in the late 1890s, developed his side-chain theory to explain this process.27 Describing neutralization as the irreversible union of toxin with antitoxin, Ehrlich argued that humoral immunity depended on the production of ‘neutralizing antibodies.’28 The quantitative methods Ehrlich developed to assess diphtheria anti-toxin made neutralizing antibodies indispensable serological tools.29 By first determining a consistent unit—the minimum lethal dose—of a toxin that killed a guinea pig, he measured the ‘neutralizing power’ of an anti-serum by injecting dilutions of toxin and the serum mixed in vitro into the susceptible animal. Neutralization was identified when 50% of the animals survived. This method made it possible to quantify the amount of neutralizing antitoxin in a serum sample and to produce standardised antiserum. Ehrlich’s quantitative work demonstrated how neutralizing antibodies could be harnessed for serological tests and the mass production of serum therapies for different bacterial diseases.30 24 P.M.H. Mazumdar, ‘The Antigen-Antibody Reaction and the Physics and Chemistry of Life’, Bulletin of the History of Medicine, 48 (1974), 1–21. 25 A. Grafe, A History of Experimental Virology (London: Springer-Verlag, 1991), 70. For a popular account of Sternberg’s work, see, Greer Williams, Virus Hunters (London: Hutchinson & Co., 1960), 95–100. 26 Grafe, A History of Experimental Virology, 70. 27 A. Cambrosio, D. Jacobi, and P. Keating, ‘Ehrlich’s “Beautiful Pictures” and the

Controversial Beginnings of Immunological Imagery’, Isis, 84 (1993), 662–699; Lenoir, ‘A Magic Bullet’; P.M.H. Mazumdar, Species and Specificity: An Interpretation of the History of Immunology (Cambridge: Cambridge University Press, 1995), 205–210; A.M. Silverstein, A History of Immunology (London: Academic Press, 1989), 64–66. 28 Mazumdar, ‘The Antigen–Antibody Reaction’, 3–8. 29 Mazumdar, Species and Specificity, 114–117. 30 Jonathan Liebenau, ‘Paul Ehrlich as a Commercial Scientist and Research Administrator’, Medical History, 34 (1990), 65–78; Paul J. Weindling, ‘From Medical Research

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Through the 1920s, neutralizing antibodies also became closely identified with virus research. They had been discovered in a number of virus diseases and neutralization tests were used in work on poliomyelitis, smallpox, vaccinia, measles, herpes and yellow fever.31 The Australian virus worker, Frank Macfarlane Burnet, who trained at the NIMR and became a leading authority on influenza virus, summarised the basic methodological principles behind such tests in his influential review of Immunological Reactions in Virus Diseases: [Virus neutralization tests] all take the form of the inoculation of mixtures of virus and antiserum into tissue of a susceptible animal. The effect of antiserum is judged by the nature and extent of the lesions that develop in the animal after some convalescent arbitrary period, in comparison with those produced in the absence of serum. The species of animal and particular tissue used for inoculation … play an important part in determining the result of inoculation of serum-virus mixtures … Neutralization of virus is … synonymous with suppression of a macroscopic … lesion.32

The histological lesion or the death of a laboratory animal served as both a signifier and endpoint for neutralization. Neutralization tests reflected the particular reliance on living animals or tissue that characterised medical and veterinary virus research. As Burnet noted, these tests varied according to the animal used, serum-virus mixtures, inoculation techniques, and endpoints, all of which meant that they were sensitive and subject to error. But, when used with care, they were specific to the disease for which they were developed. As such, the action of neutralizing antibodies in protecting against the pathogenic effects of viruses in laboratory animals and humans made them essential diagnostic and therapeutic tools. Serum quantification methods already figured centrally in the NIMR’s role as the government body for setting national standards for biological substances.33 Under the MRC virus programme much energy was

to Clinical Practice: Serum Therapy for Diphtheria in the 1890s’, In John V. Pickstone (Ed.), Medical Innovations in Historical Perspective (London: Macmillan, 1992), 72–83. 31 A. Grafe, A History of Experimental Virology, 72. 32 Burnet, Keogh, and Lush, ‘The Immunological Reactions of Filterable Viruses’, 240. 33 Pauline M.H. Mazumdar, ‘“In the Silence of the Laboratory”: The League of

Nations Standardizes Syphilis Tests’, Social History of Medicine, 16 (2003), 437–459.

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also dedicated to the creation of immunological devices specifically for virus research. Neutralization tests were established as part of the general work of identifying viruses, measuring serum antibodies and investigating the extent of immunity associated with vaccination and serum therapy. They were also the main focus of work on virus immunity.34 Charles Herbert (C.H.) Andrewes and Wilson Smith both had been recruited to explore this problem in the late 1920s and, before moving onto influenza, helped to establish the neutralization reaction as key to understanding virus immunity. Virus immunity was a lightning rod for debate in the 1920s and 1930s.35 Early workers had claimed that it differed from bacterial immunity in both duration and mechanism, and thus could be used to distinguish viruses from bacteria. This generalization derived from experience with a small sample of virus diseases—particularly poliomyelitis, smallpox, and vaccinia—in which viral infections were known to induce highly specific and long-lasting immunity rarely seen in bacterial infections.36 For some, this suggested that the underlying mechanisms of virus immunity depended less on serum antibodies than on tissue changes—socalled ‘cellular’ immunity. The Pastorian, Constantin Levaditi, was a vocal proponent of the centrality of cellular immunity in virus diseases.37 Virus workers, including Thomas Rivers and Jonas Salk, found support for this view in the increasing evidence that viral infection was fundamentally an intracellular process, which underpinned the concept of viruses as obligate intracellular parasites.38 Even a sceptic, the eminent bacteriologist, W.W.C. Topley, acknowledged that, ‘it seems very possible that this habit of [viruses] functioning as intracellular parasites has an important bearing

34 Laidlaw and Dunkin also developed and used complement-fixation tests. 35 C.H. Andrewes, ‘Immunity in Virus Diseases’, Lancet (2 May 1931), 989–992.

C.H. Andrewes, ‘Immunity in Virus Diseases’, Lancet (9 May 1931), 1046–1049; W.W.C. Topley, An Outline of Immunity (London: Edward Arnold & Co., 1933), 254–273. 36 Wilson Smith, ‘Progress in Viral Immunology’, British Medical Bulletin, 9 (1953), 176–179. 37 Samuel P. Bedson, ‘Some Reflections on Virus Immunity’, Proceedings of the Royal Society of Medicine, XXXI (1937), 61. For Levaditi’s virus work, see K. Kroker, ‘Creatures of Reason? Viruses at the Pasteur Institute during the 1920s’, in K. Kroker, J. Keelan, and P.M.H. Mazumdar (Eds.), Crafting Immunity: Working Histories of Clinical Immunology (London: Routledge, 2008), 145–164. 38 Burnet, Keogh, and Lush, ‘The Immunological Reactions of Filterable Viruses’, 240.

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on antiviral immunity.’39 However, while many researchers accepted the possibility of cellular immunity, most work aimed to align virus immunity with dominant humoral models, which tied immunity to the production of specific antibodies. Elucidating the mechanism of virus neutralization was key. Early workers claimed that the mechanism was analogous to the action of bacteriolysins against cholera vibrios, such that neutralizing antibody acted as a ‘virucide’, effectively killing the virus.40 This explained the solid or lasting immunity observed in diseases such as vaccinia but failed to account for why in other virus diseases—such as herpes simplex—immunity appeared short term and infection could occur repeatedly. These cases suggested that neutralization operated on another principle. The problem preoccupied Andrewes early in his career at the NIMR. Andrewes came from a well-established London medical research family. His father, F.W. Andrewes, had risen up the ranks of pathology at Barts to become Professor of Pathology and head of the Department of Pathology before the war. The elder Andrewes had carried out the first British bacteriological studies on influenza under the direction of E.E. Klein in the early 1890s, but then came to question the role of Pfeiffer’s bacillus and backed the virus theory in his survey of bacteriological research for the 1920 Ministry of Health Report on the Influenza Pandemic. An original member of the MRC, he was a leading supporter of its virus research programme. C.H. Andrewes’ uncle, William Hamer, had been the Chief Medical Officer of the LCC, before, during and after the 1918– 19 pandemic and was an ardent proponent of controversial holistic views on the origins of influenza and other epidemic diseases. The younger Andrewes followed in his father’s footsteps rather than in those of his uncle. He studied medicine at Barts, qualifying in 1921, and then worked under the eminent Professor of Medicine, F.R. Fraser, as a clinical assistant in charge of bacteriology in the hospital’s Medical Unit. In 1923, following the path of many young, ambitious British medical researchers seeking to expand their expertise, he travelled to New York on a Rockefeller fellowship, where he spent two years training at the Rockefeller Institute Hospital (RIH) as an Assistant Resident Physician. It was there that Andrewes was inducted into the new field of virus research. 39 W.W.C. Topley and G.S. Wilson, The Principles of Bacteriology and Immunity (London: Edward Arnold, 1936), 953. 40 Burnet, Keogh, and Lush, ‘The Immunological Reactions of Filterable Viruses’, 284–

285.

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Under the directorship of Simon Flexner, the RIH had become a key site for the Rockefeller Foundation’s pioneering program on filterable viruses.41 Thomas Rivers, the pugnacious and brilliant bacteriologist, had been recruited from Johns Hopkins University in 1922 to develop virus research at the Hospital.42 Alongside the RIMR, the Foundation’s International Health Division (IHD), and Rockefeller-funded research being done at Princeton University’s Animal Pathology Laboratories, the RIH supported path-breaking work on various virus diseases.43 The Rockefeller programme gave Andrewes—and others like him—the chance to work closely with Rivers and his colleagues to develop new skills.44 Much of the research at the hospital focused on two childhood diseases, chickenpox and rheumatic fever, and it was through studies of the suspected rheumatic fever virus that Andrewes was introduced to immune reactions in virus diseases.45 His work with Rivers resulted in the discovery of a new virus—named ‘Virus III’—which was later shown to be connected to a carcinoma in the testicles of the rabbits that had been used for experiments on rheumatic fever.46 On his return to London in 1925, and partly based on the discovery of Virus III, Andrewes was awarded a research grant to work under William Gye on tumour viruses at the NIMR’s Mill Hill laboratories. The stint he spent with Gye proved unrewarding and frustrating. He would later reflect that, during this time he ‘achieved nothing’.47 As Gye’s cancer virus research sputtered, in 1927 Andrewes was given a permanent position on the scientific staff of the Institute and shifted his focus to vaccinia, the general disease model for studying in vitro

41 Creager, Life of a Virus, 38–46. 42 Saul Benison, Tom Rivers: Reflections on a Life in Medicine and Science; An Oral

History Memoir (Boston: MIT Press, 1967). 43 John Farley, To Cast Out Disease: A History of the International Health Division of the Rockefeller Foundation (Oxford: Oxford University Press, 2004). 44 G.W. Corner, A History of the Rockefeller Institute, 1901–1953: Origins and Growth (New York: Rockefeller Institute Press, 1965), 264–265. 45 D.A.J. Tyrell, ‘Christopher Howard Andrewes’, Biographical Memoirs of Fellows of the Royal Society, 37 (1991), 43. 46 Benison, Tom Rivers, 75–76. 47 C.H. Andrewes Personnel File, NIMR, ‘C.H. Andrewes—Recollections’, Interview

with E.L. Fraser, Undated (Hereafter, ‘Andrewes—Recollections’). My thanks to former NIMR librarian and archivist, Robert Moore, for this file.

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antigen–antibody reactions in filterable viruses. Vaccinia was already a major focus at the Lister Institute, where Charles Ledingham and his colleagues had confirmed its identity as a virus disease in 1931 and led investigations closely tied to smallpox vaccine production carried out by the Government Lymph Department.48 Andrewes had become familiar with vaccinia during his time working with Rivers, who himself already had done considerable research on the virus. When Andrewes started his own vaccinia research, Rivers supplied him with a strain of Virus III to use in comparative studies of virus immunity in susceptible rabbits. Within in a year, Andrewes demonstrated that vaccinia virus and Virus III could be recovered from neutral serum-virus mixtures.49 The finding contradicted earlier claims that neutralization destroyed the virus. Andrewes suggested that the presence of virus in immune sera also indicated that neutralization did not involve the strict union of antigen with antibody but was instead reversible. This claim was challenged by Samuel Bedson, who was working on virus diseases at the London Hospital. His studies of herpes virus had shown that if a virus-serum mixture was allowed a period of contact in vitro, a ‘slow union’ occurred between virus and virus antibodies.50 When Andrewes re-examined the reaction between vaccinia virus and anti-vaccinia serum, he revised his earlier claim and concluded that while virus neutralization was based on a reversible antigen–antibody union, virus immunity depended on the durability of this union.51 His conclusion that the less durable the union between virus and antibody the weaker the immunity would have important implications for later research on immunity associated with influenza. Aligning virus immunity with established humoral models, Andrewes’ approach to virus neutralization contributed to a general framework for work on virus immunity at the NIMR. In 1931, he gave two lectures at University College London in which he outlined the known mechanisms involved in virus immunity and their potential for vaccination, which had been demonstrated in the 48 See Harriett Chick, Margaret Hume and Marjorie MacFarlane, War on Disease: A History of the Lister Institute (London: A. Deutsch, 1971), 133–134. 49 C.H. Andrewes, ‘The Action of Immune Serum on Vaccinia Virus and Virus III in vitro’, Journal of Pathology and Bacteriology, 31 (1928), 671–672. 50 S.P. Bedson, ‘Observations on the Mode of Action of a Viricidal Serum’, British Journal of Experimental Pathology, IX (1928), 235–240. 51 C.H. Andrewes, ‘Antivaccinial Serum. 3. Evidence for Slow Union with Virus in vitro’, Journal of Pathology and Bacteriology, 33 (1930), 265.

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development of various veterinary vaccines, including the dog distemper vaccine produced by Laidlaw and Dunkin. Andrewes believed and hoped, as did his NIMR colleagues, that work on virus immunity would soon lead to ‘further advances’ for vaccines in humans.52 Virus neutralization held two promises for virus workers: within the reaction were the keys to the mechanisms of virus immunity and thus, also vaccination; and with the reaction they could make neutralization tests for identifying, tracking, and controlling virus diseases. The first promise proved elusive. Hampered by technical constraints, it was not until the development of plaque and fractionation techniques in the 1950s that researchers could fathom the chemical bases of neutralization.53 Neutralization tests might have lacked an agreed theoretical explanation, but this did not stop their development and use. Virus neutralization tests in the 1920s and 1930s were only workable with laboratory animals. This imposed an important constraint on their range of application. It foreclosed investigation of suspected virus diseases that lacked susceptible research animals, including influenza. As we have seen, researchers had tried and invariably failed to produce experimental support for the primary role of a virus in influenza. Inferences had been made from clinical observations in human subjects, with a few experiments involving the transmission of filtered material from influenza cases to healthy subjects. But the clinical variability of the disease and the difficulty of controlling experimental conditions undermined the results. For experimental pathologists, the matter could only be decided through controlled studies using laboratory animals. Fletcher summed up the situation in January 1933: The prime difficulty is that no animal (except possibly the anthropoid ape) is affected by influenza … We might get … success with influenza if we could … use humans especially bred without any previous contact with influenza, who would submit themselves to experimental study. This of course is impracticable.54

52 C.H. Andrewes, ‘Immunity in Virus Diseases’, Lancet (9 May 1931), 1049. 53 F.J. Fenner and R.V. Blanden, ‘History of Viral Immunology’, in A.L. Notkins (Ed.),

Viral Immunology and Immunopathology (New York and London: Academic Press, 1975), 13–14. 54 NA FD1/3356 Influenza, Fletcher to Halley Stewart, 5 January 1933.

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Determining the specific role of a virus hinged on finding an animal in which an experimental disease could be readily and consistently reproduced. In the years since the virus theory had been first proposed in 1914, researchers had tried and failed to infect many of the animals traditionally found in research laboratories—including mice, rats, rabbits, guinea pigs, monkeys, and apes. Interest in tackling this problem was re-ignited in 1931, when the Rockefeller veterinary pathologist, Richard E. Shope, working at the Rockefeller Institute’s Department of Animal Pathology in Princeton, announced that, in experimental studies using pigs, he had determined that a combination of a bacillus—Haemophilus bacillus (suis )—and a filterable virus produced a disease—‘swine influenza’—that was analogous to human influenza.55 Suspected links between the two diseases went back to autumn 1918, when J.S. Koen, a veterinarian working for the United States Bureau of Animal Industry, observed that a new epizootic disease in pigs in Iowa presented symptoms almost identical to those observed in outbreaks of epidemic influenza in the region.56 While veterinarians at the Bureau failed to confirm Koen’s observations, Shope’s success in establishing swine influenza as a virus disease opened the way for researchers to explore whether a similar type of agent might be the cause of human influenza. Shope’s discovery was a key incentive for Laidlaw and his team, and exchanges with Shope would be vital to the work that led to the identification of influenza virus in ferrets in 1933.

2

Ferret Flu

Standard accounts treat the NIMR’s discovery as the birth of modern influenza virus research.57 Much has been made of how fast the discovery came about and how quickly approaches to influenza changed thereafter.58 There is no doubting that the development of a technique for 55 R.E. Shope, ‘Swine Influenza. III. Filtration Experiments and Etiology’, Journal of Experimental Medicine, 54 (1931), 373–385. 56 W.I.B. Beveridge, Influenza: The Last Great Plague, 4–5. 57 D.A.J. Tyrell, ‘Discovery of Influenza Viruses’, in K.G. Nicholson, R.G. Webster and

A.J. Hay (Eds.), Textbook of Influenza (Oxford: Blackwell, 1998), 19–26. 58 F.M. Burnet, Changing Patterns: An Atypical Autobiography (New York: American Elsevier, 1969), 122–125; F.M. Burnet, ‘A Portrait of Influenza’, Intervirology, 2 (1979), 201–214.

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isolating the virus in ferrets and of an effective neutralization test in mice marked a crucial turning point in scientific ways of knowing the disease: virus research would gain special authority and change the foundations of epidemiological, clinical, and pathological knowledge of influenza. Yet accounts that concentrate on the events of 1933–34 leave out the necessary conditions that facilitated the breakthroughs and the slow and uneven process by which medicine changed. Laidlaw, Andrewes, and Smith could work so quickly only because so much had been put in place in the years before. While Shope’s studies were an important spark, over a decade’s worth of research on distemper and other virus diseases at the NIMR had laid essential foundations, experience, knowledge, and skills to tackle the influenza problem. Even then, Laidlaw and his team had to invest considerable resources and effort into making ferrets and mice workable tools for influenza both inside their laboratory and outside for practical medical and public health purposes. Moreover, their discoveries had to stand-out from—and even overturn— other scientific claims to influenza’s aetiology. Their virus had to be made a necessary part of modern medical understanding of influenza, which had been developing since the 1890s. In short, identifying influenza virus and establishing influenza as a virus disease was the product of a series of transformations that involved positioning virus research in relation to and changing epidemiological, clinical, and pathological approaches that that been built over the preceding forty years. A new medical consensus had to be created. It is to this winding process that we turn. When Laidlaw and his colleagues started tackling the ‘flu problem in late 1932, their initial step was to setup an experimental system to test the virus theory. By then, in large part because of Shope’s findings, scientific opinion had swayed from Pfeiffer’s bacillus to the view that a filter-passing virus was likely the infecting agent. Wilson Smith took the lead in building the system and carrying out the technical work to test the theory. This was partly because Andrewes fell ill with influenza during the first weeks of their research. But it was also because Smith possessed considerable technical acumen in the serological and pathological methods that were essential to their approach. Smith came from a modest household near Blackburn in Lancashire, where his widowed mother inculcated a firm belief in the virtues of

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education and professional ambition.59 He joined the R.A.M.C. in 1915, serving as a private in the 107th Field Ambulance division in France and Belgium. The experience instilled a desire to pursue a medical career. Following demobilisation, between 1919 and 1923 he trained and graduated as a doctor at Manchester University, went into practice for two years, but quickly grew disenchanted with this path. He returned to Manchester in 1925 to study bacteriology under the renowned bacteriologist, W.W.C. Topley, with a view to leaving medical practice for a career in medical science. On receiving his diploma in bacteriology in 1927, and with the help of Topley, he gained an appointment as a research assistant at the NIMR. Singularly devoted to experimental research, he became part of the small group of researchers studying viruses at the Institute. Under S.R. Douglas’ direction, he first worked on vaccina and herpes simplex viruses to elucidate the mechanisms by which animals acquired immunity against virus infections. As with Andrewes, much of his research concentrated on delineating the nature of cellular and humoral immunity associated with such infections. But Smith also played an important part in the Institute’s work on biological standardisation, and it was here that he honed his skills in serology.60 Working under Percival Hartley, who ran the Institute’s biological standardisation laboratory, he helped develop tests to estimate the potency of anti-pneumococcal sera used in the treatment of lobar pneumonia.61 This work was part of the Institute’s role in evaluating and regulating medicines under the 1925 Therapeutic Substances Act and eventually led to the creation of international standards for anti-pneumococcal sera.62

59 D.G. Evans, ‘Wilson Smith, 1897–1965’, Biographical Memoirs of Fellows of the Royal Society, 2 (November 1966), 478–487. 60 Robert J. Kirk, ‘Reliable Animals, Responsible Scientists: Constructing Standard Laboratory Animals in Britain c.1919–1976’, Unpublished Doctoral Thesis, University College London, 2005, 31–43. For a personal memoir of the NIMR standardization work, see D. Bangham, A History of Biological Standardization—The Characterization and Measurement of Complex Molecules Important in Clinical and Research Medicine. Contributions from the UK 1900–1995. What, Why, How, Where and by Whom. A Personal Account (Bristol: Society for Endocrinology, 1999). 61 Evans, ‘Wilson Smith’, 481; H.H. Dale, ‘Percival Hartley 1881–1957’, Biographical Memoirs of Fellows of the Royal Society, 3 (1957), 81–100. 62 Jonathan Liebenau, ‘The MRC and the Pharmaceutical Industry: The Model of Insulin’, in Austoker and Brvder, Historical Perspectives, 163–180; Austoker and Bryder, ‘National Institute of Medical Research’, 53–56.

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But it also allowed Smith to acquire technical expertise in developing and working with standard sera for determining the potency of the various sera used in therapies and in experimental research. Testing and manipulating animals were integral to this work. Smith applied these technical skills to the key innovations that underpinned the NIMR’s influenza work. This included adapting the ferret as a medium and model for influenza.63 The team’s finding that the ferret was susceptible to human influenza was partly a matter of chance, but engineering the ferret into a viable experimental animal for influenza research was the result of concerted efforts. The chance discovery came in early 1933, when, spurred by Shope’s research and mounting pressure to solve the influenza problem, the team resurrected early efforts to find an animal readily susceptible to experimental infection with human influenza.64 Starting in January, at the height of the influenza outbreak, they used nasal and lung material prepared from influenza patients to test whether they could produce the disease in pigs—just as Shope had—as well as in rats, mice, guinea pigs, monkeys, and horses that were housed at the Institute and at Mill Hill.65 The material, supplied by pathologists at Barts’ and Guy’s Hospital, came from eight patients, including a young girl who had died of respiratory complications.66 These efforts failed. Curiously, the ferret was not among the test animals, even though it had been in use at the Institute for distemper research since 1926. In an interview late in his life, Andrewes attributed the idea of testing ferrets to reports of an outbreak of an influenza-like disease at the Wellcome Physiological Laboratories, where the animals were being used in

63 Evans, ‘Wilson Smith’, 481–483. 64 I have reconstructed this work from a number of sources. C.H. Andrewes’ labora-

tory notebooks for 1933–1934 have been an invaluable. Christopher Herbert Andrewes, Notebooks, Wellcome Library, GC/168/21–24 (hereafter Andrewes Notebook I or II). 65 P.P. Laidlaw, ‘Experimental Influenza’, Guy’s Hospital Gazette, 158 (10, 24 November 1934), 474; ‘Andrewes—Recollections’. For details on the Institute’s research animals, see, R.W. Kirk, ‘Wanted-Standard Guinea Pigs’, 280–291. 66 Andrewes appealed to his old teacher, F.R. Fraser, while Laidlaw appealed to his former colleague, T.H. Layton. C.H. Andrewes, Patrick P. Laidlaw and Wilson Smith, ‘Influenza: Observations on the Recovery of Virus from Man and on the Antibody Content of Human Sera’, British Journal of Experimental Pathology, XVI (1935), 569; P.P. Laidlaw, ‘Epidemic Influenza: A Virus Disease’, The Lancet (11 May 1935), 1119–1124.

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the manufacture of dog distemper vaccines and sera.67 While the Wellcome outbreak turned out not to be influenza, it prompted Smith to try to infect a few healthy ferrets at the Hampstead laboratory using the subcutaneous inoculation method Laidlaw and Dunkin had devised in their dog distemper studies. This method did not work. Smith changed tact. In early February, he dripped (‘instilled’) filtered nasal and throat garglings taken from Andrewes, who was now sick with influenza, into the noses of two ferrets. Smith was, in effect, experimentally replicating how people typically contracted respiratory influenza through droplet infection. Shope had used a similar technique in his experiments with pigs. Within forty-eight hours the ferrets started sneezing and displaying signs of an influenza-like disease. In his notebook, Smith apparently wrote: ‘Ferret I looks somewhat seedy – crusts round the nose and slight discharge with suggestion of pus – eyes also watery – sneezing.’68 Throat garglings from seven other patients had the same effect. The team was stunned by the results. F.M. Burnet, who was visiting the Institute at the time and had been following the research closely, recalled Laidlaw excitedly telling everyone on the floor that, ‘the ferrets are sneezing.’69 But jubilation gave way to disappointment: the experimental disease—and the chance to isolate the virus—was almost immediately lost when suspected distemper broke-out among the ferrets. The outbreak forced the team to move to the Farm Laboratories at Mill Hill, where the ferrets were placed under the ‘scheme of rigid isolation’ originally used for the dog distemper research. The research was saved by a twist of fate. On 4 March 1933, Smith himself caught influenza. This time Andrewes used Smith’s garglings and his nasal-instillation method to infect a new batch of ferrets (Fig. 3). Within a few days, the animals came down with influenza-like symptoms. Over the next few months the team worked to determine the identity and role of the agent in the disease. Assuming the suspected virus came from Smith, they named it ‘W.S.’ and it would become their master strain.

67 Andrewes—Recollections. The account below is derived from Andrewes’ Recollections, his notebooks, and the team’s first publication, Wilson Smith, C.H. Andrewes, and P.P. Laidlaw, ‘A Virus Obtained from Influenza Patients’, Lancet (8 July 1933), 66–68. 68 Evans, ‘Wilson Smith’, 482. 69 F. Macfarlane Burnet, ‘Reminiscences of Influenza Research 1935–1956’, University

of Melbourne Archives.

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Fig. 3 Infecting a ferret. The original caption read: ‘An Experiment in the Fight against Influenza: A Ferret is Injected.’ C.H. Andrewes (with the pipette) and an unidentified technician demonstrate the technique of ‘instilling’ virus material into the nose of a ferret. The ferret was anaesthetised with ether to ease injection of virus material (Source ‘Can We Beat ‘Flu?’, Picture Post [2 February 1946], 10). Licensed and used with permission from Getty Images (3401341)

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Through the spring of 1933 the team fashioned the ferret into a workable laboratory animal and used it to explore longstanding research problems associated with influenza. Smith’s ferret technique enabled them to isolate a virus from the ‘infecting material’ taken from sick patients.70 The agent met established criteria: while filterable, it was invisible under light microscopy and not cultivatable in standard growth media; however, material from sick ferrets induced disease in healthy ones, and serial passage experiments repeatedly produced a typical disease in large numbers of the animals. Moreover, the agent could be neutralized with serum from recovered ferrets, the action of which was demonstrated by the inhibition of influenza-like symptoms in treated animals. The last two techniques were especially important for virus identification. Serial passage was a classic method for isolating pathogens and virus workers relied on it to make viruses visible as lesions or other pathological changes in research animals. Serum neutralization tests, based on the presumed specificity of neutralizing antibodies, were especially important for linking a virus to a disease. The credibility of both techniques, however, rested on the NIMR workers’ ability to establish typical influenza in ferrets.71 As we shall see, this required correlating the experimental disease produced in ferrets with the clinical disease observed in patients.

70 P.P. Laidlaw, ‘Experimental Influenza’, 474; Smith, Andrewes and Laidlaw, ‘A Virus Obtained from Influenza Patients’, 67. 71 A large historical literature has explored the processes and challenges of correlating animal models of human disease. The following have informed my analysis: W.F. Bynum, ‘“C’est un malade”: Animal Models and Concepts of Human Diseases’, Journal of the History of Medicine and Allied Sciences, 45 (1990), 397–413; I. Löwy and J.-P. Gaudillière, ‘Disciplining Cancer: Mice and the Practice of Genetic Purity’, in I. Löwy and J.-P. Gaudillière (Eds.), The Invisible Industrialist: Manufactures and the Production of Scientific Knowledge (London: Macmillan, 1998), 209–249; Christoph Gradmann, ‘Experimental Life and Experimental Disease: The Role of Animal Experiments in Robert Koch’s Medical Bacteriology’, B.I.F. Futura, 18 (2003), 80–88; Anita Guerrini, Experimenting with Humans and Animals: From Galen to Animal Rights (Baltimore: Johns Hopkins University Press, 2003); Ilana Lowy, ‘The Experimental Body’, in Roger Cooter and John Pickstone (Eds.), Companion Encyclopedia of Medicine in the Twentieth Century (London: Routledge, 2003), 435–449; Karen A. Rader, Making Mice: Standardizing Animals for American Biomedical Research, 1900–1955 (Princeton, NJ: Princeton University Press, 2004); K.A. Rader, ‘Scientific Animals: The Laboratory and Its Human-Animal Relations, from Dba to Dolly’, in Linda Kalof and Brigitte Resl (Eds.), A Cultural History of Animals, Volume 6: The Modern Age (1920–2000) (London: Bloomsbury, 2007), 119–137.

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Laidlaw’s familiarity with the ferrets and the facilities at Mill Hill enabled the team to devote their attention to creating an experimental disease. This involved a combination of technical skills needed to perform serial passage experiments and representational practices to render the experimental disease into a specific clinical entity. In the first six months the team reproduced the disease in over 135 ferrets and traced ‘the full course of [the] illness’ in 64 animals.72 Serial passage enabled them to establish continuity in the clinical picture, which they described in detail in their first report in the Lancet on 6 July 1933 and on other occasions. Laidlaw shared the following description with an audience at Guy’s Hospital in summer 1934: [The disease in ferrets was] characterised by an incubation period of 48 hours, followed by fever, in which the temperature may rise as high as 107°F. This is followed by a remission, and thereafter a second febrile period, usually lasting three or four days, during which there are symptoms of severe nasal catarrh, such as sneezing, nasal obstruction … mucopurulent discharges from the nose, sticky encrustation round the nares, and so on. Throughout the illness, but varying considerably from cases to case, there is prostration and lethargy, and occasionally obvious signs of muscular weakness.73

Laidlaw called the disease ‘experimental influenza’; in more vernacular settings, he and his colleagues preferred to call it ‘ferret flu’.74 The names denoted significant analogies between the animal and human disease, and this became an important rationale for using the ferret for studies of influenza immunity and pathogenesis; it eventually became the first animal model of the disease (Fig. 4). What mattered most at this stage was to show that ferret flu was the result of a virus that affected ferrets in ways similar—if not identical— to how it affected humans. One way the team demonstrated the clinical identity of the two diseases was through fever charts. A standard representational device in clinical and veterinary medicine, fever charts were used by the NIMR workers to visualise the onset and progress of experimental 72 Smith, Andrewes, and Laidlaw, ‘A Virus Obtained from Influenza Patients’, 66. The total number is based on Andrewes’ Laboratory Notebooks. 73 Laidlaw, ‘Experimental Influenza’, 475. 74 Andrewes—Recollections.

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Fig. 4 Has the Ferret Got Influenza? Ferret, forty-eight hours after nasal instillation (Source Picture Post [2 February 1946], 10)

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infection, and to identify diagnostic markers for the disease agent.75 A chart published in the first report detailed the production of ferret flu with human material (Fig. 5). From Andrewes’ laboratory notes we know that the chart represented his inoculation of Smith’s garglings into a ferret (‘F24’) and traced the progress of the disease between 4 March and 4 April 1933.76 Temperature readings from the ferret’s rectum were taken every morning (‘M’) and evening (‘E’) until the experiment ended and the animal returned to the ferret house for future immunological work. The chart presented readings up to March 26, when the sick ferret started to recover. The first temperature spike, recorded on the morning of 7 March, preceded the onset of mild flu-like symptoms by one day. It marked the height of infection and, as the NIMR workers found out when they tested other ferrets, the point at which the virus was most concentrated and most easily isolated from the sickened ferret. The temperature spikes thus corresponded with virus activity. Fluctuations recorded in the symptomatic stages curiously resembled the ‘continuous’ or ‘relapsing’ fever long associated with human influenza. The second temperature rise, two weeks

Fig. 5 ‘Ferret Flu’ (Source Wilson Smith, C.H. Andrewes, and P.P. Laidlaw, ‘A Virus Obtained from Influenza Patients’, Lancet [8 July 1933], 67) 75 Volker Hess, ‘Standardizing Body Temperature: Quantification in Hospitals and Daily Life, 1850–1900’, 109–126. 76 Andrewes, Notebook I.

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later, announced such a ‘relapse’ of symptoms (‘S’), a pattern familiar to any clinician. As visual evidence, the fever chart had many functions. It was readily legible to any physician, who could interpret the production of ferret flu with the ‘garglings of [an] influenza patient’ and see the link being made between the experimental and the human disease. When allied with the descriptions of the ferret disease, it also illuminated a process of infection analogous to that seen in influenza patients. More generally, it placed the discovery of influenza virus in a clinical format. This last point was especially important for it was through the production of ferret flu that Laidlaw’s team were able to develop a neutralization test to determine whether sera from ferrets and from humans who had recovered from the disease contained antibodies that specifically neutralized the virus. This process was made visible and represented in charting the changing symptoms and pathogenesis of ferret flu. The test using ferrets was rudimentary and blunt. Neutralization was demonstrated when a dilution of ferret or human serum and a fixed amount of virus mixed in vitro protected a healthy ferret. Another ferret infected with a virus-saline mixture was used as a control. The team established the specific relationship between neutralizing antibodies and the virus by comparing the ‘neutralizing power’ of ferret sera taken before infection, at the acute stage (within 48 hours), and during convalescence. While ‘normal’ pre-infection sera had little effect, convalescent sera contained potent inhibiting antibodies.77 Two fever charts displayed the contrasting results of neutralization with and without immune serum (Fig. 6). When a mixture of virus and normal serum was instilled in the nose of a healthy ferret (F131), it produced the ‘dysphasic’ fever associated with ferret flu. Yet when a mixture of virus and immune serum was instilled in another ferret (F101), temperature readings never exceeded the normal range for the animal (101–103 °F). Tracing the action of these antibodies on the ‘virus’, the lower chart showed how the neutralization test could be used to identify virus infection indirectly and indicated the specific relation of neutralizing antibodies to the disease. Based on these results, the team began evaluating human sera for virus neutralizing antibodies. In March, Andrewes obtained serum samples

77 Smith, Andrewes, and Laidlaw, ‘A Virus Obtained from Influenza Patients’, 67.

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Fig. 6 Ferret Flu Neutralized. Upper chart—Ferret (F131) infected with a mixture of virus and normal ferret serum. Lower chart—Ferret (F101) infected with a mixture of virus and immune ferret serum. Virus neutralization was demonstrated in the lower chart (Source Wilson Smith, C.H. Andrewes, and P.P. Laidlaw, ‘A Virus Obtained from Influenza Patients’, Lancet [8 July 1933], 68)

from six Barts nurses who had recovered from influenza.78 He mixed their sera with virus in vitro and inoculated the mixture into individual ferrets, while controls were inoculated with virus alone. Like that of the convalescent ferrets, the nurses’ sera neutralized the virus, although less thoroughly but enough to indicate a specific infection. If the agent was

78 Andrewes’ Notebook I.

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indeed a virus, the neutralization test had proven to be a basic tool for elucidating its presence in ferret and human influenza. Before publishing their research, Laidlaw and his colleagues collected a final piece of evidence. A standard method for corroborating the identity of a suspected virus was to see if it bore a relationship to known viruses. Shope’s swine influenza virus was the obvious candidate. Andrewes had befriended Shope during his time in New York, visiting his laboratory at Princeton, and they shared samples. Shope sent his virus to London in a dried pig lung, while Andrewes returned the favour by sending Shope the W.S. strain in dried ferret turbinates.79 This marked the beginning of the transnational exchange of influenza virus materials that would grow exponentially in the years to come. Shope had shown that swine influenza was a mixed infection involving a virus and bacillus. The NIMR team’s filtration tests ruled out the role of ‘visible bacteria’ and thus the hypothesis that human influenza might also be a mixed infection.80 However, they showed that a close serological link existed between the two viruses. With Shope’s virus, Smith and Andrewes produced a disease ‘indistinguishable from the ferret disease caused by [the] virus of human origin.’81 Crossimmunity and cross-neutralization tests demonstrated these links. Ferrets that recovered from the swine virus appeared to be ‘solidly immune’ to infection with the human virus. Ferrets convalescent from the human virus were partly immune to the pig strain. Cross-neutralization tests, in which a healthy ferret inoculated with a serum-virus mixture using one virus (i.e., swine) was inoculated with the other virus (i.e., ferret/human), indicated a relatively close antigenic relationship. While these tests offered only indirect evidence that ferret ‘flu was a virus disease, the serological association with swine influenza strengthened the case. ‘The similarities completely outweigh the differences,’ explained Laidlaw to an audience at Guy’s Hospital a year later. ‘[W]e consider that the results with the human strain of virus coupled with those obtained with swine virus are

79 Andrewes—Recollections. 80 P.P. Laidlaw, Virus Diseases and Viruses, The Rede Lecture (Cambridge: Cambridge

University Press, 1938). 81 Smith, Andrewes, and Laidlaw, ‘A Virus Obtained from Influenza Patients’, 68; R.E. Shope confirmed the NIMR’s results at the end of the year. R.E. Shope, ‘The Infection of Ferrets with Swine Influenza Virus’, Journal of Experimental Medicine, 60 (1934), 49–61.

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strong arguments for the view that influenza in man is primarily a virus infection.’82 The team’s decision to publish its first report in the Lancet had important ramifications for the profile of their work. Although the Lancet and BMJ carried research on virus diseases, most British virus research appeared in the specialist British Journal of Experimental Pathology. Publication in the Lancet was a powerful form of legitimisation since the journal served as a key forum for vetting and highlighting important medical breakthroughs for non-specialist medical audiences. Aware that their announcement to have discovered the influenza virus was not the first of its kind, Laidlaw’s team needed the medical press on their side. ‘[T]he evidence,’ they argued, ‘strongly suggests that there is a virus element in epidemic influenza, and we believe that the virus is of great importance in the aetiology of the human disease.’83 The strength of their new experimental animal, methods, and research skills could not sustain this claim alone; support from the medical press acted as an important conduit for the sanction of influenza’s virus identity. It also marked the first step towards making their esoteric laboratory findings more readily accessible to wider medical and lay audiences. The crucial process of biomedical translation had started. Published on 8 July 1933, the report caused a minor media sensation. In an editorial entitled, ‘The Virus of Influenza’, the Lancet declared that the NIMR work had put influenza research on a new footing: ‘It is almost impossible … to over-estimate the importance of the discovery … that the ferret is susceptible to infection with human influenza.’ The NIMR workers had ‘offered almost conclusive evidence that the primary cause of human influenza is a filterable virus.’84 The BMJ weighed in with a similar declaration: ‘Just when the possibility of any further advance seemed rather remote, three investigators at the National Institute for Medical Research … succeeded in transmitting influenza to ferrets. The whole aspect of the situation has been transformed.’85 The Practitioner, journal of London‘s physician elite, which had printed numerous articles on the aetiology of influenza before and after the 1918–19 pandemic,

82 Laidlaw, ‘Experimental Influenza’, 476. 83 Smith, Andrewes and Laidlaw, ‘A Virus Obtained from Influenza Patients’, 68. 84 Lancet, ‘The Virus of Influenza’ (8 July 1933), 83. 85 BMJ , ‘Aetiology of Influenza’ (15 July 1933), 115.

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concluded that ‘the results with ferrets, as far as they have gone, are consistent with the view that epidemic influenza in man is caused primarily by [a] virus infection.’86 The general press, which had been given advance copies of the Lancet article, presented the discovery as a resounding victory for British medical science. Smith, Andrewes, and Laidlaw won accolades, and so too did the ferrets. A short report from The Times’ medical correspondent on 7 July announced, ‘An Important Discovery’ and stressed how use of the ferrets directly connected the discovery to Laidlaw’s previous breakthroughs on dog distemper.87 The Daily Mirror was less sedate. Its front page carried the headline: ‘DOCTOR’S ‘FLU DISCOVERY—Almost Impossible to Over-Estimate Its Importance’. The accompanying story insisted that the finding that the ferret was ‘susceptible to infection with human influenza’ was a decisive breakthrough. ‘It had long been realised that the acquisition by a laboratory of animals susceptible to the virus of influenza would open up a wonderful new ground for investigation.’88 The Manchester Guardian ran a frontpage headline on 7 July announcing a ‘NEW INFLUENZA DISCOVERY—The Primary Cause’ and a full column story that recounted the identification of a ‘filtrable virus’ and its ‘Transmission to Ferrets’, while an editorial on ‘Influenza and the Ferret’ stressed that with the ‘successful attempt to transmit influenza from human patients to ferrets… a step of importance has been taken in the campaign against a singularly insidious disease.’89 The same day, the front page of the Daily Express declared—‘Influenza Germ Found At Last’.90 Its editorial stressed that ‘the discovery is the work of three British scientists, two of them young and the other of long experience on the scientific staff of the National Institute for Medical Research….’ Short biographies of each, along with a photograph of Laidlaw, were followed by a detailed recounting of the team’s report in the Lancet. Walter Morley Fletcher, who had been instrumental in setting up and promoting the NIMR virus programme in the 1920s, would have been

86 ‘Aetiology of Influenza’, The Practitioner (August 1933), 210. 87 Our Medical Correspondent, ‘Influenza Research’, Times (7 July 1933), 16. 88 ‘DOCTORS’ ‘FLU DISCOVERY’, Daily Mirror (Friday, 7 July 1933), 3. 89 ‘NEW INFLUENZA DISCOVERY—The Primary Cause’, The Manchester Guardian (7 July 1933), 11. 90 ‘Influenza Germ Found at Last’, Daily Express (7 July 1933), 1.

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thrilled by the public accolades and attention. The discovery was vindication of the early vision of the programme as laying the foundations for research that would eventually resolve the role a filterable virus as the causative agent of influenza. But Fletcher could not celebrate. He died suddenly just before his sixtieth birthday, one month before Laidlaw and his team published their results.91 ‘[I]t is a pity’, noted a Daily Telegraph editorial, ‘that he did not live to see to-day’s triumphant justification of his choice.’92 While Fletcher‘s role and the background to the breakthrough were occasionally mentioned, most general press reports went into considerable detail on the steps involved in the experiments, tracing how the ferrets were infected, the cross-immunity tests used, and the development of immune serum. More than just a laboratory instrument, the ferret was often portrayed as a research partner. ‘Ferrets Assist Doctors in Combating Influenza,’ ran a headline in The New York Times.93 The popular illustrated newspaper, The Sphere, stressed that, just as with distemper, ‘British doctors and that useful animal, the ferret, will be the heroes of the hour throughout civilization… Here is [another] claim by the ferret to the honor of having its name immortalized … Long since, that sinuous animal has been employed to ferret out one subterranean human pest, the rabbit. Now it offers itself, for the sake of mankind, to expel from its hidden and dark labyrinths another pest as insidious, as universal, and as destructive.’94 While less garrulous, reports universally stressed that the ferret now made it possible to develop new means to control influenza. ‘The hope embodied in this week’s news,’ editorialised The Manchester Guardian, ‘is that with influenza for the first time ‘made to order’ in the laboratory, the precise nature of the disease and method of achieving immunity may be studied with greater confidence.’95 News of the discovery was also celebrated in similar tones across the empire, with reports published in the South China Morning Post, The China Press, Times of India, among others, and in the United States. On

91 T. R. E., ‘Sir Walter Morley Fletcher. 1873–1933’, Obituary Notices of Fellows of the Royal Society, 1.2 (1933), 153–163. 92 ‘Influenza Virus’, The Daily Telegraph (7 July 1933), 12. 93 ‘Ferrets Assist Doctors in Combatting Influenza’, New York Times (8 July 1933), 5. 94 ‘THE USEFUL FERRET’, The Sphere (15 July 1933), 75. 95 ‘Influenza and the Ferret’, The Manchester Guardian (8 July 1933), 12.

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9 July, The New York Times ran a long summary of the Lancet report under the headlines, ‘HOPE OF ‘FLU CURB SEEN IN NEW TESTS’ and ‘Experiment on Ferrets Is Held in Britain to Be Step in Isolation of the Germ.’ Along with underscoring the role of British researchers and their ferrets, the summary also highlighted the discovery’s connections to Shope’s swine influenza research at Princeton and the importance placed on cross-immunity experiments of the two viruses. Not surprisingly, the Daily Telegraph devoted considerable attention to the discovery and its distinctly British origin. It had, after all, led the national press campaign in support of the NIMR’s dog distemper work and was quick to emphasise the relationship between the two lines of research. The front page of its news section and two other columns described ‘How the virus was tracked down’ (Figs. 7 and 8). Smith, Andrewes, and Laidlaw were identified as British doctors’ doing work of immediate medical and national importance, with a picture of Laidlaw reproduced as a column header. Readers were reminded of how ‘the practical outlook looked gloomy’ in the 1920s and how many thought ‘[v]ast epidemics might sweep the world again and mankind would again be the helpless victim of the spreading scourge.’ The NIMR’s use of the ferret to ‘show that a virus is the true causative agent’ changed this outlook. ‘It is now certain that real progress is being made.’96 Particular attention was drawn to how ‘the serum of human convalescents was capable of neutralizing the virus of the ferret disease.’97 How can we explain these resoundingly positive reactions? Did clinicians, pathologists, and other medical groups also embrace the NIMR’s claims? Many did, but not unreservedly. A small but vocal group, represented in the Medical Times, challenged the assumption that studies on influenza in experimental animals had direct bearing on the human disease.98 This criticism was part of a wider and long-standing challenge to the clinical value of laboratory science and extrapolative reasoning from animals to humans.99 But it was not representative of the medical profession of the early 1930s. More common responses took shape in questions 96 ‘How the Virus Was Tracked Down’, Daily Telegraph (7 July 1933), 10. 97 ‘How the Virus Was Tracked Down’, Daily Telegraph (7 July 1933), 7. 98 J. Burnet, ‘What Is Influenza?’, The Medical Times (20 February 1937), 20. 99 See, Rob Boddice, Humane Professions: The Defence of Experimental Medicine, 1876– 1914 (Cambridge: Cambridge University Press, 2021). A.W.H. Bates, Anti-Vivisection and the Profession of Medicine in Britain (London: Palgrave, 2017).

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Fig. 7 ‘British Doctors’ Discovery’ (Source Daily Telegraph [Friday, 7 July 1933], 7)

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Fig. 8 ‘How the Virus Was Tracked Down’ (Source Daily Telegraph [Friday, 7 July 1933], 10)

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about the aetiological status of the virus, the role it could play in diagnosis and in understanding the complex pathogenesis of influenza, and whether it would result in effective preventive vaccines. While there was general acknowledgement that the NIMR discovery opened new research pathways, it was unclear how these might translate into medical practice. But there was nothing like the hostile reactions historians have described in medical responses to bacteriological theories and practices in the late nineteenth century, and other forms of laboratory medicine in the early twentieth century.100 For the most part, the medical profession, including those most intimately familiar with influenza, broadly accepted the NIMR workers’ claim to have identified influenza virus. Several factors might explain why. By the time of the discovery, the so-called ‘virus theory’ of influenza had been circulating for fifteen years. The place of virus diseases in medicine and public health had changed considerably in this time. By the early 1930s, they were an accepted category of disease in medical, bacteriological, and pathological textbooks. Although hotly debated, the nature of viruses was a regular topic in the Lancet and BMJ , as well in generalist science journals such as Nature and Science. The Royal Society of Medicine held regular discussions on specific virus diseases, virus immunity, and related topics, as did the British Medical Association and other professional bodies.101 Viruses had also started to enjoy currency beyond the bounds of laboratory science and medicine. Although the first popular science books on viruses would only be published in Britain in the early 1940s, during the interwar years the popular press carried reports on discoveries of viruses associated with measles and polio, and introduced these entities into public life.102 In some cases, such as with the Daily Telegraph’s participation in 100 See, for example, Lawrence, ‘Incommunicable Knowledge’ and Worboys, ‘From Heredity to Infection’. 101 E. Rutherford et al., ‘Ultra-microscopic Viruses Infecting Animals and Plants’, Proceedings of the Royal Society of London, 104 (4 May 1929), 537–560. 102 Eyler notes the importance of Paul de Kruif in popularizing viruses in the United States. Eyler, ‘De Kruif’s Boast’. For popularization more generally, see B. Hansen, Picturing Medical Progress from Pasteur to Polio: A History of Mass Media Images and Popular Attitudes in America (New Brunswick, NJ: Rutgers University Press, 2009). Metheun & Co. approached Mervyn Gordon in 1925 to write a popular book on viruses, which Fletcher counselled against NAFD1/1297, 22 July 1925. The first such book in Britain was by the plant virologist, Kenneth Smith. K.M. Smith, The Virus: Life’s Enemy (Cambridge: University Press, 1940).

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the distemper campaign of the 1920s, newspapers played an active role in promoting and popularising virus research. Coupled with the public recognition of virus diseases was the recognition of the practical importance of virus research. While virus research had yet to achieve status as a ‘public science’ in the way that bacteriology had in Britain, by the early 1930s it had gained broad relevance for medicine and public health.103 The MRC’s virus programme played a vital role in legitimising the new field. The success with dog distemper had established the authority of the NIMR and the wider credibility of virus research, and this shaped the reception of influenza virus. While the Daily Telegraph’s coverage and support of influenza virus research certainly stemmed from its earlier participation in the distemper campaign, by 1933 widely reported success with distemper also fed general expectations that the discovery of influenza virus would lead to effective preventatives, including a vaccine. These expectations engendered new trust in virus research to tackle infectious disease. Particularly important in this respect was the suggestion in the team’s Lancet report that virus neutralization and immunity in ferrets might have important application to influenza immunity in humans. This suggestion was interpreted through broader notions about ‘neutralization’ linked to the successes of serum therapies developed for diphtheria, typhoid, tetanus, and measles.104 Many press reports highlighted the team’s development of immune serum as a potential treatment or preventative against influenza. In a typical report, the Daily Express announced that there was ‘Hope of Cure for Humans’ and suggested that ‘[b]efore the next influenza epidemic comes it may be possible to secure a serum with which human beings can be inoculated and so protected against the ravages of the disease.’105 In the age of serology, neutralization resonated with images of medical control over infectious disease. News accounts of the NIMR discovery powerfully reinforced these images for readers.

103 Rosemary Wall has shown how bacteriology gained authority as a ‘public science’

in Britain in the first decades of the twentieth century. Bacteria in Britain, 1880–1939 (London: Pickering & Chatto, 2013). 104 Paul J. Weindling, ‘Between Bacteriology and Virology: The Development of Typhus Vaccines Between the First and Second World Wars’, History and Philosophy of the Life Sciences, 17 (1995), 81–89; Mazumdar, ‘In the Silence of the Laboratory’. 105 ‘Influenza Germ Found At Last’, Daily Express (7 July 1933), 1.

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By the early 1930s, London‘s medical community accepted that neither clinical nor bacteriological approaches alone could effectively combat influenza. At best, doctors could prescribe bed rest and symptom-based medications.106 Doctors were cautioned against using patent medicines. When the Ministry of Health’s 1929 Memorandum on Influenza was reissued in 1933, it reiterated guidance made in 1927, warning that ‘no drug has as yet been proved to have specific curative effect on influenza, though some may be useful in guiding its course and mitigating its symptoms.’107 Many looked to virus research for scientific advance. Laboratory solutions to diagnostic and therapeutic problems might afford more effective and efficient influenza management. If the disease challenged modern medicine, new tools to simplify diagnosis and to improve treatment or prevention could enhance medical authority. The ferret’s sneeze thus became an icon of the potential power of medical science. Realising these promises would take much longer than many hoped or expected. Changes occurred most rapidly in the laboratory science of influenza. Within a year, Shope reproduced the NIMR’s work at his Princeton laboratory, and two researchers at the RIMR, Thomas Francis Jr. and Thomas Magill, used the ferret to isolate a virus strain from cases of an outbreak in Puerto Rico, which they called PR8.108 Ferrets immunised against the PR8 virus were also immune to the W.S. strain; and sera for one virus neutralized the other. Within two years, workers in different parts of the world adopted variations of the NIMR’s system. In 1935, F.M. Burnet, having returned to Australia, used the animal at the Walter Eliza Hall Institute for Medical Research in Melbourne to isolate an identical virus strain, which he called ‘Mel’ after the city in which it was isolated.109 Workers at the Pasteur Institute in Leningrad isolated a similar

106 NA MH/55 57 Memorandum on Influenza (Revised Edition), 1927; T.J. Horder, ‘Treatment of Influenza’, Treatment in General Practice (London: H.K. Lewis & Co., 1936), 1–5; J.E. McCartney, ‘Viruses of Common Cold and Herpes’, BMJ (1 August 1925), 10. 107 MH/55 57 MINISTRY OF HEALTH. Memorandum on Influenza—Revised Edition (London: HMSO, 1929). 108 Shope, ‘The Infection of Ferrets with Swine Influenza Virus’, 49–61; T.J. Francis, ‘Transmission of Influenza by a Filterable Virus’, Science, 80 (1934), 457–459. 109 F.M. Burnet, ‘Influenza Virus Isolated from an Australian Epidemic’, Medical Journal of Australia, 2 (1935), 651–653.

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virus in ferrets during an epidemic in 1936.110 R.W. Fairbrother and Leslie Hoyle, pathologists at the Department of Bacteriology and Preventive Medicine at the University of Manchester, who were to produce influential influenza research in the late 1930s and 1940s, started using ferrets for influenza work in 1935 and isolated a virus in 1937.111 James McIntosh, who had defended Pfeiffer’s bacillus through the 1920s, used the ferret in 1936 to test ‘the pathogenicity of viruses’ from influenza cases at Middlesex Hospital.112 In the meantime, Francis and Magill, who moved to the Rockefeller’s International Health Division in New York, succeeded in isolating strains from subsequent epidemics in Philadelphia in 1935 and Alaska in 1936, while other American researchers took up their system.113 This ferment of work forged new links between laboratories and went far in consolidating the ferret as an animal model of influenza. Most crucially, wide replication of the NIMR’s results put their claims for the virus identity of influenza on firm scientific grounds. Yet turning experiments into applied medicine was more difficult than laboratory replication. The NIMR’s first move in this direction came in late 1934 when they began to explore immunity associated with influenza through a study of ‘the antibody content of normal sera’ in Londoners.114 Neutralization tests in ferrets demonstrated that some people had antibodies to both the W.S. strain and Shope’s swine virus. The tests also indicated that neutralizing antibodies increased in ferrets during convalescence from the disease and that convalescent serum ‘enhanced waning’ immunity. This suggested a correlation between antibody levels and immunity. The question of whether changing immunity was linked to 110 A.A. Smordinsteff, A.I. Drobyshevskaya, and O.I. Shishkina, ‘On the aetiology of the 1936 influenza epidemic in Leningrad’, Lancet (12 December 1936), 1383–1385. 111 L. Hoyle and R.W. Fairbrother, ‘Isolation of the Influenza Virus and the Relation of Antibodies to Infection and Immunity. The Manchester Influenza Epidemic of 1937’, British Medical Journal (27 March 1937), 655. 112 J. McIntosh and F.R. Selbie, ‘The Pathogenicity to Animals of Viruses Isolated from Cases of Human Influenza’, British Journal of Experimental Pathology, XVIII (1937), 334–344. 113 T.J. Francis, ‘Recent Advances in the Study of Influenza’, Journal of the American Medical Association, 105 (1935), 251–254; T.J. Francis, ‘Etiological and Immunological Aspects of Influenza’, Health Examiner, 5 (1936), 589. 114 C.H. Andrewes, P.P. Laidlaw, and Wilson Smith, ‘Influenza: Observations on the Recovery of Virus from Man and on the Antibody Content of Human Sera’, British Journal of Experimental Pathology, XVI (1935), 566–582.

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individual susceptibility and the rise and fall of influenza epidemics had preoccupied physicians and epidemiologists since the 1890s. If what the team found in ferrets was applicable to humans, they believed they could devise protective serum therapies or vaccines. To pursue this line of investigation, they developed a reference antiserum to evaluate antibody levels to the W.S. virus. Using the established procedure of hyperimmunising horses with repeated and increasing doses of the virus, they calibrated the ‘neutralizing power’ of the immune serum generated in horses’ bodies by measuring its ability to prevent the virus from producing disease. This involved testing serial dilutions of a serumvirus mixture to a specified endpoint, either the production of a discrete lesion or death in a research animal. The standard measure for quantifying serum tests defined the endpoint for final dilutions at 50% (LD50), in which equal numbers of animals inoculated with serum-virus mixtures showed, or did not show, lesions characteristic of a virus.115 Ferrets were ill-suited to this kind of work: expensive to breed, they produced smaller litters than other laboratory animals, and demanded complex isolation and housing facilities. Most importantly, in contrast to dog distemper, which produced a lethal infection in ferrets, ferret flu presented as a non-lethal respiratory infection, without a distinct lesion. It was therefore impossible to isolate a pathological marker against which to quantify the antiserum.116 A solution to this problem came in early 1934, when Smith at the NIMR and Francis and Magill at the IHD simultaneously devised a method for infecting mice with material from infected ferrets.117 The method involved inoculating ferret virus material into the noses of anaesthetised mice. Serial passage of the virus by this method eventually induced ‘plum-colored’ lung lesions in the mice, the consolidation of

115 Löwy, ‘The Experimental Body’, 441; Mazumdar, ‘The Antigen–Antibody Reac-

tion’. 116 P.P. Laidlaw, Wilson Smith, C.H. Andrewes, and G.W. Dunkin, ‘Influenza: The Preparation of Immune Sera in Horses’, British Journal of Experimental Pathology, XVI (1935), 277. 117 C.H. Andrewes, Wilson Smith, and P. P. Laidlaw, ‘The Susceptibility of Mice for the Viruses of Human and Swine Influenza’, Lancet (20 October 1934), 859–862; Francis, ‘Transmission of Influenza by a Filterable Virus’. To avoid a priority dispute, the British and American workers agreed to acknowledge each other’s work in their publications.

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which killed the animals.118 ‘The mouse disease,’ they later noted, was ‘essentially a virus pneumonia; unlike the ferret disease, it exhibits no [nasal] symptoms … and no gross pathological changes elsewhere than in the lungs.’119 Mouse influenza was analogous to severe forms of respiratory influenza in humans. The experimentally-induced lung lesion could be modified by changing virus-serum mixtures and this made them especially good markers for calibrating the potency of the horse serum, called ‘IH2’. In due course, the team transformed mice into an effective serological tools for estimating the amount of neutralizing antibodies in human and animal sera. In a series of experiments in late 1934, they compared the effects of increasing dilutions of IH2 and sera from convalescent and previously uninfected humans, mice, and ferrets. Determining the neutralizing power of serum dilutions in correlation with the resolution and consolidation of mouse-lung lesions observed post mortem, they found that while convalescent human sera protected the animals, IH2 proved more potent, neutralizing virus at equal or greater dilutions. It did not completely prevent infection, but it inactivated the virus enough to protect against lung lesions. This was a crucial piece of work, serving as a building block for the mouse-neutralization test and the potential therapeutic uses of IH2.120 Scores of mice were sacrificed in making this test, and many more would be as it was adopted as a standard procedure. This was hardly a concern at the time, for the test proved to be invaluable as a more accurate way to detect and compare the presence of neutralizing antibodies in human and animal sera for diagnostic or epidemiological purposes, and to distinguish different virus strains. When the team reported their work in October 1934 they hoped that the mouse test would provide a ‘readily available’ method for detecting influenza virus.121 The medical and general press seized on this idea. ‘With such an easily handled and inexpensive animal as the mouse available for work on influenza,’ noted the BMJ , ‘this line of research comes within the scope of most laboratories.’122 This was jumping the gun. Try

118 Andrewes, Smith, and Laidlaw, ‘The Susceptibility of Mice for the Viruses’, 859. 119 Stuart-Harris, Andrewes, and Smith, A Study of Epidemic Influenza, 105. 120 Laidlaw, Smith, Andrewes, and Dunkin, ‘Influenza: The preparation of immune sera in horses’, 278–279. 121 Andrewes, Smith, and Laidlaw, ‘The Susceptibility of Mice for the Viruses’, 862. 122 ‘The Mouse and Influenza Virus’, BMJ (3 November 1934), 817.

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as they might, the British workers could not directly induce infection in mice with human nasal washings. Nor could their American counterparts. Mice appeared to be susceptible only to virus first passaged in ferrets. Unlike ferret ‘flu’, mouse ‘flu was not transmissible by contact but could only be produced by inoculation of an adapted ferret virus into the respiratory tract of the mouse. At least initially, mice could not be used for either directly isolating human influenza viruses or for modelling how they spread. The promise of simplifying laboratory diagnosis and research would have to wait. Instead, the value of the mouse test derived from its use in exploring the complexities of influenza immunity.

3

Putting Mice to Work

Up to October 1934, the NIMR workers had elucidated the properties of influenza virus infection in ferrets and mice but had yet to establish a certain connection between experimental and human influenza. It would take nearly five years to fully resolve this issue and, in the process, to fully demonstrate the practical relevance of their research. Meantime, using the new neutralization test, from 1935 their strategy was to concentrate on three interrelated problems: the relationship between virus antibodies and immunity, the clinical identity of viral influenza, and the development of a vaccine. This strategy required extensive collaboration with pathologists and physicians and drove NIMR initiatives to link together laboratory and clinical investigations. The need to coordinate work with hospital clinicians and pathologists had been an issue from the start. Without direct ties to a hospital, gaining access to clinical material was a consuming part of the NIMR’s everyday operations. Alliances between laboratories, hospitals, industry, and other constituencies necessary for gaining access to research material helped to define interwar medical science.123 Strategies for securing materials were shaped by the needs and characteristics of different programmes, but also by the professional organisation and culture of medicine at the time. The NIMR workers had to negotiate the characteristics of London medicine

123 See Nelly Oudshoorn, Beyond the Natural Body: An Archaelogy of Sex Hormones (London: Routledge, 1994), 66.

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through a mixture of informal and formal relationships with voluntary, military, and London County Council hospitals.124 In the early stages of their research, the team relied on their relationships with leading clinicians at major voluntary hospitals.125 But these did not serve the team well when they attempted to track the incidence of the virus and to carry out larger-scale serological studies. In late 1934, Laidlaw sent Fletcher a ‘Memorandum on the Need for More Clinical Cooperation in the Influenza Work,’ in which he described the problem: ‘In spite of arrangements … at St. Bartholomew’s Hospital, we only got into touch last winter with very few cases that (probably) broke out in March, we failed, through lack of organization, to obtain virus from more than one case.’126 The solution Laidlaw proposed was to recruit ‘a clinical collaborator who could seek out…cases suitable for testing, collect the material, himself observe the cases clinically and make some bacteriological study.’127 The collaborator had to be familiar with the clinical aspects of influenza, be willing to be trained in virus work, and able to negotiate the arcane and labyrinthine world of clinical medicine. Along with establishing links with hospitals, a key part of the job would be to characterise cases from which the virus was isolated, with the aim of producing a definitive clinical picture of the virus disease. Fletcher approved and in autumn 1934, the team recruited Charles Herbert (C.H.) Stuart-Harris from Barts. Stuart-Harris proved to be an ideal choice. After graduating from Barts as a scholar in 1931, he served as house physician to F.R. Fraser, the professor medicine at Barts who had a close working relationship with NIMR researchers, having supplied them with clinical samples used in the team’s first influenza experiments in 1933. Stuart-Harris had been working under Fraser as a demonstrator in pathology when the NIMR team made their discovery and then moved with Fraser to the British Postgraduate Medical School in 1935, where he was part of a

124 The LCC took control of former Metropolitan Asylum Board hospitals on 1 April 1930 as part of the abolition of the Poor Law Guardians. See G.M. Ayers, England’s First State Hospitals and the Metropolitan Asylums Board (London: Wellcome Institute of the History of Medicine, 1971). 125 For official accounts, see Medical Research Council Annual Reports, 1934–1939. 126 NIMR Personnel Files, C.H. Andrewes, Report on Year’s Work, 1934–35. 127 NIMR Personnel Files, C.H. Andrewes, Report on Year’s Work, 1934–35.

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dynamic group of clinical researchers. Undoubtedly, Stuart-Harris’ relationship with Fraser was key to his recruitment to the NIMR. Awarded a Royce Fellowship in 1935, his initial role at the NIMR was to identify, investigate, and document outbreaks of influenza across London and to collect specimens from cases, which served as the raw material for experimental studies. This work demanded the fostering of existing and new relationships with clinicians and pathologists.128 Collaborative investigations grew as the team started using the mouse test to study the level of antibodies to influenza viruses in Londoners in 1935. By tracking the incidence and comparing the neutralizing power of antibodies for the W.S. strain and Shope’s virus, the team wanted to know whether a relation existed between changing antibody levels and immunity, and, in the long term, whether these changes might be linked to the rise and fall of influenza epidemics.129 The NIMR workers reckoned the mouse test enabled them to come up with new answers to these longstanding questions. Through 1935, they collected sera from hundreds of Londoners of various age groups. Hospitals and public schools supplied the bulk of sera from children; medical workers in the United States sent adult samples; and finally, military instillations provided sera from servicemen of various ages. Constrained by the costs and time it took to run mouse-neutralization tests, they examined the sera of 113 individuals for antibodies to the W.S. virus and the swine flu virus.130 Identifying ‘neutralizing antibodies to human (WS) influenza virus … in the majority of human sera examined,’ their assessment yielded the first serological picture of the distribution of influenza virus in a population.131 Graphs they produced demonstrated the use of neutralizing antibodies as evidence in support of the link between the W.S. virus isolated in ferret and human influenza (Fig. 9). The antibodies were deemed key traces of 128 James S. Porterfield, ‘Sir Charles Herbert Stuart-Harris (1909–1996), Virologist’, Oxford Dictionary of National Biography. Accessed 23 September 2019. https://www. oxforddnb.com/view/10.1093/ref:odnb/9780198614128.001.0001/odnb-978019861 4128-e-61938; David Tyrrell, ‘Sir Charles Herbert Stuart-Harris’, BMJ 314 (1997), 906-7. 129 Andrewes, Laidlaw, and Smith, ‘Influenza: Observations on the Recovery of Virus from Man’. 130 Andrewes, Laidlaw and Smith, ‘Influenza: Observations on the Recovery of Virus from Man’, 577. 131 Andrewes, Laidlaw, and Smith, ‘Influenza: Observations on the Recovery of Virus from Man’, 576.

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the presence of influenza virus infection in a cross-section of Londoners. The identification of swine influenza virus antibodies marked the beginning of the serological work that led to Shope’s hypothesis that the 1918 pandemic was a zoonotic disease caused by a swine influenza virus.132 The practical implications were readily apparent. The incidence of these antibodies in the population suggested that influenza infection conferred some form of immunity, the history and duration of which could be traced serologically. Since it was well known that influenza epidemics waxed and waned seasonally, it was important to determine whether changes occurred in antibody levels over time. When the team tested samples from Londoners in early 1937, their antibody levels had dropped considerably. That summer, at the annual meeting of the BMA in Belfast, Andrewes speculated that, ‘knowledge of such variations might … give … insight into one of the factors controlling the periodicity of influenza epidemics.’133 His prediction seemed to be confirmed when, after a large influenza epidemic exploded in London that autumn, antibody levels shot up again. While the team’s serological studies pointed to the potential epidemiological significance of neutralizing antibodies, their clinical value would remain unclear until the team correlated a specific disease to the virus and its antibodies.134 This was important not just for consolidating influenza’s virus identity, but also for the longer-term goal of developing an influenza vaccine. Stuart-Harris described the challenge: ‘It was apparent that a satisfactory application of such [laboratory] methods to human beings must largely depend upon the possibility of demarcating cases of influenza of virus aetiology from other diseases with similar symptoms. Correlated clinical and laboratory studies were clearly necessary.’135 The main sites for the studies were hospitals at military garrisons in and

132 R.E. Shope, ‘The Influenzas of Swine and Man’, The Harvey Lectures, 1935–1936 (New York: The Harvey Society, 1936), 183–213; R.E. Shope, ‘Old, Intermediate and Contemporay Contributions to Our Knowledge of Pandemic Influenza’, Medicine, 23 (1944), 415–420. 133 C.H. Andrewes, ‘Influenza: Four Years’ Progress’, British Medical Journal (11 September 1937), 513–514. 134 NA FD1/1114, ‘A Study of Epidemic Influenza’, 1938. 135 C.H. Stuart-Harris, C.H. Andrewes, and Wilson Smith, A Study of Epidemic

Influenza: With Special Reference to the 1936–7 Epidemic, Medical Research Council, Special Report Series, No. 228 (London: HMSO, 1938), 3.

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Fig. 9 Neutralizing Antibody Levels in Londoners. Each vertical column represents a serum. The height of shading indicates the quantity of influenza virus antibody in the serum. Sera were graded as better than S (standard IH2 or IH4 horse-antiserum), equal S, S/5 (one-fifth the neutralizing power of S), or S/ 25 (one twenty-fifth the neutralizing power of S). Spaces marked O indicate sera with no antibody or with less than S/25 (Source Christopher H. Andrewes, Patrick P. Laidlaw, and Wilson Smith, ‘Influenza: Observations on the Recovery of Virus from Man and on the Antibody Content of Human Sera’, British Journal of Experimental Pathology, XVI [1935], 577)

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around London, while smaller-scale studies were carried out at civilian hospitals. Military hospitals provided relatively uniform and controlled populations. The MRC’s ties with the Army Medical Services made them more accessible. Nonetheless, creating stable relations with clinicians and pathologists was crucial. During suspected influenza outbreaks in late 1936 and late 1937 the team worked with clinicians and pathologists to collect masses of nasal and throat garglings for their work. The London Daily Herald conjured an image of ‘flying squads’ moving between the Hampstead laboratory and hospitals in search of a ‘cure’. But forging links was more mundane (Fig. 10). Much of this work fell to Stuart-Harris. He collaborated with hospital physicians to make detailed clinical notes on patients and personnel entering wards with influenza-like symptoms.136 Part of his job was to characterise cases from which virus was isolated. Samples collected from these patients were sent to Smith and Andrewes to be tested for virus in ferrets. Serum samples were taken to test for the presence and levels of antibodies. Together, the NIMR workers attempted to carve-out a specific ‘virus disease’ by correlating the virus they used to produced influenza in ferrets with a particular clinical picture of influenza in humans. There were two approaches to correlating the laboratory disease with the clinical disease. The first, as we have seen, was to painstakingly and repeatedly show that material collected from people sick with influenza contained an agent that produced a specific disease in ferrets, with characteristics analogous to those found in humans, and that the agent was a filterable virus which could be indirectly identified by the presence of neutralizing antibodies. This was the mainstay of the NIMR team’s correlation work. The second was to experimentally infect human subjects with the W.S. virus recovered from ferrets. Experimental infection represented a way to close the aetiological circle by demonstrating that the ferret virus could infect and produce disease in humans, and thus to show that ferret and human influenza were caused by the same agent. Experimental infection of humans with the ferret virus was tested early on.137 The team ran trials on volunteers, mostly medical students from Barts, who agreed to be inoculated with the ferret virus. The students 136 NIMR Personnel Files. Laidlaw, ‘Memorandum on Need for More Clinical Cooperation in Influenza Work’, 1935. 137 Laidlaw, Smith, Andrewes to Dale Report on Influenza Research Carried out in the Year 1933–4. MRC Annual Report, 1934.

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Fig. 10 ‘Flying Squad’ Collects Virus (Source Daily Herald [5 January 1937], 3)

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were screened for bacteria in their respiratory tracts and for neutralizing antibodies to the W.S. virus. Most were rejected because their sera neutralized the virus, which indicated that they had already been exposed. Previous exposure proved to be a significant problem, as the NIMR workers found that almost all volunteers had neutralizing antibodies against the virus. Eventually, two male students without antibodies were selected. The first was tested in September 1933, within months of the team’s initial discovery. The second was tested in March 1934. Each man was isolated in a one-bed hospital room at Barts for 48 hours before the test and, following the method Smith had developed for ferrets, equal amounts of a filtered turbinate suspension from an infected ferret were instilled into each nostril. In both cases, nothing happened: ‘neither volunteer showed abnormal signs or symptoms whatever after inoculation.’138 While disappointed by the results, the team was steadfast in their belief that the virus was the causative agent of human influenza. Evidence from their own serological studies, along with those of the Americans and others, justified their belief. But the case would be all the stronger if they could demonstrate a clear causal role for the virus in both the laboratory disease in ferrets and the clinical disease in humans. Transmission experiments to isolate and determine the role of a ‘filterpasser’ had been tried on human subjects as early as 1918.139 But they were controversial, lacking appropriate controls and yielding uncertain results. Laidlaw would note the difficulties with human experiments in 1935: All these experiments on human volunteers are of very doubtful value. Man is an exceedingly bad experimental animal and almost useless when he is used for experiment during an epidemic. One can never be sure that the experimental subject is susceptible and therefore negative results can be discounted; while positive results, though perhaps more significant,

138 Andrewes, Laidlaw, and Smith, ‘Influenza: Observations on the Recovery of Virus from Man and on the Antibody Content of Human Sera’, British Journal of Experimental Pathology, 16.4 (1935), 580–581. 139 The first studies had been carried out by French researchers, C. Nicolle and C. Lebailly, ‘Quelques notions experimentales sur le virus de la grippe’, Comptes Rendus de l’Academie des Sciences Paris, 167 (1918), 607–610; and R. Dujarric de la Riviere, ‘La grippe est-elle une maladie a virus filtrant?’, Comptes Rendus de l’Academie des Sciences. Paris, 167 (1918), 606–607.

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are always open to the suspicion that infection was picked up in some accidental manner.140

The NIMR workers appear not to have run any further human transmission experiments for the reasons Laidlaw noted and likely because, as the Barts experiments showed, it was difficult to find people who had not been previously exposed to influenza. In 1936, a chance event presented an opportunity for the team to show that their ferret virus could directly cause human influenza. It occurred as part of the correlative investigations. In February, Stuart-Harris had been studying a suspected outbreak of epidemic influenza among army personnel at Woolwich Garrison in Greenwich.141 As part of the studies, he collected eight throat samples from men in the garrison hospital, brought them back to Hampstead, and then tested them in ferrets, as well as in two mice. None of the samples produced disease in the animals. By way of a control, the ferrets were tested with and became ill from the W.S. strain, which by this point had been passaged through 196 ferrets since being originally isolated in 1933. The control test made it clear that the Woolwich outbreak was not caused by the W.S. virus and was likely not influenza but rather an influenza-like illness. This conclusion was substantiated by later clinical and bacteriological investigations at Woolwich and by the team’s serological studies of Londoners, which indicated that influenza had not been prevalent in spring 1936. However, during his laboratory experiments Stuart-Harris came down with what appeared to be a case of influenza. Ruling out Woolwich, he suspected that he been infected in the Hampstead laboratory on 6 March while examining the eight ferrets he had experimentally infected. He would later report that, at the time the ferrets were at ‘the height of disease with pronounced symptoms: nasal obstruction, watery eyes, sneezing and nasal discharge.’ During his observations, one ferret ‘sneezed violently at close range’ into his face. Noting the date and time of the sneeze in his laboratory notebook, forty-five hours later he had the symptoms of a ‘typical attack’ of influenza.142 140 Laidlaw, ‘Epidemic Influenza: A Virus Disease’, 1119. 141 Wilson Smith and C.H. Stuart-Harris, ‘Influenza Infection of Man from the Ferret’,

Lancet (18 July 1936), 121–123. 142 Wilson Smith and C.H. Stuart-Harris, ‘Influenza Infection of Man from the Ferret’, 121–123.

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In their report, published in the Lancet with the suggestive title, ‘Influenza Infection of Man from the Ferret’, Smith and Stuart-Harris detailed the clinical characteristics and progression of Stuart-Harris’ illness. The incubation period, they noted, was ‘also the usual incubation period in ferrets experimentally inoculated’ with the W.S. virus. Like ferrets, Stuart-Harris’ illness peaked on the third and fourth days and lasted eleven days in all. Using the team’s standard method, throat and nasal washings were taken from Stuart-Harris twenty hours after the onset of his symptoms, and again on the fourth day of his illness; the first samples were prepared and inoculated into the nose of a healthy ferret, which suffered ‘a typical attack of ferret influenza’ and was killed on the third day of its illness. After post mortem examination of the infected ferret, preparations of its turbinates and affected lung material were used for passage experiments, which showed that the disease could be readily transmitted to healthy ferrets. Those ferrets allowed to recover were ‘solidy immune’ against the W.S. virus. Tests were also run on mice, which, after being directly infected with Stuart-Harris’ throat and nose material, developed lung lesions that were characteristic of experimental ‘mouse influenza’. These pathological and serological studies demonstrated that the virus isolated from Stuart-Harris and the ferrets was the same W.S. strain. As in all the team’s work, a fever chart linked the typical clinical characteristics of human and ferret influenza (Fig. 11). What stood out was that the virus recovered from Stuart-Harris ‘behaved in all respects like the passage strain [W.S.] and was quite unlike any other human influenza virus isolated’ by them or other researchers. It was clear to them that this was a laboratory infection in which their ferret virus directly caused a case of human influenza. The aetiological circle was closing. But the event also raised a new concern: ‘it is quite conceivable’, noted Smith and Stuart-Harris, ‘that a case of laboratory infection might be the starting-point of an epidemic.’143 While precautions would need to be taken against this possibility, more important for the team was that Stuart-Harris’ laboratory disease represented an opportunity to gain further insights into the role of neutralizing antibodies in conferring immunity against the virus. Early work with ferrets had raised some doubts about the importance of serum antibodies in providing protection. But evidence from mouse 143 Wilson Smith and C.H. Stuart-Harris, ‘Influenza Infection of Man from the Ferret’,

123.

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Fig. 11 ‘Ferret Flu in Man’. Fever chart of Stuart-Harris after contracting influenza from ferrets while studying a small epidemic in army personnel at Woolwich in February 1936. On 6 March ‘one ferret sneezed violently at close range while being examined.’ Forty-five hours after contact, Stuart-Harris came down with a ‘typical attack’ of influenza. On 9 March, the first day of symptoms, he reported ‘very abrupt onset with coryza; sleeplessness and stiffness of joints during the night. Second day: Malaise, coryza, severe backache and frontal headache … Third day: Malaise, headache, severe backache in sacral region, aching pains in the hamstrings; sweating, coryza, giddiness on standing. Fourth day: … onset of acute mental depression … Later in day … exacerbation of symptoms … Fifth day: Steady improvement with fall of temperature, giddiness. Fifth to eleventh days: Steady improvement; muscular weakness remained until eleventh day’ (Source Wilson Smith and C.H. Stuart-Harris, ‘Influenza Infection of Man from the Ferret’, Lancet [1936], 121)

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tests carried out by NIMR and Rockefeller workers since 1935 indicated that the antibodies were closely connected to both susceptibility and resistance. Serological tests on Stuart-Harris confirmed these findings. Unlike cases in the general population, Stuart-Harris was a unique experimental subject because his sera had been regularly collected months before his infection. This was routine practice to both screen researchers for exposure to the virus and to ensure a ready a supply of ‘normal’ human sera. Ferret-neutralization tests on sera taken from Stuart-Harris before the ferret’s sneeze on 6 March 1936 were negative, showing that his infection was recent. At the same time, mouse tests used to measure antibody levels in serum samples taken from him between the third and eighth day after the onset of his illness showed that antibodies rose considerably soon after infection. Even more importantly, they continued to confer protection against ‘thousands of infective doses of virus’ weeks afterwards.144 This finding suggested that an attenuated ferret virus could be used as the basis for a vaccine that might provide a reasonable amount of protection. The NIMR workers had already created such a virus in mice. But before any kind of vaccine testing could be carried out it was essential to develop ways to definitively identify cases. Stuart-Harris’ influenza had provided a marker for doing so. The correlated studies of 1936 and 1937 eventually yielded a new clinical picture of influenza. Once he recovered, Stuart-Harris compared clinical notes from the 1936 outbreak, from which the W.S. virus was generally not isolated, with those from an epidemic in 1937, from which it was isolated regularly. In the clinical picture he outlined, the virus was linked only to a respiratory form of influenza, while nervous and gastric forms, which had been part of classificatory frameworks since the midnineteenth century, were excluded. Also gone was the loose category of ‘febrile catarrhs’. In a widely publicised report for the MRC in 1938, he distinguished febrile catarrhs, which encompassed a cluster of respiratory conditions of unknown aetiology, from ‘epidemic influenza’, which had now become a specific clinical entity, characterised by definitive respiratory symptoms and pathogenesis, and aetiologically linked to the virus.145 Influenza emerged from this report as a distinct respiratory virus disease, 144 Wilson Smith and C.H. Stuart-Harris, ‘Influenza Infection of Man from the Ferret’,

123. 145 Stuart-Harris, Andrewes and Smith, A Study of Epidemic Influenza: With Special Reference to the 1936–7 Epidemic, 3.

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shed of its historic associations with nervous or gastric conditions and its forty-year old connection to Pfeiffer’s bacillus. The neutralization test was crucial to this work. Andrewes and Smith determined that in cases identified as ‘epidemic influenza’, serum from convalescent patients ‘acquired very definite neutralizing powers,’ while ‘no such neutralizing powers appear[ed] in the sera of patients suffering from respiratory diseases other than influenza.’146 The test had made it possible to retrospectively diagnose ‘epidemic influenza’. Coupled with the ability to isolate the virus in ferrets, the new virological tools that facilitated the laboratory and clinical work had slowly redefined ‘epidemic influenza’ as a virus disease.

4

A Virus Disease?

The potential value of this new definition for explaining the protean clinical and epidemiological forms of influenza was not lost on the medical profession. As early as 1935, medical textbooks incorporated the virus into explanations of the aetiology, pathogenesis, and immunity of the disease. The 12th edition of Osler’s Principles noted that ‘[t]here is considerable evidence that a virus is the cause.’147 A.H. Douthwaite, a physician at Guy’s Hospital, noted in the prestigious British Encyclopaedia of Medical Practice in 1937: ‘that influenza is, in fact, a virus disease is now to all intents and purposes accepted.’148 J.G. Scadding, physician at the Postgraduate Medical School, noted that for physicians, ‘the discovery of a filterable virus pathogenic for ferrets … made it possible to separate one disease from the ill-defined group of epidemic respiratory infections … The disease with which the virus is associated … forms an aetiological entity.’149 By 1939, the Ministry of Health had incorporated the NIMR workers’ definition into a revised influenza memorandum, distributed in

146 Stuart-Harris, Andrewes and Smith, A Study of Epidemic Influenza: With Special Reference to the 1936–7 Epidemic, 56. 147 W. Osler, H.A. Christian, and T. McRae, ‘Influenza’, In The Principles and Practices of Medicine, 12th edition (London: D. Appleton and Co., 1935), 110. 148 A.H. Douthwaite, ‘Influenza’, in H. Rolleston (Ed.), The British Medical Encyclopaedia of Medical Practice (London: Butterworh & Co., 1937), 174–190, p. 180. 149 J.G. Scadding, ‘Clinical Aspects of Influenza’, The Practitioner, CXLI (December 1938), 712–724, @ p. 712.

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advance of the war.150 While the practical difficulty of distinguishing influenza from catarrh, colds, and other respiratory conditions remained, its classification as a specific virus disease pointed the way (Fig. 12).

Fig. 12 Identifying Flu. Differential diagnosis suggested to MOHs and medical practitioners by the Ministry of Health in 1939. Based on the NIMR’s Study of Epidemic Influenza (1938). While the presence of virus became a key diagnostic marker, its relation to specific clinical symptoms and epidemiological characteristics was crucial for its differentiation from febrile catarrhs (Source Ministry of Health Memorandum on Influenza (Revised Edition) [London: HMSO, 1939], 6)

150 Ministry of Health, Memorandum on Influenza Revised Edition (London: HMSO, 1939).

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Nonetheless, virus workers faced considerable challenges in convincing practitioners of the broader relevance of their research. While the laboratory identification of influenza virus was generally heralded as a medical breakthrough, it was not immune from the kind of scrutiny levelled at earlier influenza germs, including Pfeiffer’s bacillus. A common observation made in medical circles soon after the isolation of the virus in ferrets was that, while a ‘brilliant piece of work,’ considerably more time and evidence would be needed to sort out its role in the disease. Crucial for clinicians was whether it could be used better to elucidate the pathogenesis of influenza and its complications. ‘It is probable,’ noted an editorial in The Practitioner, ‘that in certain cases this infection facilitates the invasion of the body by visible bacteria giving rise to various complications. Decisive evidence on this point, and indeed, on the importance of the virus … can only be secured by intensive study during an influenza epidemic.’151 The suggestion that the virus acted in concert with other germs, notably Pfeiffer’s bacillus, was commonplace: ‘The influenza bacillus (Haemophilus influenzae) has a close association with the disease, whether as a primary or secondary agent. It may be that both organisms are required to produce the disease….’152 Even when the NIMR team reported in 1936 that they had closed the aetiological circle, after Stuart-Harris caught ferret ‘flu, doubts remained.153 In 1937, as the team completed its collaborative studies, The Times reckoned that ‘the mystery of influenza has not been resolved, though great labour has been, and is being, expended upon its elucidation.’154 In a lecture at the Royal Institution the same year, the esteemed Barts clinician, Thomas Horder, who had questioned aetiological claims during the 1918–1919 pandemic, insisted that, influenza ‘was still the great outstanding plague with which medicine has to contend.’155 As key stakeholders, many bacteriologists and pathologists were also cautious about using the virus to explain the disease. Pfeiffer’s bacillus

151 ‘The Virus of Influenza’, The Practitioner (August 1933), 210. 152 Osler, Christian, and McRae, ‘Influenza’, in The Principles and Practices of Medicine,

12th edition, 110. 153 Wilson Smith and C.H. Stuart-Harris, ‘Influenza Infection of Man from the Ferret’, Lancet (18 July 1936), 121–123. 154 ‘The Influenza Epidemic’, Times (9 January 1937), 13. 155 ‘Lord Horder on the Influenza “Plague”’, Times (27 February 1937), 14.

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remained in play, especially when it came to the sequelae and complications associated with influenza. Many pathologists insisted that other agents played an important role and that they should be included in explanations of serious secondary infections.156 David and Robert Thomson, pathologists at the Pickett-Thomson Research Laboratory at St. Paul’s Hospital, who had published an authoritative monograph on influenza in early 1933, claimed in 1935 that, ‘demonstrable bacterial infection persists throughout the course of the disease’ and cautioned that, ‘it is necessary to check over-enthusiasm for the filter-passing virus hypothesis.’157 Since direct tests on humans were easily challenged, and since mice were only susceptible to virus first transferred through ferrets, some suggested that the virus was not of human origin: ‘nasal secretions of the influenza patient … contain something capable of arousing virulence in a virus normally present in relatively innocuous form, in the nose and throat of the ferret.’158 A few critics launched all-out attacks on the NIMR virus research. The surgeon, venereologist, and director of the Nature of Disease Institute, J.E.R. McDonagh, argued that influenza virus, like all viruses, was but a ‘filterable phase’ of known bacteria.159 Thus, the NIMR discovery rested on a false premise. The Irish serologist, W.M. Crofton, took a similar view in his lengthy monograph The True Nature of Viruses, describing the NIMR virus as a bacterium in disguise. Like McDonagh, Crofton was worried that the ‘virus theory’ was being accepted ‘without question throughout the world.’160 However, widely varying views of physicians and pathologists put lie to this claim. Addressing debates in its own pages about the implications of the virus work, the BMJ noted in 1940 that despite the importance attributed to the virus in the pathogenesis of influenza, ‘the possibility remains that visible microorganisms are not as indifferent in this connexion as we might believe.’161 156 J. Torrens, ‘Influenza: Its Sequelae and Treatment’, BMJ (17 February 1934), 274–276. 157 D. Thomson and R. Thomson, ‘Some Features of the Influenzal Epidemic in the Spring of 1935’, BMJ (13 July 1935), 62–63, p. 62. 158 ‘Influenza and Its Cause’, Times (17 March 1937), 11. 159 J.E.R. McDonagh, The Common Cold and Influenza, and Their Relationship to

Other Infections in Man and Animals (London: William Heinemann, 1936). 160 W.M. Crofton, The True Nature of Viruses (London: John Bale, Sons & Curnow, 1936), x. 161 ‘The Causes of Influenza’, BMJ (27 April 1940), 649.

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As late as 1942, G.E. Beaumont, consulting physician to Middlesex Hospital, classified ‘influenza’ under ‘Infectious Diseases of Known and Doubtful Etiology’ in his textbook Medicine: Essentials for Practitioners and Students and claimed that ‘there is no proof that it is due to a filter-passing virus ….’162 While the MRC and the medical and general press highlighted the potential of the NIMR’s tools for solving problems in diagnosing influenza, they did not directly change everyday clinical or public health practices. Used for delineating virus strains and for population-based epidemiological studies, ferret and mouse tests were too complicated and too laborious for routine use in hospital or public health laboratories. Their impact on existing medical knowledge and practice was indirect, and this left open questions about the role of the virus and the value of virus research in tackling the ‘flu problem. One way to assuage doubt, however, was to manufacture an effective vaccine for wide use. This aim had been on the agenda from the outset of the NIMR team’s research and as soon as their experimental system had yielded the W.S. virus in 1933, producing a vaccine became a priority. Along with its potential value in protecting the nation against a modern menace, an effective vaccine would also confirm the identity of the W.S. virus as the specific cause of influenza. If a vaccine worked, there could be little doubt of the role of virus; if it failed, questions about it would remain.

5

Collaboration and Consensus

The identification of influenza virus did not quickly or easily transform medical knowledge or practices. Rather than the straightforward outcome of the NIMR’s discoveries in 1933 and 1934, gaining acceptance of influenza’s virus identity was an organisational and practical challenge that involved the construction of new social relations. Criticisms of the role of the virus in influenza were indicative of the negotiations and extensive labour necessarily involved in this process. Establishing influenza’s virus identity and its wider credibility demanded that virus workers align their research with existing clinical, epidemiological, and pathological knowledge and interests. This was difficult, not least because the authority 162 G.E. Beaumont, Medicine: Essentials for Practitioners and Students (London: J&A. Churchill, 1942), 528.

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of virus research in medicine rested, in the first instance, on the ability to translate clinical and epidemiological problems into laboratory problems and to provide new solutions. How NIMR workers accomplished these goals depended in good part on the ways in which they negotiated and aligned their research with the interests of different medical constituencies. The approach they used to make their influenza virus work relevant beyond the laboratory walls had roots in the campaign against dog distemper and in the general principle that Walter Morley Fletcher and the MRC had put in place in the 1920s of translating experimental research in medicine and public health. But it was also shaped by existing professional interests and ideas, and the exigencies of the disease itself. The production and use of practical tools to tackle key medical and public health problems associated with influenza lay at the core of the NIMR’s approach. The ferret model and mouse test were crucial to remaking influenza into a virus disease in the laboratory. Used together in the NIMR’s research, these tools enabled Laidlaw and his team to determine influenza’s aetiology, to explore its immunity and, as we shall see in the next chapter, to develop vaccines. Both animals served as means to establish the practical value of virus research for established medical knowledge and to change it. Framed as an analogue of the human disease, ferret flu became an important basis for identifying human influenza viruses and studying clinical and immunological aspects of the disease under controlled conditions. The neutralization test illuminates how approaching virus diseases as immunological problems facilitated the translation of esoteric virus work into medical problems, and how in the process these problems were also redefined. Ultimately, neutralization tests helped establish a virus as the focal point for the identification and control of influenza. The approach to aligning virus models, tools and work with clinical and epidemiological knowledge involved two other key components. First, the NIMR team developed ways of communicating their research that facilitated the translation of specialist laboratory knowledge and practices into non-specialist terms. What is evident in their approach is the importance placed on making laboratory findings derived from ferret flu and mouse-neutralization tests commensurate with clinical and epidemiological knowledge of human influenza. This was necessary to establishing the legitimacy of their virus work and their new classification of influenza. Second, the organisation of collaborative investigations with clinicians and pathologists in the deployment of neutralization tests and, eventually,

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vaccines were crucial to ensuring that basic virus work addressed practical medical and public health problems. Such collaborative investigations made possible the incorporation of virus-based knowledge into the realms of medicine and public health. Despite lingering questions and the emergence of new problems, the NIMR approach to legitimising virus work yielded a new medical consensus on the identity of influenza in Britain and beyond. By the outbreak of the Second World War in 1939, influenza’s virus aetiology was supported by laboratory practices that were agreed upon and sustained by a small but international network of researchers and research institutions that stretched between London, New York, Melbourne, and other parts of the world. On the back of the NIMR’s efforts, laboratorybased influenza virus work would gain new authority during the war, as it was recruited for the mass production of vaccines, the organisation of which entrenched influenza virus as the focal point for the prevention of influenza. If in 1933 virus workers inhabited the periphery of influenza medicine, by 1939 they and their tools had become an increasingly necessary part of medicine and public health, and to the war effort.

CHAPTER 8

Globalising Flu: Systems of Surveillance and Vaccination

In July 1947, C.H. Andrewes travelled to the 4th International Congress of Microbiology in Copenhagen with a nascent plan for an international network of laboratories dedicated to collecting, characterising, and sharing influenza viruses.1 Andrewes and his colleagues at the NIMR had been mulling the idea as a way to tackle a crucial problem in efforts to control influenza: antigenic variation among influenza viruses. Since first being recognised in the late 1930s, it had become clear to influenza researchers that virus variation had enormous consequences both for anticipating influenza epidemics and for producing effective influenza vaccines. Andrewes was among a number of leading virologists attending the Copenhagen congress who were convinced that influenza viruses were highly susceptible to evolutionary and genetic change.2 And while these properties had only just started to be explored, experiences with mass vaccination programs during and shortly after the Second World War had suggested that, rather than being stable entities, influenza viruses were constantly changing and yielded a seemingly endless variety of subtypes. This characteristic ruled out any possibility of eradicating influenza and 1 NA FD1/544 ‘Memorandum—International Collaboration in the Influenza Field’, 25 July 1947. 2 NA FD1/544 ‘Memorandum—International Collaboration in the Influenza Field’, 25 July 1947; Christopher Howard Andrewes, ‘Adventures Among Viruses, II. Epidemic Influenza’, New England Journal of Medicine, 242 (1950), 197–203.

© The Editor(s) (if applicable) and The Author(s), under exclusive licence to Springer Nature Limited 2023 M. Bresalier, Modern Flu, Medicine and Biomedical Sciences in Modern History, https://doi.org/10.1057/978-1-137-33954-6_8

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instead meant that focus had to be on controlling the disease through a combination of surveillance and vaccination. Because new strains could emerge from any part of the world, surveillance had to be global in scale. Internationalising the collection of influenza viruses was seen as necessary for ‘forecasting’ epidemics and producing effective vaccines. During the discussions at Copenhagen Andrewes schematically sketched his plan on a piece of paper (Fig. 1). The proposed network would require, among other things, the creation and circulation of standardised methods and materials to ensure uniformity in approaches and results. Much time was devoted to agreeing whose and which standards would be used, which laboratories would be part of the programme, and which one would act as the ‘reference centre’. Initially, the network would be formed only of those laboratories with existing capacities to isolate and identify influenza viruses, the majority of which were in Europe and North America. The long-term goal, however, was to expand the network to cover every continent and every country. The congress delegates agreed that the NIMR should serve as the reference centre for the network, where strains sent from ‘reporting’ laboratories would be compared with others, classified, and then freely shared with researchers and vaccine manufacturers.3 Delegates also agreed that the network should come under the direction of the new World Health Organization (WHO), the constitution and organisation of which was being formalised in San Francisco. Immediately after the congress Andrewes travelled to California and presented a memorandum at the World Health Assembly’s Interim Commission that proposed setting up the machinery for an international influenza surveillance system. The Commission accepted the proposal and in October 1947 agreed to establish the World Influenza Programme (WIP).4 In November, the NIMR was designated to host the WIP’s reference laboratory, named the World Influenza Centre (WIC), with

3 NA FD1/544 ‘Congress Meeting Report—International Collaboration in the Influenza Field’, 6 August 1947; NA FD1/544 ‘Andrewes Proposal—International Collaboration in the Influenza Field’, 13 August 1947. 4 NA FD1/544 Proposed World Influenza Centre. Communication from the Interim Commission of the World Health Organisation of the United Nations 21 October 1947; WHO.IC/197 M. Gauthier, Executive Secretary, WHO to Edward Mellanby, Secretary, MRC, 21 October 1947.

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Fig. 1 Sketch of the proposed influenza laboratory network. C.H. Andrewes’ diagram of the influenza virus tracking system proposed to the World Health Assembly in September 1947 (Source National Archives FD1/544 ‘Memorandum—International Collaboration in the Influenza Field’, 1947)

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Andrewes as its director.5 A year later, a second reference laboratory was established in Bethesda, Maryland—the International Influenza Centre of the Americas (IIC)—to coordinate the programme throughout the Americas.6 After a conflicted start, the two centres would work closely together in classifying strains, which was deemed essential to tracing the changing epidemiology of influenza and, most crucially, determining the composition of virus subtypes to be used in vaccines.7 ‘The overall purpose of the proposal,’ noted the American James Culbertson, ‘was to set up the machinery necessary to protect the world population … against the recurrence of another disastrous pandemic of influenza such as was last experienced in 1918.’8 Under the WIP, surveillance and vaccination were made the keystones of a new order of international influenza control.9 A crucial function of the programme was to foster international collaboration.10 As with all WHO initiatives, producing and maintaining scientific consensus was a defining goal.11 Integral to the WIP, and typical of WHO programs, was the creation and circulation of standard methods, materials, and tools to coordinate the activities of participating laboratories. The WIC and IIC played key roles in generating or establishing standards that underpinned the surveillance and vaccine production systems that would be built in the 5 WHO.IC/197 M. Gauthier to Mellanby—Proposed World Influenza Centre, 21 November 1947. World Health Organisation, ‘Virus Diseases’, in The First Ten Years of the World Health Organization (Geneva: World Health Organization, 1958), 214–215. 6 The IIC would move to Montgomery, Alabama in 1950. James T. Cullbertson, ‘Plans for United States Cooperation with the World Health Organization in the International Influenza Study Program’, American Journal of Public Health, 39 (1949), 37–43; Dorland J. Davis, ‘World Health Organization: Influenza Study Program in the United States,’ Public Health Reports, 67 (1952), 1185–1190. 7 A.M.-M. Payne, ‘The Influenza Programme of the WHO’, Bulletin of the World Health Organisation, 8 (1953), 755–774. 8 James T. Cullbertson, ‘Plans for United States Cooperation with the World Health Organization’, 37. 9 Frédéric Vagneron, ‘Surveiller et s’unir ? Le rôle de l’OMS dans les premières mobilisations internationales autour d’un réservoir animal de la grippe’, Revue d’anthropologie des connaissances, 2 (2015), 139–161; Robert Peckham, ‘Viral Surveillance and the 1968 Hong Kong Flu Pandemic’, Journal of Global History, 15 (2020), 444–458. 10 Payne, ‘The Influenza Programme’, 756. 11 Theodore M. Brown, Marcus Cueto, and Elizabeth Fee, ‘The World Health Orga-

nization and the Transition from “International” to “Global” Public Health’, American journal of Public Health, 96 (2006), 62–72.

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early 1950s.12 While efforts to standardise aspects of influenza virus work had been part of British and American research partnerships through the 1930s, the need to standardise virological practices and products took on new meaning and greater urgency as influenza research pivoted in the early 1940s towards the mass manufacture of influenza vaccines as part of the Allied war effort. The Second World War was a turning point in which the machinery of influenza virus surveillance and large-scale vaccine production were constructed.13 Underpinning both systems was a deceptively simple technology: the developing chick egg. First introduced into influenza virus research in 1935, the ‘embryonated’ chick egg became the medium of choice for influenza virus cultivation during the Second World War and the material backbone of the WHO’s post-war influenza programme.14 Egg-based techniques played a number of roles in influenza control: they provided ways of isolating, identifying, and growing quantities of influenza virus, quantifying vaccine dosage sizes, as well as determining vaccine quality and efficacy, which together facilitated large-scale vaccine production. For the architects of the WIP, the availability and relative simplicity of the developing chick egg as a laboratory organism made it readily workable in disparate contexts. Standards of virus isolation, identification, and vaccines generated through the chick egg were important in managing variations in the research cultures and interests of participating national medical and scientific institutions. The WIC and IIC helped train laboratory workers in its use and establish manufacturing guidelines for burgeoning and increasingly integral vaccine manufacturers. Techniques negotiated through the chick egg provided important points of collaboration between the WIP reference centres, reporting laboratories, and vaccine producers.

12 Christopher H. Andrewes, ‘The Work of the World Influenza Centre’, Journal of the Royal Institute of Public Health, 15 (1952), 309–318. 13 Arnold S. Monto, ‘Reflections on the Global Influenza Surveillance and Response System (GISRS) at 65 Years: An Expanding Framework for Influenza Detection, Prevention and Control’, Influenza and Other Respiratory Viruses, 12 (2018), 10–12; M.E. Kitler, P. Gavinio, and D. Lavanchy, ‘Influenza and the Work of the World Health Organization’, Vaccine, 20 (2002), S5–S14. 14 The developing or ‘embryonated’ chick egg was a fertilized, living egg. W.I.B. Beveridge and F.M. Burnet, The Cultivation of Viruses and Rickettsiae in the Chick Embryo, Medical Research Council [Series 256] (London: HMSO, 1946).

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The early development and use of egg-based techniques illuminates the complex institutional and material connections between surveillance and vaccine production that were essential to the internationalisation of influenza control. Egg-based techniques represented a solution to key constraints of the tools of influenza virus research that had been used through the 1930s.15 As we have seen, ferrets and mice underpinned early methods of influenza virus isolation and identification, and these techniques sustained a small international community of influenza researchers and institutions, which laid important foundations for the WIP. They also formed the basis of the first experimental vaccines. But they proved difficult to scale-up and standardise. By comparison, egg-based techniques developed in the early 1940s were scalable and standardisable, factors necessary for internationalising influenza control.16 Both factors were first developed in the pioneering vaccine production efforts of the Rockefeller Foundation’s International Health Division (IHD) Laboratories in New York between 1941 and 1942, and then by the Commission on Influenza (COI) of the US Armed Forces’ Board of Epidemiology between 1942 and 1945.17 The IHD’s vaccine laboratory became a model for the large-scale manufacture of influenza vaccine, while the integration of surveillance and vaccination under the COI served as a crucial organisational model for the WIP. These wartime developments represented an important shift in the geography of influenza virus science. Wartime constraints on British influenza virus research coupled with American neutrality until 1941 enabled American expertise, money, and technical and organisational capacity to assume a leading role in efforts to control influenza. The creation of the WIP was a partial corrective to this shift. Through the WIC, the NIMR and with it, British expertise, was repositioned as a crucial locus for the post-war project of marrying together surveillance and vaccination as the foundations of influenza control around the world.

15 Thomas Francis Jr., ‘Influenza: Methods of Study and Control’, Bulletin of the New York Academy of Medicine (July 1945), 337–355. 16 James T. Matthews, ‘Egg-Based Production of Influenza Vaccine: 30 Years of Commercial Experience’, The Bridge, 36.3 (2006), 17–24. 17 Jean-Paul, Gaudillière, ‘Rockefeller Strategies for Scientific Medicine: Molecular Machines, Viruses and Vaccines’, Studies in History and Philosophy of the Biological and Biomedical Sciences, 31 (2000), 491–509; John Eyler, ‘De Kruif’s Boast: Vaccine Trials and the Construction of a Virus’, Bulletin of the History of Medicine, 80 (2008), 409–438.

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The development and expansion of the WIP in the 1950s made influenza visible in an entirely new way. As the surveillance system grew so too did the number and variety of influenza viruses identified across the world. The programme offered undeniable proof that influenza was a highly protean viral disease requiring international solutions. Through the WIP, the viralisation of influenza went global. Yet, as we shall see, the post-war internationalisation of influenza control was patchy and uneven and, despite its ambitions, the WIP was a global project shaped by the capacities and priorities of a handful of highly developed countries, led by Britain and the United States.

1

‘A New Complicating Factor’

In the early years of the Second World War, British and American influenza researchers were searching for ways to address two closely related problems in developing an influenza vaccine for the war effort.18 The first related to methods of influenza virus cultivation, and particularly the ability to isolate influenza viruses and to grow them in quantities sufficient for large-scale vaccine production. The second concerned the accuracy and availability of serological tests for identifying and selecting virus strains for vaccines, and for measuring and evaluating serum antibodies in control trials that compared vaccinated and unvaccinated groups. The latter was especially important for assessing the potency of vaccines, as it was generally assumed that vaccine-induced as well as naturally-acquired immunity were correlated with increased antibody levels. Finding solutions to both problems took on new urgency as the onset of the war heightened fears among British and American researchers and military planners of the development of a pandemic on the scale and magnitude of the one that killed millions at the end of the First World War. Researchers at the NIMR and Rockefeller Foundation’s IHD laboratories had been working on both problems since the identification of the ‘W.S.’ influenza virus in 1933. As closely related influenza viruses were identified in different parts of the world through the 1930s, not only

18 Thomas Francis Jr., ‘Influenza: Methods of Study and Control’, 337–355; Frank L. Horsfall Jr., ‘Present Status of Knowledge Concerning Influenza,’ American Journal of Public Health, 30 (1940), 1302–1310; C.H. Stuart-Harris, ‘Epidemic Influenza’, Journal of the Army Medical Corps (1 May 1940), 270–276.

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did the catalogue of strains grow but so too did hopes for the development of new virus-based vaccines. Sero-epidemiological studies using the mouse-neutralisation test were an important part of this process, as they established a correlation between influenza antibody levels and immunity as a benchmark for evaluating vaccines.19 NIMR and IHD researchers worked in parallel, characterising the relationship, nature, and role of known virus strains in changing levels of immunity and in influenza outbreaks in Britain and the United States. Having regularly exchanged materials, methods, and ideas, in 1937 they formally partnered to carry out a series of trans-Atlantic studies to identify new strains, compare existing ones, and to determine the immunity they generated.20 The key aims were to align their respective research methods and to prepare the ground for the rapid development of vaccines. Between 1937 and 1939, Andrewes and Wilson travelled to New York, while Magill and Francis Jr. travelled to London to work together in tracing what they called the ‘Serological Races of Influenza Virus’ in populations in Britain and the United States.21 They were surprised by their findings. By 1938, they had identified 13 strains with differing degrees of antigenic relation in greater London alone, along with 15 other strains from other parts of the world. A similar array of variations identified in New York and other parts of the USA and the Americas made the serological picture even more complex.22 The collaborative studies elucidated what Andrewes called ‘a new complicating factor’—antigenic variations among influenza virus strains.23 In a prescient observation, he

19 W. Smith, C.H. Andrewes, and P.P. Laidlaw, ‘Influenza: Experiments on the Immunization of Ferrets and Mice’, British Journal of Experimental Pathology, 16 (1935), 291–302; T.J. Francis and T.P. Magill, ‘Immunological Studies with the Virus of Influenza’, Journal of Experimental Medicine, 62.4 (1935), 505–516; T.J. Francis and T.P. Magill, ‘Antibody Response of Human Subjects Vaccinated with the Virus of Influenza’, Journal of Experimental Medicine, 65.2 (1936), 251–259. 20 Thomas J. Francis Jr., ‘The Immunology of Epidemic Influenza’, Journal of Experimental Medicine, 1 (1938), 63–79. 21 Wilson Smith and C.H. Andrewes, ‘Serological Races of Influenza Virus’, British

Journal of Experimental Pathology, 19 (1938), 293–314. 22 Thomas P. Magill and T.J. Francis Jr., ‘Antigenic Differences in Strains of Epidemic Influenza Virus: I. Cross-Neutralization Tests in Mice’, British Journal of Experimental Pathology, 14 (1938), 273–293. 23 C.H. Andrewes, ‘Influenza: Four Years’ Progress’, British Medical Journal (11 September 1937), 514.

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noted that antigenic variation introduced a ‘tangle’ that was ‘not going to be an easy one to unravel.’24 It illuminated old problems and introduced new ones. Keys to influenza’s complex epidemiological picture, which had been studied since the early 1890s and preoccupied epidemiologists since the 1918 pandemic, could be potentially found here. So too could answers to the changing susceptibility to influenza and variations in its clinical picture. While antigenic variation was a shared problem that drew together British, American, and other researchers, differences existed between laboratories intechnical and conceptual approaches to influenza virus research. Although operating on similar principles to the NIMR’s test, the IHD neutralization test involved different mice, materials, and methods. Both laboratories used mice from their in-house breeding programs. For antigens, Francis and Magill generally employed unfiltered mouse-lung suspensions, rather than the filtered material used at the NIMR.25 They developed antiserum for their PR8 virus in rabbits rather than in horses, as the NIMR workers did with their W.S. virus.26 Most significantly, they employed a different method for evaluating the antibody-content of sera. Whereas the NIMR team mixed serum dilutions with fixed amounts of virus material, Francis and Magill did the reverse. Differences in their setups produced different results. Managing such variations was an important aspect of collaboration. Both teams acknowledged the effects of differences in mice breeds, virus virulence, and the quality of antiserum in the production and modification of mouse-lung lesions. Beyond this, they worked with and tested each other’s materials and methods. Virus materials sailed back-and-forth across the Atlantic.27 Andrewes had first visited Francis and Magill’s laboratory at the IHD in 1936, as well as Shope’s laboratory at Princeton. Smith came in 1937, followed by Stuart-Harris in 1938. Francis and Magill regularly journeyed to London. Collaborative investigations on antigenic variation helped to ensure commensurable results. 24 Andrewes, ‘Influenza: Four Years’ Progress’, 514. 25 T.J. Francis and T.P Magill, ‘Antigenic Differences in Strains of Epidemic Influenza

Virus. 2. Cross Immunisation Tests in Mice’, British Journal of Experimental Pathology, 19 (1938), 284–293. 26 T.J. Francis, ‘Transmission of Influenza by a Filterable Virus’, Science, 80 (1934), 457–459. 27 C.H. Andrewes Personnel File, NIMR, ‘C.H. Andrewes—Recollections’.

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One of the first initiatives to come out of these collaborations was a new way to classify influenza. In 1940, NIMR and IHD workers proposed and agreed on a fundamental change in the ‘nomenclature of influenza’.28 Published in the Lancet in October, their system would hereafter label a disease as ‘Influenza A’ whenever a virus was identified by direct isolation or through the detection of specific antibodies. Influenza A viruses were grouped together according to their shared serological properties, which closely cross-reacted with each other. The names of A viruses would be based on the places or persons from where they were first isolated. Influenza-like conditions from which no A-virus could be identified were to be called ‘Clinical Influenza’ and characterised as an ‘etiologically indefinite symptom resembling influenza.’ The new nomenclature was an extension of ongoing efforts to clarify the epidemiological identity of influenza by distinguishing outbreaks that could be verified by the laboratory identification of a virus strain and those that could not be verified. In the proposed system, suspected influenza viruses would be sent to either the NIMR or the IHD laboratories for verification, securing their roles as arbiters of the viral identity of influenza. The nomenclature formalised virus variation into the very classification of influenza. Most notably, the system allowed for the possible existence of other types of influenza virus that caused clinically distinct forms of influenza; these would thereafter be designated ‘B’, ‘C’, and so forth. The two groups also decided to exclude swine influenza and other ‘influenza-like diseases attacking primarily animals other than humans’, on the assumption that their relationship to human influenza was not as close as originally suspected seven years earlier and that their inclusion would confuse classification. The apparent value of the new nomenclature was quickly confirmed. Only a month after the Lancet publication, in November 1940, Francis reported that he had isolated a virus from an outbreak in California that fulfilled all the criteria used to identify influenza A viruses, but it was serologically distinct.29 He named it ‘Lee’, after the patient from whom samples were taken and tested and labelled it as the first influenza B virus. He then carried out retrospective studies of sera stored from outbreaks between 1936 and 1939, from which known influenza viruses could not 28 W. Smith, F.L. Horsfall, E.H. Lennette, E.R. Rickard, C.H. Andrewes, and C.H. Stuart-Harris, ‘The Nomeclature of Influenza’, Lancet, 2 (1940), 413. 29 T.J. Francis, ‘A New Type of Virus from Epidemic Influenza’, Science, 91 (1940), 405–408.

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be identified, to show that these contained antibodies for influenza B virus.30 Francis demonstrated that these outbreaks had been due to an influenza virus, but not the type that British and American workers had been studying and tracking. His finding also helped explain why experimental vaccines prepared with influenza A viruses were ineffective in certain years. By 1940 it was increasingly clear that antigenic variation was not only key to the multiple epidemiological identities of influenza, but that it also posed a critical logistical problem for vaccine production: how to determine which virus or viruses to use in developing a vaccine for a given epidemic. As an influenza vaccine became a pressing need for British and American militaries and governments, antigenic variation emerged as a major public health and military problem.

2

Experimental Vaccines

Until the start of the war, influenza virus vaccines had been developed and tested at the NIMR, IHD, and other laboratories with little attention to antigenic variation. Several production methods were developed using viruses that had been identified since 1933. The assumption was that these were all of the same type. While approaches varied, the exchange of materials, techniques, and expertise meant that there were considerable parallels in the development of vaccines, especially in Britain and the United States. Each followed similar processes and faced similar challenges in turning influenza viruses into vaccines. The NIMR workers had started working on an experimental vaccine in early 1935.31 Their system relied on mice bred at the Farm Laboratories, which were systematically infected with a virus first passed through ferrets.32 The mice were killed with chloroform forty-eight hours after inoculation, their lungs extracted, mashed in a blender and

30 John M. Eyler, ‘De Kruif’s Boast: Vaccine Trials and the Construction of a Virus’,

416–417. 31 Wilson Smith, ‘Cultivation of the Virus of Influenza’, British Journal of Experimental Pathology, 16 (1935), 508–512. 32 C.H. Stuart-Harris, C.H. Andrewes, and Wilson Smith, A Study of Epidemic Influenza: With Special Reference to the 1936–7 Epidemic, Medical Research Council, Special Report Series, No. 228 (London: HMSO, 1938), 51–53.

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then passed through filters to be purified.33 Once prepared, the virus material was tested for sterility—the presence of unwanted bacteria or viruses—titrated for the amount of active virus it contained and then inactivated by formaldehyde. The approach was largely modelled on dog distemper vaccine. The method of ‘formolizing’ mouse-lung virus came from Laidlaw and Dunkin’s distemper work. So did the understanding that vaccines made from viruses extracted from the tissues of infected animals tended to be most effective against the same species. So-called ‘homologous’ viruses appeared to offer better protection than ‘heterologous’ viruses—those grown in and taken from a different species. Another factor stemmed from the ability to purify virus antigens. Elford’s gradocol filters had improved upon but not remedied this problem. Experience with dog distemper thus raised the important question of whether a vaccine developed in ferrets and mice would be effective in humans. The production of the vaccine demonstrates how the NIMR workers moved between their experimental animals and human influenza, between the laboratory and the clinic.34 In their experiments they found that acquired immunity conferred by virus infection in ferrets was transient, that it declined over time. Epidemiological and clinical experience suggested that the same held for humans. Yet, when they tested their experimental vaccine on ferrets and mice they found that it had two effects: it boosted waning immunity, evidenced by an increase in neutralizing antibodies; and it provided temporary protection from lung infections.35 This suggested that it could also protect people against primary infection with the virus and against complications should the infection develop into a more serious illness. The experimental virus vaccine thus differed from vaccines previously made from bacteria, which only offered protection against secondary infections. These were the assumptions on which the NIMR team based the tests of their first experimental vaccine in humans. The vaccine was prepared in batches of 200 cc to 500 cc, with 2 cc adopted as the dose to be 33 Christopher H. Andrewes, and Wilson Smith, ‘Influenza: Further Experiments on

the Active Immunisation of Mice’, British Journal of Experimental Pathology, no. XVIII (1937), 305–315. 34 The vaccine’s development, manufacture and trials is detailed in Martin Edwards, Control and the Therapeutic Trial: Rhetoric and the Therapeutic Trial in Britain, 1918–48 (Amsterdam: Rodopi, 2007), 121–140. 35 Andrewes, ‘Influenza: Four Years’ Progress’, 513.

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administered subcutaneously to volunteers. A preliminary test was carried out in early 1936 on sixty soldiers at the Woolwich barracks in southeast London. Volunteers were divided into two groups: thirty soldiers served as controls; the other thirty received the vaccine, with fifteen given a single 2 cc dose and fifteen given two doses spread two-weeks apart. Serum samples were taken from all groups before the start of the trial, while those vaccinated were ‘bled for serum’ two weeks after vaccination. At the time of the trial, there was no epidemic against which to determine the protectiveness of the vaccine; nonetheless, the team found that a single dose ‘engendered a very satisfactory rise in antibodies’; the double-dose did not produce a significant increase, so tests thereafter would be with a single dose.36 Emboldened by this result, the team began planning a ‘large-scale trial’ of the single dose vaccine to run through autumn 1936 and early winter 1937, which they hoped would coincide with a large epidemic. The trial consisted of several groups of 200 volunteers ‘in widely separated localities’, so that at least some would be infected during the anticipated return of influenza. Apart from staff at the NIMR and Mill Hill, all the subjects belonged to army units dotted around London and the home counties. All told, the vaccine was administered to 678 military men in different service hospitals, with a similar number of men used as controls.37 The experiment failed. Scarcely before it began, an epidemic that bore all the signs of influenza burst upon the soldiers. Vaccination produced no clear evidence of antibody rise, there was little difference between the unvaccinated and vaccinated, and a number of the vaccinated developed influenza.38 In December 1938 the vaccine was tested again on 483 new recruits at the naval training base at Shotley in Suffolk.39 Again, it offered no evident protection.40 Similar problems were encountered with vaccines made from mouse material in the United States and Soviet Union. In 1936, IHD workers, 36 Stuart-Harris, Andrewes and Smith, A Study of Epidemic Influenza, 55. 37 NA FD1/1113 Parliamentary Questions on NIMR Influenza Vaccination, Andrewes

to Thomson, 14 October 1937; NA FD1/1113 Parliamentary Questions on NIMR Influenza Vaccination 16 October 1937. 38 Stuart-Harris, Andrewes, and Smith, A Study of Epidemic Influenza, 143. 39 NA FD1/1115 NIMR Influenza Vaccine Trials, 1938; NA FD1/1116 Influenza

Vaccine Trials (1938–1941). 40 C.H. Stuart-Harris, W. Smith, and C.H. Andrewes, ‘The Influenza Epidemic of January–March, 1939’, Lancet, (17 August 1940), 205–211.

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led by Frank Horsfall, produced a live vaccine attenuated by multiple passages through mouse tissue, but their field trials were no more encouraging than those reported in Britain.41 Soviet researchers also produced a live vaccine, which they reported as being effective, but it was lethal in mice and produced febrile influenza in 20% of the subjects tested.42 Most researchers, including the British, chose to avoid the risks associated with live vaccines, and focused on making inactivated mouse-lung virus vaccines. Yet, neither these nor live vaccines worked. In a lengthy report published in 1938, the NIMR workers acknowledged that the timing of their trials and volunteers’ exposure to influenza infection before vaccination affected the outcome.43 By this time, they could point to another factor: in the first years of their vaccine research they simply ‘did not know that there exist[ed] several serological races of human influenza.’44 Early cross-neutralization tests with the ferrets had convinced the British and American workers that the strains isolated in different parts of the world were all of one type. While Francis and Magill had first noted antigenic variation in 1936, neither they nor their British counterparts had attached much importance to it in their early vaccine research.45 Only in 1940, after they established the new nomenclature for influenza viruses and after Francis identified an influenza B virus, would they suspect that the outbreaks against which they tested their first vaccines had been caused by an entirely different variant. The NIMR-IHD sero-epidemiological studies had brought antigenic variation into view; but it took time for it to become a crucial issue in vaccine development.

41 For details on the American vaccine efforts, see John Eyler, ‘De Kruif’s Boast’, 417–420. 42 A.A. Smordinsteff, M.D. Tushinsky, and A.I. Drobyshevkaya, ‘Investigations on Volunteers Infected with the Influenza Virus’, American Journal of Medical Science, 194 (1937), 159–170. 43 Stuart-Harris, Andrewes, and Smith, A Study of Epidemic Influenza (1938). 44 Stuart-Harris, Andrewes, and Smith, A Study of Epidemic Influenza, 144. 45 T.P. Magill and T.J. Francis, ‘Antigenic Differences in Strains of Human Influenza

Virus’, Proceedings of the Society for Experimental Biology and Medicine, 35 (1936), 463– 466.

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Difficulties in producing influenza vaccines were attributed to several methodological issues. Virus isolation relied on ferrets, but the technique was cumbersome, costly, and inexact.46 Virus cultivation involved infecting mice with ferret-adapted virus, growing it through serial passages, modifying its virulence, and harvesting it from mouse lungs; the technique required tens of thousands of mice and produced an antigen that was difficult to concentrate and to purify.47 Purification depended on a combination of filtration, adsorption, and elution techniques, which were only moderately effective.48 This meant that the potency of viruses used was difficult to control. Moreover, yields of virus from infected mice were limited. Researchers also recognised that closer attention needed to be paid to the selection of virus strains. Mouse-neutralization and a complement-fixation test developed by Wilson Smith in 1936 were important tools for this job, but both were time-consuming, labour-intensive, used many animals, and were thus unsuited to any prospect of scaling-up vaccine production.49 Finding solutions to these problems became a wartime priority. The collection and typing of virus strains, along with increasing the yields of purified and potent virus, were crucial organisational issues. Since ferrets and mice were inefficient for this kind of work, new tools needed to be found or invented. As it happened, one such tool was already available, the developing chick egg. While it had been peripheral to most influenza virus work in the 1930s, it would be quickly transformed into the single most important instrument in scaling-up vaccine production.

46 The IHD used at least 700 ferrets a year for this work. RAC RF1 RG1, Series 100, Box 9, Folder 77. June 1938. IHD—Laboratories—Minutes, 1932–1941. Excerpt from Confidential Monthly Report to Trustees. Re: “OF MICE AND MEN—AND OTHERS”. 47 The IHD estimated using nearly 150,000 mice a year for this work. RAC RF1 RG 1, Series 100, Box 9, Folder 77. June 1938. IHD—Laboratories—Minutes, 1932– 1941. Excerpt from Confidential Monthly Report to Trustees. Re: “OF MICE AND MEN—AND OTHERS”. 48 C.H. Andrewes and Wilson Smith, ‘The Effect of Foreign Tissue Extracts on the Efficacy of Influenza Vaccines’, British Journal of Experimental Pathology, XX (1939), 320–325. 49 W. Smith, ‘The Complement Fixation Reaction in Influenza’, Lancet (28 November 1936), 1256–1259.

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3

Harnessing the Chick Egg

Efforts to cultivate viruses in living chick eggs began in 1911 at the RIMR in New York, where Peyton Rous and James Murphy devised a rudimentary method for growing chicken sarcoma virus in 10-to-12-dayold chick eggs.50 But in ovo techniques only took hold in virus research in the 1930s, and only when medical and veterinary virus workers started reckoning with the fact that viruses depended on living cells for their reproduction. The first widely used technique involved growing viruses on the chorioallantoic membrane (CAM) of chick eggs, which E.W. Goodpasture and colleagues at Vanderbilt University in Tennessee pioneered for cultivating fowl pox viruses.51 Between 1930 and 1931 they fashioned methods to open the shell to expose the membrane and to infect it with tissue grafts or filtrates, all without killing the embryo. Goodpasture’s technique made it possible to culture viruses in a seemingly germ-free environment. The CAM technique quickly made its way into medical virus work. No one was more important in facilitating this translation than F.M. Burnet. He started tinkering with Goodpasture’s methods while on a research fellowship at the NIMR in 1932.52 Having witnessed the NIMR team’s discovery of influenza virus in 1933, when he returned to the Walter and Eliza Hall Institute for Medical Research in Melbourne he devoted himself to the study of influenza viruses, with the developing chick egg as his main tool.53 In 1935 he succeeded in isolating and cultivating a 50 P. Rous and J.B. Murphy, ‘Tumor Implantations in the Developing Embryo’, Journal of the American Medical Association, 56 (1911), 741–742. 51 E.W. Goodpasture, A.M. Woodruff, and G.J. Buddingh, ‘The Cultivation of Vaccine and Other Viruses in the Chorio-Allantoic Membrane of Chick Embryos’, Science, 74 (1931), 371–372; A.M. Woodruff and E.W. Goodpasture, ‘The Susceptibility of the Chorio-Allantoic Membrane of Chick Embryos to Infection with the Fowl-Pox Virus’, American Journal of Pathology, 7 (1931), 209–222. 52 F.M. Burnet, ‘A Virus Disease of the Canary of the Fowl-Pox Group’, Journal of Pathology and Bacteriology, 37 (1933), 107–122; F.M. Burnet and J.D. Ferry, ‘Differentiation of the Viruses of Fowl Plague and Newcastle Disease: Experiments Using the Technique of Chorio-Allantoic Membrane Inoculation of the Developing Egg’, British Journal of Experimental Pathology, 15 (1934), 54–56. 53 F.M. Burnet, ‘Influenza on the Developing Egg. 2. Titration of Egg-Passage Virus by the Pock-Counting Method’, Australian Journal of Experimental Biology and Medical Science, 14 (1936), 241–246; F.M. Burnet, ‘Influenza on the Developing Egg. 3. The ‘Neutralization’ of Egg Virus by Immune Sera’, Australian Journal of Experimental

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new influenza virus strain, which he called ‘Mel’ (after Melbourne), on the chorioallantoic membrane of chick eggs, and spent the rest of the decade using egg membranes as media for growing influenza viruses.54 In 1936, he wrote a manual for the British Medical Research Council on The Use of the Developing Chick Egg in Virus Research, to establish eggbased virus culture as ‘a standard technique’.55 Foregrounding the CAM method, the manual detailed the egg’s physiology, incubation period and development, and management (Fig. 2). Burnet also stressed the potential of the CAM technique for producing large quantities of virus for vaccines. This potential already had been

Fig. 2 Diagram showing membranes and cavities of the 12–15 day old developing chick egg. The diagram is from F.M. Burnet and W.I.B. Beveridge, The Cultivation of Viruses and Rickettsiae in the Chick Embryo. An updated version of Burnet’s 1936 manual, the text became a standard reference for egg-based virus work (Source F.M. Burnet and W.I.B. Beveridge, The Cultivation of Viruses and Rickettsiae in the Chick Embryo [London: HMSO, 1946], 9)

Biology and Medical Science, 14 (1936), 247–258; F.M. Burnet, ‘Influenza Virus on the Developing Egg. 1. Changes Associated with the Development of an Egg-Passage Strain of Virus’, British Journal of Experimental Pathology, 17 (1936), 282–293. 54 F.M. Burnet, ‘Propagation of the Virus of Epidemic Influenza on the Developing Chick Egg’, Medical Journal of Australia, 2 (1935), 687–689. 55 F.M. Burnet, The Use of the Developing Chick Egg in Virus Research (London: Medical Research Council, HMSO, 1936).

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explored. In 1935, his former NIMR colleague, Wilson Smith, had tried to produce a vaccine from virus grown on the CAM, but abandoned the method because it gave lower virus yields than mice.56 Francis and Magill also attempted to use it, but for similar reasons, reverted to mice.57 The fate of the chick egg method would change, however, with the wartime drive to scale-up vaccine development and production. The potential for using chick eggs for mass influenza virus culture materialised in 1940, with the development of a new ‘Complex’ influenza vaccine at the IHD.58 Developed by Frank Horsfall, who took over influenza research when Francis left for New York University in 1938, the new vaccine appeared to overcome some of the methodological difficulties of earlier mouse-lung vaccines. It was made up of a mixture of influenza A virus (PR8) and a distemper virus isolated from infected laboratory ferrets. Horsfall and colleagues had found that, for reasons unknown, mixing the two viruses boosted antibody production against influenza virus in ferrets and in humans. More significant was the success the team had in cultivating the influenza viruses used in the vaccine. Faced with the limitations of producing large amounts of the vaccine with mouselung virus, in early 1940 they turned to egg membrane culture. By this time, Burnet had shown that influenza virus spread from the CAM to the entire chick embryo, making it a rich source of virus material. Based on Burnet’s reports, the IHD had already started using chick embryos to develop a yellow fever vaccine.59 The technique employed for the Complex influenza vaccine involved inoculating ferret-passaged virus onto 10-day-old eggs and incubating them for two days to allow the virus to multiply; the embryo and its membranes were then extracted, minced, and filtered; the resulting suspension was concentrated by centrifugation and inactivated with formaldehyde. Preliminary field trials suggested the vaccine provided somewhat better protection than mouse-lung vaccines.

56 W. Smith, ‘Cultivation of the Virus of Influenza’, British Journal of Experimental Pathology, 16 (1935), 508–512. 57 T.P. Magill and T.J. Francis, ‘Studies with Human Influenza Virus Cultured in Artificial Medium’, Journal of Experimental Medicine, 63 (1936), 803–811. 58 RAC RG 1 Series 100, Box 54, Folder 535, “A Vaccine Against Influenza”; F.L. Horsfall and E.H. Lennette, ‘A Complex Vaccine Effective Against Different Strains of Influenza Virus’, Science, 91 (1940), 492–494. 59 RAC RF1 RG 1 Series 100, ‘Vaccine Laboratory’.

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Horsfall was hesitant to conclude that the evidence warranted scaling-up production. But the imperatives of the war accelerated the process. Egg-based virus culture opened the possibility of mass-producing influenza vaccines, as well as those for yellow fever. In anticipation of growing demand, the Rockefeller Foundation built a new Vaccine Laboratory at the RIMR.60 Completed in October 1940, the Vaccine Laboratory occupied an entire floor of the Institute. Fourteen staff used more than 6000 10-day-old eggs a week to cultivate yellow fever and influenza viruses. Eggs supplied from selected chicken farms were taken to an inoculation room, where one group used power-driven dental drills to open a small hole in each shell, while another inserted stock virus on the CAM. After incubating for two days in industrial incubators, the eggs were taken to a separate harvesting room where they were opened and the infected embryos extracted and processed to purify virus material. By autumn 1940, the laboratory was manufacturing tens of thousands of doses of Horsfall’s vaccine, which was sent to the Army for testing on American troops. In London, Andrewes and his NIMR colleagues tried to reproduce the vaccine.61 But wartime rationing of chick eggs prevented mass production. Instead, the British MRC requested 500,000 doses from the IHD Vaccine Laboratory to test on British troops.62 The British order was completed and shipped by December 1940. Another 250,000 doses were produced for the British in early 1941.63 The IHD Laboratory had transformed influenza vaccination into a system of production, on which the American and British war plans now relied.64 But while the scale-up was impressive, the Complex vaccine was not. IHD and MRC field trials demonstrated its limited effectiveness, with only marginal improvements in immunity as compared with the mouse-based vaccines. Horsfall and his colleagues attributed the poor results to one aspect of the system: vaccine potency. While growing viruses in chick embryos increased general yields, purifying and concentrating 60 RAC RF1 RG 1 Series 100, ‘Vaccine Laboratory’. 61 Edwards has traced the vaccine’s development, manufacture and trials in Britain,

Edwards, Control and the Therapeutic Trial, 121–140. 62 Andrewes initially requested 2 million doses. RAC RF1 RG1 Series 100. ‘Preparations Against Pestilence’; NA FD1/1116 ‘Influenza Vaccine Trials’, 26 June 1940; Andrewes to Horsfall 2 July 1940; ‘Complex Influenza Vaccine (Horsfall)’. 63 RAC RF1 RG1 Series 100. “Preparations Against Pestilence”. 64 Gaudillière, ‘Rockefeller Strategies for Scientific Medicine’, 501.

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them was difficult with existing techniques.65 Two closely linked innovations enabled the IHD workers to address this issue and to refine the production system. The first involved an important modification of egg-based cultivation. In May 1940, Burnet reported a new method of growing influenza virus in the amniotic cavity of the chick egg.66 He developed the technique to speed-up virus isolation but also noted that significant quantities of virus accumulated in the fluid of the larger allantoic cavity. He speculated that the fluid might be a source of pure virus. By early 1941, Burnet had developed a technique to harvest the allantoic fluid ‘for the rapid production of high titre virus.’67 The technique was notable for its simplicity. Using a basic lighting set-up with an incandescent bulb, it involved first illuminating the embryonic structure of the developing egg and then locating the chorioallantois, which was marked on the shell with a pen. A small cut through the shell was made at this point, and virus material was directly injected into the allantoic cavity, where it was allowed to multiply for 2-to-3 days. The presence and quantity of virus were determined with inoculation and neutralization tests on ferrets, mice, or the chorioallanotic membrane of uninfected eggs (Fig. 3). Burnet’s allantoic technique led to another key innovation, which put virus concentration—and thus also vaccine production—on an entirely new footing. Soon after the IHD started using amniotic and allantoic techniques, George Hirst, a young virologist working on the IHD influenza vaccines, stumbled upon a remarkable phenomenon. When allantoic fluid infected with virus was mixed with chick blood in test tubes it caused the red blood cells to clump (or ‘agglutinate’).68 Two Canadian researchers working at Connaught Laboratories at the University of

65 F.L. Horsfall, E.H. Lennette, E.R. Rickard, and G.K. Hirst, ‘Studies of the Efficacy of a Complex Vaccine Against Influenza A’, Public Health Reports, 56 (1941), 1863–1875. 66 F.M. Burnet, ‘Influenza Infection of the Chick Embryo by the Amniotic Route’, Australian Journal of Experimental Biology and Medical Science, 18 (1940), 353–360; F.M. Burnet, ‘Influenza Infection of the Chick Embryo Lung’, British Journal of Experimental Pathology, 21 (1940), 147–153. 67 F.M. Burnet, ‘Growth of Influenza Virus in the Allantoic Cavity of the Chick Embryo’, Australian Journal of Experimental Biology and Medical Science, 19 (1941), 291. 68 G.K. Hirst, ‘Agglutination of Red Cells by Allantoic Fluid of Chick Embryos Infected with Influenza Virus’, Science, 94 (1941), 22.

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Fig. 3 Diagrams of Burnet’s amniotic and allantoic techniques (Source ‘Recent epidemics and the World Influenza Centre’, World Health Organization Chronicle, 5 [2 February 1951], 51–53)

Toronto also identified this ‘haemagglutination’ phenomenon.69 Agglutination was determined by the pattern of red blood cells settling at the bottom of a test tube. Hirst showed that agglutination could be used for both detecting and titrating influenza virus and antibodies against it. Soon after developing a basic haemagglutination test, he found that serum antibodies from convalescent animals or people inhibited agglutination; thus, an equally simple in vitro haemagglutination-inhibition (HAi) test could be used to evaluate vaccine potency and acquired or artificial immunity.70 These new egg-based techniques transformed crucial aspects of influenza virus research and vaccine development. Instead of the laborious and costly mouse-neutralization test, determining antibody levels

69 L. McClelland and R. Hare, ‘The Adsorption of Influenza Virus by Red Cell and a New in Vitro Method of Measuring Antibodies for Influenza Virus’, Canadian Public Health Journal, 32 (1941), 530. 70 G.K. Hirst, ‘The Quantitative Determination of Influenza Virus and Antibodies by Means of Red Cell Agglutination’, Journal of Experimental Medicine, 75 (1942), 49–64.

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or strength now involved testing serial dilutions of chick blood, chickegg virus, and human sera in a rack of test tubes. This made it possible to run large-scale serological assays on populations to determine antibody levels and to distinguish and select different virus strains before and during an epidemic. For vaccine manufacture, the haemagglutination test represented a fast and efficient way to collect and concentrate influenza virus. The method devised by Hirst and his colleagues at the IHD in late 1941 involved the concentration of virus particles by means of adsorption on avian red blood cells at a low temperature and their extraction at a higher temperature.71 The agglutination method also made it possible to use the chick embryo to directly isolate influenza strains from human throat samples, instead of using virus that had been first passed through ferrets or mice. In 1942, Hirst developed a technique that rendered the chick embryo into ‘a medium for virus multiplication and the red cell agglutination reaction into the primary index for virus infection and multiplication.’72 The ability to grow, identify, and quantify influenza viruses with the developing chick egg opened the door for producing large quantities of relatively pure virus, which was essential for scaling-up vaccine manufacture. As Jean-Paul Gaudilliere has argued, these innovations resulted in the potential industrialisation of influenza vaccine production, taking on aspects of an assembly line.73 At the IHD vaccine laboratory, thousands of fertilised eggs purchased from designated chick hatcheries were placed in industrial incubators, while specially trained technicians, most of whom were women, inoculated eggs, followed days later by the semi-automised harvesting and purification of virus-laden allantoic fluid. Even though the IHD production system was relatively small, Horsfall assured American military officials that it could manufacture hundreds of thousands

71 G.K. Hirst, ‘Adsorpton of Influenza Hamagglutinins and Virus by Red Blood Cells’, Journal of Experimental Medicine, 76 (1942), 195–209. In virology, adsorption refers to the process by which specific components (proteins) on a virus attach to and accumulate on receptors on the surface of a cell. L. Philipson, ‘Attachment of Viruses to Cell Receptors and Penetration of Viruses into Cells’, Textbook of Medical Virology (1983), 51–56. 72 G.K. Hirst, ‘Direct Isolation of Human Influenza in Chick Embryos’, Journal of Immunology, 45 (1942), 293. 73 Gaudillière, ‘Rockefeller Strategies for Scientific Medicine’, 501.

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of vaccine doses each month.74 Over the next four years, the system would move from the IHD to the American military and be scaled-up to manufacture millions of doses.

4

American Methods

The mobilisation of medical science was crucial to the American war effort and the work being done at the IHD was soon incorporated into military planning. In early 1941, before the United States entered the war, the Army Epidemiological Board established a Commission on Influenza (COI), which was tasked with coordinating wartime influenza virus and vaccine research. Thomas Francis Jr., who had moved to the University of Michigan, headed the Commission. A number of IHD workers, including Hirst, were recruited and the Commission adopted the IHD’s production model, making it the basis for a new system of influenza control within the American armed forces.75 Hirst’s haemagglutination tests were established as standards for virus diagnosis, quantification, and assessment, each of which Francis used in developing and testing a new concentrated vaccine in 1942. At the same time, in preparation for scaling-up vaccine manufacture, select pharmaceutical houses were asked to incorporate egg-based techniques into their production systems.76 The Commission devised a novel approach to influenza control. While mass vaccination was the primary instrument, it was to be continually monitored by controlled field trials and linked to a system of surveillance, which employed United States Public Health Service (USPHS) clinics and laboratories to monitor the epidemiology of influenza and to collect virus strains.77 To support virus surveillance, the Commission established the Strain Study Centre (SSC) at New York University. 74 RAC. I.H.D. Laboratories, Annual Report for Year 1943, Laboratories of the International Health Division of the Rockefeller Foundation New York: Laboratories of the International Health Division, at the RIMR (1943). 75 Hirst-Francis, Correspondence on Influenza Vaccine Program, Rockefeller Foundation, Record Group 5, Series 4, International Health Board/Division, Rockefeller Institute Virus Laboratory (1943–1944) New York. 76 T.J. Francis, ‘Vaccination Against Influenza’, Bulletin of the World Health Organization, 8 (1953), 725–742; T.J. Francis, ‘The Development of the 1943 Vaccination Study of the Commission on Influenza’, American Journal of Hygiene, 42 (1945), 1–11. 77 Cullbertson, ‘Plans for United States Cooperation in the World Health Organization’, 38.

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Headed by Francis’ former colleague, Thomas Magill, the SSC functioned as the Commission’s virus reference centre. It was dedicated to typing and cataloguing strains, determining their prevalence, and selecting those for use in vaccines. Virus surveillance was thus made integral to vaccine manufacture. The Commission’s approach was well demonstrated in the production of a new ‘Army’ vaccine.78 Through 1942, Frances’ laboratory worked out its composition, manufacture, and method of use. The vaccine incorporated IHD innovations: it was polyvalent, containing two strains of influenza A virus (PR8 and Weiss) and Francis’ influenza B virus (Lee), which were cultivated and concentrated with the allantoic techniques.79 A large multi-site field trial of enlisted university students in 1943 used a novel design: it was randomised, placebo controlled, and double-blind.80 Most importantly, it yielded impressive results. The vaccine significantly reduced the incidence of influenza among those tested; whereas the aggregate case rates in controls was 7.1%, it was only 2.2% in the vaccinated.81 The Commission immediately initiated a crash production programme. Three commercial companies—Lederle Laboratories, Sharp Dohme, and Parke Davis and Company—were contracted to produce the polyvalent vaccine in 1944 and a monovalent influenza B vaccine in 1945.82 Production of the latter was prompted by SSC surveillance, which identified the prevalence of a B virus in summer 1945. Trials of the monovalent vaccine in military personnel during an autumn epidemic demonstrated that it considerably reduced morbidity. Although the results were not comparable, the 1943 and 1945 trials convinced the Commission to advise the Army to immunise every man with the mixed vaccine. In November 1945, the Commission issued the first commercial licenses,

78 Eyler, ‘De Kruif’s Boast: Vaccine Trials and the Construction of a Virus’, 425–426. 79 United States Army Medical Department, Preventive Medicine in World War II

General, O.o.t.S. (Washington, DC: Department of the Army, 1955), 325. 80 Eyler, ‘De Kruif’s Boast: Vaccine Trials and the Construction of a Virus’, 426. 81 Eyler, ‘De Kruif’s Boast: Vaccine Trials and the Construction of a Virus’, 426; T.J.

Francis, ‘The Present Status of Vaccination Against Influenza’, American Journal of Public Health, 37 (1947), 1109–1112. 82 United States Army Medical Department, Preventive Medicine in World War II , 324–326.

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and by 1946, most of the estimated 8 million American military personnel were vaccinated.83 The Commission’s strategy of linking together surveillance, vaccine production, and field trials became an organisational model for influenza control, and aspects of the system spread. By 1946, the NIMR, WEHIMR and every other influenza virus research laboratory where resources permitted, employed egg-based isolation, diagnostic, and serological techniques for research, surveillance, and vaccine production. Egg-based techniques made their way into the laboratories of national public health services, and egg-based systems were adopted by commercial and staterun vaccine manufacturers.

5

World Influenza Programme

By the end of the Second World War, it had become possible to conceive of monitoring and managing influenza virus on a global scale. There was much optimism that epidemics could be controlled or even vanquished. The collective elaboration and ready exchange of methods and material between American, British, Australian, and other laboratories engendered a spirit of internationalism, which carried into post-war planning for influenza control. The Commission on Influenza may have provided an organisational model, but its approach rested on one flawed assumption. Francis and his colleagues viewed antigenic variation as finite.84 They held to the notion that surveillance could be nation-based and that effective vaccines could be made from known subtypes. From this view, internationalising surveillance was an important gesture of scientific cooperation, but not a practical necessity. Andrewes and Burnet, in particular, took a decidedly different view.85 They saw antigenic variation as evolutionarily infinite and

83 George Dehner, Influenza: A Century of Science and Public Health Response (Pittsburgh: University of Pittsburgh Press, 2012), 68. 84 Jonas E. Salk, ‘An Interpretation of the Significance of Influenza Virus Variation for the Development of an Effective Vaccine’, Bulletin of the New York Academy of Medicine, 28 (1952), 748–765. See John M. Eyler, ‘Influenza and the Remaking of Epidemiology, 1918–1960’, in Craddock, Susan, Tamara Giles-Vernick, and Jennifer Gunn (Eds.), Influenza and Public Health: Learning from Past Pandemics (London: Earthscan: 2010), 175–176. 85 Eyler, ‘De Kruif’s Boast: Vaccine Trials and the Construction of a Virus’, 431.

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unstable, presenting the real possibility that entirely new strains emerging in one part of the world could endanger the rest.86 Their position seemed confirmed in 1947, when a mixed influenza A and B vaccine used to immunise 1,238,000 American troops failed to provide protection against a large epidemic.87 The reason for the failure soon became clear.88 The epidemic was caused by a new influenza A variant, first identified by Burnet’s laboratory in Melbourne. Vaccine-generated antibodies provided no protection against it. The COI called it A-prime (A1 ). The experience highlighted the problems posed by antigenic variation. It showed that new virus strains could emerge from any part of the world. Virus variation was framed as a global problem requiring a global solution.89 The prospect that influenza virus strains could evolve and vary across geographical regions, and that a pandemic strain could emerge and spread from any part of the world, meant that controlling influenza had to be based on linking vaccination with the continuous worldwide surveillance of influenza viruses. This was the founding rationale for the World Influenza Programme.90 The programme’s first director, the American virologist Anthony Payne, explained that an international system of coordinated surveillance and vaccine production was necessary because ‘influenza recognizes no man-made boundaries; indeed, many of the achievements of man increase the speed and extent of its spread.’91 Creating a universal and uniform system of influenza control lay at the heart of the WIP. Both goals were not just a means to coordinate action at a distance, but also a means to facilitate international cooperation in 86 H. Mellanby, C.H. Andrewes, J.A. Dudgeon, and D.G. MacKay, ‘Vaccination Against Influenza A’, Lancet, 1 (1948), 978–982; F.M. Burnet, ‘Some Biological Implications of Studies on Influenza Viruses’, Bulletin of the Johns Hopkins Hospital, 88 (1951), 119– 180; C.H. Andrewes, ‘Adventures Among Viruses, II. Epidemic Influenza’, New England Journal of Medicine, 242 (1950), 197–203. 87 F.M. Davenport, A.V. Hennessy, C.H. Stuart-Harris, and T.J. Francis, ‘Epidemiology of Influenza. Comparative Serological Observations in England and the United States’, Lancet, 55 (1955), 469; T.J. Francis, ‘The Current Status of the Control of Influenza’, Annals of Internal Medicine, 43 (1955), 534–538. 88 Dehner, Influenza, 69–71. 89 C.H. Andrewes, ‘The Significance of Strain Differences in Virus Prophylaxis’,

Proceedings of the Royal Society of Medicine, 42 (1949), 519. 90 Christopher H. Andrewes, ‘Epidemiology of Influenza’, Bulletin of the World Health Organization, 8 (1953), 595–612. 91 Payne, ‘The Influenza Programme of the WHO’, 755.

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the context of the Cold War.92 As Andrewes put it during an interview on the BBC’s ‘Woman’s Hour’ a few years later: Influenza is a confused nuisance, but there is a good thing about it, and that is that to get any further we’ve got to collaborate with other countries in order to get anywhere, and I think that collaboration on this sort of level is bound to be the sort of thing that’s going to lead to more amicable international relations generally.93

Andrewes’ hope was that international cooperation on influenza might lead to a better world. His vision mattered. As director of the World Influenza Centre at the NIMR, which had moved to new premises at Mill Hill in 1950, he played a leading role in setting up the machinery of the programme.94 The combination of influenza’s epidemiological characteristics, its potential social and economic impact as a pandemic disease, and the availability of new laboratory science and technology made it an ideal fit in the WHO’s developing vision of world health.95 While the WIP did not achieve the same notoriety as the WHO’s high-profile eradication programmes against malaria and later, smallpox, it nonetheless reflected the predominance during the WHO’s first decades of prioritising technoscientific solutions to problems of health and disease.96 Historians have

92 Nitsan Chorev, The World Health Organization Between North and South (Ithaca: Cornell University Press, 2012); Claire Beaudevin, Jean-Paul Gaudillière, Christoph Gradmann, Anne M. Lovell, and Laurent Pordié, ‘Global Health and the New World Order’, in idem. (Eds.), Global Health and the New World Order (Manchester, England: Manchester University Press, 2020), 1–27; John Farley, Brock Chisholm, the World Health Organization, and the Cold War (Vancouver: University of British Columbia Press; 2008), 2–3. 93 C.H, Andrewes, “How Much Do We Know About Influenza” (Women’s Hour, BBC Home Service, 9 February, 1955). 94 Helio G. Pereira, ‘The World Influenza Centre’, WHO Chronicle, 21 (October 1967), 413–415. 95 Randall M. Packard, A History of Global Health: Interventions into the Lives of Other Peoples (Baltimore: Johns Hopkins University Press, 2016), 105–132; Marcus Cueto, Theodore Brown, and Elizabeth Fee, The World Health Organization: A History (Cambridge: Cambridge University Press, 2019). 96 Randall M. Packard, ‘Malaria Dreams: Postwar Visions of Health and Development in the Third World’, Medical Anthropology, 17 (1997), 279–296; Sanjoy Bhattacharya, ‘The World Health Organization and Global Smallpox Eradication’, Journal of Epidemiology

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characterised the WHO approach as one dominated by the extension of Western medical and laboratory knowledge and practices across the world.97 While some critics have portrayed this project as a continuation of Western medical imperialism, the case of the WIP shows that creating an international system was highly negotiated: it involved establishing diplomatic relations with partner countries in designating reporting laboratories and various technical and scientific negotiations with scientists and observers over methods and materials employed in tracking influenza viruses. The WIP reflected the countervailing tendencies within the WHO between a democratising scientific medicine, the benefits of which would be shared equitably, and the challenges of establishing its global hegemony. Despite the worldly aspirations of Andrewes and his colleagues, the expansion of the WIP into an international system was not without significant obstacles. Tensions existed early on between Andrewes and his American counterparts over American participation in the programme. As George Dehner has shown, this was partly a reflection of broader USPHS concerns about proposals to place the Pan-American Health Organization under the governance of the WHO, which threatened American hemispheric interests and was widely resisted. For his part, Thomas Francis Jr. was loathe to have the COI subsumed under the WIP.98 But tensions also stemmed from a genuine assumption among American influenza experts that, given the crucial contributions they had made to influenza virus and vaccine science and the expertise they possessed, an American institution should have a role equal to that of the NIMR in the organisation of the programme. After much negotiation, in April 1948, the USPHS,

and Community Health, 62 (2008), 909–912; Sanjoy Bhattacharya and Carlos Eduardo D’Avila Pereira Campani, ‘Re-assessing the Foundations: Worldwide Smallpox Eradication, 1957–67’, Medical History, 64 (2020), 71–93. 97 Sung Lee, ‘WHO and the Developing World: The Contest for Ideology’, in Andrew Cunningham and Birdie Andrews (Eds.), Western Medicine as Contested Knowledge (Manchester: Manchester University Press, 1997), 24–75; Sunil S. Amrith, Decolonizing International Health: India and Southeast Asia, 1930–65 (Basingstoke: Palgrave Macmillan, 2006). 98 Dehner, Influenza, 69–71.

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with support from the National Institute of Health’s Virus and Rickettsial Study Section, agreed to participate.99 The Strain Study Center at NYU was integrated into the newly formed Communicable Diseases Center (CDC) and became the Influenza Information Center (IIC) for the Americas.100 Eventually located at the CDC’s Virus and Rickettsia Laboratory in Montgomery, Alabama, it was the American counterpart to the WIC. The British and American reference centres divided their responsibilities geographically, with the WIC coordinating Europe, Africa, and Asia and the IIC coordinating the Americas.101 The laboratory network was organised on a hub and spoke system, with the reference centres coordinating collaborating reporting laboratories in different regions. Reporting laboratories had two principal roles: first, they were to isolate virus strains and rapidly ship these to the reference centres; and second, they acted as sentinels, reporting the occurrence of influenza epidemics and outbreaks in their countries. The overarching objective was to ‘devise control methods to limit the spread and severity, and consequences’ of influenza throughout the world.102 The entire system depended on proper laboratory identification of virus strains. The reference centres were vital. By 1949, they were already generating extensive catalogues of isolated and typed viruses. The laboratory system was linked together by the WHO’s radio and telegraphic network through which virological and epidemiological information was sent to the Epidemiological Information and Morbidity Statistics section at the WHO, to its regional offices, and to either one of the reference centres.103 National health agencies of participating WHO member states were responsible for collecting epidemiological information on the daily number of influenza-like diseases reported by local authorities and medical practitioners. Any significant increase in

99 Cullbertson, ‘Plans for United States Cooperation with the World Health Organization in the International Influenza Study Program’, 37–43; Davis, ‘World Health Organization. 100 World Health Organisation. ‘Virus Diseases’, in The First Ten Years of the World Health Organization (Geneva: World Health Organization), 215. The SSC would be absorbed into the IIC in 1958. 101 Payne, ‘The Influenza Programme of the WHO’, 755–774. 102 World Health Organisation, ‘Virus Diseases’, 214. 103 Payne, ‘The Influenza Programme of the WHO’, 755–774.

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case levels was to be reported through the WHO’s daily epidemiological bulletins and epidemiological weeklies, and airmailed from Geneva, Washington, Alexandria, and Singapore. During epidemics this information was to be sent to the laboratory network to initiate virus isolation measures and to identify the specific strain. These results would then be made available to all national health authorities and to registered state or commercial vaccine manufacturers. The programme slowly expanded in its first years. By 1952, a total of 53 reporting laboratories in 42 countries had been enrolled. However, their distribution was uneven and reflected the colonial legacies of postwar scientific medicine: of the 53 laboratories, 27 were in Europe and 11 were in North America; Central and South America supported 6; the Eastern Mediterranean Region supported 2; the African Region supported 3, two of which were in South Africa; the Western Pacific was supported by a laboratory in Tokyo and two others in Melbourne; there were only two laboratories for all of Southeast Asia, both of which were in India; the USSR, through a designated laboratory in Leningrad, maintained informal relations, until it re-joined the United Nations in 1956. China only started participating on an informal basis in the late 1950s (Fig. 4).104 This situation was at odds with the WIP’s goal of obtaining ‘an overall picture of the world epidemiology of flu.’105 The uneven distribution of laboratories was one of several organisational problems. Influenza remained notoriously difficult to diagnose in inter-epidemic periods or during small outbreaks. Variations in clinical cultures and practices exacerbated these problems, as they represented a major obstacle to uniform virus collection, isolation, and identification. Many countries in the developing world lacked facilities or staff to undertake laboratories studies. One response was for the WIP to support the training of dedicated ‘Influenza Observers’ in countries without laboratory capacity, who were tasked with identifying influenza outbreaks, based on excess numbers of clinicallydefined cases of influenza or influenza-like respiratory cases, and worked as sentinels furnishing epidemiological reports to the WHO. In countries with laboratory capacity but without expertise, another solution was to train workers in basic procedures in isolating and shipping influenza virus samples.

104 World Health Organisation, Influenza: A Review of Current Research Monograph Series No. 20 (Geneva: World Health Organization, 1954). 105 Payne, ‘The Influenza Programme of the WHO’, 755–774.

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Fig. 4 World Influenza Programme ca. 1953. Each dot represents an affiliated laboratory. The NIMR is the ‘World Centre’, while Montgomery, Alabama is represented as the ‘Regional centre’ for the Americas (Source A.M.-M. Payne, ‘The Influenza Programme of the WHO’, Bulletin of the World Health Organisation, 8 [1953], 576)

The main priority, however, was to standardise existing laboratory practices in order to achieve the twin aims of uniformity and universality in influenza virus surveillance.106 The WIP adopted existing standards and created its own. The first initiative came in 1949, when a US Committee on Standard Serological Procedures in Influenza Studies, led by Francis and Magill, proposed establishing a HAi test as a standard reference for viral diagnosis.107 While the ideal was to have all laboratories use one 106 Standardization was a major part of the WHO agenda, which it inherited from the

League of Nations Health Organization. Marcus Cueto, Theodore Brown, and Elizabeth Fee, The World Health Organization: A History (Cambridge: Cambridge University Press, 2019). For an example of WHO standardization work, see Christoph Gradmann, ‘Sensitive Matters: The World Health Organisation and Antibiotic Resistance Testing, 1945–1975’, Social History of Medicine, 26.3 (2013), 555–574. On the history of standardization in biology and medicine, see Christian Bonah, Christophe Masutti, Anne Ramussen and Jonathan Simon (Eds.), Harmonizing Drugs: Standards in 20th-Century Pharmaceutical History (Paris: Editions Glyphe 2009). 107 Committee on Standard Serological Procedures in Influenza Studies, ‘An Agglutination-Inhibition Test Proposed as a Standard of Reference in Influenza Diagnostic Studies’, Journal of Immunology, 65 (1950), 347–353.

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test, variations in methods and materials made this impractical. A standard reference was seen as the best alternative. One of the problems in influenza diagnostic studies is that of interpreting results in one laboratory in terms of those obtained in another laboratory. Obviously, this difficulty could be eliminated by common use of a standard method. However, it is the general opinion that some of the difficulty can be eliminated by use of a procedure of reference; in that way each laboratory would be free to use its own method and yet be able to evaluate the results of that method in terms of the reference test.108

Agreeing on a reference test was the first step towards standardising the system. In 1951, the WHO created an Expert Committee on Influenza, comprised of representatives from the NIMR, IIC, and laboratories in France, Italy, the Netherlands, and Denmark.109 At its first meeting in Geneva in September 1952, chaired by Andrewes, the Committee adopted the American test as the ‘Procedure of Reference’. The State Serum Institute in Copenhagen was delegated with producing standard antigens and antisera for the procedure, while the WIC and IIC distributed it to participating laboratories in their regions. In adopting the test, the Committee stressed the importance of measures to increase the uniformity of laboratory methods and to address gaps in the geographical reach of the system. The present organization needs improvement in several respects. Information obtained from laboratories already well equipped can be better interpreted if workers therein are using the same, or at any rate comparable, techniques. Again, it is highly desirable to stimulate and assist the study of influenza in less developed countries; only if information comes from all over the world can the epidemiological picture be seen as a whole.110

The Committee targeted seven technical areas to improve: virus classification; virus isolation, collection, and typing; laboratory materials,

108 Committee on Standard Serological Procedures, ‘An Agglutination-Inhibition Test Proposed as a Standard of Reference in Influenza Diagnostic Studies’, 347. 109 Expert Committee on Influenza. First Report, Technical Report Series 64 (Geneva: World Health Organization, 1953). 110 Expert Committee on Influenza. First Report, 4.

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particularly reagents; virus diagnosis procedures; laboratory training; the collection of epidemiological information; and vaccination. Emphasis was placed on standardising surveillance, with less attention given to standardising vaccines. One reason was that the Committee viewed influenza vaccination as still an ‘experimental procedure.’ The core problem, it reported, was that there existed no ‘satisfactory means of standardizing influenza vaccines.’111 While vaccine production was being carried out in many countries, corresponding standards had not been internationalised. Existing evaluation methods were national in scope. Vaccine potency tests were viewed as a key obstacle. The first American standard had been established by the COI in 1944. The haemagglutination test allowed vaccine potency to be measured in chick agglutination units (CCAs), wherein the concentration of the antigen was determined by the quantity of red blood cells clumped by the virus. But the COI was unable to settle on a unit size: initially an arbitrary level of 300 CCA units per millimetre of vaccine was set as a minimum threshold; this was then changed to 400; and later elevated to 700–750. For the WHO Committee, these variations had implications for establishing an agreedupon dosage and assessing the value of adjuvants to increase vaccine potency. While the WIP stressed the centrality of vaccination to controlling influenza, through the 1950s its interventions in production processes were limited to supplying typed-viruses and standard materials and establishing protocols for different elements of vaccine composition. It stressed the importance of collecting, studying, and supplying antigenic variants as the basis for anticipating new epidemics and for providing guidance ‘as to what strains should be incorporated in vaccines being made, or as to which stock vaccines can profitably be used.’112 Rather than regulate, the WIP’s role made recommendations and established manufacturing guidelines based on information and analysis derived from virus surveillance. This orientation explains why the WIP concentrated so heavily on standardising surveillance. It was believed that good surveillance would lead to better vaccines. In 1954, the WHO issued a report based on the Committee’s recommendations. It established the amniotic technique as

111 Expert Committee on Influenza. First Report, 4. 112 Expert Committee on Influenza. First Report, 4.

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the standard for virus isolation, while the HAi test was deemed the reference for virus identification. The report included demonstrations of how to perform each technique and recommended wide training of uninitiated laboratory workers. By facilitating wide distribution of egg-based techniques, the WIP laid the foundations of international influenza virus surveillance. The generalisation of such tools enabled its reference centres to track the influenza virus and to ‘forecast’ epidemics: …when we’re able to trace these movements [of the virus] and influenza, and particularly the movements of particular varieties of influenza, we are in a position to warn countries just what the virus is like, when it is likely to get there, and what kind of vaccine they should have ready… that’s a programme of perfection [but] we hope to be able to do that in the future.113

Despite the aspirations of the WIP, international surveillance remained partial and unreliable. National reporting laboratories, which shared viruses with the reference centres, were concentrated in the developed world. Developing countries lacked the resources, expertise, public health and medical systems to fully participate in the programme. The WHO tried to address these gaps by providing technical expertise, training, laboratory materials, and other resources. But the gaps remained. Vaccine production and supply were even more limited. Capacities were concentrated in the developed world. By the 1950s, industrial nations had in place either commercial or state-based vaccine systems, with the United States leading the way. Most bore the marks of the production system developed by the Americans during the war, versions of which now could be found in many developed nations. In 1949, the Dutch drug company, Philips-Roxane, which had established its reputation in the 1930s making Vitamin D, opened a new influenza virus vaccine facility in Eindhoven to supply influenza vaccine to Dutch and other European markets (Fig. 5).114 It incorporated crucial elements of the American production system, as did manufacturers in Britain. Initially, the WrightFleming Institute in London took on the bulk of British influenza vaccine

113 C.H. Andrewes, ‘How Much Do We Know About Influenza?’ Woman’s Hour, BBC Home Service, 9 February 1955. 114 Thomas Francis Jr., ‘The Current Status of the Control of Influenza’, Annals of Internal Medicine, 43 (1955), 534–538.

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production.115 Having made bacteria-based influenza vaccines since the 1910s, its switch to making influenza virus vaccines reflected the new virological paradigm (Fig. 6). The Institute’s vaccines were subject to MRC clinical trials through the 1950s, with a view to establishing the efficacy and the capacity for rapid, large-scale manufacture in the event of an epidemic.116 However, no country with vaccine production capacity could not meet the needs of their own populations, let alone the rest of the world.

6

Test and Tensions

The emergence of an epidemic in Hong Kong in April 1957 highlighted the patchiness of the surveillance and vaccination systems. The 1957 ‘Asian influenza’ pandemic was the first test of the WIP, and by most accounts, it failed. The pandemic likely emerged in mainland China. But at the time the People’s Republic was not part of the UN and thus the WHO and did not report the early outbreaks. Anthony Payne, director of the WIP, noted the cruel irony: The 1957 pandemic of influenza is the first that it has been possible to study using modern virological techniques in an almost world-wide network of laboratories which had been organized by the World Health Organization with just such an eventuality in mind. It was almost ironical therefore that the epidemic should originate in an area not covered by the programme.117

Strains of the new virus were eventually isolated in Hong Kong in midApril, and then in Korea, Singapore, and Malaysia. Reporting delays had a knock-on effect for vaccine preparation. Crash production programmes were initiated in the United States, Britain, and elsewhere in anticipation of influenza reaching their shores in autumn. While efforts were impressive, all encountered significant challenges. The lead-time was too short.

115 The Wright Institute was renamed the Wright-Fleming Institute in 1947, in recognition of Alexander Fleming co-discovery of penicillin. 116 The Wright Institute was renamed the Wright-Fleming Institute in 1947, in recognition of Alexander Fleming co-discovery of penicillin. 117 A.M.-M. Payne, ‘Symposium on the Asian Influenza Epidemic, 1957’, Proceedings of the Royal Society of Medicine, 51 (1958), 29.

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Fig. 5 Manufacturing influenza vaccine ca. 1951. Female technician injects virus material into 10-to-12-day-old chick eggs at Philips-Roxane (Source ‘The Manufacture of Virus Vaccine Against Influenza’, Philips Technical Review, 12 [April 1951], 278)

Production capacity could not meet demand. Only small amounts of vaccine were produced and only small numbers of people were vaccinated. The 1957 Asian influenza confirmed the original scientific consensus that international virus surveillance was a necessary condition for successful vaccine production. A 1958 WHO programme review detailed the organisational principle of the WIP:

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Fig. 6 Wright-Fleming Institute. Egg-based Influenza vaccine, ca. 1957 (Source World Health Organization Archives. WHO_A_012550)

[S]uccessful vaccination depends on knowledge of the virus causing the epidemic. … Contiguous vigilance is necessary to detect new and potentially dangerous strains of virus at the earliest possible moment … epidemiological reports can be correctly interpreted only in terms of laboratory studies of the viruses responsible. [Vaccination requires] the collection and analysis information regarding the nature of the virus causing an outbreak, and a careful analysis of its characters – especially its antigenic structure;

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and … this information must be gathered from as wide a geographical area as possible.118

The 1957–1958 pandemic underscored the complex institutional and material connections between influenza virus surveillance and vaccine production in the internationalisation of influenza control. But it also highlighted deep gaps in the programme. The orchestrators of the WIP hoped that the wide availability and relative simplicity of egg-based techniques would make it possible to track and control influenza across disparate contexts. Yet, through the 1950s and 1960s, the laboratory network remained heavily concentrated in developed nations and mostly served their interests. The collection and supply of viruses was strongly oriented towards national health agencies and pharmaceutical houses in the developed world. Only a fraction of the world would receive the benefits of the system. ∗ ∗ ∗ Like all post-war international health projects, the WIP was marked by significant contradictions. The programme put in place a new way of knowing influenza. It built upon but also changed previous conceptualisations of influenza as a ‘global’ disease, which had been constructed since the 1890s through epidemiological investigations that mapped the disease around the world. The 1918–1919 pandemic had consolidated influenza’s epidemiological identity as a pandemic disease that could affect every corner of the globe, and this threat lay behind the creation of the WIP. But the experts who developed the programme framed influenza’s epidemiology in a radically different way from those who had mapped it at the turn of the century: they saw it through the lens of highly variable, mutable, and ever-changing viruses that could emerge from and spread to any part of the world and, under the right conditions, become pandemic. At the same time, unlike epidemiologists or bacteriologists before them, Andrewes and his colleagues were also able to frame influenza as a world health problem in which all countries and communities had—or should have—a stake. The vision and machinery of the WHO made it possible for

118 World Health Organisation, ‘Virus Diseases’, in The First Ten Years of the World Health Organization (Geneva: World Health Organization, 1958), 214.

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them to put influenza onto the international health agenda. The viralisation of influenza went global in the second half of the twentieth century. But the worldly aspirations of the architects of the WIP would run up against and reproduce deep inequalities in the distribution and access to crucial medical resources necessary for the global control of influenza.

CHAPTER 9

Conclusion: ‘The Most Protean Disease’

Influenza has been an intractable part of modern life across the world. Almost everyone will suffer a bout, and likely more than one. So-called ‘flu seasons factor into the organisation of the healthcare systems of every nation. Researchers and research institutions around the world study every aspect of the disease. Doctors are trained to diagnose and treat the most severe cases. Vast resources are poured into annual vaccination campaigns and planning to prevent epidemics and pandemics. A global surveillance system, coordinated by the WHO, monitors its movements in humans and other animals. Influenza sustains a multi-billion-dollar pharmaceutical trade in vaccines, antivirals, and over-the-counter medicines. The threat of pandemics has spawned multi-sector collaboration on the governance of infectious diseases, but it has also become a lightning rod for debates over access to medical resources and the prioritisation of life-saving drugs. Influenza now plays a vital role in global health politics. For much of the last century, such efforts have been directed at understanding and controlling not influenza itself but the viruses that cause it. Modern Flu has traced the emergence of this virological way of knowing to developments and changes in medical and scientific knowledge and practices that slowly transformed influenza’s identity as a disease between 1890 and 1945. While intimately connected to the increasingly important role of scientific medicine in tackling major health threats, pandemics, wars, and the modernising state were equally important. Pandemics in © The Editor(s) (if applicable) and The Author(s), under exclusive licence to Springer Nature Limited 2023 M. Bresalier, Modern Flu, Medicine and Biomedical Sciences in Modern History, https://doi.org/10.1057/978-1-137-33954-6_9

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the 1890s and in 1918 presented novel conditions and opportunities for governments and researchers to carry out large-scale studies on the most pressing questions concerning the epidemiology, aetiology, and control of influenza. Failures to resolve such questions may have resulted in moments of epistemological and even existential crisis in medicine and public health but they were also translated into new opportunities that eventually led to the development of virus research. Wars were also important contexts for research. Wartime organisation of medical science fundamentally shaped strategies for tackling influenza, with priority in both the First and Second World Wars given to identifying causative agents and mass-producing vaccines for military personnel and later, civilians. These priorities carried into peacetime. In the aftermath of the 1918 pandemic, and between the two wars, state-sponsored and organised virus research in Britain would become crucial to establishing influenza’s identity as a viral disease. In the aftermath of the Second World War, virus surveillance and vaccine systems would become crucial to controlling influenza around the world. This book has traced two general phases in this process of viralising influenza: from 1890 to 1918, when influenza was framed as a ‘bacterial’ disease; and from 1918 to 1945, when it was reframed as a ‘virus’ (and later, ‘viral’) disease. The bacterial phase unfolded during and after the 1889–18 94 ‘Russian’ influenza pandemic, which reached every corner of the globe and spurred large-scale, government-backed investigations into every aspect of the disease. New epidemiological, clinical, and bacteriological methods and findings were drawn together and aligned to categorise influenza as an infectious disease caused by a specific pathogenic agent. Medical and public health approaches became increasingly focused on the so-called ‘influenza germ’ and its role in how influenza spread and how it caused disease in those it infected. One germ in particular, B. influenzae or ‘Pfeiffer’s bacillus’, proved especially important in positioning bacteriological concepts and practices as essential to the understanding, management, and control of influenza. As influenza became increasingly visible as a problem of germs and germ science, it also gained increasing visibility as a problem in modern life. For many who observed this transformation, the new conceptualisation of influenza as an infectious disease represented a radical break with older conceptualisations that had been fashioned when the term ‘influenza’ first came into medical usage at the end of the eighteenth century. ‘The history of influenza’, wrote the American epidemiologist, Warren T. Vaughan,

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‘can justly be divided into two phases, the first ancient, and the second modern. The latter period begins with the 1889 pandemic.’1 Whereas modern influenza was framed as being caused and spread by a bacterial agent, ancient influenza referred to a congeries of symptoms loosely ordered into a medical entity that was itself highly protean: its many and varied clinical manifestations were linked to individual constitutions, while its varied origins and epidemiology were linked to contagia, miasma, zymotic poisons, the weather, telluric conditions, or the stars. Claims that modern influenza was radically different served several purposes. They sharply contrasted concepts grounded in laboratory-based scientific medicine with those grounded in empirical, natural-historical, and Hippocratic medical systems. Proponents of scientific medicine were convinced that it had produced new understandings of the essential nature and characteristics of influenza that older systems had been unable to reveal. Having integrated the ideas and tools of bacteriology into epidemiology and clinical medicine, modern medical science was not just mapping behaviours of an old disease in new ways, but those of a new influenza altogether. Crucially, influenza was now identified as an infectious disease whose transmission and dissemination were intimately tied to the conditions of modernity: densely-populated and interconnected towns and cities; human aggregations in industries, offices, schools and institutions; the acceleration and extension of the movement of people and goods by steam rail and shipping across nations and continents; and the strains of a rapidly changing world that exhausted bodies and exposed them to infection. By the turn of the century, a loose medical consensus had formed on the identity of influenza as a modern infectious disease. It would be mistaken, however, to take this development as the product of the straightforward adoption of bacteriology in medicine and public health. Rather, this framing resulted from an alignment of clinical, epidemiological, and bacteriological ways of knowing, which together and on their own provided new approaches to the disease. In this framing, modern influenza could only be effectively tackled with modern medical scientific knowledge and expertise. Yet, the promise of bringing the disease under medical scientific control remained elusive. Modern influenza proved to be no less protean 1 Warren T. Vaughan, Influenza: An Epidemiologic Study, American Journal of Hygiene, Monographic series, no. 1 (Baltimore: The American Journal of Hygiene, 1921), 2.

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than its older predecessor. The more closely it was studied the more complex it appeared. Its clinical and epidemiological forms may have been different from those characterised earlier, but they presented significant challenges to those wanting to reduce them—and thus influenza—to a single causative agent. Bacteriological measures that were shown to be moderately effective against other diseases, such as tuberculosis and diphtheria, had little impact on influenza. Constitutional and environmental ideas did not disappear, as some hoped, but were remade into multifactorial epidemiological frameworks that attempted to explain variations in influenza and other bacterial infections that took form as epidemic diseases.2 While few disputed the idea that influenza was an infectious disease, what counted as modern influenza was continually changing through the turn-of-the-century. Change was not just the product of variations or fissures in ways of knowing or of inter- and intra-professional rivalries, but also of the challenges posed by the disease itself. The catastrophic 1918–1919 pandemic crystallised these challenges. It was at once a test and a turning point in ways of knowing influenza that had been developing since the 1890s. In combatant nations such as Britain, responses to the pandemic were intimately shaped by the war. Strategies were organised according to the wartime imperatives and the logics of wartime medicine. The conjunction of the pandemic and the war meant that medical science was mobilised on an unprecedented scale. Commitment to finding bacteriological solutions to war-related infections ensured that the focus among government bodies, including the War Office, the Army Medical Services, and the LGB Medical Department, was on identifying the disease agent to mass-produce vaccines for military and civilian populations. This strategy yielded mixed results. Along with B. influenzae, other bacteria were identified as potential candidates. The War Office formulated and produced a mixed influenza vaccine that

2 J. Andrew Mendelsohn, ‘From Eradication to Equilbrium: How Epidemics Became Complex after World War I’, In C. Lawrence & G. Weisz, G. (Eds.), Greater than the Parts: Holism in Biomedicine, 1921–1950 (Oxford: Oxford University Press, 1998, 303– 331); Olga Amsterdamska, ‘Achieving Disbelief: Thought Styles, Microbial Variation, and American and British epidemiology, 1900–1940’, Studies in History and Philosophy of Biological and Biomedical Sciences, 35, (2004), 483–507; John M. Eyler, ‘Influenza and the Remaking of Epidemiology, 1918–1960’, In Susan Craddock, Tamara Giles-Vernick, and Jennifer Gunn (Eds.), Influenza and Public Health: Learning from Past Pandemics (London: Earthscan: 2010), 157–177.

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reduced secondary complications but did not prevent infection. In retrospect, the strategy did little to mitigate the toll of the pandemic. And yet, while disputes raged about the identity and nature of the pandemic germ and the composition of vaccines, its basic principles were rarely questioned. Why was this the case? First, the general strategy employed in 1918 had been proven effective in managing and significantly reducing the burden of other infectious diseases during the war. Indeed, by 1918 it was already becoming evident that this was the first war in history in which infections accounted for fewer deaths than bullets and bombs.3 Second, along with official bodies, the medical community was broadly committed to the important role played by bacteriology in public health, from sanitation and disinfection to screening and inoculation. Finally, the pandemic did not fit expected patterns of influenza: it struck suddenly during a war; officials and medical experts had little time to respond; and, in Britain at least, winning the war against Germany was prioritised over winning the battle against influenza. In retrospect, the limited efficacy of bacteriological interventions during the pandemic also had to do with the fact that the strategy was organised around the wrong agent. The prospect that the pandemic might have been caused by a ‘filterable virus’ only started to be explored during the second wave in autumn 1918, but there was little understanding of this type of pathogen and little agreement on how they should be studied. Contrary to some historians’ assessments, the inability of bacteriology to halt the pandemic should not be taken as evidence of a ‘failure’ of scientific medicine.4 The apparent inability of bacteriology to affect the course of the pandemic was interpreted in different ways in the medical community. For critics of bacteriology, of which there was a small but influential number, the experience of the pandemic demonstrated the limits of approaches that sought to reduce a complex epidemic disease such as influenza to a single causative agent and the need to develop new, multifactorial approaches. For supporters of scientific medicine, led by Walter Morley Fletcher, the MRC, and their allies, failure stemmed 3 Mark Harrison, The Medical War, 10. 4 Sandra M. Tomkins, ‘The Failure of Expertise: Public Health Policy in Britain during

the 1918–1919 Influenza Epidemic’, Social History of Medicine, 5 (1992), 435–454; E. Tognotti, ‘Triumphalism and Learning from Facts: Bacteriology and the ‘Spanish Flu’ challenge of 1918’, Social History of Medicine, 16 (2003), 97–110.

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not from the basic principle of determining disease agents but insufficient investment, organisation, and direction: the pandemic laid bare the need to modernise British medical science and, especially, to place pathology on firm experimental footings. Rather than abandon the search for the specific causes of disease on which, they believed, effective therapies and vaccines had to be based, the pandemic underscored for the MRC the urgency of developing new lines of pathological research. Its virus programme embodied this modernising agenda, and it was widely supported. In either case, however, whether the focus was on developing a new experimental epidemiology to model the multiple factors contributing to the rise and fall of epidemics or on developing a new experimental pathology to reveal the role of filterable viruses in major infectious diseases, the challenges posed by the pandemic were quickly turned into new medical scientific opportunities.5 Scientific medicine was not abandoned; it was reconstructed. Both responses are examples of how researchers and their institutions harnessed memories of the pandemic and kept them alive in the decades after.6 Memory of the pandemic drove epidemiological and virus research, with increased government funding for scientific programs, institutes, and departments in Britain. Government and public support for virus research, perhaps best exemplified by the dog distemper campaign and the idea that it would lay the foundations for successful approaches to influenza, should force us to rethink the legacies of the pandemic and, especially, the historiographical frame of the ‘forgotten pandemic’.7 In Britain, the identity of influenza in medical and public consciousness was transformed by the experience of the pandemic; while previously accepted as an inescapable malady of modern life, after 1918 it came to be widely viewed as a major threat to modern life itself. Fears about the recurrence of another ‘Spanish ‘Flu’ cropped up in newspapers and the medical press with every new outbreak and epidemic in the 1920s and helped to

5 Olga Amsterdamska, ‘Demarcating Epidemiology’, Science, Technology, & Human Values, 30, 1 (2005), 17–51. 6 Guy Beiner, ‘The Great ‘Flu between Remembering and Forgetting’’, in idem (Ed.), Pandemic Re-Awakenings: The Forgotten and Unforgotten ‘Spanish’ Flu of 1918–1919 (Oxford: Oxford University Press, 2021), 1–48; Jeffrey S. Reznick, ‘The Past, Present and Future of Memory: Medical Histories of the 1918–1919 Influenza Epidemic in the United States’, in Guy Beiner (Ed.), Pandemic Re-Awakenings, 234–243. 7 For a recent discussion, see Cohn, Epidemics, 423–444.

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prepare the ground for the MRC virus programme. As the history of the programme shows, historians could do well to pay closer attention to how the pandemic was—and has been—mobilised and used over the last century to pursue different medical, scientific, political, and ideological agendas. Virological and epidemiological research on influenza ran in parallel through the 1920s and 1930s, occasionally intersecting and at times clashing. In Britain, each was enrolled in competing visions of medical reconstruction promoted by the Ministry of Health and the MRC. I have chosen to concentrate Modern Flu on the development of virus research and its role in transforming influenza’s medical identity. The real and rhetorical connections of virus research to the 1918 pandemic mark the second phase in the history of modern influenza, when it was reframed as a virus disease. Epidemiological research played little part in this transformation. Rather, through the crucial decades of the 1930s and 1940s, virus research was positioned as essential to determining what counted as influenza: the identity of human influenza was inextricably allied with the identity of viruses isolated in ferrets, pigs, mice and chick eggs. It was not until after the Second World War, largely as the result of problems encountered in vaccine production, that interest started to develop in deciphering the problem of antigenic variation and its connections to the epidemiology and ecology of influenza viruses; and only in the 1950s did influenza start to be framed as a zoonotic infection. This history still needs to be written, for it represents a critical new phase in the viralisation of influenza. But that is beyond the scope of this book. My task has been to detail the developments and processes that made the viralisation of influenza possible in the first place. ∗ ∗ ∗ Modern Flu has traced how a new approach to the question—what is influenza?—was fashioned in the first half of the twentieth century at the interface of laboratory, clinical, and public health medicine in Britain. From the early 1930s, the isolation of a virus from human and animal bodies became essential to answering this question. In the process, influenza and the virus that caused it became inextricably linked: hereafter, the medical identity of influenza went viral. This was not merely a definitional or conceptual change, but one that involved the creation of new practices and social relations between medical professionals whose

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job it was to diagnose, treat, manage, and control the disease. A new medical consensus was built. Crucial to its construction was trust that virus research would provide effective tools to tackle this intractable epidemic disease. By the end of the Second World War, this promise was seemingly being delivered. The NIMR played a leading role in the process of viralising influenza. Between 1933 and 1945 it emerged as a transnational hub of influenza virus research connected to researcherss and laboratories in the United States, Australia, the Soviet Union, Europe, and beyond. From its early work on determining the primary role of a virus in influenza in the 1930, by the end of the Second World War the NIMR had become tasked with collecting and examining specimens from around the world for evidence of different types of influenza viruses. Ferrets, mice, and chick eggs were essential to this enterprise and they played multiple roles: as experimental animals, as serological tools, and as sources of virus material, all of which underpinned new systems of virus surveillance and vaccine production that would become key to controlling influenza in the second half of the twentieth century. These developments in virology—as the science of viruses was becoming known—had put Britain and the world in an unprecedented position. Having answered the question—what is influenza?—it was now possible to ask another, more pressing question: ‘Can we beat influenza?’ (Fig. 1). Virus workers were cautiously optimistic that they had the knowledge and tools in hand to do so. The development and testing of effective vaccines during the Second World War by the Rockefeller Foundation’s IHD laboratories and the Commission on Influenza had put the prospects of controlling influenza on a new footing. Large-scale trials and mass vaccination of American and British troops demonstrated the possibility of manufacturing vaccines to protect entire nations from influenza. The British government quickly recognised this potential. After the war, the NIMR was made the fulcrum of new efforts to manage the disease. Precious resources were released for the completion of a vastly larger Institute at Mill Hill, opened in 1950, which housed a separate Department of Virus Research.8 The WHO also recognised the value of the NIMR’s work. The creation of the World Influenza Programme in 1948 and the designation of Andrewes’ virus research laboratory as the World 8 C.H. Harrington, ‘The Work of the National Institute for Medical Research’, Proceedings of the Royal Society of London, 136 (1950), 333–349.

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Fig. 1 ‘Can we beat influenza?’ Photograph of a haemagglutination test (Source Picture Post [2 February 1946], 9)

Influenza Centre consolidated the NIMR’s position and authority as national and international approaches to influenza became increasingly organised around the identification and control of the virus. Periodicals and newspapers shared and promoted the new optimism. A lead story in the Picture Post, with which I opened this book, conveyed the possibilities. Readers were told that virus research grew out of the changing history of efforts to determine the cause of influenza: from early astral and miasmatic concepts and efforts in the eighteenth century to decipher a specific clinical entity, to its definition in the late nineteenth century as a specific infectious disease and claims for the primary role of Pfeiffer’s bacillus, to the challenges and controversies of the 1918 pandemic. The pandemic was invoked as a defining moment: ‘Memory of that world catastrophe … stimulated research for means of cure and prevention.’ It had led to the organisation of virus research at the NIMR

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in the 1920s and then to its ground-breaking discovery in 1933.9 The possible recurrence of a similar pandemic following the end of the recent world war was the big concern. Readers were reassured that the new science had equipped the nation with the means to track influenza viruses and to vaccinate against them. New drugs, including penicillin, were also now available to control pneumonia and other secondary complications of the disease. ‘If the ‘flu peak comes, there is every reason for thinking we shall pull through fairly well.’10 The Picture Post offered a reassuring and confident prognosis of the future of influenza that was widely shared. Left out of such accounts—and histories of influenza virus research more generally—is how the NIMR gained authority over influenza and how virology became indispensable to its definition and control. Modern Flu has brought into view the historical conditions behind the emergence and consolidation of virus-based knowledge and practices as new arbiters of influenza’s identity. While tied to the interwar construction of virus research, which was borne out of the 1918–1919 pandemic, these conditions need to be placed into a longer-term perspective that connects them to transformations in the organisation and production of medical knowledge of influenza from the late nineteenth century. Virus research took form in a context already shaped by epidemiological, clinical, and pathological ways of knowing that had staked out important definitions of influenza. The positioning of virus-based knowledge and practices as central to defining influenza was the outcome of a complex process of negotiation and alignment between different medical professionals who had developed and were bound to these different ways of understanding and working. Negotiation, alignment, and consensus-building defined the making of influenza virus research. Taking a long-term perspective also illuminates the remarkably protean identities and meanings of influenza and how the disease attracted an equally protean number of approaches to its definition. I have concentrated on the conjunctions of epidemiological, clinical, and pathological knowledge, first, because they played crucial roles in shaping the identities of influenza in modern medicine, and second, because it was primarily with these ways of knowing that virus research negotiated its legitimacy and established its authority. In this analysis, the identification of

9 ‘Can we beat influenza?’, Picture Post 30 (2 February 1946), 9. 10 ‘Can we beat influenza?’, Picture Post 30 (2 February 1946), 11.

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influenza virus at the NIMR in 1933 is best explained as the outcome of crucial changes in the institutional, material, and practical foundations of modern medicine, in which epidemiology, clinical medicine, and pathology became increasingly organised around the laboratory identification and control of the specific causes of infectious disease. But rather than revolutionise medicine, new virological knowledge and practices were moulded to meet its interests and imperatives. Viralising influenza thus needs to be understood as the long-term product of realignments in medical definitions and practices, in which virus research was integrated into and modified medical ways of knowing. From its identification in 1933, the meanings and knowledge of influenza virus were shaped by enduring problems in the epidemiology and clinical nature of influenza. Making virus knowledge relevant required special attention to ensuring that its production, organisation, and communication demonstrated the practical uses of influenza virus in solving such problems. The development of serological tests and vaccines was especially important inside and outside of medicine. Along with the potential value in preventing infection, vaccines were especially useful for bringing together different medical experts and practitioners, and government bodies (and later, industry) around the common goal of disease control. Demonstrating that virus-based knowledge and practice worked for medicine was key to gaining wider support and credibility. If the viralisation of influenza can be explained in terms of the creation of a new medical consensus, which became international in character, it was also the product of the changing organisation of medicine in Britain, and particularly in London. The emergence of London as a hub of influenza virus research in the interwar years was no accident. It had been the basis for investigations of influenza since the 1890s, and the political centre through which public health measures for the nation were formulated and loosely coordinated. At the same time, when modernisers like Walter Morley Fletcher surveyed London medicine in the 1920s, they characterised it as being dominated by a nineteenth century division of labour that, among other things, subordinated pathology to a service role in hospitals and in public health. For Fletcher and the MRC, lack of support for experimental pathological research in dedicated laboratories and institutions contributed to the ‘backwardness’ of British medicine and functioned as an obstacle to developing new scientific approaches to infectious disease. The MRC virus programme, and the positioning of the NIMR as its institutional hub, stemmed directly from the perceived

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need to scientifically modernise pathology in the capital and, by extension, across the nation. To build virus research into the landscape of London medicine, the MRC framed it as a collaborative enterprise, with work on viruses and virus diseases defined by cooperation among a wide range of scientists and medical practitioners. The research style developed at the NIMR drew together pathologists, bacteriologists, veterinary scientists, chemists, physicists, and microscopists. The links NIMR workers created and maintained with hospital clinicians and pathologists, the MAB and the MoH, and with the various military medical services ensured that virus-based knowledge became part of clinical medicine and public health. It is worth recalling that Laidlaw, Andrewes, Smith, and Stuart-Harris were first trained as doctors and relied on their medical credentials to create their medical alliances. While their calling might have been ‘bench’ science they consistently viewed and framed their work in terms of its medical relevance. Stuart-Harris, whose job it was in the 1930s to align laboratory and clinical work on influenza, stressed this in an address to general practitioners in 1947: ‘[L]aboratory workers concerned with influenza viruses have always recognized the fact that influenza is a disease which lies particularly within the province of the general practitioners. Whenever the opportunity has presented, the laboratory findings and problems, both solved and unsolved, have been laid before practitioners in the traditional manner.’11 Stuart-Harris’s observation underscored a crucial feature of alliance-building in medical virus research in Britain specifically and its key role in biomedicine more generally. Laboratory science both shaped and was shaped by clinical or public health problems and interests; the ongoing translation of one into the other would be central to processes of biomedical knowledge-making through much of the twentieth century.12 Historians have argued that the practical orientation of pathological research at the NIMR extended the imperatives of ‘mainstream medical bacteriology’ to the new field of virology, the result of which was to keep

11 C.H. Stuart-Harris, ‘The General Practitioner and the Influenza Problem’, British Medical Journal (20 December 1947), 994–996. 12 Annemarie Mol, ‘Pathology and the Clinic: An Ethnographic Presentation of Two Atheroscleroses’, In M. Lock, A. Young and A. Cambrosio (Eds.), Living and Working with the New Medical Technologies. Intersections of Inquiry (Cambridge: University of Cambridge, 2000), 82–102.

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research innovation in check.13 My analysis points to a different conclusion. Rather than bacteriology’s handmaiden, medical virus research was part of the organisation of a new kind of experimental pathology. While rooted in bacteriological principles and practices, the range of expertise and skills demanded by virus work meant that it could not be the property of any one discipline but had to be multidisciplinary. The style of virus research developed at the NIMR embodied this approach. The articulation of physical and immuno-pathological lines of investigation made understanding the basic nature of viruses essential to the control of virus diseases. This approach produced and relied upon a definition of viruses as obligate intracellular parasites, living micro-organisms that, unlike bacteria, were conceptualised as being uniquely dependent on living cells or tissue. While rooted in bacteriological thinking, this definition, which became widely accepted in the 1920s, was crucial to establishing the disciplinary identity of virus research. It determined the basic conditions of medical and veterinary virus work, particularly its reliance on experimental animals. Most importantly, rather than acting as an obstacle to innovation, it helped to drive it. Defining viruses as microorganisms—rather than as chemicals—placed them in a common language of germs and immunity that made them intelligible outside the realms of virus research. This also allowed virus workers to determine and explain differences between viruses and bacteria, which was important for carving out a place for their entities in medicine and public health and, eventually, for establishing the disciplinary boundaries of virology.14 A crucial feature of medical virus research was how it worked to translate experimental knowledge produced in research animals into medical and public health knowledge, practices, and products relevant to doctors, patients, and the state. Nonetheless, the viralisation of influenza was an uneven and ongoing process. It would take decades for virological knowledge and practices to become routine in diagnosing, treating, and preventing influenza. In 13 R.E. Kohler, ‘Bacterial Physiology: The Medical Context’, Bulletin of the History of Medicine, 59, (1985), 54–74. R.E. Kohler, R.E. ‘Innovation in Normal Science: Bacterial Physiology’, Isis, 76, (1985), 162–181. T. van Helvoort, ‘A Bacteriological Paradigm in Influenza Research in the First Half of the Twentieth Century’, History and Philosophy of the Life Sciences, 15, (1993), 3–21. 14 Pierre-Olivier Méthot, ‘Writing the History of Virology in the Twentieth Century: Discovery, Disciplines, and Conceptual Change’, Studies in History and Philosophy of Biological and Biomedical Sciences, 59 (2016), 145–153.

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what ways had virology changed the medical identity of influenza by 1945? At the turn of the century, when a doctor, pathologist, or medical officer of health searched for an explanation of the cause of influenza in a standard textbook they would typically find a description and photomicrograph of Pfeiffer’s bacillus. The bacillus anchored the definition of influenza as an infectious disease and was used to distinguish and explain its clinical forms, epidemiology, and pathogenesis. It was also the target of preventive measures aimed at breaking its transmission through disinfection, isolation, and immunisation with bacterial vaccines. Britain’s medical and public health strategies took the bacillus as their focal point for fighting influenza through the 1918 pandemic and beyond. For over four decades, influenza’s medical identity had been shaped around knowledge and practices of representing and intervening in the life of this germ. Between 1933 and the start of the Second World War, reference to Pfeiffer’s bacillus as the primary cause of influenza had all but disappeared. In medical, pathology, and public health textbooks the bacillus had been replaced by a virus. In clinical medicine, the most evident effect of this change was in the classification of influenza as a ‘virus disease’. But the bearing of this new classification on diagnostic practices was indirect and relatively minimal. Nowadays, the basic distinction between a viral and bacterial disease is generally known among medical professionals and they may use it to explain a diagnosis or treatment approach to a patient (for example, why antibiotics are only effective against bacterial and not viral infections). In the middle of the twentieth century, the fundamental difference between bacteria and viruses was much debated, and it is unlikely physicians made much use of ‘viruses’ in clinical practice. An influenza diagnosis proceeded, as it had for more than a century and as it largely still does, based on symptoms. The difference, however, was that, in theory, a physician now could send a saliva or tissue sample to the NIMR or one of a number of public health, hospital pathology, or research laboratories for a virus diagnosis. The new classification of influenza also reoriented ways of understanding the pathogenesis of the disease—how influenza developed in individual cases. But like their counterparts in the late nineteenth and early twentieth centuries, physicians and pathologists found that the virus alone could not explain the variations and forms of influenza. The clinicopathological model, developed first for Pfeiffer’s bacillus, was revised for influenza virus. It explained influenza as a two-step disease process,

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in which an initial virus infection that caused a mild-to-severe respiratory or gastric disease could be followed, in certain cases, by potentially serious sequelae associated with secondary bacterial or viral infections. Other factors were identified as contributing to the severity of influenza, including age, underlying health problems such as tuberculosis, nutrition, living conditions, and heredity. Textbooks might have classified influenza as a viral disease, but virological knowledge alone could not account for how the disease might progress in patients. Things played out differently in public health medicine. By the outbreak of the Second World War, approaches to the prevention of influenza had started to be reconceptualised in terms of the transmission and distribution of influenza viruses through human populations. The NIMR, along with other research and public health laboratories equipped to carry out serological tests for influenza, played an increasingly important role in identifying outbreaks and epidemics and in the early construction of an influenza virus surveillance system. Recognition of influenza as a virus disease by the Ministry of Health in 1939 built a virological definition into prevention frameworks. Underlying the pervasive wartime prevention motto—‘Coughs and sneezes spread diseases’—was the idea that, along with bacterial diseases such as tuberculosis, these commonplace habits also spread virus diseases, especially influenza. Public health messages of the 1940s rarely if ever directly referred to the ‘influenza virus’. More important for popularising the idea of influenza as a viral disease was the growing use of vaccines as a public health measure. Of course, as we have seen, influenza vaccines made from different types of bacteria had been widely used since the early twentieth century and were key preventive tools during the 1918 pandemic. But by the end of the Second World War, they had all but been replaced by vaccines made from different strains of influenza viruses. The viralisation of influenza vaccination ensured that virology would play a crucial role in post-war influenza prevention. In Britain, mass vaccination was only slowly implemented in the postwar period, but the principle lay behind support for virus research at the NIMR and in public health. Across the globe, the creation of the WHO’s World Influenza Programme in 1947 made the NIMR, and practices of identifying and vaccinating against influenza viruses, the foundation of global influenza surveillance and control. Ever since, global health approaches to influenza have been shaped through knowledge of the biology, epidemiology, and ecology of influenza viruses.

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The consequences of these developments would change the future of influenza. From the esoteric realms of specialist laboratories, influenza viruses emerged as crucial objects in the post-war formation of virology as a major biomedical discipline. Monitoring influenza viruses became key to planning for seasonal outbreaks and epidemics, and for pandemics. Governments and pharmaceutical companies poured vast resources into the production of annual vaccines. Influenza viruses became known disease-agents that people everywhere contracted and suffered from, that doctors indirectly treated, that virologists studied, that epidemiologists tracked, that public health systems managed, that nations mobilised against, that drug and vaccine manufacturers commodified and made profitable, and that international bodies used as rallying points for global health policy-making. As the future of influenza was being viralised, so too was its past. From the early 1930s, virological knowledge and tools opened the possibility for researchers to retrospectively determine the role of influenza viruses in previous epidemics. Identifying the virus behind the 1918–1919 pandemic was and has remained a singular concern. As early as 1935, Patrick Laidlaw speculated that the pandemic had likely been caused by the virus he and his NIMR colleagues had identified two years earlier, or a close relative. His speculation stemmed, in part, from work being done by Richard Shope on the serological history of the swine influenza virus he had identified in 1931 and which, at the time, was thought to be closely related to human influenza viruses. Through the 1930s, Shope tracked the origins of both viruses back to outbreaks of swine and human influenza in 1918 on pig farms and in army installations in the American mid-west.15 On the basis of this work, in the early 1940s Shope hypothesised that the 1918 pandemic resulted from a zoonotic event, involving the transmission of a swine influenza virus into humans.16 Other researchers took up this line of reasoning. In 1942, F.M. Burnet and Ellen Clark used evidence from new haemagglutination tests to trace the history of influenza A viruses and to speculate on the origins of the 1918

15 R.E. Shope, ‘The Influenzas of Swine and Man’, The Harvey Lectures, 1935–1936 (New York: The Harvey Society 1936), 183–213. 16 R.E. Shope, ‘Old, Intermediate and Contemporay Contributions to our Knowledge of Pandemic Influenza’, Medicine, 23 (1944), 415–420; R.E. Shope, ‘Influenza: History, Epidemiology and Speculation’, Public Health Reports, 73 (1958), 165–178.

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pandemic.17 They surmised that it was either the result of a zoonotic event of the kind Shope described, or the product of the recombination of human and swine viruses in an animal host into a new and highly pathogenic virus. Such hypotheses underscored how interest in reconstructing influenza’s viral history developed and grew as new methods became available. Crucially, they pointed to the possible role of animals as sources or reservoirs of influenza virus, a concept that would start to be systematically explored in the 1950s and would eventually lead to framing influenza as a zoonotic infection. Most of all, they demonstrated how virology was becoming a tool and category of historical analysis, with the biological history of the virus its primary object. It would take over sixty years and the development of recombinant DNA technologies for the 1918 pandemic to be finally viralised. The process was completed in the late 1990s. In a series of ground-breaking studies, Jeffery Taubenberger, Ann Reid, and colleagues at the Walter Reed Army Medical Center in Washington, D.C. genetically sequenced influenza virus from an embalmed lung sample of a soldier who had died during the second wave.18 By establishing the genetic identity of the 1918 virus with an avian influenza virus sub-type, they have rewritten the virological history of the pandemic and forcefully linked it to the threat of avian influenza.19 In creating a new kind of history, in which virological tools can be used to explain influenza’s past and to predict its future, they have also fulfilled one of the promises of virological research that was born in the 1930s.20

17 F.M. Burnet and E. Clark, Influenza: A Survey of the Last 50 years in the Light of Modern Work on the Virus of Epidemic Influenza (Melbourne: Macmillan, 1942). 18 J.K. Taubenberger, A.H. Reid, A.H. Krafft, et al., ‘Initial Genetic Characterization of the 1918 “Spanish” Influenza Virus’, Science, 275 (1997), 1793–1796. 19 A.H. Reid, J.K. Taubenberger and T.G. Fanning, ‘The 1918 Spanish Influenza: Integrating History and Biology’, Microbes and Infection, 3 (2001), 81–87; J.K. Taubenberger, ‘Genetic Characterisation of the ‘Spanish’ Influenza Virus’, in H. Phillips and D. Killingray (Eds.), The Spanish Influenza Pandemic of 1918–1919: New Perspectives (London: Routledge, 2003), 39–46; J.K. Taubenberger, A.H. Reid, and T.G. Fanning, ‘The 1918 Influenza Virus: A Killer Comes into View’, Virology, 274 (2000), 241–245. 20 D.M. Morens and J.K. Taubenberger, ‘Understanding Influenza Backward’, Journal of the American Medical Association, 302 (2009), 679–680; J.K. Taubenberger, ‘The Origins and Virulence of the 1918 “Spanish” Influenza’, Proceedings of the American Philosophical Society, 150 (2006), 86–112; J.S. Oxford, C.S., Sykes, T. Sykes, et al., In Search of Spanish flu (UK: BBC 4, 2008).

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∗ ∗ ∗ Much has been left out of the analysis developed in this book. Patients’ and popular experiences and conceptions of the disease have received cursory attention. Much work is still to be done on this vital part of the medical history of influenza, as well as on how virological ideas and practices became part of post-Second World War cultures. But to do such work I think it is first necessary to understand how influenza came to be viralised in biomedicine and became a crucial biomedical object. This is, in part, because virology and biomedicine more generally increasingly provided languages through which ideas and experiences of health, disease, and bodies were made intelligible. The viralisation of influenza would extend into many facets of modern life. Today, it is enough to open a medical encyclopaedia, a virology textbook, or a popular science magazine to learn that influenza is a viral disease, transmitted from person-to-person by droplet infections containing virus particles. Correct diagnosis, treatment, and prevention are ultimately determined by the laboratory identification of the virus. The primary symptoms of influenza are explained in terms of the infection and multiplication of the virus in the upper respiratory tract. Virological knowledge is not absolute, cannot always be relied upon, and is almost always used in conjunction with clinical and epidemiological knowledge. Yet, while recognised clinical and epidemiological characteristics of influenza remain crucial to its identification, in the absence of the laboratory determination of a virus, diagnosis of a case of influenza or confirmation of an epidemic would be incomplete and uncertain. Since 1945, the virological laboratory has become a crucial arbiter of what counts as influenza. Transforming influenza into a virus disease not only involved negotiations between different practitioners, and the creation of new social relations between them, but also negotiations with a disease that has been remarkably resistant to straightforward medical definition. Sir Clifford Allbutt’s description of influenza as ‘the most protean of protean diseases’ was apt at the start of the twentieth century and remained so through to the start of the twenty-first century. That influenza can be at once a familiar seasonal nuisance, a troublesome epidemic, a zoonosis, and a vast and potentially devastating pandemic disease has meant that each medical generation has had to invent ways to answer the question,

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what is influenza? Despite the growth of virology and the vast infrastructures and systems now in place to control influenza, questions about what constitutes the disease, what causes it, how it emerges, and why it changes remain. As outbreaks of avian influenza and the 2009 swine influenza have demonstrated, after nearly a century of virological innovation, influenza continues to perplex.

CHAPTER 10

Coda: Influenza and Covid-19

In early February 2021, as Britain and the rest of the world grappled with the second wave of the coronavirus pandemic, the British Health Secretary, Matt Hancock, claimed in a widely reported interview in The Telegraph, that, with vaccines and treatments, Covid-19 would ‘become another illness that we have to live with… like flu.’1 Hancock was not alone in making this kind of prognostication. Such statements became something of a mantra, with politicians, policymakers and even scientists suggesting that we will come to live with Covid-19 like we have learned to live with influenza. For most historians, drawing historical analogies between two different diseases—let alone two pandemics—needs to be approached with caution or avoided altogether.2 Indeed, from as early as March 2020 scientific experts were quick to note that, despite certain similarities, Covid-19 and 1 Quoted in Ben Riley-Smith, ‘We Hope to Live with Covid Like Flu by the End of the Year, Says Matt Hancock’, The Telegraph (12 February 2021). https://www.telegr aph.co.uk/politics/2021/02/12/matt-hancock-hope-live-covid-like-flu-end-year/. 2 Robert Peckham, ‘COVID-19 and the Anti-Lessons of History’, Lancet, 395 (14 March 2020), 850–852; Guillaume Lachenal and Gaëtan Thomas, ‘Covid-19: When History Has No Lessons’, History Workshop Online (30 March 2020). https://www. historyworkshop.org.uk/covid-19-when-history-has-no-lessons/; David S. Jones ‘COVID19, History and Humility’, Centaurus, 62 (2020), 370–380; Howard Markel, ‘History Won’t Help Us Now’, The Atlantic (19 August 2021). https://www.theatlantic.com/ ideas/archive/2021/08/1918-influenza-pandemic-history-coronavirus/619801/.

© The Editor(s) (if applicable) and The Author(s), under exclusive licence to Springer Nature Limited 2023 M. Bresalier, Modern Flu, Medicine and Biomedical Sciences in Modern History, https://doi.org/10.1057/978-1-137-33954-6_10

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influenza are different diseases caused by different viruses, with different biological, clinical, and epidemiological characteristics. Nonetheless, more than any other epidemic disease, influenza was quickly summoned as the paradigmatic infection for understanding and forecasting the possible impact and pathways of Covid-19.3 The rush to ‘learn’ from influenza was hardly surprising. Influenza did, of course, produce the single-worst pandemic of the twentieth century, and perhaps the worst in human history. But what is perplexing from a historian’s perspective is that, over the course of the first two years of the Covid-19 pandemic, a number of different influenzas were invoked or used as historical reference points. The influenza that started to be summoned in early 2021 as an example of how we might live with Covid-19 was radically different from the influenza many summoned when Covid-19 first became pandemic in 2020.

1

Which Influenza?

At the start of the Covid-19 pandemic experts and others referenced the 1918–1919 ‘Spanish’ influenza as a possible worst-case scenario of what might happen should governments not act quickly, should social distancing and mitigation measures not be put in place, should countries not lock their borders. It was on the basis of extrapolations from the 1918 pandemic that Neil Ferguson and colleagues at Imperial College London presented epidemiological models that shockingly predicted mass deaths should such measures not be urgently implemented.4 Many historians also turned to the 1918 pandemic, largely for examples of what countries failed to do, why so many died so quickly, the limited means available to

3 David M. Morens, Peter Daszak, and Jeffery K. Taubenberger, ‘Escaping Pando-

ra’s Box—Another Novel Coronavirus’, New England Journal of Medicine, 382 (2 April 2020), 1293–1295. 4 Neil M. Ferguson et al., ‘Report 9: Impact of Non-Pharmaceutical interventions (NPIs) to Reduce COVID-19 Mortality and Healthcare Demand’, Imperial College Covid19 Response Team (16 March 2020). The report was picked up in the British press and Ferguson was called ‘Professor Lockdown’ for its dire predictions. The report was partly based on Ferguson’s own comparative studies of ‘non-pharmaceutical interventions’ (NPIs) in American cities during the 1918–1919 pandemic. Martin C.J. Bootsma and Neil M. Ferguson, ‘The Effect of Public Health Measures on the 1918 Influenza Pandemic in U.S. Cities’, Proceedings of the National Academy of Sciences of the United States of America, 104.18 (2007), 7588–7593.

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stop a wartime pandemic, and how much medicine, science, and public health had changed over the last century.5 Some pointed to examples of measures that worked to slow a highly infectious, deadly respiratory disease, and for how communities and societies came together.6 Yet, a little over a year later, the 1918–1919 pandemic was replaced by another influenza, one which the world has adapted to over the last century, and which was referenced as a possible best-case scenario for how we might come to live with Covid-19. Perhaps this tells us something about historical amnesia, the wilful forgetting of trauma or of historical reality. But it also tells us something about influenza: it is a disease of and with many identities. Its characterisation by the late nineteenth physician, Sir Clifford Allbutt, as the most protean of protean diseases remains as appropriate today as it did more than a century ago.7 And as influenza became better understood over the last century as a viral disease that is mappable epidemiologically and controllable by vaccines, its identities have not only changed but also have multiplied. In epidemiological terms, influenza can take the form of pandemics: the last century has seen four—1918, 1957, 1968, and 2009. It also takes form as seasonal influenza, which appears almost every year as a familiar yet unwanted visitor. And there are animal influenzas, the most notable being avian (bird) influenza, which, before Covid-19, pandemic planners anticipated as becoming the next global pandemic.8 Just to add to its complexity, 5 Laura Spinney, ‘Closed borders and ‘Black Weddings’: What the 1918 Flu Teaches Us About Coronavirus’, Guardian (11 March 2020); Mark Honigsbaum, ‘A Once-in-aCentury Pathogen: The 1918 Pandemic & This One’, New York Review of Books Daily (17 March 2020). https://www.nybooks.com/online/2020/03/17/a-once-in-a-centurypathogen-the-1918-pandemic-this-one/; Michael Bresalier, ‘Covid-19 and the 1918 ‘Spanish ‘Flu’: Differences Give Us a Measure of Hope’, History and Policy—Opinion (2 April 2020). https://www.historyandpolicy.org/opinion-articles/articles/covid-19-andthe-1918-spanish-flu-differences-give-us-a-measure-of-hope. 6 Ida Milne, ‘Tackling Covid-19: What Can We Learn from the 1918 Spanish Flu?’, Irish Examiner (14 March 2020); Nancy K. Bristow, ‘What the 1918 Flu Pandemic Tells Us About Whether Social Distancing Works’, The Guardian (29 April 2020); Samuel Cohn Jr., ‘Face Masks: What the Spanish Flu Can Teach Us About Making Them Compulsory’, The Conversation (1 May 2020). 7 T.C. Allbutt, ‘Influenza’, The Practitioner, LXXVII (1907), 1. 8 Ian Scoones (Ed.), Avian Influenza: Science, Policy and Politics (London: Earthscan,

2010); Ann D. Herring and Stacy Lockerbie, ‘The Coming Plague of Avian Influenza’, in Ann D. Herring and Alan C. Swedlund (Eds.), Plagues and Epidemics: Infected Spaces Past and Present (Oxford: Berg, 2010), 179–191.

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since the 1960s influenza has been recognised as a zoonotic infection, caused by viruses that move across or between animals (birds, pigs, and others) and humans. (Of course, the virus that causes COVID-19— SARS-CoV-2—has also been classified as a zoonotic agent, although its natural reservoir and intermediate hosts have not been confirmed.)9 This multiplicity raises important questions for anyone looking to influenza as a historical exemplar: which influenza should we use when making comparisons with Covid-19 or when looking for a model for how to live with a new infectious disease? I doubt any policy maker or politician has had the 1918 pandemic in mind, which killed between 50 and 100 million worldwide, the vast majority of whom were in the colonial world. Rather, it is likely that reference is being made to some version of influenza that we have co-existed with since 1918—what I have called modern flu. The suggestion that we might live with Covid-19 as we have with modern flu carries with it a set of assumptions: in particular, it suggests a specific way of managing our relationship with an infectious disease. Epidemiologists have characterised three possible ways of managing this relationship. A little over twenty years ago, two experts from the US Centers for Disease Control and Prevention, Walter Dowdle and Donald Hopkins, led an international workshop that established standard definitions of each approach. First, there is control, which Dowdle and Hopkins characterised as entailing ‘the reduction of disease incidence, prevalence, morbidity or mortality to a locally acceptable level as a result of deliberate efforts.’10 Such efforts include vaccination, sanitation, better nutrition, improved living conditions, among others. As Dowdle and Hopkins noted, control is not getting rid of a disease completely; it is adapting to it—keeping sickness and deaths to an acceptable level within a population. It encompasses calculated efforts to turn an epidemic disease into an endemic disease. This is how people in high-income countries live with many infections, including influenza and HIV/AIDS.

9 J. Cui, W. Chei, and B.-P. Tian, ‘The Potential Intermediate Hosts for SARS-CoV-2’, Frontiers in Microbiology, 11 (2020), https://doi.org/10.3389/fmicb.2020.580137. 10 Walter R. Dowdle, ‘The Principles of Disease Elimination and Eradication’, Bulletin of the World Health Organization, 76, Suppl. 2 (1998), 23; Walter R. Dowdle and Donald R. Hopkins (Eds.), The Eradication of Infectious Diseases: Report of the Dahlem Workshop on the Eradication of Infectious Diseases (Chichester: John Wiley & Sons, 1998).

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Along with control, a second method to tackle infectious disease is elimination. As Dowdle and Hopkins put it, elimination aims at ‘reducing the incidence of a disease to zero in a country or region as a result of control efforts.’ It requires continued control measures to prevent re-introduction of the disease into the country or region from which it has been eliminated. Some examples would include the elimination of polio, yellow fever, and malaria from continental Europe and North America. Finally, there is eradication. Dowdle and Hopkins, who established their reputations in the WHO’s smallpox and guinea worm eradication programmes respectively, provided this definition: eradication is ‘the permanent reduction to zero of the worldwide incidence of an infection caused by a specific agent as a result of deliberate efforts, so that control measures are no longer needed.’ Only a few infections have been eradicated: the best known is smallpox. The animal disease, rinderpest, has also been eradicated; and polio, as well as measles and rubella, are possibly on the horizon. Over the course of the Covid-19 pandemic, most of the world worked to bring the disease under control, not to eliminate or to eradicate it. There were a few exceptions. Taiwan and New Zealand sought to eliminate Covid-19 from their respective borders. China pursued a strategy of national eradication (Zero-Covid) through mass isolation, quarantine, and vaccination. Neither goal was achieved. In the summer of 2021, New Zealand abandoned its elimination strategy. China continued to have cases and, on abandoning its Zero-Covid policy in early 2023, experienced large outbreaks and a significant number of deaths. Whether or not control should be the ultimate goal remains in question. But, if we take at face value the statement that we should aim to live with Covid-19 like we have come to live with modern flu, the assumption is that the only viable approach to Covid-19 is to control it, because this is how influenza has been approached for over a century. What does this mean? What is the essential goal of controlling an infectious disease? In the short term, epidemiologists and public health experts argue that the priority is to manage the reproduction (R0) or infection rate and, by implication, to minimise the number of people who get sick, the number of sick who develop serious complications, and the number who die.11 In the long term, the aim of control is to bring disease and death rates down 11 Adam Kucharski, Rules of Contagion: Why Things Spread and Why They Stop (London: Profile Books, 2020), 54ff.

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to an acceptable level. Put another way, the aim is to make an epidemic disease an endemic disease. The latter term—endemic—has sprung into public health, policy, and political discussions of the possible future with Covid-19. Some quarters have argued that making Covid-19 endemic should be the priority and end-game.12 But the meaning of the term—and what it implies—is by no means fixed or agreed.13 The US Centres for Disease Control produced a working definition in 2006, which has served as something of a benchmark: ‘Endemic refers to the constant presence and/or usual prevalence of a disease or infectious agent in a population within a geographic area.’14 As this definition suggests, and as a number of observers have noted, endemic does not mean that a population is free from sickness, suffering, or death. Quite the opposite. Malaria and tuberculosis are ‘endemic’ diseases that cause an enormous disease burden and annual loss of life. In its seasonal form, influenza is also endemic in so far as it causes sickness and death annually.15 If to control disease is to make it endemic, then the direction of travel for how we come to live with Covid-19 raises not just practical questions about how this is to be achieved, but also ethical ones: what is an acceptable level of disease or death? Who decides what is acceptable? And who shares the burden of the disease?

12 For example, Wellcome Trust, ‘How Can the World Adapt to Covid-19 in the Long Term?’, 13 January 2022. https://wellcome.org/news/how-can-world-adapt-covid19-long-term-endemic. 13 Maryn McKenna, ‘COVID Will Become Endemic. The World Must Decide What That Means’, Wired (31 December 2021); Jacob Steere-Williams, ‘Endemic Fatalism and Why It Won’t Resolve Covid-19’, Medical Humanities Blog (8 February 2022), https://blogs.bmj.com/medical-humanities/2022/02/08/endemic-fatalism-andwhy-it-wont-resolve-covid-19/; Alberto Giubilini and Erica Charters, ‘The End of Covid19’, Practical Ethics (4 August 2021). http://blog.practicalethics.ox.ac.uk/2021/08/ the-end-of-the-covid-19-pandemic; Erica Charters and Kristin Heitman, ‘How Epidemics End’, Centaurus: International Magazine of the History of Science and Medicine, 63.1 (2021), 210–224. 14 Centers for Disease Control and Prevention, Principles of Epidemiology in Public Health Practice, Third Edition (Atlanta: U.S. Department of Health and Human Services, 2012 [2006]), 73. https://cdc.gov/csels/dsepd/ss1978/lesson1/section11.html. 15 Jacob Stern and Jennifer Wu, ‘Endemicity Is Meaningless’, The Atlantic (1 February 2022); Kavita Sivaramakrishnan, ‘Endemic Risks: Influenza Pandemics, Public Health, and Making Self-Reliant Indian Citizens’, Journal of Global History, 15 (2020), 459–477.

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Challenges of Control

The history of modern flu offers instructive lessons for the practical and ethical challenges entailed in controlling a new or re-emerging infectious disease. As this book has shown, for much of the last century efforts directed at influenza have been aimed at controlling not the disease per se but the viruses that cause it. And this has involved three crucial elements. Science: understanding the basic nature or biology of influenza viruses, which became the domain of virology. Surveillance: understanding and tracking how influenza viruses develop and spread through human and animal populations, which now falls in the domain of epidemiology. And vaccination: which, as we have seen, relies on virus science and surveillance and partnerships with vaccine manufacturers to develop and deploy vaccines on a mass scale to keep sickness and deaths at an acceptable level. Controlling influenza has involved the close interconnection of these elements. But also recall that influenza is now characterised as a zoonotic infection, in which animals play crucial roles as the natural and intermediary hosts and main sources of all influenza viruses. Over the past decades, controlling influenza has come to involve measures also targeted at such animals (wild birds, ducks, chickens, pigs, among others). Measures have included identifying and monitoring animal hosts and reservoirs, and their environments; culling or stamping-out infected, infectious, or susceptible animals; and vaccinating herds.16 A brief survey of how these disparate elements developed and came together underscores the enormous organisational demands and challenges involved in controlling a zoonotic infection such as influenza (and such as Covid-19). First, the science of viruses. As we seen, understanding influenza viruses has been over 90 years in the making. The discoveries made by NIMR and Rockefeller workers in the early 1930s were widely heralded as crucial steps towards coming to grips with influenza. Much thereafter came to revolve around understanding the virus—its biology, how it spreads, how it infects and causes disease, where it comes from and what its natural hosts and environments are. Researchers around the world pursued the virus, with the goal of finding ways to produce

16 Frédéric Keck, Avian Reservoirs: Virus Hunters & Birdwatchers in Chinese Sentinels Posts (Durham: Duke University Press, 2020); Melissa Leach and Ian Scoones, ‘The Social and Political Lives of Zoonotic Disease Models: Narratives, Science and Policy’, Social Science & Medicine, 88 (2013), 10–17.

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treatments but especially, vaccines. Yet, as they shared and compared viruses, they stumbled upon a major new problem. There wasn’t one influenza virus, but many. The world appeared to be full of variants. By the 1940s it was becoming clear that, rather than being stable or fixed entities influenza viruses were constantly changing—they were mutating and evolving. Antigenic variation, as this phenomenon came to be known, would prove to be the single most important practical and research problem associated with influenza through the twentieth century. While it offered important clues as to how and why influenza epidemics developed and why influenza returned year after year, it also threw up major challenges for vaccine production: how to determine which variants to use in a vaccine for a given influenza season or epidemic. Choose the wrong variants, and the vaccine would be a dud. The potential problems variation posed to vaccine development became evident shortly after the Second World War. The wartime United States Commission on Influenza had demonstrated that, with close collaboration between academic scientists, government, and industry, mass vaccination was possible. But, with vaccine failures in 1947, new vaccination programmes in the United States, Britain, and elsewhere were forced to quickly adapt to the challenges posed by antigenic variation. For many experts, this was not something that any one country could tackle on its own: it was a global problem requiring a global solution—a system for tracking influenza viruses around the world. The prospect that influenza virus strains could evolve and vary across geographical regions, and that a pandemic strain could emerge and spread from any part of the world, meant that controlling influenza had to be based on linking vaccination with the continuous global surveillance of influenza viruses. Influenza experts saw the creation of the World Influenza Programme (WIP) in 1947 as just such a solution. Despite its aspirations, the WIP, which would later be named the Global Influenza Surveillance Network (GISN), was an imperfect system.17 Two pandemics in 1957 and 1968 highlighted major organisational problems. The 1957 ‘Asian’ influenza pandemic likely emerged in mainland China. But at the time the People’s Republic of China was not part of the UN and thus the WHO and did not report the early 17 Lorna Weir and Eric Mykhalovskiy, Global Public Health Vigilance: Creating a World on Alert (New York: Routledge, 2010).

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outbreaks.18 Strains of the new virus were eventually isolated in Hong Kong in mid-April, then in Korea, Singapore, and Malaysia. Reporting delays had a serious knock-on effect for vaccine preparation. Mass production was initiated in the United States, Britain, many Western European countries, and elsewhere in anticipation of influenza reaching their shores in autumn. While efforts were impressive, all encountered significant challenges. The lead-time was too short. Production capacity could not meet demand. Only small amounts of vaccine were produced, and only small numbers of people were vaccinated.19 In Britain, roughly 1.5 million doses were produced for a population of 50 million.20 In the United States, approximately 30 million doses were released for a population of 175 million, enough for about 17% of that population.21 For the first time, the question of prioritisation emerged: government health ministries were faced with deciding which groups should get vaccinated and which should not. The developing world was left out of such decisions. For the most part, countries like Britain and the United States let the pandemic run its course. It initially affected younger people—especially school-age children—but then quickly moved into other age groups, with over-65s suffering the most serious complications and most deaths. In the United States, an estimated 45 million people—or 25% of the population—were infected in October and November.22 In Britain, it was estimated that ‘not less than 9 million people … had the Asian Influenza’ in autumn 1957, with about 5.5 million seen by doctors. One general practitioner recalled that ‘we were amazed at the extraordinary infectivity

18 George Dehner, Influenza: A Century of Science and Public Health Response (Pittsburgh: University of Pittsburgh Press, 2012), 75–77. 19 Dehner, Influenza, 82–89; Donald A. Henderson et al., ‘Public Health Responses to the 1957–58 Influenza Pandemic’, Biosecurity and Bioterrorism: Biodefense Strategy, Practice, and Science, 7.3 (2009), 1–9. 20 Ministry of Health, The Influenza Epidemic in England and Wales, 1957–1958 (London: HMSO, 1960), 49; NA MH 136/56 ‘Influenza Vaccine: Asian Flu Epidemic, 1957–1958’. 21 Henderson et al., ‘Public Health Responses to the 1957–58’, 5; Dehner, Influenza,

82. 22 Henderson et al., ‘Public Health Responses to the 1957–58’, 7.

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of the disease, overawed by the suddenness of its outset and surprised at the protean nature of its symptomatology.’23 In Britain, medical practices and hospitals were swamped with cases, and nurses and doctors fell ill. But only a handful of mitigation measures were put in place to slow the spread: local closures of schools, nurseries, and workplaces and some restrictions on public gatherings were implemented.24 There were no restrictions on travel or the closing of borders. The Conservative government played down the threat of the pandemic and its Minister of Health delegated its management to local MOHs, who were left to devise schemes for their communities. When the Ministry of Health issued its official report on the pandemic in 1958, it concluded that: ‘the idea of control of influenza may be more the expression of a hope than of a practical issue.’25 When the next pandemic struck in 1968, surveillance and vaccine systems were better prepared. Virus surveillance included more of the world, but still not most of the so-called ‘developing’ world. Technical innovations enabled faster and larger-scale vaccine production. But once again, influenza exploited weaknesses in both systems. Surveillance programmes missed the new strain until it became a regional epidemic, exploding out of Hong Kong. Vaccine efforts in the United States, Britain, and Europe failed again because production lagged behind the pandemic. While much more vaccine was produced, few citizens were vaccinated.26 Both pandemics were widely characterised as ‘mild’, especially when compared to 1918–1919.27 But the death tolls were not insignificant. An estimated 1–2 million died in 1957–1958; while an estimated 1– 4 million died in the next pandemic in 1968–1969.28 The burden of 23 Quoted in Clare Jackson, ‘History Lessons: The Asian Flu Pandemic’, British Journal

of General Practice (August 2009), 622. 24 Clare Jackson, ‘History Lessons’, 622–623. 25 Ministry of Health, The Influenza Epidemic in England and Wales, 1957–1958

(London: HMSO 1958), 54. 26 Dehner, Influenza, 90–94. 27 Mark Honigsbaum, ‘Revisiting the 1957 and 1968 Influenza Pandemics’, Lancet,

395 (2020), 1824–1826. 28 CDC’s conservative estimates are between 1 and 2 million for each. https://www.cdc.gov/flu/pandemic-resources/1957-1958-pandemic.html. C. Viboud, L. Simonsen, M.A. Miller et al., ‘Global Mortality Impact of the 1957–1959 Influenza

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mortality was not shared equally. In Britain the two pandemics claimed an estimated 66,000 lives in total; in the United States they claimed an estimated 216,000 in total.29 While data is scarce and has just started to be analysed, it is likely that most deaths occurred in Southeast Asia, where both pandemics struck first and where poverty, malnutrition, famine, and weak and under-resourced healthcare systems made populations more vulnerable.30 Part of the problem was that until the late 1990s, national reporting labs and reference centres participating in the GISN were concentrated in the developed world. Developing countries lacked the resources, expertise, public health, and medical systems to participate in the programme fully. Vaccine production capacities were almost wholly concentrated in the developed world. But even these systems could not meet the needs of their own populations, let alone the rest of the world. Inequalities in the global burden of influenza, likely linked to inequalities in access to vital healthcare resources, including vaccines, have been very much part of the story of modern flu. Indeed, such disparities only became a major issue and started to be addressed at the end of the twentieth century, when focus turned to controlling avian influenza, which many experts feared would spark the next human pandemic.

3

Zoonotic Connections

One of the biggest breakthroughs in influenza science was the recognition in the 1960s that influenza viruses affected animals and, most crucially, that animals served as reservoirs and hosts from which viruses could spread into humans. We now know that all influenza viruses that

Pandemic’, Journal of Infectious Diseases, 212.11 (2015), 738–745; P.R. SaundersHastings & D. Krewski, ‘Reviewing the History of Pandemic Influenza: Understanding Patterns of Emergence and Transmission’, Pathogens, 5 (2016), 66; C. Viboud, R. Grais, B. Lafont et al., ‘Multinational Impact of Hong Kong Influenza Pandemic: Evidence for a Smoldering Pandemic’, Journal of Infectious Diseases, 192 (2005), 233–249. 29 US numbers are taken from CDC estimates for both epidemics: https://www. cdc.gov/flu/pandemic-resources/1957-1958-pandemic.html; UK numbers are taken from Ministry of Health, The Influenza Epidemic in England and Wales, 1957–1958; Jackson ‘History Lessons’, and Honigsbaum, ‘Revisiting’. 30 C. Viboud, L. Simonsen, M.A. Miller et al., ‘Global Mortality Impact of the 1957– 1959 Influenza Pandemic’.

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affect humans started out as non-human animal viruses.31 While the idea that this might be the case was first proposed by Richard Shope in the early 1930s, interest in the role of animals as influenza virus reservoirs began to be systematically explored in the 1950s and 1960s, as part of efforts to better understand virus variation.32 Christopher H. Andrewes and F. Macfarlane Burnet were among a growing number of scientists who speculated that variants that hampered vaccine efforts might have resulted from either the genetic recombination of human and animal viruses or through a zoonotic event in which an animal virus crossed over into humans. Both hypotheses pointed to the possible role of animal hosts. The prospect that animals might be the source of human influenza gave rise to new collaborations between experts and organisations working on human and animal health. Among the most important were partnerships between veterinary experts at the WHO and the Food and Agricultural Organization (FAO) to study zoonotic diseases. A FAO/ WHO Joint Expert Committee on Zoonoses was created in 1950, which brought together the WHO’s Veterinary Public Health Unit and the FAO’s Animal Health Branch. The Committee was tasked with identifying zoonoses that were evident ‘world problems’ and for which effective control measures existed or could be developed. Over the next decade, it established a standard definition of zoonoses, which brought over 100 different infections under one general category. It is worth noting that many of the zoonoses prioritised were infections originating from or affecting domestic livestock—cows, pigs, chickens, and sheep.33 Through the 1950s and 1960s, the WHO and FAO coordinated epidemiological studies and basic laboratory research on zoonoses, which included developing and standardising diagnostics, treatments, and

31 Robert G. Webster, W.J. Bean, O.T. Gorman, T.M. Chambers, and Y. Kawaoka, ‘Evolution and Ecology of Influenza A Viruses’, Microbiological Reviews, 56.1 (1992), 152–279; Kennedy F. Shortridge, ‘Avian Influenza Viruses in Hong Kong: Zoonotic Considerations’, in Remco S. Schrijver and G. Koch (Eds.), Avian Influenza: Prevention and Control (Dordrecht: Springer, 2005), 9–18. 32 W.I.B. Beveridge, ‘Influenza in Animals’, in idem., Influenza: The Last Great Plague (London: Heineman, 1977), 54–67. 33 WHO/FAO Expert Committee on Zoonoses, ‘Report on the Second Session’, WHO Tech Report Series, 40 (1951).

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vaccines. They invested in technical assistance to resource-poor countries that helped build or expand veterinary services, and to train local veterinarians and technicians in how to make and administer biological products for zoonotic disease control. This general approach to zoonoses was applied and developed in approaches to controlling influenza.34 The WHO carried out surveys of viruses related to human A-viruses in wild and domesticated animals around the world.35 Viruses, related to human strains, were soon found in pigs, ducks, horses, chickens, among others. In 1959, the Joint Committee on Zoonoses agreed to formally recognise influenza as a zoonotic disease.36 By the time the 1968 ‘Hong Kong’ influenza struck, A-viruses related to human strains had been identified in different animal species. What interested researchers most was the prospect that one of these animals might be the natural reservoir for human influenza viruses. The big question was whether one or more of these animals played a role in the changes to the virus that caused epidemics and pandemics, and how this happened. Influenza virologists had distinguished two types of change. One was called antigenic drift : it referred to the small mutations or adaptations in influenza viruses already established in and affecting human populations; slight changes in a prevailing strain explained why influenza infection never produced lasting immunity and why influenza returned each year. The other was called antigenic shift : it referred to rare instances when a new virus type suddenly replaced an established type, potentially causing a pandemic because populations had little or no immunity against it.37

34 The 1959 WHO/FAO Expert Committee defined zoonoses as ‘those diseases which are naturally transmitted between vertebrate animals and man.’ WHO/FAO Expert Committee on Zoonoses, ‘Second Report’, WHO Tech Report Series, 169 (1959), 3. The WHO still uses a version of this definition, characterising a zoonosis as ‘any disease or infection that is naturally transmissible from vertebrate animals to humans.’ The general assumption is that zoonosis is an ‘infectious disease that has jumped from a non-human animal to humans.’ https://www.who.int/news-room/fact-sheets/detail/zoonoses. 35 Martin M. Kaplan and Anthony A.-M. Payne, ‘Serological Survey in Animals for Type A Influenza in Relation to the 1957 Pandemic’, Bulletin of the World Health Organization, 20 (1959), 465–488. 36 WHO/FAO Expert Committee on Zoonoses, ‘Second Report’, WHO Tech Report Series, 169 (1959). 37 For a general account, see Beveridge, Influenza, 68–79.

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Researchers hoped both phenomena could be better understood once the natural reservoir of influenza A-viruses was found.38 After the 1968 Hong Kong influenza, determining the ecology of influenza viruses became a priority and epidemiological surveys scaled up considerably.39 The assumption that the 1957 and 1968 pandemics originated in China— as their formal names suggested—had also given rise and reinforced the idea that all influenza viruses resided ‘in an animal reservoir on the mainland of China.’40 It was an idea that would shape pandemic imaginaries of influenza thereafter.41 Paradoxically, however, the animal reservoir was not first found in China but on the Great Barrier Reef. In 1972, two Australian virologists, Graeme Laver and Robert Webster, announced they had determined that migratory aquatic birds were the natural hosts of influenza viruses.42 The announcement heralded a new era of approaches to influenza as a zoonosis. Its impact on approaches to influenza control took time, but the implications were huge: now virus surveillance had to also include wild birds and domesticated animals such as chickens and pigs, that might serve as mixing vessels from which a pandemic virus could spread into humans.43 The global ecology of influenza as a zoonotic infection was starting to come into view. New collaborations between human and veterinary medical experts and their organisations slowly gained urgency. WHO

38 Martin Kaplan and W.I.B. Beveridge, ‘WHO Coordinated Research on the Role of Animals in Influenza Epidemiology’, Bulletin of the World Health Organization, 47 (1972), 439–448. 39 Martin Kaplan, ‘The Role of the World Health Organization in the Study of Influenza’, Philosophical Transactions of the Royal Society of London B, 288 (1980), 419. 40 Kaplan and Payne, ‘Serological Survey in Animals for Type A Influenza in Relation to the 1957 Pandemic’, 488. 41 Robert Peckham, Epidemics in Modern Asia (Cambridge: Cambridge University Press, 2016), 276–284; Lyle Fearnley, Virulent Zones: Animal Disease and Global Health at China’s Pandemic Epicenter (Durham: Duke University Press, 2020). 42 Robert G. Webster and Graeme W. Laver, ‘The Origin of Pandemic Influenza’, Bulletin of the World Health Organization, 47 (1972), 449–452; William G. Laver, ‘From the Great Barrier Reef to a “Cure” for the Flu: Tall Tales, but True’, Perspectives in Biology and Medicine, 47.4 (2004), 590–596. 43 V.N. Milouchine, ‘The Role of WHO in International Studies on the Ecology of Influenza in Animals’, Comparative Immunology, Microbiology & Infectious Diseases, 3 (1980), 25–31.

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reference centres worked with medical and veterinary services, the FAO, and Office International des Epizooties (OIE) to create large collections of human and animal viruses and sera, which became crucial research tools for comparative analyses to sort out the roles of these viruses in human and animal outbreaks.44 The event that galvanised action was an outbreak of cases of a bird influenza virus—the infamous H5N1—in a small number of people in Hong Kong in 1997.45 The outbreak sent shockwaves and panic around the world. Its re-emergence in 2003 only added to the fear.46 Avian influenza was now on the global health agenda and spurred intensive pandemic planning over the next decade.47 The appearance of avian influenza coincided with a radical technological change in the identification, surveillance, and control of influenza viruses. For over fifty years, the standard tools for such work had been virus culture, serum-antibody tests, and virus antigen-based tests. These were crucial for determining the antigenic structure of influenza viruses and, in particular, identifying and tracking changes that occurred on two surface proteins—Haemagglutinin (HA) and Neuramindase (NA)— that were shown to be key to influenza virus infection and immunity.48 By the 1970s, influenza virus nomenclature and the classification of virus types, sub-types, and variants relied on egg-based methods of virus isolation, followed by the serological identification of HA and NA proteins—with the H-N system of virus classification becoming the norm.49 Improvements in virus cultivation and serological techniques enabled faster identification of antigenic drift and shift, and more rapid 44 The OIE was renamed the World Organization for Animal Health in 2003. 45 Jane Parry, ‘Ten Years Fighting Bird Flu’, Bulletin of the World Health Organization,

85.1 (2007), 3–4; D.J. Alexander and I.H. Brown, ‘History of Highly Pathogenic Avian Influenza’, Revue scientifique et technique (International Office of Epizootics), 28.1 (2009), 19–38. 46 Mike Davis, Monster at the Door: The Global Threat of Avian Flu (New York: New Press, 2005). 47 Ian Scoones and Paul Forster, ‘The International Response to Highly Pathogenic Avian Influenza: Science, Policy and Politics’, STEPS Working Paper No. 10 (Brighton: STEPS Centre, 2008). 48 Alfred Gottschalk, ‘The Influenza Virus Neuraminidase’, Nature, 181.4606 (1958), 377–378. W.G. Laver, ‘Influenza Virus Surface Glycoproteins, Haemagglutinin and Neuraminidase: A Personal Account’, Perspectives in Medical Virology, 7 (2002), 1–47. 49 ‘A Revised System of Nomenclature for Influenza Viruses’, Bulletin of the World Health Organization, 45.1 (1971), 119–124; ‘Reconsideration of Influenza A Virus

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selection of virus strains for use in the production of annual vaccines. Yet, growing viruses in embryonated eggs remained time-consuming and labour-intensive. Antigen-based tests that enabled quick identification of influenza A (and influenza B) viruses lacked the precision and sensitivity needed to distinguish subtypes, which was essential for both surveillance and vaccination. This situation changed dramatically in the 1990s with the introduction of polymerase chain reaction (PCR) technologies into influenza virus research.50 Adapted from work in genomics, the development of PCR tests, reverse-transcriptase PCR (RT-PCR), and then ‘real-time’ RT-PCR techniques made it possible to rapidly and accurately identify influenza virus variants, determine and compare their genetic structure, and carry-out retrospective analyses of past epidemics.51 PCR and RTPCR techniques enabled Jefferey Taubenberger and his colleagues to retrospectively identify the 1918–1919 influenza virus as ‘H1N1’, and thus re-write the history of the ‘Spanish’ influenza.52 More importantly, by the turn of the twentieth century real-time PCR and real-time RTPCR techniques were becoming crucial tools for influenza virus detection and surveillance, making available vast genetic databases of influenza virus variants.53 They quickly became essential tools in avian influenza virus surveillance and control, enabling scientists to screen and detect changing and novel avian influenza strains, and the mixing of genes among non-human animal and human viruses. In turn, the screening systems and databases that have arisen over the last two decades have become the basis for determining the composition of human and avian Nomenclature: A WHO Memorandum’, Bulletin of the World Health Organization, 57.2 (1979), 227–223. 50 For an overview, see Jeffery K. Taubenberg and Scott P. Layne, ‘Diagnosis of Influenza: Coming to Grips with the Molecular Age’, Molecular Diagnosis, 6 (2001), 291–305; Michel Morange, A History of Molecular Biology (Cambridge, MA: Harvard University Press, 1998), 219–230. 51 Paul Rabinow, Making PCR: A Story of Biotechnology (Chicago: University of Chicago Press, 1996). Influenza virus is an RNA-virus and requires the enzyme, reverse transcriptase transcribe RNA into DNA, enabling the virus to replicate within the host cell. 52 Jeffery K. Taubenberger, Anne H. Reid, and T.G. Fanning, ‘The 1918 Influenza Virus: A Killer Comes into View’, Virology, 274 (2000), 241–245. 53 Ruixue Wang and Jeffery Taubenberger, ‘Methods for Molecular Surveillance of Influenza’, Expert Review of Anti-infective Therapy, 8.5 (2010), 517–527.

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influenza vaccines. PCR technologies were attractive because they were relatively inexpensive and, unlike resource-demanding egg-based technologies, could be incorporated into most laboratories around the world. They underpinned the rapid processing of vast numbers of samples from human and non-human animals, the creation of massive sequence collections, and the significant extension of the scope and capacity of virus surveillance.54 But as influenza virus surveillance was becoming simultaneously molecularised and globalised at the turn of the twenty-first century, old problems of sharing and accessing virological knowledge and materials remained. When avian influenza broke out in humans in 1997 and again in 2003, the WHO and other agencies quickly mobilised around the potential threat. Countries were hastened to develop and test pandemicpreparedness plans if H5N1 or another avian influenza virus should acquire the means to rapidly spread in human populations. Avian influenza was framed as both a global public health and bio-security problem.55 It underscored the truism that the health of one country was intimately tied to the health of another; but also a new truism: that the health (or disease) of one species was closely tied to another. Over the next ten years enormous efforts were put into securing the world against a possible avian influenza pandemic. Considerable resources were invested in the capacity of low- and middle-income countries to participate in GISN. Because WHO, FAO, OIE and most influenza experts assumed that the next pandemic virus would emerge from Southeast Asia, a number of countries in the region—China, Vietnam, Thailand, and Indonesia, among others—became key sentinels in the system, with well-trained experts and equipped labs tasked with tracking and sharing human and animal influenza viruses.56 This facilitated rapid responses to 54 On avian influenza virus sample collections, Frédéric Keck, Avian Reservoirs: Virus Hunters & Birdwatchers in Chinese Sentinels Posts (Durham: Duke University Press, 2020), 139–148. 55 Institute of Medicine, Microbial Threats to Health: The Threat of Pandemic Influenza (Washington: National Academies Press, 2005); Sarah Davies, ‘Securitizing Infectious Disease’, International Affairs, 84 (2008), 295–313; Andrew Lakoff and Stephen J. Collier, Biosecurity Interventions: Global Health & Security in Question (New York: Columbia University Press, 2008). 56 Robert G. Webster and Diane Hulse, ‘Controlling Avian Flu at the Source’, Nature, 435 (26 May 2005), 415–416; Frédéric Keck, ‘Animal Health and Global Health: Avian Influenza in Asia’, Revue Tiers Monde, 215.3 (2013), 35–52.

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small outbreaks of avian influenza in humans and larger ones in growing livestock industries in the region, where poultry and pigs suspected of being infected were stamped out. The surveillance system also had the effect of concentrating world attention on the dangers associated with poultry and pig production in Southeast Asia. But rather than focus on massive production facilities that had sprung up since the 1990s to meet the voracious demand for chickens and pigs in the West and among growing middle-classes in the region, experts and officials focused on backyard producers and so-called wetmarkets as spaces of viral emergence.57 Fears about such sites resurfaced with vengeance in responses to Covid-19.

4

System Failures

These were not the only problems with systems developed to control avian influenza. Asian countries played a vital role in virus surveillance by freely sharing strains isolated within their borders with WHO reference labs. These strains were then passed onto vaccine manufacturers. But Asian countries gained little benefit from this arrangement: while viruses were freely shared, vaccines were not.58 They were still being produced by and for high-income countries, and this even though people in Southeast Asia were most at risk. A form of influenza vaccine nationalism reigned.59

57 See Peckham, Epidemics in Modern Asia, 276–284; Lyle Fearnley and Christos Lynteris, ‘Why Shutting Down ‘Wet Markets’ Could Be a Terrible Mistake’, The Conversation (31 January 2020). https://theconversation.com/why-shutting-down-chinese-wetmarkets-could-be-a-terrible-mistake-130625; Christos Lynteris, ‘Yellow Peril Epidemics: The Political Ontology of Degeneration and Emergence’, In F. Billé and S. Urbansky (Eds.), Yellow Perils (Hawaii: University of Hawaii Press, 2018), 34–53. 58 Laurie Garrett and David Fidler, ‘Sharing H5N1 Viruses to Stop a Global Influenza Pandemic’, Plos Medicine, 4 (2007), 330–332; David P. Fidler, ‘Influenza Virus Samples, International Law, and Global Health Diplomacy’, Emerging Infectious Diseases, 14.1 (2008), 88–94. 59 D.S. Fedson, ‘Pandemic Influenza and the Global Vaccine Supply’, Clinical Infectious Diseases, 36 (2003), 1552–1561; David S. Fedson and Peter Dunnill, ‘From Scarcity to Abundance: Pandemic Vaccines and Other Agents for ‘Have Not’ Countries’, Journal of Public Health Policy, 28.3 (2007), 322–340.

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In 2006, Indonesia sparked a crisis when it stopped sharing virus samples with the WHO.60 No beacon of democracy, Indonesia nonetheless argued that the WHO’s system failed to ensure reciprocal sharing of the key benefits of the system, particularly access to vaccines. Supported by several other Asian countries, Indonesia demanded that the WHO ensure that the benefits of sharing viruses be more equitably distributed. Change did not come quickly. No agreement was in place when the 2009 influenza pandemic struck, which only deepened developing countries’ mistrust because, once again, vaccines were not shared. After four years of negotiation, in May 2010, the ‘Pandemic Influenza Preparedness Framework’ (PIP) was formally approved by the World Health Assembly.61 On most accounts, the initial Framework was a mixed result. It only indirectly addressed the problem of vaccine sharing. The framework was not adopted as international law, so it was not legally binding. Developed countries were not obliged or encouraged to donate portions of purchased vaccines. Vaccine manufacturers agreed to assist developing countries in exchange for virus samples. Assistance was mostly in the form of technical support for participation in surveillance, with little investment in vaccine capacity. Vaccine manufacturers agreed to facilitate transfers of pandemic vaccines, but not seasonal vaccines. Crucially, intellectual property rights on vaccines remained protected. As international legal scholars David Fidler and Lawrence Gostin have argued, while an important step, this framework maintained the status quo on fundamental issues of sharing essential resources for controlling influenza.62 The problem of

60 Stefan Elbe, ‘Haggling over Viruses: The Downsides of Securitizing Infectious Disease’, Health Policy and Planning, 25 (2010), 476–485; Maurice Cassier, ‘Flu Epidemics, Knowledge Sharing and Intellectual Property’, In Tamara Giles-Vernick, Tamara, Susan Craddock, and Jennifer Lee Gunn (Eds.), Influenza and Public Health: Learning from Past Pandemics (London: Earthscan, 2010), 219–238. 61 World Health Organization, Pandemic Influenza Preparedness Framework for the Sharing of Influenza Viruses and Access to Vaccines and Other Benefits (Geneva: WHO, 2011). 62 David P. Fidler and Lawrence O Gostin, ‘The WHO Pandemic Influenza Preparedness Framework: A Milestone in Global Governance for Health’, Journal of the American Medical Association, 306.2 (2011), 200–201; Adam Kamradt-Scott and Kelly Lee, ‘The 2011 Pandemic Influenza Preparedness Framework: Global Health Secured or a Missed Opportunity?, Political Studies, 59.4 (2011), 831–847.

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unequal access to a vital health resource—and thus, also who lives and who dies with influenza—remained.

5

Cautionary Lessons

What can the history of modern flu teach us about learning to live with Covid-19? This snapshot of the global system built to control influenza highlights the enormous demands and challenges of living with influenza and the ever-changing viruses that cause it. Over the last eighty-years, a combination of residual fears about another Spanish flu, pandemics in 1957 and 1968, and the perceived threat of avian influenza spurred the consolidation of important forms of collaboration between international organisations, and between human and animal experts and agencies, which gave rise to new conceptions of the interconnections between human and animal health and disease—what has become known as ‘One Health’.63 These developments had important bearing on the global response to Covid-19. Without doubt, the expansion, integration, and effective working of WHO’s influenza virus surveillance system made possible the remarkably rapid characterisation and tracking of Sars-Cov-2. It is hard to imagine the equally remarkable pace of the development of Covid-19 vaccines without the model of influenza. Moreover, despite its flaws, the WHO’s PIP framework set in place a framework for sharing Covid-19 vaccines. Yet, by any measure, historical perspective should remind us of how hard it has been to live well with modern flu. International cooperation has been crucial, but it is also evident that the interests of the developed world have continually shaped global priorities and the organisation of control systems. Controlling influenza has required massive investments not just in science, surveillance, and vaccines, but in healthcare systems. Inequities persist in the resources, expertise, and infrastructures required for such systems within and between countries. While vaccines have been essential, capacities and supplies have not been shared equitably. The history of modern flu highlights how inequities have shaped all aspects of influenza control. 63 Abigail Woods and Michael Bresalier, ‘One Health, Many Histories’, The Veterinary Record, 174 (2014), 650–654; Michael Bresalier, Angela Cassidy, and Abigail Woods, ‘One Health in History’, In Jacob Zinstagg et al. (Eds.), One Health: The Theory and Practice of Integrated Health Approaches (Cabi International, 2015), 1–15.

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Reckoning with the history of modern flu control should be instructive for our future with Covid-19.64 This history should offer cautionary lessons. The reality is that influenza outbreaks and epidemics will not end. Control measures such as surveillance, annual vaccination, and culling of sick animals has made influenza endemic in parts of the world, in which the prevalence of influenza viruses ensures relatively constant levels of sickness and death. The brute numbers are not reassuring. In high-income countries, thousands still die annually from seasonal influenza. The WHO estimates that between 500,000 and 650,000 die each year around the world, mostly outside the high-income countries.65 Efforts to control influenza as an endemic disease have highlighted but not resolved global health inequalities. The toll of avian influenza has been no less daunting. Responses to avian influenza outbreaks in Southeast Asia have mostly targeted backyard and small-scale poultry producers and wet-markets, with tens of millions of chickens owned by small farmers slaughtered during H5N1 outbreaks over the last two decades.66 This has happened despite evidence that large-scale livestock operations might be sources of viral emergence and that globalised livestock systems may be key conduits for spreading new virus variants.67 The economic toll of stamping-out policies has been enormous and not shared equally. In 2022, poultry producers in Europe and North America were in the grips of the worst-ever avian influenza (H5N1) epidemic.68 In Britain 64 Sarah Zang, ‘The “End” of Covid Is Still Far Worse Than We Imagined’, The Atlantic (22 September 2022). https://www.theatlantic.com/health/archive/2022/09/ covid-pandemic-end-worse-than-flu/671514/?utm_source=pocket-newtab-global-en-GB. 65 J. Paget, P. Spreeuwenberg, V. Charu et al., ‘Global Mortality Associated with Seasonal Influenza Epidemics: New Burden Estimates and Predictors from the GLaMOR Project’, Journal of Global Health, 9.2 (2019). https://www.ncbi.nlm.nih.gov/pmc/art icles/PMC6815659/pdf/jogh-09-020421.pdf. 66 Ann D. Herring and Stacy Lockerbie, ‘The Coming Plague of Avian Influenza’, 189–190; and Stacy Lockerbie and Ann D. Herring, ‘Global Panic, Local Repercussions: Economic and Nutritional Effects of Bird Flu in Vietnam’, In Robert A. Hahn and Marcia C. Inhorn (Eds.), Anthropology and Public Health: Bridging Differences in Culture and Society, Second edition (New York: Oxford University Press, 2008 [1999]), 566–587. 67 Robert Peckham, Epidemics in Modern Asia, 280–284. 68 European Centre for Disease Prevention and Control, ‘2021–2022 Data Show

Largest Avian Flu Epidemic in Europe Ever’, https://www.ecdc.europa.eu/en/newsevents/2021-2022-data-show-largest-avian-flu-epidemic-europe-ever; US CDC, https:// www.cdc.gov/flu/avianflu/spotlights/2021-2022/update-human-avian-influenza.htm.

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alone, nearly 3 million poultry and other captive birds were culled or died; the figure in North America was nearly 50 million.69 The epidemic also spread rapidly through wild bird populations, killing scores of threatened and endangered species. And while only a few mild cases were reported in humans, the WHO warned, as it had for almost two decades, that ‘if the H5N1 virus were to change and become easily transmissible from person to person, while retaining its capacity to cause severe disease, the consequences for public health could be very serious.’70 The history of avian influenza serves as a stark reminder of how modern flu has become entwined with human interactions with animals, with changing environments, and with globalised systems of animal food production and consumption. Controlling modern flu now requires scientific and public health collaboration and systems that work across species to tackle its complex global ecologies and the biological, economic, and geopolitical challenges they present. Looking critically at the history of modern flu control brings us back to the question of whether the collective goal should be to attempt to live with Covid like we have with influenza. Does this mean accepting that Covid-19 is yet another infectious disease that carries away some people, but not others? Concepts of control and endemicity assume that a certain amount of sickness and death is inevitable. The biology and epidemiology of influenza in some ways dictate this to be the case. Indeed, a certain level of influenza morbidity and mortality has become an accepted part of the rational calculus of modern healthcare systems. Is this our future with Covid-19? It most likely is. But we need to ask how much sickness and death is acceptable? And when do such numbers become unacceptable? These are not just scientific questions but also profoundly moral and ethical ones. They should be front and centre when we look to the history of one disease as a guide, benchmark, or warning for the future of another. Every pandemic is a step into the unknown. Each brings with it unique problems that require unique solutions. The challenge is not just to learn to live with a new disease, but to create better ways of living with it for all humanity. 69 Lauren Jarvis, ‘The UK’s Largest Avian Influenza Outbreak Has Left Millions of Birds Dead—And Scientists Extremely Worried’, National Geographic (27 September 2022). https://www.nationalgeographic.co.uk/environment-and-conservation/2022/09/ the-uks-largest-avian-flu-outbreak-has-left-millions-of-birds-dead-and-scientists-extremelyconcerned. 70 World Health Organization, ‘Avian influenza’, Press Release, October 29, 2005.

Select Bibliography

Archival Repositories National Archives (NA) Medical Research Committee/Council (FD Series) Local Government Board (MH Series) Ministry of Health (MH Series) War Office (WO Series) Wellcome Library Archives Sir Walter Morley Fletcher, Correspondence Sir Christopher Howard Andrewes, Diaries and Notebooks Frederick William Twort, Papers and Correspondence Rockefeller Archives Centre World Health Organization National Institute for Medical Research (Personnel Papers) Patrick Playfair Laidlaw Christopher Howard Andrewes Wilson Smith Christopher Hebert Stuart-Harris

Journals and Newspapers Asclepiad British Journal of Experimental Pathology British Medical Journal Guy’s Hospital Reports © The Editor(s) (if applicable) and The Author(s), under exclusive licence to Springer Nature Limited 2023 M. Bresalier, Modern Flu, Medicine and Biomedical Sciences in Modern History, https://doi.org/10.1057/978-1-137-33954-6

397

398

SELECT BIBLIOGRAPHY

Journal of the American Medical Association Journal of the Army Medical Corps Journal of Laryngology and Otology Journal of Pathology and Bacteriology, Journal of Experimental Medicine Lancet Medical Annual Medical Supplement Medical Times Picture Post Proceedings of the Royal Society of Medicine Public Health St. Bartholomew’s Hospital Reports The Daily Express The Daily Mirror The Daily Telegraph The London Magazine The Manchester Guardian The Observer The Practitioner The Sphere The Times (London) Transactions of the Medical Society of London Veterinary Record

Government Publications Local Government Board, Provisional Memorandum Upon Precautions Advisable at Times When Epidemic Influenza Threatens or Is Prevalent (London: HMSO, 1890). Local Government Board, Memorandum on Influenza (London: HMSO, 1896). Local Government Board [Parsons], Report on the Influenza Epidemic of 1889– 1890, Local Government Board (London: HMSO, 1891). Local Government Board [Parsons], Further Report and Papers on Epidemic Influenza, 1889–92, Local Government Board (London: HMSO, 1893). Medical Research Committee, Interim Report on the Work in Connection with the War at Present Undertaken by the Medical Research Committee (London: HMSO, 1919). Medical Research Committee, First Report of the Medical Research Committee, 1914–15 (London: HMSO, 1916). Medical Research Committee, Annual Report of the Medical Research Committee, 1916–17 (London: HMSO, 1918)

SELECT BIBLIOGRAPHY

399

Medical Research Committee, Annual Report of the Medical Research Committee, 1917–18 (London: HMSO, 1919). Medical Research Committee, Studies of Influenza in Hospitals of the British Armies in France, 1918 (London: HMSO, 1919). Medical Research Council, Report of the Medical Research Council for the Year 1918–1919, Report of the Medical Research Council (London: HMSO, 1920). Medical Research Council, Report of the Medical Research Council for the Year 1919–1920, Report of the Medical Research Council (London: HMSO, 1921). Medical Research Council, Report of the Medical Research Council for the Year 1921–1922, Report of the Medical Research Council (London: HMSO, 1923). Medical Research Council, Report of the Medical Research Council for the Year 1922–1923, Report of the Medical Research Council (London: HMSO, 1924). Medical Research Council, Report of the Medical Research Council for the Year 1923–1924, Report of the Medical Research Council (London: HMSO, 1925). Medical Research Council, Report of the Medical Research Council for the Year 1924–1925, Report of the Medical Research Council (London: HMSO, 1926). Medical Research Council, Report of the Medical Research Council for the Year 1925–1926, Report of the Medical Research Council (London: HMSO, 1927). Medical Research Council, Report of the Medical Research Council for the Year 1927–1928, Report of the Medical Research Council (London: HMSO, 1929). Medical Research Council, Report of the Medical Research Council for the Year 1928–1929, Report of the Medical Research Council (London: HMSO, 1930). Medical Research Council, Report of the Medical Research Council for the Year 1930–1931, Report of the Medical Research Council (London: HMSO, 1932). Medical Research Council, Report of the Medical Research Council for the Year 1931–1932, Report of the Medical Research Council (London: HMSO, 1933) Medical Research Council, Report of the Medical Research Council for the Year 1932–1933, Report of the Medical Research Council (London: HMSO, 1934). Medical Research Council, Report of the Medical Research Council for the Year 1933–1934, Research (London: HMSO, 1935).

400

SELECT BIBLIOGRAPHY

Medical Research Council, Report of the Medical Research Council for the Year 1934–1935, Research (London: HMSO, 1936). Medical Research Council, Report of the Medical Research Council for the Year 1935–1936, Research (London: HMSO, 1937). Medical Research Council, Report of the Medical Research Council for the Year 1936–1937 , Research Council (London: HMSO, 1938). Medical Research Council, Report of the Medical Research Council for the Year 1937–1938, Research (London: HMSO, 1939). Medical Research Council, Report of the Medical Research Council for the Year 1938–1939, Research (London: HMSO, 1940). Ministry of Health, Influenza Vaccine: Instructions to Medical Officers of Health, Signed by George Newman (London: HMSO, 1919). Ministry of Health, Influenza Vaccine: Instructions for Medical Officers of Health (London: HMSO, 1920). Ministry of Health, Influenza: Hints and Precautions (London: HMSO, 1920). Ministry of Health, Report on the Pandemic of Influenza, 1918–19, Reports on Public Health and Medical Subjects, No. 4 (London: HMSO, 1920). Ministry of Health, Memorandum on Influenza (Revised Edition) (London: HMSO, 1927). Ministry of Health, Memorandum on Influenza (Revised Edition) (London: HMSO, 1929). Ministry of Health, Memorandum on Influenza (Revised Edition) (London: HMSO, 1939). Registrar-General [William Farr], Tenth Annual Report of the Registrar-General of Births, Deaths, and Marriages in England (London: HMSO, 1852). Registrar-General [William Farr], Sixteenth Annual Report of the Registrar General of Births, Deaths, and Marriages in England (London: HMSO, 1856). Registrar-General, Fifty-Fourth Annual Report of the Registrar-General (1891) (London: HMSO, 1892). Registrar-General, Sixty-Third Annual Report of the Registrar General (1900) (London: HMSO, 1902). Registrar-General, Report on the Mortality from Influenza in England and Wales During the Epidemic of 1918–19, Supplement to the Eighty-First Annual Report of the Registrar-General (London: HMSO, 1920).

Primary Literature Abrahams, Adolph, ‘Epidemic at Aldershot: Discussion’, Transactions of Royal Society of Medicine, 12 (1917), 97. Abrahams, Adolph, N.F. Hollows, and Herbert French, ‘A Further Investigation into Influenzo-Pneumococcal and Influenzo-Streptococcal Septicaemia:

SELECT BIBLIOGRAPHY

401

Epidemic Influenzal “Pneumonia” of Highly Fatal Type and Its Relation to “Purulent Bronchitis’, Lancet (4 January 1919), 1–11. Abrahams, Adolph, N.F. Hollows, J.W.H. Eyre, and Herbert French, ‘Purulent Bronchitis: Its Influenza and Pneumococcal Bacteriology’, Lancet (8 September 1917), 377–380. Adami, John George, ‘Influenza’, in W.G. MacPherson, W.B. Leishman, and S.L. Cummins (Eds.), History of the Great War Based on Official Documents. Medical Services. Pathology (London: HMSO, 1923), 413–466. Allbutt, Thomas C. ‘Influenza’, The Practitioner, LXXVII (1907), 1–10. Althaus, Julius, ‘Pathology of Influenza, with Special Reference to Its Neurotic Character’, Lancet (21 November 1891), 1156–1158. Althaus, Julius, ‘Pathology of Influenza, with Special Reference to Its Neurotic Character’, Lancet (14 November 1891), 1091–1093. Althaus, Julius, Influenza: Its Pathology, Symptoms, Complications, and Sequels (London: Longmans, 1892). Andrewes, Christopher H., ‘The Action of Immune Serum on Vaccinia Virus and Virus III in vitro’, Journal of Pathology and Bacteriology, 31 (1928), 671–72. Andrewes, Christopher H., ‘Antivaccinial Serum. 3. Evidence for Slow Union with Virus in vitro’, Journal of Pathology and Bacteriology, 33 (1930), 265. Andrewes, Christopher H., ‘Immunity in Virus Diseases’, Lancet (2 May 1931), 989–992. Andrewes, Christopher H., ‘Immunity in Virus Diseases’, Lancet (9 May 1931), 1046–1049. Andrewes, Christopher H., ‘Influenza: Four Years’ Progress’, British Medical Journal (11 September 1937), 513–514. Andrewes, Christopher H., ‘Thoughts on the Origin of Influenza Epidemics [President’s Address]’, Proceedings of the Royal Society of Medicine, 36 (1942), 1–10. Andrewes, Christopher H., ‘Influenza in Perspective’, Edinburgh Medical Journal, LVI (1949), 337–346. Andrewes, Christopher H., ‘The Significance of Strain Differences in Virus Prophylaxis’, Proceedings of the Royal Society of Medicine, 42 (1949), 519. Andrewes, Christopher H., ‘Adventures among Viruses, II. Epidemic Influenza’, New England Journal of Medicine, 242 (1950), 197–203. Andrewes, Christopher H., ‘Epidemiology of Influenza in Light of the 1951 Outbreak’, Proceedings of the Royal Society of Medicine, 44 (1951), 803–804. Andrewes, Christopher H., ‘Influenza Virus and the Beginnings of Its Study in the Laboratory’, The Medical Press (1951), 225. Andrewes, Christopher H., ‘The Work of the World Influenza Centre’, Journal of the Royal Institute of Public Health, 15 (1952), 309–318. Andrewes, Christopher H., ‘William Ewart Gye, 1884–1952’, Obituary Notices of Fellows of the Royal Society, 8 (1952), 418–430.

402

SELECT BIBLIOGRAPHY

Andrewes, Christopher H., ‘William Joseph Elford’, Obituary Notices of Fellows of the Royal Society, 8 (1952–1953), 149–158. Andrewes, Christopher H., ‘Epidemiology of Influenza’, Bulletin of the World Health Organization, 8 (1953), 595–612. Andrewes, Christopher H., ‘How Much Do We Know About Influenza’ (Women’s Hour, BBC Home Service, 9 February, 1955). Andrewes, Christopher H., and Wilson Smith, ‘Influenza: Further Experiments on the Active Immunisation of Mice’, British Journal of Experimental Pathology, XVIII (1937), 305–315. Andrewes, Christopher H., and Wilson Smith, ‘The Effect of Foreign Tissue Extracts on the Efficacy of Influenza Vaccines’, British Journal of Experimental Pathology, XX (1939), 320–325. Andrewes, Christopher H., Patrick P. Laidlaw, and Wilson Smith, ‘Influenza: Observations on the Recovery of Virus from Man and on the Antibody Content of Human Sera’, British Journal of Experimental Pathology, XVI (1935), 566–582. Andrewes, Christopher H., Wilson Smith, and Patrick P. Laidlaw, ‘The Susceptibility of Mice for the Viruses of Human and Swine Influenza’, Lancet (20 October 1934), 859–862. Andrewes, Fredrick W., ‘The Work and Needs of the Pathological Department’, St Bartholomew’s Hospital Journal, 11 (1904), 105–109. Andrewes, Fredrick W., ‘The Bacteriology of Influenza’, in Report on the Pandemic of Influenza, 1918–19, Ministry of Health, Reports on Public Health and Medical Subjects, No. 4 (London: HMSO, 1920), 110–125. Andrewes, Fredrick W., ‘The Beginnings of Bacteriology at Barts’, St Bartholomew’s Hospital Journal, 35 (1928), 100–104; 116–117. Anon., ‘Meeting of the British Medical Association—Bacteriology of Influenza’, Lancet (2 September 1922), 518. Arkwright, Joseph A., ‘A Criticism of Certain Recent Claims to Have Discovered and Cultivated the Filter-Passing Virus of Trench Fever and of Influenza’, British Medical Journal (23 August 1919), 233–235. Barnard, Joseph E., ‘The Microscopical Examination of Filterable Viruses’, Lancet (18 July 1925), 117–123. Bashford, E.F., ‘Experimental Reproduction of Influenza, Nephritis, and Encephalitis by Inoculating Subcultures of the Isolated Virus’, British Medical Journal (17 May 1919), 601–02. Beaumont, G.E., Medicine: Essentials for Practitioners and Students (London: J&A Churchill, 1942). Bedson, Samuel P., ‘Observations on the Mode of Action of a Viricidal Serum’, British Journal of Experimental Pathology, IX (1928), 235–240. Bedson, Samuel P., ‘Some Reflections on Virus Immunity’, Proceedings of the Royal Society of Medicine, XXXI (1937), 59–68.

SELECT BIBLIOGRAPHY

403

Bedson, Samuel P., ‘John Charles Grant Ledingham. 1875–1944’, Obituary Notices of Fellows of the Royal Society, 5 (1945–1948), 325–340. Besson, Albert, Practical Bacteriology, Microbiology and Serum Therapy (Medical and Veterinary): A Textbook for Laboratory Use (London: Longmans, Green and co., 1913). Beveridge, William I.B., and F.M. Burnet, The Cultivation of Viruses and Rickettsiae in the Chick Embryo (London: HMSO, 1946). Bradford, John R., E.F. Bashford, and J.A. Wilson, ‘Preliminary Report on the Presence of a Filter-Passing Virus in Certain Diseases with special reference to Trench Fever, Influenza and Nephritis’, Lancet (1 February 1919), 127–128. Bradford, John R., E.F. Bashford, and J.A. Wilson, ‘The Filter-Passing Virus of Influenza’, Quarterly Journal of Medicine, 12 (1919), 259–306. Brownlee, John, ‘The Next Epidemic of Influenza’, Lancet (8 November 8 1919), 856–857. Buchanan, George, ‘Introduction by the Medical Officer’, in Report on the Influenza Epidemic of 1889–90 (London: Her Majesty’s Stationery Office, 1891). Burnet, F. Macfarlane, ‘A Virus Disease of the Canary of the Fowl-Pox Group’, Journal of Pathology and Bacteriology, 37 (1933), 107–122. Burnet, F. Macfarlane, ‘Influenza Virus Isolated from an Australian Epidemic’, Medical Journal of Australia, 2 (1935), 651–653. Burnet, F. Macfarlane, ‘Influenza Virus on the Developing Egg. 1. Changes Associated with the Development of an Egg-Passage Strain of Virus’, British Journal of Experimental Pathology, 17 (1936), 282–293. Burnet, F. Macfarlane, ‘Influenza on the Developing Egg. 2. Titration of Egg-Passage Virus by the Pock-Counting Method’, Australian Journal of Experimental Biology and Medical Science, 14 (1936), 241–246. Burnet, F. Macfarlane, ‘Influenza on the Developing Egg. 3. The ‘Neutralization’ of Egg Virus by Immune Sera’, Australian Journal of Experimental Biology and Medical Science, 14 (1936), 247–258. Burnet, F. Macfarlane, The Use of the Developing Chick Egg in Virus Research (London: Medical Research Council, HMSO, 1936). Burnet, F. Macfarlane, ‘Influenza Infections of the Chick Embryo by the Amniotic Route’, Australian Journal of Experimental Biology and Medical Science, no. 18 (1940), 353–360. Burnet, F. Macfarlane, ‘Influenza Infection of the Chick Embryo Lung’, British Journal of Experimental Pathology, 21 (1940), 147–153. Burnet, F. Macfarlane, ‘Growth of Influenza Virus in the Allantoic Cavity of the Chick Embryo’, Australian Journal of Experimental Biology and Medical Science, 19 (1941), 291.

404

SELECT BIBLIOGRAPHY

Burnet, F. Macfarlane, Virus as Organism: Evolutionary and Ecological Aspects of Some Human Virus Diseases (Cambridge, MA.: Harvard University Press, 1946). Burnet, F. Macfarlane, ‘Some Biological Implications of Studies on Influenza Viruses’, Bulletin of the Johns Hopkins Hospital, 88 (1951), 119–80. Burnet, F. Macfarlane, ‘Some biological implications of studies on influenza viruses’, Bulletin of the Johns Hopkins Hospital, 88 (1951), 119–180. Burnet, F. Macfarlane, and E. Clark, Influenza: A Survey of the Last 50 Years in the Light of Modern Work on the Virus of Epidemic Influenza (Melbourne: Macmillan, 1942). Burnet, F. Macfarlane, and J.D. Ferry, ‘Differentiation of the Viruses of Fowl Plague and Newcastle Disease: Experiments Using the Technique of ChorioAllantoic Membrane Inoculation of the Developing Egg’, British Journal of Experimental Pathology, 15 (1934), 54–56. Burnet, F. Macfarlane, E.V. Keogh, and D. Lush, ‘The Immunological Reactions of Filterable Viruses’, Medical Journal of Australia, 15 (1937), 1–310. Burnet, John, ‘What Is Influenza?’, The Medical Times (20 February 1937), 20. Burnford, John, ‘A Note on Epidemics’, British Medical Journal (20 July 1918), 50–51. Cameron, H.C., ‘Patrick Playfair Laidlaw’, Guy’s Hospital Reports, 90 (1940– 1941), 1–14. Carré, Henri, ‘Sur la maladie des jeunes chiens’, Comptes rendus de l’Académie des Sciences, CXL (29 Mai 1905), 689–690. Clemow, Frank, ‘Epidemic Influenza’, Public Health, 24 (April 1890), 358–366. Clemow, Frank, ‘The Epidemic Influenza in Eastern Europe’, British Medical Journal (7 December 1889), 1305. Clemow, Frank, ‘The Recent Pandemic of Influenza: Its Place of Origin and Mode of Spread’, Lancet (20 January 1894), 140–143. Coles, Alfred C., Clinical Diagnostic Bacteriology (London: J&A Churchill, 1904). Committee on Standard Serological Procedures in Influenza Studies, ‘An Agglutination-Inhibition Test Proposed as a Standard of Reference in Influenza Diagnostic Studies’, Journal of Immunology, 65 (1950), 347–353. Copeman, Sidney Monckton, ‘The Micro-organism of Distemper in the Dog and the Production of a Distemper Vaccine’, Proceedings of the Royal Society of London, 67 (1900), 459–461. Creighton, Charles, A History of Epidemics in Britain, Vol. II (London: Cambridge University Press, 1894). Creighton, Charles, ‘Influenzas and Epidemic Agues’, in A History of Epidemics in Britain, Vol II (London: Cambridge University Press, 1894), 306–433. Crofton, William M., The True Nature of Viruses (London: John Bale, Sons & Curnow, 1936).

SELECT BIBLIOGRAPHY

405

Crofton, William M., The True Nature of Viruses (London: John Bale, Sons & Curnow, 1939). Crookshank, Edgar M., A Textbook of Bacteriology (London: HK Lewis, 1896). Crookshank, Francis Graham, Influenza: Essays by Several Authors (London: Heinemann, 1922). Crookshank, Francis Graham, ‘The Name and Names of Influenza’, in Francis Graham Crookshank (Ed.), Influenza: Essays by Several Authors (London: Heinemann, 1922), 64–102. Cullbertson, James T., ‘Plans for United States Cooperation with the World Health Organization in the International Influenza Study Program’, American Journal of Public Health, 39 (1949), 37–43. Cummins, S.L., ‘Major H.G. Gibson’, British Medical Journal (8 March 1919), 294–295. Cummins, S.L., Studies of Influenza in Hospitals of the British Armies in France, Medical Research Committee, Special Report Series No. 36 (London: HMSO, 1919). Dale, Henry H., ‘Patrick Playfair Laidlaw’, Obituary Notices of Fellows of The Royal Society, 3 (1941), 427–447. Dale, Henry H., ‘Experiment in Medicine’, Cambridge Historical Journal, 8 (1946), 166–178. Dalling, Thomas, ‘George William Dunkin, 1886–1942’, Journal of Pathology and Bacteriology, 54 (1942), 401–402. Davenport, F.M., A.V. Hennessy, C.H. Stuart-Harris, and T. Francis Jr., ‘Epidemiology of Influenza. Comparative Serological Observations in England and the United States’, Lancet, 55 (1955), 469. Davis, Dorland J. ‘World Health Organization: Influenza Study Program in the United States’, Public Health Reports, 67 (1952), 1185–1190. Donaldson, Robert, ‘The Bacteriology of Influenza—With Special Reference to Pfeiffer’s Bacillus’, in Francis Graham (Ed.), Influenza: Essays by Several Authors (London: William Heinemann, 1922), 139–213. Douthwaite, A.H., ‘Influenza’, in H. Rolleston (Ed.), The British Medical Encyclopaedia of Medical Practice (London: Butterworth & Co., 1937), 174–190. Dunkin, G.W., and P.P. Laidlaw, ‘Studies in Dog-Distemper. II. Experimental Distemper in the Dog’, Journal of Comparative Pathology and Therapeutics, 39 (1926), 201–213. Dunn, R.A., and M.H. Gordon, ‘Remarks on Clinical and Bacteriological Aspects of an Epidemic Simulating Influenza Which Recently Occurred in East Herts District’, British Medical Journal (26 August 1905), 421–427. Dujarric de la Riviere, R., ‘La grippe est-elle une maladie a virus filtrant?’, Comptes Rendus de l’Academie des Sciences. Paris, 67 (1918), 606–607. East, C.F.T., ‘Pneumococcal Influenza’, British Medical Journal, 2 (1922), 1117.

406

SELECT BIBLIOGRAPHY

Edington, J.W., ‘An Investigation into the Causal Organism of Influenza’, Lancet (14 August 1920), 340–345. Editorial, ‘Influenza and Immunity: The Prophylactic Value of Protective Injections’, The Hospital (1919), 331–332. Editorial, ‘Progress Against Influenza’, Journal of the Royal Army Medical Corps (1 April 1945), 199–220. Eichhorn, A., ‘Credit Where Credit Is Due (Letter to the Editor)’, Journal of the American Veterinary Medical Association, 85 (1934), 823–824. Elford, William J., ‘Structure in Very Permeable Collodion Gel Films and Its Significance in Filtration Problems’, Proceedings of the Royal Society B, 106 (1930), 216. Elford, William J., ‘A New Series of Graded Collodion Membranes Suitable for General Bacteriological Use, Especially in Filterable Virus Studies’, Journal of Pathology and Bacteriology, 34 (1931), 505. Elford, William J., ‘Ultraviolet Light Photography’, in R. Doerr and C. Hallauer (Eds.), Handbuch der Virusforschung (Vienna: Verlag von Julius Springer, 1938), 181–190. Elford, William J., and J.D. Ferry, ‘The Calibration of Graded Collodion Membranes’, British Journal of Experimental Pathology, XVI (1935), 1–14. Emery, W.D.E., ‘The Micro-organisms of Influenza’, The Practitioner, LXXVII (1907), 109–117. Emery, W.D.E., ‘Influenza and the Use of Vaccines’, The Practitioner, LXXXIV (1919), 64–76. Evans, D.G., ‘Wilson Smith, 1897–1965’, Biographical Memoirs of Fellows of the Royal Society, 2 (November 1966), 478–487. Eyre, J.W.H., The Elements of Bacteriological Technique: A Laboratory Guide for Medical, Dental, and Technical Students (London: W.B. Saunders & Company, 1902). Eyre, J.W.H., and C.E. Lowe, ‘Prophylactic Vaccinations Against Catarrhal Affections of the Respiratory Tract’, Lancet, II (1918), 484–487. Ferry, Newell S., ‘Etiology of Canine Distemper’, Journal of Infectious Diseases, 4 (1911), 399–420. Fildes, Paul, ‘Unititled Editorial’, British Journal of Experimental Pathology, I (1920), i–ii. Fildes, Paul, ‘James McIntosh 1882–1948’, Journal of Pathology and Bacteriology, 61 (1949), 285–299. Fildes, Paul, ‘Frederick William Twort, 1877–1950’, Obituary Notices of Fellows of the Royal Society, 7 (1951), 507–517. Fildes, Paul, and J.C.G. Ledingham, ‘Viruses and Virus Diseases’, in Medical Research Council, A System of Bacteriology in Relation to Medicine (London: HMSO, 1930).

SELECT BIBLIOGRAPHY

407

Fildes, Paul, and James McIntosh, ‘A New Apparatus for the Isolation and Cultivation of Anearobic Micro-Organisms’, Lancet, 1 (1916), 768–770. Fildes, Paul, and James McIntosh, ‘The Aetiology of Influenza’, British Journal of Experimental Pathology, II (1920), 159–174. Fildes, Paul, S.L. Baker, and W.R. Thompson, ‘Provisional Notes on the Pathology of the Present Epidemic’, Lancet (23 November 1918), 695–700. Finkler, D., ‘Influenza’, in T.L. Stedman (Ed.), Twentieth Century Practice: An International Encyclopedia of Modern Medical Science (London: Sampson Low, Martson & Co, 1898), 1–249. Fleming, Alexander, ‘On Some Simply Prepared Culture Media for B. Influenzae, with a Note Regarding the Agglutination Reaction of Sera from Patients Suffering from Influenza to This Bacillus’, Lancet (25 January 1919), 138–139. Fleming, Alexander, ‘On the Antibacterial Action of Cultures of a Penicillum, with Special Reference to Their Use in the Isolation of B. Influenzae’, British Journal of Experimental Pathology, X (1929), 226–234. Fleming, Alexander, and F.J. Clemenger, ‘An Experimental Research into the Specificity of the Agglutinins Produced by Pfeiffer’s Bacillus’, Lancet (15 November 1919), 869–871. Fleming, Alexander, and I.H. Maclean, ‘On the Occurence of Influenza Bacilli in the Mouths of Normal People’, British Journal of Experimental Pathology, XI (1930), 127–134. Fletcher, Walter M., ‘The National Organisation of Medical Research in Peace After War’, in W.E. Welch, et al. (Eds.), Contributions to Medical and Biological Research, Dedicated to Sir William Osler (New York: Paul B. Hoeber, 1919), 461–470. Francis, Thomas Jr., ‘Transmission of Influenza by a Filterable Virus’, Science, 80 (1934), 457–459. Francis, Thomas Jr., ‘Recent Advances in the Study of Influenza’, Journal of the American Medical Association, 105 (1935), 251–254. Francis, Thomas Jr., ‘Etiological and Immunological Aspects of Influenza’, Health Examiner, 5 (1936), 589. Francis, Thomas Jr., ‘The Immunology of Epidemic Influenza’, Journal of Experimental Medicine, 1 (1938), 63–79. Francis, Thomas Jr., ‘A New Type of Virus from Epidemic Influenza’, Science, 91 (1940), 405–408. Francis, Thomas Jr., ‘The Problem of Epidemic Influenza’, Transactions of the College of Physicians of Philadelphia, 8 (1941), 218–227. Francis, Thomas Jr., ‘The Development of the 1943 Vaccination Study of the Commission on Influenza’, American Journal of Hygiene, 42 (1945), 1–11. Francis, Thomas Jr., ‘Influenza: Methods of Study and Control’, Bulletin of the New York Academy of Medicine, (July 1945), 337–355.

408

SELECT BIBLIOGRAPHY

Francis, Thomas Jr., ‘The Present Status of Vaccination Against Influenza’, American Journal of Public Health, 37 (1947), 1109–1112. Francis, Thomas Jr., ‘Vaccination Against Influenza’, Bulletin of the World Health Organization, 8 (1953), 725–742. Francis, Thomas Jr., ‘The Current Status of the Control of Influenza’, Annals of Internal Medicine, 43 (1955), 534–538. Francis, Thomas Jr., and T.P. Magill, ‘Immunological Studies with the Virus of Influenza’, Journal of Experimental Medicine, 62.4 (1935), 505–516. Francis, Thomas Jr., and T.P. Magill, ‘Antibody Response of Human Subjects Vaccinated with the Virus of Influenza’, Journal of Experimental Medicine, 65.2 (1936), 251–259. Francis, Thomas Jr., and T.P. Magill, ‘Antigenic Differences in Strains of Epidemic Influenza Virus. 2. Cross Immunisation Tests in Mice’, British Journal of Experimental Pathology, 19 (1938), 284–293. French, Herbert, ‘Influenza’, Guy’s Hospital Gazette, XXXIII (1919), 118–127. French, Herbert, ‘The Clinical Features of the Influenza Epidemic of 1918– 1919’, in Ministry of Health, Report on the Pandemic of Influenza, 1918– 1919, Reports on Public Health and Medical Subjects, No. 4. (London: HMSO, 1920), 66–78. French, Herbert, ‘Influenza’, in W.G. MacPherson, W.P. Herringham, and A. Balfour (Eds.), History of the Great War Based on Official Documents. Medical Services. Diseases of the War (London: HMSO, 1920), 174–208. Gale, A.H., Epidemic Diseases (London: Penguin Books, 1959). Garrod, L.P., ‘Filter-Passing Anaerobes in the Upper Respiratory Tract’, British Journal of Experimental Pathology, IX (1928), 155–160. Garrod, L.P., ‘Mervyn H. Gordon 1872–1953’, Obituary Notices of Fellows of the Royal Society, 9 (1954), 153–163. Gibson, H.G., F.B. Bowman, and J.I. Connor, ‘A Filtrable Virus as the Cause of the Early Stage of the Present Epidemic of Influenza’, British Medical Journal (14 December 1918), 645–646. Gibson, H.G., F.B. Bowman, and J.I. Connor, ‘The Etiology of Influenza: A Filterable Virus as the Cause’, in Medical Research Committee, Studies of Influenza in Hospitals of the British Armies in France, 1918 (London: HMSO, 1919), 19–36. Gladstone, G.P., C.J.G. Knight, and G.S. Wilson, ‘Paul Gordon Fildes, 1882– 1971’, Biographical Memoirs of Fellows of the Royal Society, 19 (1973), 317– 374. Goodhart, J.F., ‘Influenza’, in T.C. Albutt (Ed.), A System of Medicine (London: Macmillan and Co., 1896), 679–700. Goodhart, J.F., ‘Influenza’, in T.C. Allbutt and H.D. Rolleston (Eds.), A System of Medicine (London: Macmillan and Co., 1905), 942–967.

SELECT BIBLIOGRAPHY

409

Goodpasture, E.W., A.M. Woodruff, and G.J. Buddingh, ‘The Cultivation of Vaccine and Other Viruses in the Chorio-Allantoic Membrane of Chick Embryos’, Science, 74 (1931), 371–372. Gordon, Mervyn H., ‘Notes on Acute Poliomyelitis with Reference to Its Etiology, Histology, and as to Immunity’, Reports of Local Government Board, Medical Officer (London: Local Government Board, 1911–1912), 115–121. Gordon, Mervyn H., ‘On Experimental Investigations in Relation to Mumps or Epidemic Parotitis’, Reports of Local Government Board, Public Health, New Series, 96 (London: Local Government Board, 1914). Gordon, Mervyn H., ‘The Filter Passer of Influenza’, Journal of the Royal Army Medical Corps, 39 (1 July 1922), 1–12. Gordon, Mervyn H., ‘The Filter Passer of Influenza’, Journal of the Royal Army Medical Corps, 39 (1 November 1922), 400–401. Gordon, Mervyn H., Studies of the Viruses of Vaccinia and Variola, Medical Research Council Special Report Series, 98 (London: HMSO, 1925). Gotch, O.H., and H.E. Whittingham, ‘A Report on the “Influenza” Epidemic of 1918’, British Medical Journal (27 July 1918), 82–85. Gray, W., Influenza, with Special Reference to Some Peculiar Symptoms (London: H.K. Lewis, 1897). Greenwood, Major, ‘Discussion on Influenza’, Proceedings of the Royal Society of Medicine, 12 (1918), 21–24. Greenwood, Major, ‘The Epidemiology of influenza’, British Medical Journal (November 23 1918), 563–566. Greenwood, Major, ‘A General Discussion of the Epidemiology of Influenza’, in Ministry of Health, Report on the Pandemic of Influenza, 1918–19, Reports on Public Health and Medical Subjects, No. 4 (London: HMSO, 1920) 182– 196. Greenwood, Major, ‘The History of Influenza, 1658–1911’, in Ministry of Health, Report on the Pandemic of Influenza, 1918–19, Reports on Public Health and Medical Subjects, No. 4 (London: HMSO, 1920), 3–30. Greenwood, Major, ‘The Periodicity of Influenza’, Journal of Hygiene, 29 (1929), 227–235. Greenwood, Major, Epidemics and Crowd Diseases: An Introduction to the Study of Epidemiology (London: Williams and Norgate, 1935). Gye, William E., ‘The Aetiology of Malignant New Growths’, Lancet (18 July 1925), 109–117. Gye, William E., ‘Contribution to a Discussion On: Filter-Passing Viruses and Cancer’, British Medical Journal (1 August 1925), 189–192. Hamer, William H., The Relationship Between Influenza, Cerebrospinal Fever, and Poliomyelitis. Appendix to the Report of the County Medical Officer of Health, and School Medical Officer for the Year 1918 (London: County Hall, 1919).

410

SELECT BIBLIOGRAPHY

Hamer, William H., Report on Influenza by the County Medical Officer of Health (London: County Hall, 1919). Hamer, William H., ‘The Influenzal Constitution’, Proceedings of the Royal Society of Medicine, 20 (1927), 1349–1368. Hammond, J.A.B., W. Rolland, and T.H.G. Shore, ‘Purulent Bronchitis: A Study of Cases Occurring Among the British Troops at a Base in France’, Lancet (14 July 1917), 41–46. Harding, Arthur R. Ferret Facts and Fancies: A Book of Practical Instructions on Breeding, Raising, Handling and Selling; Also Their Uses and Fur Value (Columbus: A.R. Harding, 1919). Harrington, C.H., ‘The Work of the National Institute for Medical Research’, Proceedings of the Royal Society of London, 136 (1950), 333–349. Harris, W., ‘The Nervous System in Influenza’, The Practitioner (August 1907), 70–85. Hewlett, R.T., A Manual of Bacteriology, Clinical and Applied (London: J. & A. Churchill, 1898). Hewlett, R.T., A Manual of Bacteriology, Clinical and Applied (London: J. & A. Churchill, 1918). Heywood, A., Influenza: Its Causes, Cure and Prevention (Manchester: Abel Heywood & Son, 1902). Hirsch, A., Handbook of Geographical and Historical Pathology, trans. Charles Creighton (London: New Sydenham Society, 1883). Hirst, George K., ‘Agglutination of Red Cells by Allantoic Fluid of Chick Embryos Infected with Influenza Virus’, Science, 94 (1941), 22. Hirst, George K., ‘The Quantitative Determination of Influenza Virus and Antibodies by Means of Red Cell Agglutination’, Journal of Experimental Medicine, 75 (1942), 49–64. Hirst, George K., ‘Adsorpton of Influenza Hamagglutinins and Virus by Red Blood Cells’, Journal of Experimental Medicine, 76 (1942), 195–209. Hirst, George K., ‘Direct Isolation of Human Influenza in Chick Embryos’, Journal of Immunlogy, 45 (1942), 293. Horder, Thomas S., ‘Influenza and Preventive Inoculation’, Lancet (9 November 1918), 642. Horder, Thomas S., ‘Some Observations on the More Severe Cases of Influenza Occurring During the Present Epidemic’, Lancet (28 December 1918), 871– 873. Horder, Thomas S., ‘General Principles in the Treatment of Influenza’, Lancet (23 November 1918), 694–695. Horder, Thomas J., ‘Treatment of Influenza’, in Treatment in General Practice (London: H.K. Lewis & Co., 1936), 1–5. Horsfall, Frank L., ‘Present Status of Knowledge Concerning Influenza’, American Journal of Public Health, 30 (1940), 1302–1310.

SELECT BIBLIOGRAPHY

411

Horsfall, Frank L., and E.H. Lennette, ‘A Complex Vaccine Effective Against Different Strains of Influenza Virus’, Science, 91 (1940), 492–494. Horsfall, Frank L., E.H. Lennette, E.R. Rickard, and G.K. Hirst, ‘Studies of the Efficacy of a Complex Vaccine Against Influenza A’, Public Health Reports, 56 (1941), 1863–1875. Hoyle, L., and R.W. Fairbrother, ‘Isolation of the Influenza Virus and the Relation of Antibodies to Infection and Immunity. The Manchester Influenza Epidemic of 1937’, British Medical Journal, (27 March 1937), 655. Influenza Committee of the Advisory Board to the D.G.A.M.S., ‘The Influenza Epidemic in British Armies in France, 1918’, British Medical Journal, (9 November 1918), 505. Jack, W.R., Wheeler’s Handbook of Medicine and Therapeutics (Edinburgh: E&S Livingstone, 1903). Jordan, E.O., A Text-Book of General Bacteriology (London: W.B. Saunders, 1908). Jordan, E.O., A Text-Book of General Bacteriology (London: W.B. Saunders, 1921). Jordan, E.O., Epidemic Influenza: A Survey (Chicago: American Medical Association, 1927). Kirk, Hamilton, Canine Distemper: Its Complications, Sequelae and Treatment (London: Baillière, Tindall & Cox, 1922). Kitasato, S., ‘On the Influenza Bacillus and the Mode of Cultivating It’, British Medical Journal, (16 January 1892), 128. Klein, Edward E., ‘Some Remarks on the Influenza Bacillus’, British Medical Journal, (23 January 1892), 171. Klein, Edward E., ‘Report on Influenza in Its Clinical and Pathological Aspects’, in Local Government Board, Further Report and Papers on Epidemic Influenza, 1889–92 (London: HMSO, 1893), 85–153. Klein, Edward E., Micro-organisms and Disease: An Introduction into the Study of Specific Micro-organisms (London: Macmillan and Co., 1896). Krumbhaar, E.B., ‘The Bacteriology of the Prevailing Epidemic’, Lancet, (27 July 1918), 123. Kruse, W., ‘Die Erreger v. Husten und Schnupfen’, Münchener medizinische Wochenschrift, 65 (1914), 1228. Laidlaw, Patrick P., ‘Dog Distemper’, A System of Bacteriology (London: HMSO, 1930). Laidlaw, Patrick P., ‘Experimental Influenza’, Guy’s Hospital Gazette, 158 (November 10, 24, 1934), 459–463, 474–477. Laidlaw, Patrick P., ‘Epidemic Influenza: A Virus Disease’, The Lancet, (11 May 1935), 1119–1124. Laidlaw, Patrick P., ‘Stewart Rankin Douglas, 1871–1936’, Obituary Notices of Fellows of the Royal Society, 2 (1936), 175–182.

412

SELECT BIBLIOGRAPHY

Laidlaw, Patrick P., Virus Diseases and Viruses, The Rede Lecture (Cambridge: Cambridge University Press, 1938). Laidlaw, Patrick P., and G.W. Dunkin, ‘Studies in Dog-Distemper. III. The Nature of the Virus’, Journal of Comparative Pathology and Therapeutics, 29 (1926), 222. Laidlaw, Patrick P., and G.W. Dunkin, ‘Studies in Dog Distemper. IV. The Immunization of Ferrets Against Dog Distemper’, Journal of Comparative Pathology and Therapeutics, 41 (1927), 1–16. Laidlaw, Patrick P., and G.W. Dunkin, ‘A Report Upon the Cause and Prevention of Dog Distemper’, in Field Distemper Fund, Progress Report of the Distemper Research Committee (1928). Laidlaw, Patrick P., and G.W. Dunkin, ‘Studies in Dog Distemper. V. The Immunization of Dogs’, Journal of Comparative Pathology and Therapeutics, 41 (1928), 209–227. Laidlaw, Patrick P., W. Smith, C.H. Andrewes, and G.W. Dunkin, ‘Influenza: The Preparation of Immune Sera in Horses’, British Journal of Experimental Pathology, XVI (1935), 275–290. Leichtenstern, O., ‘Influenza’, in J. Mannaberg and O. Leichtenstern (Eds.), Malaria, Influenza and Dengue (Philadelphia and London: W.B. Saunders & Co. 1905), 521–716. Leishman, W.B., ‘The Results of Protective Inoculation Against Influenza in the Army at Home, 1918–1919’, Lancet, (24 January 1920), 214–215. Leishman, W.B., ‘Organization of the Pathological Service’, in W.G. MacPherson, W.B. Leishman, and S.L. Cummins (Eds.), History of the Great War Based on Official Documents. Medical Services. Pathology (London: HMSO, 1923), 1–31. Little, T.R., C.J. Garofalo, and P.A. Williams, ‘Absence of the Bacillus Influenzae in the Exudate from the Upper Air-Passages in the Present Epidemic’, Lancet (13 July 1918), 34. Lord, F.T. ‘Influenza’, in W. Osler (Ed.), A System of Medicine (London: Henry Frode, Oxford University Press, 1915), 534–549. McFaydean, J., ‘African Horse Sickness’, Journal of Comparative Pathology and Therapeutics, XIII (1900), 1–20. McFaydean, J., ‘The Ultravisible Viruses’, Journal of Comparative Pathology and Therapeutics, XXI (1908), 58–68, 168–175, 232–242. Mackenzie, H., ‘The Respiratory Complications of Influenza’, The Practitioner (1907), 30–41. MacNeal, W.J., Pathogenic Micro-organisms: A Text-book of Microbiology for Physicians and Students of Medicine (London: Pitman, 1921). MacPherson, W.G., W.B. Leishman, and S.L. Cummins, History of the Great War Based on Official Documents. Medical Services. Pathology (London: HMSO, 1923).

SELECT BIBLIOGRAPHY

413

Magill, Thomas P., and Thomas Francis Jr., ‘Antigenic Differences in Strains of Human Influenza Virus’, Proceedings of the Society for Experimental Biology and Medicine, 35 (1936), 463–466. Magill, Thomas P., and Thomas Francis Jr., ‘Studies with Human Influenza Virus Cultured in Artificial Medium’, Journal of Experimental Medicine, 63 (1936), 803–811. Magill, Thomas P., and Thomas Francis Jr., ‘Antigenic Differences in Strains of Epidemic Influenza Virus: I. Cross-Neutralization Tests in Mice’, British Journal of Experimental Pathology, 14 (1938), 273–293. Maitland, H.B. ,and G.C. Cameron, ‘The Aetiology of Epidemic Influenza: A Critical Review’, Canadian Medical Association Journal, XI (July 1921), 485– 492. Maitland, H.B., M.L. Cowan, and H.K. Detweiler, The Aetiology of Epidemic Influenza: Experiments in Search of a Filter-Passing Virus (Toronto: The University Library [Toronto], 1921). Matthews, John, ‘Influenza or Epidemic Catarrh’, Lancet (3 April 1915), 727. Matthews, John, ‘Influenza and Preventive Inoculation’, Lancet (2 November 1918), 602. Matthews, John, ‘On a Method for Preparing Medium for the Culture of Pfeiffer’s Influenza Bacillus’, Lancet (27 July 1918), 104. McCartney, J.E., ‘Viruses of Common Cold and Herpes’, British Medical Journal (1 August 1925), E10. McClelland, L., and R. Hare, ‘The Adsorption of Influenza Virus by Red Cell and a New in Vitro Method of Measuring Antibodies for Influenza Virus’, Canadian Public Health Journal, 32 (1941), 530. McDonagh, J.E.R., The Common Cold and Influenza, and Their Relationship to Other Infections in Man and Animals (London: William Heinemann, 1936). McIntosh, James, ‘The Incidence of Bacillis Influenzae (Pfeiffer) in the Present Influenza Epidemic’, Lancet, (23 November 1918), 695–697. McIntosh, James, Studies in the Aetiology of Epidemic Influenza, Medical Research Council Special Report Series, No. 63 (London: HMSO, 1922). McIntosh, James, and F.R. Selbie, ‘The Pathogenicity to Animals of Viruses Isolated from Cases of Human Influenza’, British Journal of Experimental Pathology, XVIII (1937), 334–344. Medical Annual, ‘Influenza’, The Medical Annual (London: Simpkin, Marshall, Hamilton, Kent & Co, 1890). Medical Annual, ‘Influenza’, The Medical Annual (London: Simpkin, Marshall, Hamilton, Kent & Co, 1892). Medical Research Committee, ‘Memorandum’, Lancet, (5 August 1918)), 717. Mellanby, H., C. H. Andrewes, J.A. Dudgeon, D.G., and MacKay, ‘Vaccination Against influenza A’, Lancet, 1 (1948), 978–982.

414

SELECT BIBLIOGRAPHY

M’Gowan, J.P., ‘Some Observations on a Laboratory Epidemic, Principally Among Dogs and Cats, in Which the Animals Affected Presented Symptoms of the Disease Called “Distemper”’, Journal of Pathology and Bacteriology, 15 (1911), 372. Millais, Everett, ‘The Pathogenic Microbe of Distemper in Dogs, and Its Use for Protective Inoculation’, British Medical Journal, 1 (1890), 856–859. Mills, J., ‘James Henry Dible 29 October 1889–1 July 1971’, Journal of Pathology and Bacteriology, 111 (1973), 65–76. Moore, J.W.S., ‘Influenza’, in J.W. Ballantyne (Ed.), Encyclopaedia Medica (Edinburgh and London: Green & Son, 1919), 502–533. Muir, R., Text-book of Pathology (London: E. Arnold, 1924). Muir, R., and J. Ritchie, Manual of Bacteriology (Edinburgh: Young J. Pentland, 1897). Newsholme, Arthur S., ‘Discussion on Influenza’, Proceedings of the Royal Society of Medicine, 12 (1918–1919), 1–102. Newsholme, Arthur S., ‘Epidemic Catarrhs and Influenza’, Lancet (2 November 1918), 599–603. Nicolle, Charles, and Charles Lebailly, ‘Quelques notions experimentales sur le virus de la grippe’, Comptes Rendus de l’Academie des Sciences Paris, 167 (1918), 607–610. Noguchi, H., ‘A Method for the Pure Cultivation of Pathogenic Treponema Pallidum (Spirochata Pallida)’, Journal of Experimental Medicine, 14 (August 1911), 99–108. Olitsky, Peter, and F.L. Gates, ‘Experimental Study of the Nasopharyngeal Secretions from Influenza Patients: Preliminary Report’, Journal of the American Medical Association, 74 (May 1920), 1497–1499. Olitsky, Peter, and F.L. Gates, ‘Experimental Studies of Nasopharyngeal Secretions from Influenza Patients: IV. Anaerobic Cultivation’, Journal of Experimental Medicine, 33 (May 1921), 713–729. Olitsky, Peter, and F.L. Gates, ‘Studies of the Nasopharyngeal Secretions from Influenza Patients: Preliminary Report on Cultivation Experiments’, Journal of the American Medical Association, 76 (March 1921), 640–641. Olitsky, Peter, and F.L. Gates, ‘Methods for the Isolation of Filter-Passing Anaerobic Organisms: From Nasopharyngeal Secretions’, Journal of the American Medical Association, 78 (April 1922), 1020–1022. Osler, William, The Principles and Practice of Medicine (Edinburgh and London: Young and Pentland, 1985). Osler, William, The Principles and Practice of Medicine (London: D. Appleton and Co., 1905). Osler, William, H.A. Christian, and T. McRae, The Principles and Practices of Medicine (London: D. Appleton and Co., 1938). Panton, P.N., Clinical Pathology (London: J&A Churchill, 1913).

SELECT BIBLIOGRAPHY

415

Parkes, L., Hygiene and Public Health (London: H.K. Lewis, 1892). Parsons, Henry F., ‘The Influenza Epidemics of 1889–90 and 1891, and Their Distribution in England and Wales’, British Medical Journal (8 August 1891), 303–308. Parsons, Henry F., Report on the Influenza Epidemic of 1889–1890 (Local Government Board London: HMSO, 1891). Parsons, Henry F., Further Report and Papers on Epidemic Influenza, 1889–92 (Local Government Board London: HMSO, 1893). Parsons, Henry F., ‘The Epidemiology of Influenza’, British Medical Journal (6 May 1905), 980–982. Patterson, J.W., et al., ‘Report on the Bacteriology and Pathology of 46 Fatal Cases of Influenza’, in Medical ResearchCommittee, Studies of Influenza in Hospitals of the British Armies in France, 1918 (London: His Majesty’s Stationery Office, 1919). Patterson, S.W., ‘The Pathology of Influenza in France’, Medical Journal of Australia, 1 (6 March 1920), 207–210. Payne, Anthony M.-M., ‘The Influenza Programme of the WHO’, Bulletin of the World Health Organisation, 8 (1953), 755–774. Payne, Anthony M.-M., ‘Symposium on the Asian Influenza Epidemic, 1957’, Proceedings of the Royal Society of Medicine, 51 (1958), 29. Peacock, T.B., On the Influenza, or Epidemic Catarrhal Fever of 1847–1848 (London: J. Churchill, 1848). Peacock, T.B., ‘Influenza’, in R. Quain (Ed.), A Dictionary of Medicine (London: Longmans, Green and Co., 1894), 994–960. Pereira, H.G., ‘The World Influenza Centre’, WHO Chronicle, 21 (October 1967), 413–415. Pfeiffer, Richard, ‘Preliminary Communication on the Exciting Causes of Influenza’, British Medical Journal (16 January 1892), 128. Pfeiffer, Richard, ‘Die Aetiologie der Influenza’, Zeitschrift für Hygiene, 12 (1893), 357–386. Pfeiffer, Richard, ‘Das Influenzaproblem’ [The Influenza Problem], Ergebnisse der Hygiene, Bakteriologie, Immunitätsforschung und experimentellen Therapie, 5 (1922), 1–18. Pfeiffer, Richard, and M. Beck, ‘Weitere Mittheilungen über den InfluenzaErreger’, Deutsche Medicinische Wochnenschrift, 18 (1892), 465. Phisalix, Charles, ‘Maladie des jeunes chiens: Statistique des vaccinations pratiquées du 15 mai au 15 août 1902’, Comptes rendus de l’Académie des sciences, 134(1902), 1252. Quain, R., A Dictionary of Medicine (London: Longmans, Green and Co., 1894). Richardson, Benjamin Ward, ‘Influenza as an Organic Nervous Paresis’, Asclepiad, 8 (1891), 178–183.

416

SELECT BIBLIOGRAPHY

Richardson, Benjamin Ward, ‘Epidemic Neuroparesis’, Asclepiad, 9 (1892), 19– 37. Rivers, Thomas M., ‘Filterable Viruses: A Critical Review’, Journal of Bacteriology, 14 (1927), 217–258. Rivers, Thomas M., ‘Filterable Viruses’, in E.O. Jordan and I.S. Falk (Eds.), The New Knowledge of Bacteriology and Immunology (Chicago: University of Chicago Press, 1928). Rivers, Thomas M., ‘Some General Aspects of Filterable Viruses’, in T.M. Rivers (Ed.), Filterable Viruses (London: Bailliere, Tindall & Cox, 1928), 3–52. Rivers, Thomas M., ‘The Nature of Viruses’, Physiological Reviews, 12 (1932), 423–452. Rivers, Thomas M., ‘Viruses and Koch’s Postulates’, Journal of Bacteriology, 33 (1937), 1–12. Rous, Peyton, ‘A Transmissible Avian Neoplasm (Sarcoma of the Common Fowl)’, Journal of Experimental Medicine, 12 (1910), 697–705. Rous, Peyton, ‘Transmission of a Malignant New Growth by Means of a CellFree Filtrate’, Journal of the American Medical Association, 56 (January 1911), 198. Rous, Peyton, and J.B. Murphy, ‘Tumor Implantations in the Developing Embryo’, Journal of the American Medical Association, 56 (1911), 741–742. Rous, Peyton, and J.B. Murphy, ‘On the Causation by Filterable Agents of Three Distinct Chicken Tumours’, Journal of Experimental Medicine, 19 (1914), 52–68. Rutherford, E., C. Martin, P.A. Murphy, J.A. Arkwright, J.E. Barnard, et al., ‘Ultra-Microscopic Viruses Infecting Animals and Plants’, Proceedings of the Royal Society of London, 104 (4 May 1929), 537–560. Salk, Jonas E., ‘An Interpretation of the Significance of Influenza Virus Variation for the Development of an Effective Vaccine’, Bulletin of the New York Academy of Medicine, 28 (1952), 748–765. Savill, T.D., A System of Medicine (London: J&A Churchill, 1903). Scadding, J.G., ‘Clinical Aspects of Influenza’, The Practitioner, CXLI (December 1938), 712–724. Scott, W.M., ‘Observations on the Distribution and Serological Characters of Influenza Bacilli’, Ministry of Health Reports on Public Health and Medical Subjects, No. 13 (London: HSMO, 1922), 76–89. Scott, W.M., ‘The Influenza Group of Bacteria’, in Paul Fildes and J.C.G. Ledingham (Eds.), A System of Bacteriology in Relation to Medicine (London: HSMO, 1929), 326–394. Shope, Richard E., ‘Swine Influenza. III. Filtration Experiments and Etiology’, Journal of Experimental Medicine, 54 (1931), 373–385. Shope, Richard E., ‘The Infection of Ferrets with Swine Influenza Virus’, Journal of Experimental Medicine, 60 (1934), 49–61.

SELECT BIBLIOGRAPHY

417

Shope, Richard E., ‘The Influenzas of Swine and Man’, in The Harvey Lectures, 1935–1936 (New York: The Harvey Society, 1935–1936), 183–213. Shope, Richard E., ‘The Incidence of Neutralizing Antibodies for Swine Influenza Virus in the Sera of Human Beings of Different Ages’, Journal of Experimental Medicine, 63 (1936), 669–684. Shope, Richard E., ‘The Swine Lungworm as a Reservoir and Intermediate Host for Swine Influenza Virus. III. Factors Influencing Transmission of the Virus and the Provocation of Influenza’, Journal of Experimental Medicine, 77 (1941), 111–114. Shope, Richard E., ‘Old, Intermediate and Contemporay Contributions to Our Knowledge of Pandemic Influenza’, Medicine, 23 (1944), 415–420. Shope, Richard E., ‘Influenza: History, Epidemiology and Speculation’, Public Health Reports, 73 (1958), 165–178. Sisley, Richard, Epidemic Influenza: Notes on Its Origin and Method of Spread (London: Longmans, Green and Co., 1891). Sisley, Richard, A Study of Influenza and the Laws of England Concerning Infectious Diseases (London: Longman’s, Green, and Co., 1892). Smith, G., ‘The Influenza Epidemic’, Transactions of the Medical Society of London, 13 (17 February 1890), 277–306. Smith, K.M., The Virus: Life’s Enemy (Cambridge: University Press, 1940). Smith, Wilson, ‘Progress in Viral Immunology’, British Medical Bulletin, 9 (1953), 176–179. Smith, Wilson, and C.H. Andrewes, ‘Serological Races of Influenza Virus’, British Journal of Experimental Pathology, XIX (1938), 293–314. Smith, Wilson, and C.H. Stuart-Harris, ‘Influenza Infection of Man from the Ferret’, Lancet (18 July 1936), 121–123. Smith, Wilson, C.H. Andrewes, and P.P. Laidlaw, ‘A Virus Obtained from Influenza Patients’, Lancet (8 July 1933), 66–68. Smith, Wilson, C.H. Andrewes, and P.P. Laidlaw, ‘Influenza: Experiments on the Immunization of Ferrets and Mice’, British Journal of Experimental Pathology, XVI (1935), 291–302. Smith, Wilson, F.L. Horsfall, E.H. Lennette, E.R. Rickard, C.H. Andrewes, and C.H. Stuart-Harris, ‘The Nomeclature of Influenza’, Lancet, 2 (1940), 413. Smordinsteff, A.A., A.I. Drobyshevskaya, and O.I. Shishkina, ‘On the Aetiology of the 1936 Influenza Epidemic in Leningrad’, Lancet (12 December 1936), 1383–1385. Soltau, A.B., ‘Discussion on Influenza’, Proceedings of the Royal Society of Medicine, 12 (1919), 27–28. Stevens, M.W., Medical Diagnosis (London: H.K. Lewis, 1910). Stevenson, T.H.C., ‘The Incidence of Mortality Upon the Rich and Poor Districts of Paris and London’, Journal of the Royal Statistical Society, 84 (1921), 90–99.

418

SELECT BIBLIOGRAPHY

Stitt, E.R., Practical Bacteriology, Blood Work and Animal Parasitology: Including Bacteriological Keys, Zoological Tables and Explanatory Clinical Notes (London: H.K. Lewis, 1923). Stuart-Harris, Charles H., ‘Epidemic Influenza’, Journal of the Royal Army Medical Corps, 74 (1 May 1940), 109–114. Stuart-Harris, Charles H., ‘Current Investigations of the Influenza Problem’, Journal of the Royal Army Medical Corps, 77 (September 1941), 123–134. Stuart-Harris, Charles H., ‘The General Practitioner and the Influenza Problem’, British Medical Journal (20 December 1947), 994–996. Stuart-Harris, Charles H., C.H. Andrewes, and W. Smith, A Study of Epidemic Influenza: With Special Reference to the 1936–7 Epidemic, Medical Research Council, Special Report Series, No. 228 (London: HMSO, 1938). Stuart-Harris, Charles H., W. Smith, and C.H. Andrewes, ‘The Influenza Epidemic of January-March, 1939’, Lancet (17 August 1940), 205–211. Taylor, Samuel, ‘Notes on Epidemic Influenza’, Lancet, (25 January 1890), 187. Thompson, Theophilus, Annals of Influenza or Epidemic Catarrhal Fever in Great Britain from 1510–1837 , The Sydenham Society (London: Printed for The Sydenham Society, 1852). Thompson, E. Symes, Influenza, or Epidemic Catarrhal Fever: An Historical Survey of Past Epidemics in Great Britain from 1510 to 1890 (London: Precival & Co, 1890). Thomson, David, and Robert Thomson, ‘Influenza (Part I)’, Annals of the Pickett-Thomson Research Laboratory (London: Bailliere, Tindall and Cox, 1933). Thomson, David, and Robert Thomson, ‘Influenza (Part II)’, Annals of the Pickett-Thomson Research Laboratory (London: Bailliere, Tindall and Cox, 1934). Thomson, David, and Robert Thomson, ‘Some Features of the Influenzal Epidemic in the Spring of 1935’, British Medical Journal (13 July 1935), 62–63. Tolstoy, Leo, War and Peace (Oxford: Oxford University Press, 2010). Topley, W.W.C., An Outline of Immunity (London: Edward Arnold & Co., 1933). Topley, W.W.C., and G.S. Wilson, The Principles of Bacteriology and Immunity (London: Edward Arnold, 1929). Topley, W.W.C., and G.S. Wilson, The Principles of Bacteriology and Immunity (London: Edward Arnold, 1936). Torrens, J., ‘Influenza: Its Sequelae and Treatment’, British Medical Journal (17 February 1934), 274–276. Twort, F.W., ‘An Investigation of the Nature of Ultramicroscopic Viruses’, Lancet (4 December 1915), 1241–1243.

SELECT BIBLIOGRAPHY

419

Twort, F.W., ‘The Ultramicrscopic Viruses’, The Journal of State Medicine, 31 (1923), 351–366. United States Army Medical Department, Preventive Medicine in World War II General, O.o.t.S. (Washington, DC: Department of the Army, 1955). van Rooyen, C.E., and A.J. Rhodes, Virus Diseases of Man (London: Oxford University Press, 1940). Vaughan, W.T., Influenza: An Epidemiologic Study, American Journal of Hygiene, Monographic series; No. 1 (Baltimore: The American Journal of Hygiene, 1921). Watson, T.S., Lectures on the Principles of Physic (London: Longmans, Green and Co., 1871). West, Samuel, ‘The Influenza Epidemic of 1890’, St. Bartholomew’s Hospital Reports, XXVI (1890), 193–258. West, Samuel, ‘An Address on Influenza’, Lancet (28 April 1894), 1047–1052. Whitelegge, B.A., Hygiene and Public Health (London: Cassell, 1894). Whitelegge, B.A., Hygiene and Public Health (London: Cassell, 1899). Whitelegge, B.A., and G. Newman, Hygiene and Public Health (London: Cassell, 1905). Whittingham, H.E., and C. Sims, ‘Some Observations on the Bacteriology and Pathology of Influenza’, Lancet (28 December 1918), 865–871. Wilson, J.A., ‘The Bacteriology of Certain Filter-Passing Organisms’, British Medical Journal (17 May 1919), 602–604. Williams, D., ‘The Epidemics of 1889–90–91–92’, in R. Quain, A Dictionary of Medicine (London: Longmans, Green and Co., 1894), 960–964. Williams, Greer, Virus Hunters (London: Hutchinson & Co, 1960). Woodcock, H.M., ‘Are the Active Principles of Filter-Passing and “Ultramicroscopic” Viruses Living Organisms or Enzymes?’, Journal of the Royal Army Medical Corps (1 October 1922), 243–260. Woodruff, A.M., and E.W. Goodpasture, ‘The Susceptibility of the ChorioAllantoic Membrane of Chick Embryos to Infection with the Fowl-Pox Virus’, American Journal of Pathology, 7 (1931), 209–222. World Health Organization, Expert Committee on Influenza; First Report, Technical Report Series, No. 64. (1947). World Health Organisation, ‘Virus Diseases’, The First Ten Years of the World Health Organization (Geneva: World Health Organization, 1958), 214–215. World Health Organisation, Influenza: A Review of Current Research, Monograph Series No. 20 (Geneva: World Health Organization, 1954). Wynn, W.H., ‘Influenza and Preventive Inoculation’, Lancet (9 November 1918), 642–643. Wynn, W.H., ‘The Use of Vaccines in Acute Influenza’, Lancet (28 December 1918), 874–876.

420

SELECT BIBLIOGRAPHY

Secondary Literature Ackernecht, Erwin H., Medicine at the Paris Hospital (Baltimore: Johns Hopkins University Press, 1967). Alter, Peter, The Reluctant Patron: Science and the State in Britain 1850–1920 (Oxford: Berg, 1987). Amsterdamska, Olga, ‘Between Medicine and Science: The Research Career of Oswald T. Avery’, in I. Löwy and J.-P. Gaudillière (Eds.), Medicine and Change: Historical and Sociological Studies of Medical Innovation (Montrouge, France John Libbey Eurotext, 1993), 181–212. Amsterdamska, Olga, ‘Chemistry in the Clinic: The Research Career of Donald Dexter Van Slyke’, in S. de Chadarevian and H. Kamminga (Eds.), Molecularizing Biology and Medicine: New Practices and Alliances, 1910s–1970s (Amsterdam: Harwood Academic Publishers, 1998), 47–82. Amsterdamska, Olga, ‘Standardizing Epidemics: Infection, Inheritance and Environment in Prewar Experimental Epidemiology’, in J.-P. Gaudillière and I. Löwy (Eds.), Heredity and Infection: Historical Essays on Disease Transmission in the Twentieth Century (London: Routledge, 2001), 135–180. Amsterdamska, Olga, ‘Acheiving Disbelief: Thought Styles, Microbial Variation, and American and British Epidemiology, 1900–1940’, Studies in History and Philosophy of Biological and Biomedical Sciences, 35 (2004), 483–507. Amsterdamska, Olga, ‘Demarcating Epidemiology’, Science, Technology, & Human Values, 30.1 (2005), 17–51. Arrizabalaga, John, ‘Problematizing Retrospective Diagnosis in the History of Disease’, Asclepio, 54.1 (2002), 51–70. Anderson, Warwick, ‘Natural Histories of Infectious Disease: Ecological Vision in Twentieth-Century Biomedical Science’, Osiris, 19 (2004), 39–61. Austoker, Joan, A History of the Imperial Cancer Research Fund, 1902–1986 (Oxford: Oxford University Press, 1988). Austoker, Joan, ‘Walter Morley Fletcher and the Origins of a Basic Biomedical Research Policy’, in J. Austoker and L. Bryder (Eds.), Historical Perspectives on the Role of the MRC: Essays in the History of the MRC of the United Kingdom and Its Predecessor, the Medical Research Committee, 1913–1953 (Oxford: Oxford University Press, 1989), 22–33. Austoker, Joan, and Linda Bryder, ‘The National Institute for Medical Research and Related Activities of the MRC’, in J. Austoker and L. Bryder (Eds.), Historical Perspectives on the Role of the MRC: Essays in the History of the MRC of the United Kingdom and Its Predecessor, the Medical Research Committee, 1913–1953 (Oxford: Oxford University Press, 1989), 39–52. Balinska, M.A., ‘Ludwik Rajchman: Pioneer of International Health’, International Health History Newsletter, 1 (June 1995), 8–9. Barry, John M., The Great Influenza (New York: Viking, 2004).

SELECT BIBLIOGRAPHY

421

Beaudevin, Claire, Jean-Paul Gaudillière, Christoph Gradmann, Anne M. Lovell, and Laurent Pordié. ‘Global Health and the New World Order’, in idem. (Eds.), Global Health and the New World Order (Manchester, England: Manchester University Press, 2020), 1–27. Becsei-Kilborn, Eva. ‘Scientific Discovery and Scientific Reputation: The Reception of Peyton Rous’ Discovery of the Chicken Sarcoma Virus’, Journal of the History of Biology, 43.1 (2010), 111–157. Beiner, Guy, ‘The Great ‘Flu Between Remembering and Forgetting’, in idem. (Ed.), Pandemic Re-Awakenings: The Forgotten and Unforgotten ‘Spanish’ Flu of 1918–1919 (Oxford: Oxford University Press, 2021), 1–49. Benison, Saul, Tom Rivers: Reflections on a Life in Medicine and Science (Cambridge, MA: MIT Press, 1967). Beveridge, William I.B., Influenza: The Last Great Plague, an Unfinished Story of Discovery (London: Heinnemann, 1977). Beveridge, William I.B., ‘Unravelling the Ecology of Influenza A Virus’, History and Philosophy of the Life Sciences, 15 (1993), 23–32. Brand, J.L., Doctors and the State: The British Medical Profession and Government Action in Public Health, 1870–1912 (Baltimore: Johns Hopkins Press, 1965). Bresalier, Michael, ‘Neutralizing Flu: “Immunological Devices” and the Making of a Virus Disease’, in Kenton Kroker, Jennifer Keelan, and Pauline Mazumdar (Eds.), Crafting Immunity: Working Histories of Clinical Immunology (London: Ashgate, 2008), 107–144. Bresalier, Michael, ‘“A Most Protean Disease”: Aligning Medical Knowledge of Modern Influenza, 1890–1914’, Medical History, 56.4 (2012), 481–510. Bresalier, Michael, ‘Uses of a Pandemic: Forging the Identities of Influenza and Virus Research in Interwar Britain’, Social History of Medicine, 25.2 (2012), 400–424. Bresalier, Michael, ‘Fighting Flu: Military Pathology, Vaccines, and the Conflicted Identity of the 1918–19 Pandemic in Britain’, Journal of the History of Medicine and Allied Sciences, 68.1 (2013), 87–128. Bresalier, Michael and Michael Worboys, ‘“Saving the Lives of Our Dogs”: The Development of Canine Distemper Vaccine in Interwar Britain’, British Journal for the History of Science, 47 (2014), 305–334. Bristow, Nancy K., American Pandemic: The Lost Worlds of the 1918 Influenza Epidemic (Oxford: Oxford University Press, 2012). Brown, R.J., ‘The Great War and the Great Flu Pandemic of 1918’, Wellcome History, 24 (October 2003), 5–7. Brown, R.J., ‘Revisiting Spanish Flu’, Wellcome Science (October, 2005), 43. Brown, Theodore M., M. Cueto, and E. Fee, ‘The World Health Organization and the Transition from “International” to “Global” Public Health’, American journal of Public Health, 96 (2006), 62–72.

422

SELECT BIBLIOGRAPHY

Bryder, Linda, ‘Public Health Research and the MRC’, in J. Austoker and L. Bryder (Eds.), Historical Perspectives on the Role of the MRC: Essays in the History of the MRC of the United Kingdom and Its Predecessor, the Medical Research Committee, 1913–1953 (Oxford: Oxford University Press, 1989), 59–81. Burnet, F. Macfarlane, Changing Patterns: An Atypical Autobiography (Melbourne: Heinemann, 1968). Burnet, F. Macfarlane, ‘A Portrait of Influenza’, Intervirology, 2 (1979), 201– 214. Burney, Ian, ‘Medicine in the Age of Reform’, in A. Burns and J. Innes (Eds.), Rethinking the Age of Reform: Britain, 1780–1850 (Cambridge, 2003), 163– 182. Byerly, Carol R., Fever of War: The Influenza Epidemic in the U.S. Army During World War I (New York: New York University Press, 2005). Bynum, Helen, Spitting Blood: The History of Tuberculosis (Oxford: Oxford University Press, 2012). Bynum, William F., ‘“C’est un malade”: Animal Models and Concepts of Human Diseases’, Journal of the History of Medicine and Allied Sciences, 45 (1990), 397–413. Bynum, William F., Science and the Practice of Medicine in the Nineteenth Century (Cambridge: Cambridge University Press, 1994). Bynum, William F., ‘The Rise of Science in Medicine, 1850–1913’, in W.F. Bynum, A. Hardy, S. Jacyna, C. Lawrence, and E.M. Tansey (Eds.), The Western Medical Tradition: 1800 to 2000 (Cambridge: Cambridge University Press, 2006), 111–239. Bynum, William F., and V. Nutton, Theories of Fever from Antiquity to the Enlightenment, Medical History. Supplement; No. 1. (London: Wellcome Institute for the History of Medicine, 1981). Caduff, Carlo, The Pandemic Perhaps: Dramatic Events in a Public Culture of Danger (Berkeley: University of California Press, 2015). Cambrosio, Alberto, D. Jacobi, and P. Keating, ‘Ehrlich’s “Beautiful Pictures” and the Controversial Beginnings of Immunological Imagery’, Isis, 84 (1993), 662–699. Canavan, Barbara, ‘Collaboration Across the Pound: Influenza Virus Research, Interwar United States and Britain’, Rockefeller Archive Center Research Reports Online (31 December 2014). Cantor, David, ‘Western Medicine Since the Renaissance’, in P. Promann (Ed.), The Cambridge Companion to Hippocrates (Cambridge: Cambridge University Press, 2008), 362–383. Carter, Kodell Carter, ‘Koch’s Postulates in Relation to the Work of Jacob Henle and Edwin Klebs’, Medical History, 29 (1985), 353–373.

SELECT BIBLIOGRAPHY

423

Chen, Wei, ‘The Laboratory as Business: Sir Almorth Wright’s Vaccine Programme and the Construction of Penicillin’, in A. Cunningham and P. Williams (Eds.), The Laboratory Revolution in Medicine (Cambridge: Cambridge University Press, 1992), 245–292. Cherry, Steve, Medical Services and the Hospitals in Britain, 1860–1939 (Cambridge: University of Cambridge 1996). Chick, Harriett, M. Hume, and M. MacFarlane, War on Disease: A History of the Lister Institute (A. Deutsch: London, 1971). Clarke, Adele E., ‘Research Materials and Reproductive Science in the United States, 1910–1940’, in G.L. Geison (Ed.), Physiology in the American Context, 1850–1940 (Bethesda, Maryland: American Physiological Society, 1987), 323– 361. Clarke, Sabina, ‘Pure Science with a Practical Aim: The Meanings of Fundamental Research in Britain, Circa 1916–1950’, Isis, 101 (2010), 285–311. Cliff, A.D., M.R. Smallman-Raynor, P. Hagget, D.F. Stroup, and S.B. Thacker, Emergence and Re-Emergence. Infectious Diseases. A Geographical Analysis (Oxford: Oxford University Press, 2009). Cohn, Samuel K., Epidemics: Hate and Compassion from the Plague of Athens to Aids (Oxford: Oxford University Press, 2018). Coleman, William, Death Is a Social Disease: Public Health and Political economy in Early Industrial France (London: University of Wisconsin Press, 1982). Coleman, William, Yellow Fever in the North: The Methods of Early Epidemiology (Madison: University of Wisconsin Press, 1987). Collier, Richard, The Plague of the Spanish Lady: The Influenza Pandemic of 1918–19 (New York: Atheneum, 1974). Cook, Harold J., ‘Physicians and the New Philosophy: Henry Stubbe and the Virtuosi-Physicians’, in Roger French and Andrew Wear (Eds.), The Medical Revolution of the Seventeenth Century (Cambridge: Cambridge University Press, 1989), 246–247. Cooter, Roger, Surgery and Society in Peace and War: Orthopaedics and the Organisation of Modern Medicine, 1880–1948 (London: Macmillan, 1993). Cooter, Roger, ‘War and Modern Medicine’, in W.F. Bynum and R. Porter (Eds.), Companion Encyclopedia of the History of Medicine (London: Routledge, 1993), 1536–1573. Cooter, Roger, ‘Of War and Epidemics: Unnatural Couplings, Problematic Conceptions’, Social History of Medicine 16 (2003), 283–302. Cooter, Roger, ‘Keywords in the History of Medicine: “Teamwork”’, Lancet, 363 (10 April 2004), 1245. Cooter, Roger, and S. Sturdy, ‘Of War, Medicine and Modernity: Introduction’, in R. Cooter, M. Harrison, and S. Sturdy (Eds.), War, Medicine and Modernity (London: Sutton, 1998), 1–21.

424

SELECT BIBLIOGRAPHY

Corner, G.W., The Rockefeller Institute: Origins and Growth, 1901–1953 (New York Rockefeller Institute Press, 1964). Cox-Maksimov, D., ‘The Making of the Clinical Trial in Britain, 1910–1945: Expertise, the State and the Public’, Ph.D. Thesis. Department of History and Philosophy of Science, University of Cambridge (1998). Creager, Angela N.H., ‘Producing Molecular Therapeutics from Human Blood: Edwin Cohn’s Wartime Enterprise’, in S. de Chadarevian and H. Kamminga (Eds.), Molecularizing Biology and Medicine: New Practices and Alliances, 1910s–1970s (Amsterdam: Harwood Academic Publishers, 1998), 107–136. Creager, Angela N.H., The Life of a Virus: Tobacco Moasaic Virus as an Experimental Model, 1930–65 (Chicago: University of Chicago Press, 2002). Creager, Angela N.H., ‘Mobilizing Biomedicine: Virus Research Between Lay Health Organizations and the U.S. Federal Government, 1935–1955’, in C. Hannaway (Ed.), Biomedicine in the Twentieth Century: Practices, Policies, and Politics (Amsterdam: IOS Press, 2008), 171–202. Creager, Angela N.H., and J.-P. Gaudillière, ‘Experimental Arrangements and Technologies of Visualisation: Cancer as a Viral Epidemic, 1930–1960’, in J.P. Gaudillière and I. Löwy (Eds.), Heredity and Infection: Historical Essays on Disease Transmission in the Twentieth Century (London: Routledge, 2001), 203–242. Crosby, Alfred W., America’s Forgotten Pandemic—The Influenza of 1918 (Cambridge: Cambridge University Press, 1989). Crosby, Alfred W., ‘Influenza’, in K.F. Kiple, (Ed.), Cambridge World History of Human Disease (Cambridge: Cambridge University Press, 1993), 807–811. Cunningham, Andrew, ‘Thomas Sydenham: Epidemics, Experiment and the ‘Good Old Cause’’, in Roger French and Andrew Wear (Eds.), The Medical Revolution of the Seventeenth Century (Cambridge, Cambridge University, 1989), 164–190. Cunningham, Andrew, ‘Transforming Plague: The Laboratory and the Identity of Infectious Disease’, in A. Cunningham and P. Williams (Eds.), The Laboratory Revolution in Medicine (Cambridge: Cambridge University Press, 1992), 209–244. Cunningham, Andrew, ‘Identifying Disease in the Past: Cutting the Gordian Knot’, Asclepio, LIV (2002), 13–34. Daston, Lorraine, and Peter Galison, ‘The Image of Objectivity’, Representations, 40 (1992), 81–128. Daston, Lorraine, and Peter Gailson, Objectivity (New York: Zone Books, 2007). Davies, Pete, Catching Cold: 1918’s Forgotten Tragedy and the Scientific Hunt for the Virus That Caused It (London: Michael Joseph, 1999). Davies, Pete, The Devil’s Flu: The World’s Deadliest Influenza Epidemic and the Scientific Hunt for the Virus That Caused It (New York: Henry Holt & Co., 2000).

SELECT BIBLIOGRAPHY

425

Davis, Mike, The Monster at Our Door: The Global Threat of Avian Flu (London: New Press, 2005). de Chadarevian, Soraya, and H. Kamminga, Molecularizing Biology and Medicine: New Practices and Alliances, 1910s–1970s (Amsterdam: Harwood Academic Publishers, 1998). DeLacy, Margaret, ‘The Conceptualization of Influenza in Eighteenth Century Britain: Specificity and Contagion’, Bulletin of the History of Medicine, 67 (1993), 74–118. DeLacy, Margaret, ‘Influenza Research and the Medical Profession in EighteenthCentury Britain’, Albion: A Quarterly Journal Concerned with British Studies, 25.1 (1993), 37–66. Delacy, Margaret, ‘Nosology, Mortality, and Disease Theory in the Eighteenth Century’, Journal of the History of Medicine and Allied Sciences, 54.2 (1999), 261–284. DeLacy, Margaret, Contagionism Catches On: Medical Ideology in Britain, 1730– 1800 (Basingstoke: Palgrave, 2017). Dehner, George, Influenza: A Century of Science and Public Health Response (Pittsburgh: University of Pittsburgh Press, 2012). Digby, Anne, The Evolution of British General Practice, 1850–1948 (Oxford: Oxford University Press, 1999). Edgerton, David, Warfare State: Britain, 1920–1970 (Cambridge: Cambridge University Press, 2005). Edwards, Martin, Control and the Therapeutic Trial: Rhetoric and the Therapeutic Trial in Britain, 1918–48 (Amsterdam: Rodopi, 2007). Ewald, Paul W., Evolution of Infectious Disease (Oxford: Oxford University Press, 1994). Eyler, John M., Victorian Social Medicine: The Ideas and Methods of William Farr (Baltimore: Johns Hopkins University Press, 1979). Eyler, John M., Sir Arthur Newsholme and State Medicine, 1885–1935 (Cambridge: Cambridge University Press, 1997). Eyler, John M., ‘De Kruif’s Boast: Vaccine Trials and the Construction of a Virus’, Bulletin of the History of Medicine, 80 (2006), 409–438. Eyler, John M., ‘The Fog of Research: Influenza Vaccine Trials During the 1918– 19 Pandemic’, Journal of the History of Medicine and Allied Sciences, 64 (2009), 401–428. Eyler, John M., ‘Influenza and the Remaking of Epidemiology, 1918–1960’, in Susan Craddock, Tamara Giles-Vernick, and Jennifer Gunn (Eds.), Influenza and Public Health: Learning from Past Pandemics (London: Earthscan, 2010), 157–177. Fenner, Frank J., and R.V. Blanden, ‘History of Viral Immunology’, in A.L. Notkins (Ed.), Viral Immunology and Immunopathology (New York, London: Academic Press, 1975), 1–25.

426

SELECT BIBLIOGRAPHY

Finn, M.A., and J.F. Stark, ‘Medical Science and the Cruelty to Animals Act 1876: A Re-examination of Anti-vivisectionism in Provincial Britain’, Studies in History and Philosophy of Biological & Biomedical Sciences, 49 (2015), 12– 23. Fisher, Donald, ‘The Rockefeller Foundation and the Development of Scientific Medicine in Britain’, Minerva, 16 (1978), 20–41. Fisher, Donald, ‘Rockefeller Philanthropy and the British Empire: The Creation of the London School of Hygiene and Tropical Medicine’, History of Education, 7 (1979), 129–143. Fisher, J.R., ‘Not Quite a Profession: The Aspirations of Veterinary Surgeons in England in the Mid-Nineteenth Century’, Historical Research, 66 (1993), 284–302. Fleck, Ludwik, Genesis and Development of a Scientific Fact [1935] (Chicago: University of Chicago Press., 1979 [1935]). Foster, W.D., A Short History of Clinical Pathology (London: E&S Livingstone, 1961). Foster, W.D., Pathology as Profession in Great Britain and the Early History of the Royal College of Pathologists (London: E&S Livingstone, 1965). Foucault, Michel, The Birth of the Clinic: An Archaeology of Medical Perception (New York: Vintage, 1973). French, R.D., Antivivisection and Medical Science in Victorian Society (Princeton, NJ and London: Princeton University Press, 1975). Fujimura, Joan H., ‘Constructing “do-able” Problems in Cancer Research: Articulating Alignment’, Social Studies of Science, 17 (1987), 257–293. Gaudillière, Jean-Paul, ‘Rockefeller Strategies for Scientific Medicine: Molecular Machines, Viruses and Vaccines’, Studies in History and Philosophy of the Biological and Biomedical Sciences, 31 (2000), 491–509. Gaudillière, Jean-Paul, Inventer le Biomedicine: La France, l’Amerique et la Production des Saviors du Vivant (1945–1965) (Paris: Editions la Decouverte, 2002). Geison, G.L., Michael Foster and the Cambridge School of Physiology: the Scientific Enterprise in Late Victorian society (Princeton, NJ: Princeton University Press, 1978). Ghendon, Youri, ‘Introduction to Pandemic Influenza Through History’, European Journal of Epidemiology, 10.4 (1994), 451–453. Gilfoyle, Daniel, ‘Veterinary Immunology as Colonial Science: Method and Quantification in the Investigation of Horsesickness in South Africa, c. 1905– 1945’, Journal of the History of Medicine and Allied Sciences, 61 (2005), 26–65. Golinski, Jan, Making of Natural Knowledge: Constructivism and the History of Science (Cambridge: Cambridge University Press, 1998).

SELECT BIBLIOGRAPHY

427

Golinski, Jan, British Weather and the Climate of Enlightenment (Chicago: University of Chicago Press, 2007). Gradmann, Christoph, ‘Robert Koch and the Pressures of Scientific Research: Tuberculosis and Tuberculin’, Medical History, 45.1 (2001), 1–32. Gradmann, Christoph, ‘Experimental Life and Experimental Disease: The Role of Animal Experiments in Robert Koch’s Medical Bacteriology’, B.I.F. Futura, 18 (2003), 80–88. Gradmann, Christoph, ‘A Harmony of Illusions: Clinical and Experimental Testing of Robert Koch’s Tuberculin, 1890–1900’, Studies in History and Philosophy of Biological and Biomedical Sciences, 35 (2004), 465–481. Gradmann, Christoph, Laboratory Disease: Robert Koch’s Medical Bacteriology, trans. Elborg Forster (Baltimore: Johns Hopkins University Press, 2009). Gradmann, Christoph, ‘A Spirit of Scientific Rigour: Koch’s Postulates in Twentieth-Century Medicine’, Microbes and Infection, 16 (2014), 885–892. Grafe, Alfred, A History of Experimental Virology (London: Springer-Verlag, 1991). Granshaw, Lindsay P., ‘‘‘Fame and Fortune by Means of Bricks and Mortar”: The Medical Profession and Specialist Hospitals in Britain, 1800–1948’, in L. Granshaw and R. Porter (Eds.), The Hospital in History (London: Routledge, 1989), 199–220. Granshaw, Lindsay P., ‘“Upon This Principle I Have Based a Practice”: The Development and Reception of Antisepsis in Britain, 1867–90’, in J.V. Pickstone (Ed.), Medical Innovations in Historical Perspective (Basingstoke: Macmillan, 1992), 17–46. Graves, Charles, Invasion by Virus: Can It Happen Again? (London: Icon Books, 1969). Griffin, Emma, Blood Sport: Hunting in Britain Since 1066 (New Haven: Yale University Press, 2008). Guerrini, Anita, Experimenting with Humans and Animals: From Galen to Animal Rights (Baltimore: Johns Hopkins University Press, 2003). Hamlin, Christopher, ‘Edwin Chadwick, “Mutton Medicine,” and the Fever Question’, Bulletin of the History of Medicine, 70.2 (1996), 233–265. Hamlin, Christopher, Public Health and Social Justice in the Age of Chadwick: Britain, 1800–1854 (Cambridge: Cambridge University Press, 1998). Hamlin, Chris, More Than Hot: A Short History of Fever (Baltimore: Johns Hopkins University Press, 2014). Hansen, Bert, Picturing Medical Progress from Pasteur to Polio: A History of Mass Media Images and Popular Attitudes in America (New Brunswick, NJ: Rutgers University Press, 2009).

428

SELECT BIBLIOGRAPHY

Hardy, Anne, ‘Public Health and the Expert: The London Medical Officers of Health, 1856–1900’, in R. Macleod (Ed.), Government and Expertise: Specialists, Administrators and Professionals, 1860–1919 (Cambridge: Cambridge University Press, 1988), 128–142. Hardy, Anne, Epidemic Streets: Infectious Disease and the Rise of Preventive Medicine, 1859–1914 (Oxford: Clarendon Press, 1993). Hardy, Anne, ‘Poliomyelitis and the Neurologists: The View from England, 1896–1966’, Bulletin of the History of Medicine, 71 (1997), 249–272. Hardy, Anne, ‘On the Cusp: Epidemiology and Bacteriology at the Local Government Board, 1890–1905’, Medical History, 42 (1998), 328–346. Hardy, Anne, Health and Medicine in Britain Since 1860 (London: Palgrave, 2001). Hardy, Anne, ‘Professional Advantage and Public Health: British Veterinarians and State Veterinary Services, 1865–1939’, 20th Century British History, 14 (2003), 1–23. Harrison, Mark, ‘Medicine and the Management of Modern Warfare’, History of Science, 34 (1996), 379–410. Harrison, Mark, The Medical War: British Military Medicine in the First World War (Oxford: Oxford University Press, 2010). Heaman, Elisabeth, St. Mary’s: The History of a London Teaching Hospital (Montreal: McGill-Queen’s University Press, 2003). Hess, Volker, ‘Standardizing Body Temperature: Quantification in Hospitals and Daily Life, 1850–1900’, in G. Jorland, G. Weisz, and A. Opinel (Eds.), Body Counts: Medical Quantification in Historical and Sociological Perspective (Montreal: McGill-Queen’s University Press, 2005), 109–126. Hicks, R.M., ‘Journal of Experimental Pathology: The Journal Comes of Age’, British Journal of Experimental Pathology, 71 (1990), i–iv. Hildreth, Martha L., ‘The Influenza Epidemic of 1918–1919 in France: Contemporary Concepts of Aetiology, Therapy, and Prevention’, Social History of Medicine, 4 (1991), 277–294. Hoehling, A.A., The Great Epidemic (Boston: Little Brown, 1961). Honigsbaum, Mark, Living with Enza: The Forgotten Story of Britain and the Great Flu Pandemic of 1918 (London and New York: Macmillan, 2009). Honigsbaum, Mark, A History of the Great Influenza Pandemics: Death, Panic and Hysteria, 1830–1920 (London: I.B. Tauris, 2014). Hooker, Claire, and A. Bashford, ‘Diphteria and Australian Public Health: Bacteriology and Its Complex Applications, c. 1890–1930’, Medical History, 46 (2002), 41–64. Howell, Joel D., Technology and the Hospital: Transforming Patient Care in the Early Twentieth Century (Baltimore: Johns Hopkins University Press, 1995). Howell, Joel D., ‘“Soldier’s Heart”: The Redefinition of Heart Disease and Speciality Formation in Early Twentieth Century Great Britain’, in R. Cooter,

SELECT BIBLIOGRAPHY

429

M. Harrison, and S. Sturdy (Eds.), War, Medicine and Modernity (London: Sutton, 1998), 85–105. Hull, Andrew, ‘Teamwork, Clinical Research, and the Development of Scientific Medicines in Interwar Britain: The “Glasgow School” Revisited’, Bulletin of the History of Medicine, 81 (2007), 569–593. Humphries, Mark Osborne, ‘Paths of Infection: The First World War and the Origins of the 1918 Influenza Pandemic’, War in History, 21.1 (January 2014), 55–81. Humphreys, Margaret, ‘The Influenza of 1918: Evolutionary Perspectives in a Historical Context’, Evolution, Medicine, and Public Health, 1 (2018), 219– 229. Hyslop, A.M., ‘Old Ways, New Means: Fighting Spanish Influenza in Australia, 1918–1919’, in L. Bryder (Ed.), New Countries and Old Medicine (Auckland: Pyramid Press, 1995), 54–60. Jackson, Mark, ‘“A Private Line to Medicine”: The Clinical and Laboratory Contours of Allergy in the Early Twentieth Century’, in K. Kroker, J. Keelan, and P.M.H. Mazumdar (Eds.), Crafting Immunity: Working Histories of Clinical Immunology (Aldershort: Ashgate, 2008), 55–76. Jackson, Mark, ‘Perspectives on the History of Disease’, in idem., The Routledge History of Disease (London: Routledge 2016), 1–18. Jacyna, L. Stephen, ‘The Laboratory and the Clinic: The Impact of Pathology on Surgical Diagnosis in the Glasgow Western Infirmary, 1875–1910’, Bulletin of the History of Medicine, 62 (1988), 384–406. Jacyna, L. Stephen, Lost Words: Narratives of Language and the Brain, 1825–1926 (Princeton, NJ: Princeton University Press, 2000). Jenner, Mark S., ‘The Medical Marketplace’, in M.S. Jenner and J. Wallis (Eds.), Medicine & the Market in England & Its Colonies, c.1450–c.1850 (Basingstoke: Palgrave, 2007), 1–23. Jewson, Nicholas D., ‘Medical Knowledge and the Patronage System in Eighteenth-Century England’, Sociology, 8 (1974), 369–385. Jewson, Nicholas D., ‘The Disappearance of the Sick-Man from Medical Cosomology, 1770–1870’, Sociology, 10 (1976), 225–244. Johnson, Niall P.A.S., ‘Aspects of the Historical Geography of the 1918– 19 Influenza Pandemic in Britain’, Ph.D. Thesis, Department of History, University of Cambridge (2001). Johnson, Niall P.A.S., ‘The Overshadowed Killer: Influenza in Britain in 1918– 19’, in H. Phillips and D. Killingray (Eds.), The Spanish Influenza of 1918– 1919: New Perspectives (London: Routledge, 2002), 132–154. Johnson, Niall P.A.S., Britain and the 1918–19 Influenza Pandemic: A Dark Epilogue (London: Routledge, 2006).

430

SELECT BIBLIOGRAPHY

Johnson, Niall P.A.S., and J. Mueller, ‘Updating the Accounts: Global Mortality of the 1918–1920 “Spanish” Influenza Epidemic’, Bulletin of the History of Medicine, 76 (2002), 105–115. Jones, Greta, “Captain of all These Men of Death”: The History of Tuberculosis in Nineteenth and Twentieth Century Ireland (Amsterdam: Rodopi, 2001). Jones, Susan D., Valuing Animals: Veterinarians and Their Patients in Modern America (Baltimore: Johns Hopkins University Press, 2003). Jones, Esyllt W. Influenza 1918: Disease, Death and Struggle in Winnipeg (Toronto: University of Toronto Press, 2007). Jutel, Annemarie, Putting a Name to It: Diagnosis in Contemporary Society (Baltimore: Johns Hopkins University Press, 2011). Kamminga, Harmke, ‘Vitamins and the Dynamics of Molecularization: Biochemistry, Policy and Industry in Britain, 1914–1939’, in S. de Chadarevian and H. Kamminga (Eds.), Molecularizing Biology and Medicine: New Practices and Alliances, 1910s–1970s (Amsterdam: Harwood Academic Publishers, 1998), 83–105. Kay, Lily E., ‘W.M. Stanley’s Crystallization of the Tobacco Mosaic Virus, 1930– 1940’, Isis, 77 (1986), 450–472. Kevles, Daniel J., and G.L. Geison, ‘The Experimental Life Sciences in the Twentieth Century’, Osiris, 10 (1995), 97–121. Kilbourne, Edwin D., ‘Pandora’s Box and the History of the Respiratory Viruses: A Case Study of Serendipity in Research’, History and Philosophy of the Life Sciences, 14 (1992), 299–308. Kilbourne, Edwin D., ‘A Virologist’s Perspective on the 1918–19 Pandemic’, in H. Phillips and D. Killingray (Eds.), The Spanish Influenza Pandemic of 1918–1919: New Perspectives (London: Routledge, 2002), 29–38. King, Lester, The Medical World of the Eighteenth Century (Chicago: University of Chicago Press, 1958). Kirk, Robert G.W., ‘“Wanted-Standard Guinea Pigs”: Standardisation and the Experimental Animal Market in Britain ca. 1919–1947’, Studies in History and Philosophy of Biological and Biomedical Sciences, 39 (2008), 280–291. Kohler, Robert E., ‘Walter Fletcher, F.G. Hopkins, and the Dunn Institute of Biochemistry: A Case Study in the Patronage of Science’, Isis, 69 (1978), 331–355. Kohler, Robert E., From Medical Chemistry to Biochemistry: The Making of a Biomedical Discipline (Cambridge: Cambridge University Press, 1983). Kohler, Robert E., ‘Bacterial Physiology: The Medical Context’, Bulletin of the History of Medicine, 59 (1985), 54–74. Kohler, Robert E., ‘Innovation in Normal Science: Bacterial Physiology’, Isis, 76 (1985), 162–181. Kohler, Robert E., Partners in Science: Foundations and Natural Scientists, 1900– 1945 (Chicago: University of Chicago Press, 1991).

SELECT BIBLIOGRAPHY

431

Kolata, Gina, Flu: The Story of the Great Influenza Pandemic of 1918 and the Search for the Virus That Caused It (New York: Touchstone Books, 1999). Kroker, Kenton, ‘Epidemic Encephalitis and American Neurology, 1919–1940’, Bulletin of the History of Medicine, 78 (2004), 108–147. Kenton Kroker, ‘Creatures of Reason? Viruses at the Pasteur Institute During the 1920s’, in K. Kroker, J. Keelan, and P.M.H. Mazumdar (Eds.), Crafting Immunity: Working Histories of Clinical Immunology (London: Routledge, 2008), 145–164. Lachmund, Jens, ‘Making Sense of Sound: Auscultation and Lung Sound Codification in Nineteenth-Century French and German Medicine’, Science, Technology, & Human Values, 24 (1999), 419–450. Langford, Christopher, ‘The Age Pattern of Mortality in the 1918–19 Influenza Pandemic: An Attempted Explanation Based on Data for England and Wales’, Medical History, 46 (2002), 1–20. Latour, Bruno, The Pasteurization of France (Cambridge, MA: Harvard University Press, 1998). Lawrence, Christopher, ‘Incommunicable Knowledge: Science, Technology and the Clinical Art in Britain, 1850–1914’, Journal of Contemporary History, 20 (1985), 503–520. Lawrence, Christopher, ‘Moderns and Ancients: The “New Cardiology” in Britain, 1880–1930’, Medical History, 5 (1985), 1–33. Lawrence, Christopher, Medicine in the Making of Modern Britain, 1700–1920 (London: Routledge, 1994). Lawrence, Christopher, ‘The Enlightenment’, in idem., Medicine and the Making of Modern Britain (London: Routledge, 1994), 7–25. Lawrence, Christopher, ‘Still Incommunicable: Clinical Holists and Medical Knowledge in Interwar Britain’, in C. Lawrence and G. Weisz (Eds.), Greater Than the Parts: Holism in Biomedicine, 1921–1950 (Oxford: Oxford University Press, 1998), 94–111. Lawrence, Christopher, ‘A Tale of Two Sciences: Bench and Bedside in Twentieth Century Britain’, Medical History, 43 (1999), 421–449. Lawrence, Christopher, ‘Edward Jenner’s Jockey Boots and the Great Tradition in English Medicine, 1918–1939’, in C. Lawrence and A.K. Mayer (Eds.), Regenerating England: Science, Medicine and Culture in Inter-War Britain (Amsterdam: Rodopi, 2000), 45–66. Lawrence, Christopher, ‘Continuity in Crisis: Medicine, 1914–1945’, in W.F. Bynum, A. Hardy, S. Jacyna, C. Lawrence, and E.M. Tansey (Eds.), The Western Medical Tradition: 1800 to 2000 (Cambridge: Cambridge University Press, 2006), 247–389. Lawrence, Christopher, Rockefeller Money, the Laboratory, and Medicine in Edinburgh, 1919–1930: New Science in an Old Country (Rochester: University of Rochester Press, 2006).

432

SELECT BIBLIOGRAPHY

Lee, Sung, ‘WHO and the Developing World: The Contest for Ideology’, in A. Cunningham and B. Andrews (Eds.), Western Medicine as Contested Knowledge (Manchester: Manchester University Press, 1997), 24–75. Leigh-Star, Susan, and J.R. Griesemer, ‘Institutional Ecology, ‘Translation,’ and Boundary Objects: Amateurs and Professionals in Berkeley’s Museum of Vertebrate Zoology, 1907–1939’, Social Studies of Science, 19 (1989), 387–420. Lenoir, Timothy, ‘A Magic Bullet: Research for Profit and the Growth of Knowledge in Germany Around 1900’, Minerva, 26 (1988), 66–88. Lie, Anne Kveim, and Jeremy A. Greene, ‘From Ariadne’s Thread to the Labyrinth Itself—Nosology and the Infrastructure of Modern Medicine’, The New England Journal of Medicine, 382.13 (2020), 1273–1277. Liebenau, John, ‘The MRC and the Pharmaceutical Industry: The Model of Insulin’, in J. Austoker and L. Bryder (Eds.), Historical Perspectives on the Role of the MRC (Oxford: OUP, 1989). Liebenau, John, ‘Paul Ehrlich as a Commercial Scientist and Research Administrator’, Medical History, 34 (1990), 65–78. Loeb, Lori, ‘Beating the Flu: Orthodox and Commercial Responses to Influenza in Britain, 1889–1919’, Social History of Medicine, 18.6 (2006), 203–224. Logan, C.A., ‘Before There Were Standards: The Role of Test Animals in the Production of Empirical Generality in Physiology’, Journal of the History of Biology, 35 (2002), 329–363. Löwy, Ilana, ‘Ludwik Fleck on the Social Construction of Medical Knowledge’, Sociology of Health & Illness, 10.2 (1988), 133–155. Löwy, Ilana, ‘Variances in Meaning in Discovery Accounts: The Case of Contemporary Biology’, Historical Studies in the Physical and Biological Sciences, 21 (1990), 87–121. Löwy, Ilana, ‘The Strength of Loose Concepts—Boundary Concepts, Federative Experimental Strategies and Disciplinary Growth: The Case of Immunology’, History of Science, XXX (1992), 371–396. Löwy, Ilana, ‘Medicine and Change’, in I. Löwy and J.-P. Gaudillière (Eds.), Medicine and Change: Historical and Sociological Studies of Medical Innovation (Montrouge, France: John Libbey Eurotext, 1993), 1–19. Löwy, Ilana, Between Bench and Bedside: Science, Healing and Interleukin-2 in a Cancer Ward (Cambridge, MA: Harvard University Press, 1997). Löwy, Ilana, Virus, Moustiques et Modernite: La Fievre Jaune au Brasail entre Science et Politique (Paris: Editions des archives contemporaines, 2001). Löwy, Ilana, ‘The Experimental Body’, in R. Cooter and J.V. Pickstone (Eds.), Companion to Medicine in the Twentieth Century (London: Routledge, 2003), 435–450.

SELECT BIBLIOGRAPHY

433

Löwy, Ilana, ‘Ludwik Fleck’s Epistemology of Medicine and Biomedical Sciences’, Studies in History and Philosophy of Biological and Biomedical Sciences, 35C (2004), 437–446. Löwy, Ilana, ‘Historiography of Biomedicine: ‘Bio,’ ‘Medicine,’ and In Between’, Isis, 102.1 (2011), 116–122. Löwy, Ilana, and J.-P. Gaudillière, Medicine and Change: Historical and Sociological Studies of Medical Innovation (Montrouge, France: John Libbey Eurotext, 1993). Löwy, Ilana, and Jean-Paul Gaudillière, ‘Disciplining Cancer: Mice and the Practice of Genetic Purity’, in J.-P. Gaudillière and I. Löwy (Eds.), The Invisible Industrialist: Manufactures and the Production of Scientific Knowledge (London: Macmillan, 1998), 209–249. Löwy, Ilana, and P. Zylberman, ‘Medicine as a Social Instrument: Rockefeller Foundation, 1913–45’, Studies in History and Philosophy of the Biological and Biomedical Sciences, 31 (2000), 365–379. Maehle, A.-H., Drugs on Trial: Experimental Pharmacology and Therapeutic Innovation in the Eighteenth Century (Amsterdam and Atlanta: Rodopi, 1999). Marks, Harry, The Progress of Experiment: Science and Therapeutic Reform in the United States, 1900–1990 (Cambridge: Cambridge University Press, 1997). Marks, Harry, ‘Until the Sun of Science...the True Apollo of Medicine Has Risen’: Collective Investigation in Britain and America, 1880–1910’, Medical History, 50.2 (2006), 47–166. Matthews, John R., Quantification and the Quest for Medical Certainty (Princeton: Princeton University Press, 1995). Matthews, James T., ‘Egg-Based Production of Influenza Vaccine: 30 Years of Commercial Experience’, The Bridge, 36.3 (2006), 17–24. Maulitz, Russell, ‘“Physician Versus Bacteriologist”: The Ideology of Science in Clinical Medicine’, in M.J. Vogel and C.E. Rosenberg (Eds.), The Therapeutic Revolution (Philadelphia: University of Pennsylvania Press, 1979), 91–107. Mazumdar, Pauline M.H., ‘The Antigen-Antibody Reaction and the Physics and Chemistry of Life’, Bulletin of the History of Medicine, 48 (174), 1–21. Mazumdar, Pauline M.H., Species and Specificity: An Interpretation of the History of Immunology (Cambridge: Cambridge University Press, 1995). Mazumdar, Pauline M.H., ‘“In the Silence of the Laboratory”: The League of Nations Standardizes Syphilis Tests’, Social History of Medicine, 16 (2003), 437–459. McCraken, Kevin, and P. Curson, ‘Flu Down Under: A Demographic and Geographic Analysis of the 1919 Epidemic in Sydney, Australia’, in H. Phillips and D. Killingray (Eds.), The Spanish Influenza Pandemic of 1918–19: New Perspectives (London: Routledge, 2003), 110–131.

434

SELECT BIBLIOGRAPHY

Mendelsohn, J. Andrew, ‘Cultures of Bacteriology: Formation and Transformation of a Science in France and Germany, 1870–1914’, Unpublished Ph.D. Dissertation (Princeton, 1996). Mendelsohn, J. Andrew, ‘From Eradication to Equilibrium: How Epidemics Became Complex After World War I’, in C. Lawrence and G. Weisz (Eds.), Greater Than the Parts: Holism in Biomedicine, 1921–1950 (Oxford: Oxford University Press, 1998), 303–331. Mendelsohn, J. Andrew, ‘Medicine and the Making of Bodily Inequality in Twentieth Century Europe’, in J.-P. Gaudillière and I. Löwy (Eds.), Heredity and Infection: Historical Essays on Disease Transmission in the Twentieth Century (London: Routledge, 2001), 21–80. Méthot, Pierre-Olivier, ‘Writing the History of Virology in the Twentieth Century: Discovery, Disciplines, and Conceptual Change’, Studies in History and Philosophy of Biological and Biomedical Sciences, 59 (2016), 145–153. Mills, Ian D. ,‘The 1918–1919 Influenza Pandemic—The Indian Experience’, Indian Economic and Social History Review, 23 (1986), 1–40. Mol, Annemarie, ‘Pathology and the Clinic: An Ethnographic Presentation of Two Atheroscleroses’, in M. Lock, A. Young, and A. Cambrosio (Eds.), Living and Working with the New Medical Technologies. Intersections of Inquiry (Cambridge: University of Cambridge, 2000), 82–102. Morens, David M., and J.K. Taubenberger, ‘Understanding Influenza Backward’, Journal of the American Medical Association, 302 (2009), 679–680. Mussell, James, ‘Pandemic in Print: The Spread of Influenza in the Fin de Siècle’, Endeavour 31.1 (March 2007), 12–17. Oldstone, Michael, Viruses, Plagues and History (Oxford: Oxford University Press, 1998). Oudshoorn, Nelly, Beyond the Natural Body: An Archaeology of Sex Hormones (London: Routledge, 1994). Owen, C., ‘The Domestication of the Ferret’, in P.J. Ucko and G.W. Dimbleby, The Domestication and Exploitation of Plants and Animals (London: Gerald Duckworth 1969), 489–494. Oxford, John S., ‘Influenza A Pandemics of the 20th Century with Special Reference to 1918. Virology, Pathology, and Epidemiology’, Reviews in Medical Virology, 10 (2000), 119–133. Oxford, John S., ‘The So-Called Great Spanish Influenza Pandemic of 1918 May Have Originated in France in 1916’, Philosophical Transactions of the Royal Society of London, B, 336 (2001), 1857–1859. Oxford, John S., et al., ‘World War I May Have Allowed the Emergence of “Spanish” Influenza’, The Lancet Infectious Diseases Journal, 2.2 (2002), 111– 114. Packard, Randall M., A history of Global Health: Interventions into the Lives of Other Peoples (Baltimore: Johns Hopkins University Press, 2016).

SELECT BIBLIOGRAPHY

435

Pasveer, B., Shadows of Knowledge: Making a Representing Practice in Medicine X-ray Pictures and Pulmonary Tuberculosis, 1895–1930 (Amsterdam: [s.n.], 1992). Patterson, David K., Pandemic Influenza, 1700–1900: A Study in Historical Epidemiology (Totowa, NJ: Rowman & Littlefield, 1986). Pattison, Iain, John McFadyean, Founder of Modern Veterinary Research (London: JA Allen, 1981). Pelling, Margaret, Cholera, Fever and English Medicine, 1835–1865 (Oxford: Oxford University Press, 1978). Pelling, Margaret, ‘Contagion/Germ Theory/Specificity’, in W.F. Bynum and R. Porter (Eds.), Companion Encyclopedia of the History of Medicine (London: Routledge, 1993), 309–334. Peterson, M.J., The Medical Profession in Mid-Victorian London (Berkeley: University of California Press, 1978). Phillips, Howard, Black October: The Impact of the Spanish Influenza Epidemic of 1918 on South Africa (Pretoria: The Government Printer, 1990). Phillips, Howard, ‘The Re-appearing the Shadow of 1918: Trends in the Historiography of the 1918–19 Influenza Pandemic’, Canadian Bulletin of Medical History, 21.1 (2004), 121–130. Phillips, Howard, ‘The Recent Wave of “Spanish” Flu Historiography’, Social History of Medicine, 27.4 (2014), 789–808. Phillips, Howard, and D. Killingray, ‘Introduction’, in H. Phillips and D. Killingray (Eds.), The Spanish Influenza Pandemic of 1918–1919: New Perspectives (London: Routledge, 2003), 1–25. Phillips, Howard, and D. Killingray, The Spanish Influenza Pandemic of 1918– 1919: New Perspectives (London: Routledge, 2003). Pickles, William N., Epidemiology in Country Practice (London: The Keynes Press, 1983). Pickstone, John V., Medical Innovations in Historical Perspective (London: Macmillan, 1992). Pickstone, John V., ‘Ways of Knowing: Towards a Historical Sociology of Science, Technology, and Medicine’, British Journal for the History of Science, 26 (1993), 433–458. Pickstone, John V., Ways of Knowing: A New History of Science, Technology and Medicine (Manchester: Manchester University Press, 2000). Pickstone, John V., ‘Working Knowledges Before and After Circa 1800: Practices and Disciplines in the History of Science, Technology, and Medicine’, Isis, 98.3 (2007), 489–516. Pickstone, John V., ‘Natural Histories, Analyses and Experimentation: Dissecting the Working Knowledges of Chemistry, Medicine and Biology Since 1750’, History of Science, 49 (2011), 235–376.

436

SELECT BIBLIOGRAPHY

Pickstone, John V., ‘A Brief Introduction to Ways of Knowing and Ways of Working’, History of Science, 49.3 (2011), 235–245. Podolsky, Scott H., ‘The Role of the Virus in Origin-of-Life Theorizing’, Journal of the History of Biology, 29 (1996), 79–126. Podolsky, Scott H., Pneumonia Before Antibiotics: Therapeutic Evolution and Evaluation in Twentieth-Century America (Baltimore: Johns Hopkins University Press, 2006). Porter, Roy, ‘Cleaning Up the Great Wen: Public Health in Eighteenth-Century London’, Medical History, Suppl. 11 (1991), 69–70. Porter, Dorothy, ‘Public Health, Preventive Medicine, and Professionalization: England and America in the Nineteenth Century’, in A. Wear (Ed.), Medicine in Society (Cambridge: Cambridge University Press, 1992), 249–275. Porter, Roy, ‘The Eighteenth Century’, in L. Conrad, M. Neve, V. Nutton, R. Porter, and A. Wear (Eds.), The Western Medical Tradition 800BC to AD (Cambridge: Cambridge University Press, 1995), 371–475. Porter, Roy, The Greatest Benefit to Mankind (London: W.W. Norton, 1997). Porter, Dorothy, Health, Civilization and the State: A History of Public Health from Ancient to Modern Times (London: Routledge, 1999). Potter, C.W., ‘A History of Influenza’, Journal of Applied Microbiology, 91.4 (2001), 572–579. Prüll, C.-R., ‘Pathology and Surgery in London and Berlin 1800–1930: Pathological Theory and Clinical Practice’, in C.-R. Prüll (Ed.), Pathology in the 19th and 20th Centuries: The Relationship Between Theory and Practice (Sheffield: European Association for the History of Medicine and Health Publications, 1998), 71–100 . Prüll, C.-R., ‘Pathology at War 1914–1918: Germany and Britain in Comparison’, in R. Cooter, M. Harrison, and S. Sturdy (Eds.), Medicine and Modern Warfare (Amsterdam: Rodolfi, 1999), 131–162. Pyle, G.F., The Diffusion of Influenza: Patterns and Paradigms (Rowman & Littlefield, 1981). Quirke, Viviane, Collaboration in the Pharmaceutical Industry: Changing Relationships in Britain and France, 1935–1965 (London: Routledge, 2007). Quirke, Viviane, and Jean-Paul Gaudillière, ‘The Era of Biomedicine: Science, Medicine, and Public Health in Britain and France After the Second World War’, Medical History, 52.4 (2008), 441–452. Rabinbach, Anson, The Human Motor: Energy, Fatigue, and the Origins of Modernity (Berkeley: University of California Press, 1990). Rader, Karen A., Making Mice: Standardizing Animals for American Biomedical Research, 1900–1955 (Princeton, NJ: Princeton University Press, 2004). Rader, Karen A. ‘Scientific Animals: The Laboratory and Its Human-Animal Relations, from Dba to Dolly’, in Linda Kalof and Brigitte (Eds.), A Cultural

SELECT BIBLIOGRAPHY

437

History of Animals, Volume 6: The Modern Age (1920–2000) (London: Bloomsbury, 2007), 119–137. Ramanna, M., ‘Coping with the Influenza Pandemic: The Bombay Experience’, in H. Phillips and D. Killingray (Eds.), The Spanish Influenza of 1918–1919: New Perspectives (London: Routledge, 2003), 86–95. Rasmussen, Nicolas, Picture Control: The Electron Microscope and the Transformation of Biology in America, 1940–1960 (Stanford: Stanford University Press, 1997). Rasmussen, Nicolas, ‘The Moral Economy of the Drug Company: Medical Scientist Collaboration in Interwar America’, Social Studies of Science, 34 (2004), 161–185. Rasmussen, Anne, ‘Prevent or Heal, Laissez-Faire or Coerce? The Public Health Politics of Influenza in France, 1918–1919’, in T. Giles-Vernick and S. Craddock (Eds.), Influenza and Public Health: Learning from Past Pandemics (London: Earthscan, 2010), 69–83. Reid, Anne H., J.K. Taubenberger, & T.G. Fanning, T.G., ‘The 1918 Spanish influenza: Integrating History and Biology’, Microbes and Infection, 3 (2001), 81–87. Reiser, Stanley J., Medicine and the Reign of Technology (Cambridge: Cambridge University Press, 1978). Reznick, Jeffrey S., ‘The Past, Present and Future of Memory: Medical Histories of the 1918–19 Influenza Epidemic in the United States’, in Guy Beiner (Ed.), Pandemic Re-Awakenings (Oxford: Oxford University Press, 2021), 234–243. Rheinberger, Hans-Jorg, ‘From Microsomes to Ribosomes: ‘Strategies’ of ‘Representation’’, Journal of the History of Biology, 28 (1995), 49–89. Rice, Geoffery, and L. Bryder, Black November: The 1918 influenza Epidemic in New Zealand (Wellington, NZ: Allen & Unwin, 1988). Risse, Guenther, ‘Medicine in the Enlightenment’, in A Wear (Ed.), Medicine in Society: Historical Essays (Cambridge: Cambridge University Press, 1992), 149–196. Rollet, Catherine, ‘The ‘Other War’ II: Setbacks in Public Health’, in J. Winter and J.-L. Robert (Eds.), Capital Cities at War: Paris, London, and Berlin 1914–1919 (Cambridge: Cambridge University Press, 1997), 456–486. Rosenberg, Charles E., ‘Cholera in Nineteenth Century Europe: A Tool for Social and Economic Analysis’, in idem., Explaining Epidemics and Other Studies in the History of Medicine (Cambridge: Cambridge University Press, 1992), 109–121. Rosenberg, Charles E., ‘Framing Disease: Illness, Society, and History’, in idem., Explaining Epidemics and Other Studies in the History of Medicine (Cambridge: Cambridge University Press, 1992), 305–318.

438

SELECT BIBLIOGRAPHY

Rosenberg, Charles E., ‘What Is Disease?: In Memory of Owsei Temkin’, Bulletin of the History of Medicine, 77 (2003), 491–505. Rusnock, Andrea A., ‘Hippocrates, Bacon, and Medical Meteorology at the Royal Society, 1700 –1750’, in D. cantor (Ed.), Reinventing Hippocrates (Aldershot, Hampshire: Ashgate Press, 2002), 136–153. Schickore, Jutta, ‘“Through Thousands of Errors We Reach the Truth”—But How? On the Epistemic Roles of Error in Scientific Practice’, Studies in History and Philosophy of Science, 36.3 (2005), 539–556. Schlich, Thomas, ‘Making Mistakes in Science: Eduard Pflüger, His Scientific and Professional Concept of Physiology, and His Unsuccessful Theory of Diabetes (1903–1910)’, Studies in History and Philosophy of Science, 24 (1993), 411– 441. Schneider, William H. (Ed.), Rockefeller Philanthropy and Modern Biomedicine: International Initiatives from World War I to the Cold War (Bloomington: University of Indiana Press, 2002). Silverstein, A.M., A History of Immunology (London: Academic Press, 1989). Smith-Hughes, Sally, The Virus: A History of a Concept (London: Heineman, 1977). Smith, F.B., ‘The Russian Influenza in the United Kingdom’, Social History of Medicine, 8 (1995), 55–73. Steere Williams, Jacob, ‘Performing State Medicine During Its ‘Frustrating’ Years: Epidemiology and Bacteriology at the Local Government Board, 1870–1900’, Social History of Medicine, 28.1 (2015), 82–107. Steere-Williams, Jacob, The Filth Disease: Typhoid Fever and the Practices of Epidemiology in Victorian England (Rochester, NY: University of Rochester Press, 2020). Stevens, Rosemary, Medical Practice in Modern England: The Impact of Specialization and State Medicine (New Haven: Yale University Press, 1966). Sturdy, Steve, ‘The Political Economy of Scientific Medicine: Science, Education and the Transformation of Medical Practice in Sheffield, 1890–1922’, Medical History, 36 (1992), 125–159. Sturdy, Steve, ‘Medical Chemistry and Clinical Medicine: Academics and the Scientisation of Medical Practice in Britain, 1900–1925’, in I. Löwy and J.-P. Gaudillière (Eds.), Medicine and Change: Historical and Sociological Studies of Medical Innovation (Montrouge, France: John Libbey Eurotext, 1993), 371–394. Sturdy, S., ‘From Hippocrates to State Medicine: George Newman on the Early Policy of the Ministry of Health’, in G. Weisz and C. Lawrence (Eds.), Greater Than the Parts: Holism in Inter-War Medicine (Oxford: Oxford University Press, 1998), 112–134. Sturdy, Steve, ‘War as Experiment: Physiology, Innovation and Administration in Britain, 1914–1918: The Case of Chemical Warfare’, in R. Cooter, M.

SELECT BIBLIOGRAPHY

439

Harrison, and S. Sturdy (Eds.), War, Medicine and Modernity (London: Sutton, 1998), 65–84. Sturdy, Steve, ‘Knowing Cases: Biomedicine in Edinburgh, 1887–1920’, Social Studies of Science, 37 (2007), 659–689. Sturdy, Steve, ‘Scientific Method for Medical Practitioners: The Case Method of Teaching Pathology in Early Twentieth-Century Edinburgh’, Bulletin of the History of Medicine, 81 (2007), 760–792. Sturdy, Steve, ‘Looking for Trouble: Medical Science and Clinical Practice in the Historiography of Modern Medicine’, Social History of Medicine, 24.3 (2011), 739–57. Sturdy, Steve, and R. Cooter, ‘Science, Scientific Management, and the Transformation of Medicine in Britain c. 1870–1950’, History of Science, 36 (1998), 421–466. Summers, William C., Felix d’Herelle and the Origins of Molecular Biology (London: Yale University Press, 1999). Summers, William C., ‘Inventing Viruses’, Annual Review of Virology, 1 (2014), 25–35. Sweet, C., R.J. Fenton, and G.E. Price, ‘The Ferret as an Animal Model of Influenza Virus Infection’, in O. Zak and M.A. Sande (Eds.), Handbook of Animal Models of Infection: Experimental Models in Antimicrobial Chemotherapy (London: Academic Press, 1999), 288–298. Szreter, Simon, ‘The GRO and the Public Health Movement in Britain, 1837– 1914’, Social History of Medicine, 4 (1990), 435–464. Tanner, Andrea, ‘The Spanish Lady Comes to London: the Influenza Pandemic 1918–1919’, London Journal, 27 (2002), 51–76. Tansey, E.M., ‘Protection Against Dog Distemper and Dogs Protection Bills: The Medical Research Council and Anti-vivisectionist Protest, 1911–1933’, Medical History, 38 (1994), 1–26. Taubenberger, Jeffery K., ‘Genetic Characterisation of the ‘Spanish’ Influenza Virus’, in H. Phillips and D. Killingray (Eds.), The Spanish Influenza Pandemic of 1918–1919: New Perspectives (London: Routledge, 2003), 39–46. Taubenberger, Jeffery K., ‘The Origins and Virulence of the 1918 “Spanish” Influenza’, Proceedings of the American Philosophical Society, 150 (2006), 86– 112. Taubenberger, Jeffery K., and D.M. Morens, ‘1918 Influenza: The Mother of All Pandemics’, Emerging Infectious Diseases, 12 (2006), 15–22. Taubenberger, Jeffery K., A.H. Reid, and T.G. Fanning, ‘The 1918 Influenza Virus: A Killer Comes into View’, Virology, 274 (2000), 241–245. Taubenberger, Jeffery K., A.H. Reid, A.H. Krafft, K.E. Bijwaard, and T.G. Fanning, ‘Initial Genetic Characterization of the 1918 “Spanish” Influenza Virus’, Science, 275 (1997), 1793–1796.

440

SELECT BIBLIOGRAPHY

Thomson, A. Landsborough, Half a Century of Medical Research. Origins and Policy of the Medical Research Council (UK), Vol. 1 (London: HMSO, 1973). Thomson, A. Landsborough, Half a Century of Medical Research. The Programme of the Medical Research Council (UK), Vol. 2 (London: HMSO, 1975). Thomson, A.P., ‘A History of the Ferret’, Journal of the History of Medicine, VI (151), 471–480. Thomson, Matthew, ‘Neurasthenia in Britain: An Overview’, in M. GijswijtHofstra and R. Porter (Eds.), Cultures of Neurasthenia from Beard to the First World War (Amsterdam: Rodofi, 2001), 77–96. Tizard, Ian, and Roland D. Schultz, ‘Grease, Anthraxgate, and Kennel Cough: A Revisionist History of Early Veterinary Vaccines’, Advances in Veterinary Medicine, 41 (1999), 7–24. Todes, Daniel P., ‘Pavlov’s Physiology Factory’, Isis, 88 (1997), 205–246. Tognotti, Eugenia, ‘Scientific Triumphalism and Learning from Facts: Bacteriology and the “Spanish Flu” Challenge of 1918’, Social History of Medicine, 16 (2003), 97–110. Tomes, Nancy, The Gospel of Germs: Men, Women, and the Microbe in American Life (Cambridge, MA: Harvard University Press, 1998). Tomkins, Sandra M., ‘Britain and the Influenza Epidemic’, Ph.D. Thesis. Department of History, University of Cambridge (1989). Tomkins, Sandra M., ‘The Failure of Expertise: Public Health Policy in Britain During the 1918–19 Influenza Epidemic’, Social History of Medicine, 5 (1992), 435–454. Twort, A., In Focus, Out of Step: A Biography of Frederick William Twort F.R.S., 1877–1950 (Phoenix Mill [UK]: A. Sutton, 1993). Tyrell, David A.J., ‘Christopher Howard Andrewes’, Biographical Memoirs of Fellows of the Royal Society, 37 (1991), 33–54. Tyrell, David A.J., ‘Discovery of Influenza Viruses’, in K.G. Nicholson, R.G. Webster, and A.J. Hay (Eds.), Textbook of Influenza (Oxford: Blackwell, 1998), 19–26. Vagneron, Frédéric, ‘Surveiller et s’unir? Le rôle de l’OMS dans les premières mobilisations internationales autour d’un réservoir animal de la grippe’, Revue d’anthropologie des connaissances, 2 (2015), 139–161. Valier, Helen, and Carsten Timmermann, ‘Clinical Trials and the Reorganization of Medical Research in Post-Second World War Britain’, Medical History, 52 (2008), 493–510. van Hartsveldt, F.R., ‘The Government and the ‘Flu: British Public Response to the Epidemic of 1918–1919’’, Social Science Perspectives, I (1986), 46–49. van Hartesveldt, Fred R. (Ed.), The 1918–1919 Pandemic of Influenza: The Urban Impact in the Western World (Lewiston, NY: The Edwin Mellen Press, 1992).

SELECT BIBLIOGRAPHY

441

van Helvoort, Ton, ‘What Is a Virus?: The Case of Tobacco Mosaic Disease’, Studies in History and Philosophy of Science, 22 (1991), 557–588. van Helvoort, Ton, ‘Bacteriology and Physiological Research Styles in the Early Controversy on the Nature of the Bacteriophage Phenomenon’, Medical History, 36 (1992), 243–270. van Helvoort, Ton, ‘A Bacteriological Paradigm in Influenza Research in the First Half of the Twentieth Century’, History and Philosophy of the Life Sciences, 15 (1993), 3–21. van Helvoort, Ton, ‘The Construction of Bacteriophage as Bacterial Virus: Linking Endogenous and Exogenous Thought Styles’, Journal of the History of Biology, 27 (1994), 91–139. van Helvoort, Ton, ‘History of Virus Research in the Twentieth Century: The Problem of Conceptual Continuity’, History of Science, XXXII (1994), 185– 235. van Helvoort, Ton, ‘A Comment on the Early Influenza Virus Vaccines: The Role of the Concept of Virus’, in S.A. Plotkin and B. Fantini, B. (Eds.), Vaccinia, Vaccination, Vaccinology: Jenner, Pasteur and their Successors (Paris: Elsevier, 1996), 193–197. van Helvoort, Ton, ‘Start of a Cancer Research Tradition: Peyton Rous, James Ewing and Viruses as a Cause of Cancer’, in Darwin H. Stapleton (Ed.), Creating a Tradition of Biomedical Research (New York: Rockefeller University Press, 2004), 191–221. van Hartesveldt, Fred R., ‘The Doctors and the ‘Flu’: The British Medical Profession’s Response to the Influenza Pandemic of 1918–19’, International Social Science Review, 85.1/2 (2010), 28–39. Waddington, Keir, Medical Education at St Bartholomew’s Hospital 1123–1995 (London: Boydell Press, 2003). Wailoo, Keith, Drawing Blood: Technology and Disease Identity in TwentiethCentury America (Baltimore: Johns Hopkins University Press, 1997). Wailoo, Keith, Dying in the City of the Blues: Sickle Cell and the Politics of Race and Health (Chapel Hill and London: University of North Carolina Press, 2001). Wall, Rosemary, ‘“Natural”, “Normal”: Discourse and Practice at Sr. Bartholomew’s Hospital, London, and Addenbrooke’s Hospital, Cambridge, 1880–1920’, Forum: Qualitative Social Research, 8 (2007). http://nbnresolv ing.de/urn:nbn:de:0114-fqs0701174. Wall, Rosemary, Bacteria in Britain, 1880–1939 (London: Pickering & Chatto, 2013). Warner, John Harley, ‘The Fall and Rise of Professional Mystery: Epistemology, Authority and the Emergence of Laboratory Medicine in Nineteenth-Century America’, in A. Cunningham and P. Williams (Eds.), The Laboratory Revolution in Medicine (Cambridge: Cambridge University Press, 1992), 110–141.

442

SELECT BIBLIOGRAPHY

Warner, John Harley, ‘The History of Science and the Sciences of Medicine’, Osiris, 10 (1995), 164–193. Waterson, A.P., and L. Wilkinson, An Introduction to the History of Virology (Cambridge: Cambridge University Press, 1978). Wear, Andrew, ‘Place, Health, and Disease: The Airs, Waters, Places Tradition in Early Modern England and North America’, Journal of Medieval and Early Modern Studies, 38 (2008), 443–465. Weatherall, Mark, ‘Scientific Medicine and the Medical Sciences in Cambridge, 1851–1939’, Ph.D. Thesis, Department of History and Philosophy of Science, University of Cambridge (1994). Weatherall, Mark, Gentlemen, Scientists, and Doctors: Medicine at Cambridge, 1800–1940 (Rochester, NY: Boydell Press, 2000). Weindling, Paul J., ‘From Medical Research to Clinical practice: Serum Therapy for Diphtheria in the 1890s’, in J.V. Pickstone (Ed.), Medical Innovations in Historical Perspective (London: Macmillan, 1992), 72–83. Weindling, Paul J., ‘Between Bacteriology and Virology: The Development of Typhus Vaccines Between the First and Second World Wars’, History and Philosophy of the Life Sciences, 17 (1995), 81–90. Weir, Lorna, and Eric Mykhalovskiy, Global Public Health Vigilance: Creating a World on Alert (New York: Routledge, 2010). Weisz, George, ‘The Emergence of Medical Specialization in the Nineteenth Century’, Bulletin of the History of Medicine, 77 (2003), 536–575. Weisz, George, Divide and Conquer: A Comparative History of Medical Specialization (New York: Oxford University Press, 2006). Whitehead, Ian R., ‘The British Medical Officer on the Western Front: The Training of Doctors for War’, in R. Cooter, M. Harrison, and S. Sturdy (Eds.), Medicine and Modern Warfare (Amsterdam: Rodopi, 1999), 163–184. Whitehead, Ian R., Doctors in the Great War (London: Leo Cooper, 1999). Wilkinson, Lise, ‘The Development of the Virus Concept as Reflected in Corpora of Studies on Individual Pathogens. Part 3. Lessons of Plant Viruses—Tobacco Mosaic Virus’, Medical History, 20 (1976), 111–134. Wilkinson, Lise, ‘The Development of the Virus Concept as Reflected in Corpora of Studies on Individual Pathogens. 4. Rabies—Two Millennia of Ideas and Conjecture on the Aetiology of a Virus Disease’, Medical History, 21 (1977), 15–31. Wilkinson, Lise, ‘Animal Viruses, Veterinary Pathology, and the Formulation of Ideas Concerning Filterable Viruses’, Historia Medicinae Veterinariae, 3 (1978), 1–15. Wilkinson, Lise, ‘The Development of the Virus Concept as Reflected in Corpora of Studies on Individual Pathogens. 5. Smallpox and the Evolution of Ideas on Acute (Viral) Infections’, Medical History, 23 (1979), 1–28.

SELECT BIBLIOGRAPHY

443

Wilkinson, Lise, Animals and Disease: An Introduction to the History of Comparative Medicine (Cambridge: Cambridge University Press, 1992). Wilkinson, Lise, ‘Review: In Focus, Out of Step: A Biography of Frederick William Twort, F.R.S.’ Medical History, 38 (1994), 340–341. Wilkinson, Lise, ‘Burgeoning Visions of Global Public Health: The Rockefeller Foundation, the London School of Hygiene and Tropical Medicine, and the ‘Hookworm Connection’’, Studies in History and Philosophy of Biological and Biomedical Sciences, 31 (2000), 397–407. Wilkinson, Lise, and A. Hardy, Prevention and Cure: The London School of Hygiene & Tropical Medicine: A 20th Century Quest for Global Public Health (London: Kegan Paul, 2001). Wilson, Adrian, ‘On the History of Disease-Concepts: The Case of Pleurisy’, History of Science, xxxviii (2000), 271–319. Winter, Jay M., The Great War and the British People (London: Macmillan, 1985). Witte, Wilfried, ‘The Plague That Was Not Allowed to Happen: German Medicine and the Influenza Pandemic of 1918–19 in Baden’, in H. Phillips and D. Killingray (Eds.), The Spanish Influenza Pandemic of 1918–19: New Perspectives (London: Routledge, 2003). Woods, Abigail, A Manufactured Plague: The History of Foot and Mouth Disease in Britain, 1839–2001 (London: Earthscan, 2004). Woods, Abigail, ‘Animals and Disease’, in M. Jackson (Ed.), Routledge History of Disease (London: Routledge, 2016), 147–164. Woods, Abigail, ‘Between Human and Veterinary Medicine: The History of Animals and Surgery’, in T. Schlich (Ed.), Palgrave Handbook of the History of Surgery (Basingstoke: Palgrave Macmillan, 2017). Woods, Abigail, ‘Animals in the History of Human and Veterinary Medicine’, in H. Kean and P. Howell (Eds.), The Routledge Companion to Animal-Human History (London: Routledge, 2018), 147–170. Woods, Abigail, and Stephen Matthews, ‘“Little, If at All, Removed from the Illiterate Farrier or Cow-Leech”: The English Veterinary Surgeon, c.1860– 1885, and the Campaign for Veterinary Reform’, Medical History, 54 (2010), 29–54. Worboys, Michael, ‘Vaccine Therapy and Laboratory Medicine in Edwardian Britain’, in J.V. Pickstone (Ed.), Medical Innovations in Historical Perspective (London: Macmillan, 1992), 84–103. Worboys, Michael, ‘Treatments for Pneumonia in Britain 1910–1940’, in I. Löwy and J.-P. Gaudillière (Eds.), Medicine and Change: Historical and Sociological Studies of Medical Innovation (Montrouge, France: John Libbey Eurotext, 1993), 317–336.

444

SELECT BIBLIOGRAPHY

Worboys, Michael, ‘Almroth Wright at Netley: Modern Medicine and the Military in Britain, 1892–1902’, in R. Cooter, M. Harrison, and S. Sturdy (Eds.), Medicine and Modern Warfare (Amsterdam Rodopi, 1999), 77–97. Worboys, Michael, Spreading Germs: Disease Theories and Medical Practice in Britain, 1865–1900 (Cambridge: Cambridge University Press, 2000). Worboys, Michael, ‘From Heredity to Infection: Tuberculosis, 1870–1890’, in J.-P. Gaudillière and I. Löwy (Eds.), Heredity and Infection: The History of Disease Transmission (London: Routledge, 2001), 81–100. Worboys, Michael, ‘Klein, Edward Emanuel (1844–1925)’, Oxford Dictionary of National Biography (Oxford University Press, 2004) [online edn, January 2008 http://www.oxforddnb.com/view/article/57359]. Worboys, Michael, ‘Was There a Bacteriological Revolution in Late Nineteenth Century Medicine?’ Studies in History and Philosophy of Biological and Biomedical Sciences, 38 (2007), 20–42. Worboys, Michael, ‘Practice and the Science of Medicine in the Nineteenth Century’, Isis, 102.1 (2011), 109–115. Zylberman, Patrick, ‘A Holocaust in a Holocaust: The Great War and the 1918 ‘Spanish’ Influenza Epidemic in France’, in H. Phillips and D. Killingray (Eds.), The Spanish Influenza Pandemic of 1918–19: New Perspectives (London: Routledge, 2003), 191–201.

Index

A Allbutt, Clifford, 103, 105, 372, 377 Althaus, Julius, 82 Andrewes, Charles Herbert (C.H.), 3, 4, 18, 22, 253, 265, 266, 315 Andrewes, Frederick W., 91, 147, 181, 196, 266 Director, Department of Pathology at St. Bartholomew’s Hospital, 266, 296 Report on the Pandemic of Influenza, 155, 196 role on Medical Research Council, 147 support for influenza virus theory, 18, 185, 244, 266 work with Edward Klein on influenza bacillus, 196 Animal experimentation, 88, 176 and 1876 Cruelty to Animals Act, 176 and standardised animal breeding, 177

Animals (experimental), 2, 93, 162, 226, 232, 238, 286, 326, 362, 367 as human analogues, 195, 312 in comparative pathology, 176 in experimental pathology, 195, 220 in virus research, 176, 238, 362, 367 standardised animals, 177 Army Medical Services, 117, 123, 180, 185, 300, 358 Director-General of the AMS, 119 re-organisation (1914–1916), 117 Avian influenza, 116, 371, 373, 385, 389–392, 394–396 control of H5N1, 389, 391, 395 ecology of, 388 Graeme Laver and Robert Webster, 388 studies and discovery, 371

© The Editor(s) (if applicable) and The Author(s), under exclusive licence to Springer Nature Limited 2023 M. Bresalier, Modern Flu, Medicine and Biomedical Sciences in Modern History, https://doi.org/10.1057/978-1-137-33954-6

445

446

INDEX

B Bacillus influenzae. See Haemophilus bacillus, Influenza bacillus, Pfeiffer’s baccilus Bacteriology, 9–14, 20, 50, 51, 55, 56, 85, 87–91, 97, 98, 100, 103–105, 118, 128, 131, 139, 140, 144, 147, 154, 167, 173, 174, 176, 186, 187, 193, 194, 196, 200–202, 220, 245, 259, 263, 266, 272, 290, 357, 359, 366, 367 and influenza research, 10, 140, 246, 292 and Koch’s postulates, 88 and the Local Government Board, 10, 51 and virus research, 174, 290, 367 development in Britain, 9, 54, 56, 88, 90, 201, 290 principle of specific aetiology, 10, 88, 104 role in hospital medicine, 50 role in public health, 11, 51, 88, 100, 105, 118, 186, 359, 396 Barnard, Joseph E., 182, 194, 199, 212, 215–218, 221 and Division of Applied Optics, 212 cancer studies, 215, 218 ultraviolet microscope, 216, 217 visualisation of chicken sarcoma virus, 218 visualisation of Gordon’s influenza filter-passer, 198, 199, 218 British Expeditionary Force, 117, 128 and influenza (1918), 128 British Journal of Experimental Pathology, 194, 283, 299 and comparative and experimental approach to virus research., 176, 221 and specific aetiology, 195

promotion of multidisciplinary and collaborative research, 195 British Medical Association, 69, 112, 200, 289 Bronchitis/Bronchial infections. See purulent bronchitis Brown Animal Sanatory Institution, 56, 91, 177, 178, 202 and the Local Government Board Medical Department, 10, 51 Frederick W. Twort and bacteriophage research, 177 pathological and bacteriological investigation, 51, 90 Buchanan, George, 59, 70, 71, 99, 156 Bulloch, William and influenza (1905), 102 and variable virulence, 167 Burnet, Frank Macfarlane (F.M.) antigenic variation, 339 developing chick egg, 330, 331, 334 influenza virus, 4, 115, 264, 330–332, 334, 371 on 1918–19 influenza pandemic, 4 Burroughs Wellcome Company and canine (dog) distemper vaccine, 239 and Wellcome Physiological Research Laboratories, 237 relations with the Medical Research Council, 156

C Cancer virus research, 214, 267 chicken sarcoma, 214 Rous’ sarcoma, 214 William Gye studies, 267 Canine distemper. See Dog distemper Carlyle, Thomas, 44

INDEX

Case-tracking/Case-based epidemiology, 11, 34, 35, 54, 55, 60, 65 Catarrh (Epidemic), 33 Chick egg (developing), 319, 329, 330, 336 amniotic and allanotic methods of influenza virus cultivation, 334 and F.M. Burnet, 330 chorioallantoic membrane (CAM) method, 330, 331 haemagglutination test and George Hirst, 335, 337 introduction into influenza virus research, 319, 362 introduction into virus research, 319, 330, 361 role in development and industrialisation of vaccine production, 319, 320, 329 role in influenza virus surveillance and World Influenza Programme, 319 standardisation of egg-based influenza virus methods, 331 Classification (Nosologies/ Enlightenment medicine), 29, 30, 41 Clinical (Hospital) medicine, 81, 104, 105, 178, 191, 221, 365 Collaboration (scientific), 318, 382, 396 Collective investigation, 51, 59 Commission on Influenza, 320, 337, 339, 342, 347, 362, 382 as model, 22, 320 development of influenza vaccine, 320, 347 mass immunisation, 3 organisation, 22, 320 Comparative pathology, 176 Contagionism, 62

447

contagion theories, 62 Contingent contagionism, 62 Covid-19 (Coronavirus; and SARS-CoV-2), 23, 375–381, 392, 394–396 Creighton, Charles, 27 Cullen, William, 30, 31, 33, 34, 38, 41, 72 D Dale, Henry Hallett, 193, 202, 204, 228, 238, 253, 261, 272 Distemper Fund, The Field, 225, 229 creation and organisation, 226 patronage system, 226 Dog distemper (Canine distemper), 16, 221, 223, 231, 239 and influenza virus research, 320 and veterinary interest, 235 as national threat (to foxhounds and fox hunt, pedigree breeds, dog owners), 223, 235 as proxy for influenza, 16 bacteriological studies of, 64 controversies about distemper agent, 363 Henri Carré filterable virus studies, 225 vaccine failures, 382 Dog distemper (vaccines) commercialisation, 237 experimental vaccine, 232, 253, 254, 320, 325, 326 role of Burroughs Wellcome Company, 237 vaccine trials, 155 Dog distemper (Virus research) correlating ferret and dog studies, 276, 300 creation of Farm Laboratories at Mill Hill, 228, 274 dog and ferret breeding, 228

448

INDEX

dog experiments and ‘experimental distemper’, 228, 236 ferret experiments, 232 Field Distemper Research Council, 226, 231 Patrick Laidlaw and G.W. Dunkin studies, 228, 231 Douglas, S.R., 123, 136, 147, 148, 193, 231, 272 E Eighteenth century medicine. See Enlightenment medicine Elford, William J., 216, 218–221, 231, 326 Enlightenment medicine, 27, 41. See also Eighteenth century medicine Epidemic catarrh (epidemic catarrhal fever), 38, 43 Epidemiology, 2, 6, 21, 35, 43–45, 50, 54, 60, 62, 65, 69, 105, 114, 166, 167, 194, 259, 344, 352, 356, 357, 360, 361, 365, 368, 369, 381, 396 cast-tracking methods, 11, 34, 54 historical, 43 victorian, 27, 43, 55 Epidemiology (influenza), 2, 38, 45, 65, 69, 94 1889–90, 52, 55 1918–19, 49, 352 Experimental animals (research, laboratory animals), 16, 17, 154, 187, 195, 212, 257, 264, 269, 276, 293 Experimental pathology, 15, 163, 192–194, 206, 209, 360, 367 F Farr, William, 45, 46 Ferret

and ‘experimental distemper’, 230 and influenza virus neutralization, 258 as a virus research tool, 389 breeding of for research, 231 development into influenza ‘model’, 273, 292 ferret ‘flu and human influenza, 277, 282–284, 297, 300, 303, 312 history in Britain, 231 in studies of influenza immunity, 277 introduction into distemper research, 273, 274 role in isolation of (human) influenza virus, 320, 329 role in viralising influenza, 256, 362 roles in distemper virus studies, 332 uses in distemper vaccine development and trials, 274, 326 Fevers, 1, 30, 33, 73, 75, 77, 85, 202, 241 The Field and dog (canine) distemper, 223 Field Distemper Council, 226, 231 Field Distemper Fund, 225, 229 relations with the Medical Research Council, 227 research patronage, 227 Fildes, Paul, 132–134, 136, 137, 141, 150, 153, 154, 184, 185, 194, 244 editor, British Journal of Experimental Pathology, 194 influenza bacillus studies (1918), 133 Filterable virus/viruses/agents, 14, 16, 18, 162, 163, 172–174, 178, 179, 181, 187, 193, 194, 196, 198, 199, 206, 209, 212, 214,

INDEX

215, 218, 220, 222, 230, 231, 244, 253, 257, 267, 268, 270, 283, 285, 300, 307, 359, 360 First World War, 2, 3, 13, 50, 105, 205, 321 and 1918–19 influenza pandemic, 2 and medicalisation of, 117 and militarisation of medicine, 117 medical and scientific mobilisation, 117, 337 Fleck, Ludwik, 7, 8 Fleming, Alexander, 123, 172, 188, 189, 244 influenza vaccines and penicillin, 189 Fletcher, Walter Morley, 14, 15, 119, 120, 125, 140, 142, 144, 155, 156, 158, 159, 161–163, 165, 167, 171, 172, 179, 180, 182, 190, 191, 193, 201, 202, 204–206, 209, 213, 214, 221, 222, 225–228, 239, 240, 260, 261, 269, 284, 285, 296, 312, 359, 365 and creation of the Medical Research Committee, 118, 182 conflicts with Ministry of Health, 165, 171 creation of the Medical Research Council, 14 developing of virus research programme at the National Institute for Medical Research, 284 First World War medical research organisation, 206 relations with The Field Distemper Council, 226 support of 1918 pathological and bacteriological studies of influenza, 296

449

support of 1918 studies on the role of a ‘filter-passer’ in influenza, 161 Fothergill, John, 30, 35 Francis Jr., Thomas. See Magill, Thomas and antigenic variation of influenza viruses, 323 and the World Influenza Programme, 339 and US Commission on Influenza, 345 collaboration with the NIMR, 291, 293 identification of ‘PR8’ influenza virus, 291, 323 influenza B virus, 324, 325 Rockefeller International Health Division, 292 French, Herbert, 112, 141, 143, 152 and ‘heliotrope cyanosis’ (1918), 141 and ‘purulent bronchitis’ (1916), 126, 141 G General Register Office, 45, 55 Gordon, Mervyn H., 102, 103, 138, 154, 196–202, 212, 218, 244, 245 and bacteriological studies of influenza (1905), 102 filter-passer studies for the Local Government Board, 198, 199 influenza filter-passer studies (1920–22), 200 Olitsky and Gates’ Bacterium pneumosintes , 197 Gray, Edward, 32, 36–38 Greenwood, Major, 49, 70, 113, 155, 156, 166–168, 241 and ‘epidemic influenza’, 168

450

INDEX

and epidemiology, 166, 167 challenges to War Office vaccine trials, 151, 155 Report on the Pandemic of Influenza (1920), 113, 155, 168 Grippe, 25, 26, 34, 43, 57 Gye, William, 193, 212, 214, 215, 267 cancer studies, 218, 221, 267 tumour viruses, 212, 267

H Haemophilus influenzae, 309 Hamer, William, 108, 141, 158, 167, 168, 266 and neo-Hippocratic theory of epidemics, 168 Haygarth, John, 37–39 Hippocratic medicine, 29 Hospitals (Voluntary, London), 73, 76 Huxham, John, 28

I Influenza and purulent bronchitis (1915), 126, 127, 141 Influenza (antigenic variation), 22, 315, 322, 323, 325 antigenic ‘drift’ and antigenic ‘shift’, 387, 389 history of, 361 role of polymerase chain reaction (PCR) technologies, 390 surveillance of. See World Influenza Programme Influenza as ‘democratic’ disease, 70 Influenza bacillus, 89, 90, 96, 99, 100, 102, 154, 185. See also Pfeiffer’s bacillus B. influenzae, 102, 126–129, 131–134, 136–138, 146–150,

153–155, 157, 158, 172, 179, 185–189, 244, 248, 356, 358 challenges with cultivation, 12 cultivation of, 153 Haemophilus bacillus , 101, 270 role in influenza, 101, 137, 147, 154, 212 Influenza bacteriology ‘anti-Pfeiffer school’ James McIntosh and Paul Fildes’ studies, 138 controversies during 1918-19 pandemic, 363 Edward Klein’s studies (1891), 196 ‘Pfeiffer school’, 131 Richard Pfeiffer studies, 86 Influenza classification 18th-19th centuries, 368 1890s-1910s, 10, 97 Ministry of Health (1939), 307, 308, 369 ‘Pyrexia of Unknown Origin’, 129 ‘three-day fever’, 130 Influenza complications heliotrope cyanosis, 141 Influenza diagnosis (challenges) 18th and 19th centuries, 77, 97, 368 1890s–1900s, 87 1918-19, 127 changes after 1933, 291 Influenza epidemics, 9, 18, 46, 68, 107, 113, 116, 127, 139, 198, 248, 261, 290, 293, 297, 298, 309, 315, 343, 382 Influenza forms gastric, 80, 306 nervous, 80, 82, 306 respiratory, 306 Influenza pandemic (1889–1894), 356 Influenza pandemic (1918–1919)

INDEX

bacteriological research, 266 definition and diagnosis, 242 First wave (Spring 1918), 128 military medicine and; war and, 110 pathology and, 107 preventative strategies, 290 Report on the Pandemic of Influenza, 1918-1919, 196 second wave (Autumn 1918, 359 third wave (Winter 1919), 169 war and, 112 Influenza pandemic (1957–1958) and World Influenza Programme, 345 ‘Asian’ influenza, 382 deaths, 53 public health measures (Britain), 369 vaccine production (Britain; United States), 23, 350 Influenza pandemic (1968–69) and World Influenza Programme, 387 deaths, 385 ‘Hong Kong’ influenza, 387 vaccine production (Britain; United States), 336 Influenza pathology, 49, 90 Influenza pneumonia ‘influenzal pneumonia’, 76, 83, 84, 91, 92, 127, 170, 241, 248 Influenza prevention, 99, 170, 369 1890s–1920s, 23 Influenza (pseudo), 101–103 Influenza secondary infections Microcococcus catarrhalis, pneuomococci, streptococci, 186 Influenza surveillance Ministry of Health scheme (1920s). See World Influenza Programme

451

Influenza symptomatology (clinical forms) Medical Annual (four clinical types), 81 Samuel West (varieties), 76 Thomas Peacock (forms), 78 Influenza treatment (1918–19) official recommendations, 246 Influenza treatment (1920s–1930s), 18 Influenza treatment (Eighteenth and Nineteenth centuries) heroic medicine, 39, 41 hippocratic medicine, 29 Patent medicines, 100, 291 Influenza vaccines (bacterial) criticisms of War Office vaccine, 150 Influenza vaccine (virus), 144, 257 ‘mixed’ vaccines, 144, 148, 189 ‘Pfeiffer vaccines’, 154, 248 War Office (mixed bacterial) vaccine (1918), 125 War Office vaccine and transfer to Local Government Board, 154 War Office vaccine testing, 306 Influenza vaccine (virus) Commission of Influenza vaccines, 149 Commission of Influenza vaccine trials, 155 NIMR experimental vaccine development and testing, 362 Rockefeller Foundation vaccine research and development, 18, 179 vaccination, 347 Influenza virus (human) antigenic variation, 22, 315, 325, 328, 340 British investigations (1918), 180 classification of, 72, 312, 324, 368

452

INDEX

comparative studies, 268 debates about the identity of, 200 discovery of. See National Institute for Medical Research French investigations (1918), 14 role of the MRC, 15, 19 theory of, 179, 185 Influenza virus research, 18, 270, 290, 335, 364, 365, 390 Influenza virus (swine), 18, 270, 282, 298, 324, 370 classification of, 324 hypotheses on origins of 1918–19 pandemic, 116 Richard E. Shope and discovery of, 18, 270, 386 Influenza (zoonosis) bird reservoirs, 371 definition as, 388 ecology of influenza viruses, 361

K Kitasato, Shibashuro, 89, 91–93, 262 Klein, Edward, 56, 88–95, 100, 147, 196, 266 and British bacteriology, 56 influenza bacillus studies (1891–92), 90 Koch, Robert, 87, 88, 92, 173 Koch’s postulates, 88, 89, 153, 185, 262

L Laidlaw, Patrick (P.P.), 4, 18, 193, 202, 203, 206, 211, 222, 227–232, 234–239, 253, 254, 261, 265, 269–271, 273, 274, 276, 277, 280, 282–286, 292–294, 296–298, 300, 302, 303, 322, 326, 366, 370

appointment to the National Institute for Medical Research, 284 Lamb, Charles, 41, 42 Leichtenstern, Otto, 50, 89 Leishman, William Boog anti-typhoid vaccine, 119, 121 as Advisor on Pathology to the War Office, 144 development and testing of mixed-influenza vaccine (1918–19), 152 organisation of pathological laboratories (First World War), 118 Local Government Board, Medical Department, 10 London, 2, 6, 10, 13–15, 17, 27–31, 35–37, 43–46, 49–59, 62–64, 66, 67, 69, 70, 72–76, 78–83, 86–92, 95, 97, 99–102, 107, 108, 110, 111, 113–119, 121–124, 128, 129, 132, 133, 135, 137, 138, 141, 142, 146, 157, 158, 161, 163, 164, 166–173, 175, 177–180, 184, 186–188, 190–196, 201–203, 206, 210–212, 216, 218, 220–222, 224, 227, 228, 231–233, 235, 237–239, 241, 242, 244–246, 253, 259, 262–269, 272, 276, 282, 283, 286, 289–291, 295–298, 300, 307, 308, 310, 311, 313, 319, 322, 323, 325, 327, 331, 333, 339, 348, 358, 362, 365, 366, 371, 376, 377, 379, 383, 384, 386, 388, 393 London County Council, 167, 168, 188 London (hospitals), 296

INDEX

M Magill, Thomas. See Francis Jr., Thomas and Strain Study Centre, 338 antigenic variation of influenza viruses, 323, 328 collaboration with the NIMR, 291 identification of ‘PR8’ influenza virus, 291 Rockefeller International Health Division, 292 Matthews, John Almroth Wright’s Inoculation Department (St. Mary’s Hospital), 188 anti-catarrh vaccines, 159 development of influenza bacillus cultivation technique (Matthews’ medium), 136, 144, 150 McFadyean, John and comparative pathology, 175, 178 and Ultravisible Viruses, 176 Journal of Comparative Pathology and Therapeutics , 175, 178 Royal Veterinary College, 175 McIntosh, James, 129, 132–134, 136–138, 153, 154, 184, 185, 200, 244, 292 Medical Department, Local Government Board Further Report and Papers and Epidemic Influenza, 1889–92, 95 history, 58, 59 1889–90 influenza investigations, 51, 53 1918–19 influenza pandemic, 2, 4, 51, 206, 283 Report on the Influenza Epidemic of 1889–1890, 53, 68

453

Medical Research Committee (1913–1918) and ‘filter-passer’ studies of influenza, 200 creation, 191, 209 1918 memorandum on ‘second waves’ of influenza, 130 organisation of war-related medical research, 124 support of bacteriological studies of influenza, 64 wartime coordination of laboratory pathology and bacteriology, 14 Medical Research Council (MRC). See also National Institute for Medical Research and ‘team work’, 15 and experimentalising pathology, 189 and modernisation agenda, 160 and patronage, 191 and translational research, 202 and Walter Morley Fletcher, 14, 118, 312, 359, 365 creation in 1919, 191 relations with Ministry of Health, 19, 164, 165, 198, 205, 260, 266, 361 relations with Rockefeller Foundation, 163, 164, 191, 227 uses of the 1918-19 influenza pandemic, 266, 361 virus research programme, 227, 266 Metropolitan Asylum Board (MAB) hospitals, 204, 213 relations with the Medical Research Council, 203, 213 relations with the National Institute for Medical Research, 162 Miasma, 33, 38, 45, 58, 62, 67, 111, 357

454

INDEX

Miasma theories, 33, 38, 45, 65, 99 Mice as a research tool in influenza virus research, 7, 257, 258, 294, 295, 320, 362 ‘mouse influenza’, 294, 304 mouse-neutralization test, 294 role in collaborative research, 257 role in development of influenza vaccines, 257, 332, 336 role in influenza serological and immunity studies, 295 role in viralising influenza, 356, 362 Militarization, 110, 111, 117 pathology (1914–1918), 124 wartime medicine (1914–1918), 358 Military pathology. See War pathology Mill Hill ‘Farm Laboratories. See Dog distemper; Influenza virus research; National Institute for Medical Research and the Distemper Research Fund, 228, 273 animal breeding facilities, 228 discovery and reception of (human) influenza virus, 290 Ministry of Health. See Newman, George Memorandum on Influenza’, 1927, 1929, 1939, 246 relations with the Medical Research Council, 19 Report on the Pandemic of Influenza (1920), 113, 155, 196 N National Institute of Medical Research (NIMR). See Dog Distemper; Mill Hill ‘Farm Laboratories, discovery and reception of (human) influenza virus

and experimental pathology, 16, 163, 367 and virus research, 15–17, 23, 213, 220, 228, 232, 238–240, 251, 253, 258, 259, 264, 267, 273, 290, 310, 312, 339, 362–364, 366, 369 creation of, 8, 320 Department of Bacteriology and Experimental Pathology, 204, 211 multidisciplinary collaboration as a principle, 211 relations with Rockefeller Foundation Animal Pathology Laboratories, 18 relations with Rockefeller Foundation International Health Division, 320 relations with Rockefeller Institute for Medical Research, 266 Newman, George. See Report on the Pandemic of Influenza (1920) and Ministry of Health, 165, 170, 171, 203, 205 Emergency Research Committee and coordinated bacteriological and clinical research., 171 on 1918–19 pandemic, 205 relations with Walter Morley Fletcher, 165, 205 vision of national health, 165 Newsholme, Arthur, 54, 105, 107–110, 113, 130, 156 Nosologies. See Classification (Nosologies/Enlightenment medicine)

O One Health, 394 Osler, William, 86, 307, 309

INDEX

P Pandemic (1889–94). See Influenza pandemic (1889–1894) Pandemic (1918–19). See Influenza pandemic (1918–1919) Parke, Davis and Company anti-catarrh vaccines, 159, 188 influenza (mixed/Pfeiffer) vaccines, 135 relations with Almorth Wright’s Inoculation Department (St. Mary’s Hospital), 159 Parsons, Henry Franklin, 53, 58–60, 63, 65–67, 69–72, 75, 90 Pathology, military, 107, 111, 117, 123, 125, 128, 157–160, 205 experimental, 15, 298 Patronage, 23, 164 and The Field Distemper Fund, 226 and the Rockefeller Foundation, 191 Pfeiffer’s bacillus, 13, 87–96, 100–105, 128, 131, 132, 134–139, 142, 144, 146, 147, 150, 154, 179, 186, 187, 196, 246, 257, 266, 271, 292, 307, 309, 356, 363, 368 Pfeiffer, Richard, 86, 87, 89–94, 96, 98, 100–102, 104, 126, 131, 135, 146, 148, 185, 245 blood-agar growth medium, 126, 136 influenza bacillus, 89, 90, 96, 99, 100, 102, 113 Pneumonia, 30, 32, 40, 58, 77, 80, 83, 101, 137, 141, 143, 149, 152, 153, 170, 173, 241, 248, 250, 272, 294, 364 influenza complication, 76, 83, 129, 147, 249, 309 influenza sequelae, 129, 310 Pringle, John, 30, 31

455

Pseudo-influenza, 101, 102 public health medicine, 7, 8, 15, 51, 87, 96, 165, 166, 206, 259, 361, 369 Purulent bronchitis, 126–128, 143, 145, 169

R Rajchman, Ludwik, 131, 137–139 and the Medical Research Committee, 137 review of influenza bacteriology research (1918)., 137 Report on the Pandemic of Influenza (1920), 113, 155 Richardson, Benjamin Ward, 82 Rivers, Thomas, 175, 195, 211, 262, 265, 267, 268 Rockefeller Foundation, 18, 163, 164, 174, 190, 191, 227, 267, 321, 333, 337, 362 Rockefeller Foundation Animal Pathology Laboratories, 18 Rockefeller Institute for Medical Research and virus research, 266 Simon Flexner, 267 Rous, Peyton, 214, 215, 330 chicken sarcoma studies. See Gye, William Royal Army Medical College (RAMC) influenza (bacterial) vaccines, 119 pathological department, 121 serum therapies, 121 vaccine department, 147, 148 Royal Army Medical Corps, 112, 199 1918–19 influenza pandemic, 112 Royal College of Physicians, 37, 41, 84, 90, 146 “Russian influenza” (1889–90), 67, 69

456

INDEX

S Second World War. See Influenza vaccine; Rockefeller Foundation; United States Commission on Influenza Shope, Richard E. collaborative studies with NIMR researchers, 257 discovery of swine influenza virus, 18, 270, 282, 298, 370 swine influenza virus theory of origins of 1918–19 influenza, 270 Smith, Wilson biological standardisation, 272 development of ferret for influenza virus research, 273, 274 influenza virus studies, 18, 254 serological expertise, 253, 271 virus immunity, 265 ‘W.S. influenza virus, 274, 304 Society of Medical Officers of Health (SMOH), 63, 64, 67, 69, 71 ‘Spanish influenza’ (1918–19). See Influenza pandemic (1918–19) Standardisation and the World Influenza Programme, 316 dog distemper vaccine, 16, 17, 213, 250 of influenza bacillus cultivation (1918), 136, 162, 210, 237, 261 of medical diagnosis, 3 of research animals, 222 St Bartholomew’s Hospital Department of Pathology, 266 influenza bacteriology studies (1890s), 200 influenzal pneumonia studies (1890), 83

Mervyn Gordon influenza filter-passer studies (1920-22), 200 Surveillance (influenza viruses), 348. See World Influenza Programme (WIP) international virus surveillance, 350 Sydenham, Thomas, 28, 29, 43, 168

T “Team work”, 124, 192, 274, 300 and 1918–19 influenza pandemic, 15 and First World War, 3 and virus research, 3, 19 Telegraphy (surveillance), 57 Thompson, Symes, 31, 35, 75 Thompson, Theophilus, 28, 36, 43, 52, 78 Twort, Frederick W., 175, 177, 178, 199–202 and bacteriophage research, 177, 178, 199

U United States Commission on Influenza, 22

V Vaccines (bacterial), 188, 247, 248, 368 “mixed”, 144, 147, 154 “Pfeiffer”, 154, 248 Vaccines (virus), 22, 232–234, 238, 326, 328, 348, 349 Viralization, 4 Virology, 3, 4, 21, 210, 336, 362, 364, 366–373, 381 Virus

INDEX

filterable agents, 173, 174, 176–180, 196, 210, 212, 213, 215, 217, 225 filterable virus, 14, 16, 18, 161–163, 178, 179, 181, 187, 193, 194, 196, 198, 199, 206, 209, 212, 214, 215, 218, 220–222, 230, 231, 244, 253, 257, 267, 268, 270, 283, 285, 300, 307, 359, 360 filter-passer, 161, 175, 209 filter-passing, 161, 179, 231, 271, 310, 311 Virus concept biological theory (viruses as micro-organisms), 144, 200 chemical theory (viruses as proteins), 206 definition as ‘obligate intracellular parasites’, 367 history, 175, 220 operational definition of, 175 Virus disease/diseases, 4, 7, 15–17, 19, 21, 162, 164, 173–175, 177–179, 195, 200–202, 204, 206, 207, 210–212, 221, 226, 233, 235, 238, 239, 250, 253, 254, 258, 261, 262, 264–271, 282, 283, 289, 290, 296, 300, 306–308, 312, 361, 366–369, 372 human and animal studies, 16, 195, 201 Virus filtration. See Elford, William J. “gradocol” membranes, 220 ultrafiltration, 219 Virus neutralization general principles of, 312 influenza virus neutralization test (ferrets), 258, 264, 269 influenza virus neutralization test (mouse), 294, 297, 312, 335

457

Virus research and bacteriology, 179 and experimental pathology, 163, 194, 195, 204, 206, 209, 221, 360, 367 filterable viruses in animal and human diseases (foot-and-mouth disease; yellow fever; polio), 15, 173, 202, 217 role of experimental animals, 16, 162, 238, 240, 367 virus concept, 175, 206 W War Office coordination of military pathology, 125, 157 1918–19 influenza pandemic, 125 War Office influenza vaccine, 148, 150, 154, 156 War pathology and development (1914–1916), 117 and influenza (1915–1918), 117 Wartime medical system, 117 rationalisation (1914–1918), 117 Wellcome Physiological Laboratories, 202, 273 and canine distemper, 16, 221 West, Samuel, 76–79, 81 World Health Organization (WHO) and avian influenza, 391, 392 and Pandemic Influenza Preparedness Framework, 393 and the World Influenza Programme, 22, 369, 382 World Influenza Programme (WIP), 340, 342, 344, 349 American role and tensions, 340 1957-58 ‘Asian influenza’, 349, 350 and C.H. Andrewes, 22, 317

458

INDEX

concept of, 362 expansion of the WIP, 321 Global Influenza Surveillance Network, 382 role in 1957–58 ‘Asian’ influenza, 382 role in 1967–68 ‘Hong Kong’ influenza, 387 role in the viralisation of influenza, 23, 321, 369 unequal distribution of virus surveillance system, 23, 362

World Health Organization and creation of, 22, 316, 369 World Influenza Centre, 316, 363 Wright, Almroth Army Medical Service, 119, 123 influenza vaccines, 188, 189, 348 St. Mary’s Hospital, 123, 188

Z Zymotic diseases, 46 and William Farr, 45, 46