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--> Assessment of Future Scientific Needs for Live Variola Virus Committee on the Assessment of Future Scientific Needs for Live Variola Virus Board on Global Health Institute Of Medicine National Academy Press Washington, D.C. 1999
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--> NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, D.C. 20418 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to enlist distinguished members of the appropriate professions in the examination of policy matters pertaining to the health of the public. In this, the Institute acts under both the Academy's 1863 congressional charter responsibility to be an adviser to the federal government and its own initiative in identifying issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. This study was supported by the U.S. Department of Defense, the U.S. Department of Energy, and the U.S. Department of Health and Human Services. The views presented in this report are those of the Institute of Medicine Committee on the Assessment of the Future Need for Variola (Smallpox) Virus and are not necessarily those of the funding agencies. Additional copies of this report are available for sale from the National Academy Press, Box 285, 2101 Constitution Avenue, N.W., Washington, D.C., 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP online bookstore at www.nap.edu. The complete text of Assessment of Future Scientific Needs for Live Variola Virus is available on line at www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at www4.nas.edu/IOM/IOMHome.nsf. Copyright 1999 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. COVER: Bio-Safety Level 4 Containment Laboratory at U.S. Army Medical Research Institute of Infectious Diseases, Fort Derrick, Maryland. Copyright Brian R. Wolff / IIPI. All rights reserved.
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--> Committee On The Assessment Of Future Needs For Variola (Smallpox) Virus Charles C. J. Carpenter (Chair), Brown University International Health Institute, Providence, Rhode Island Ann M. Arvin, Stanford University School of Medicine, Palo Alto, California R. Palmer Beasley, University of Texas-Houston Health Science Center School of Public Health Kenneth I. Berns, University of Florida College of Medicine, Gainesville Raphael Dolin, Harvard University Medical School, Boston, Massachusetts Myron E. Essex, Harvard School of Public Health, Boston, Massachusetts Diane E. Griffin, Johns Hopkins University School of Public Health, Baltimore, Maryland Ashley T. Haase, University of Minnesota Medical School, Minneapolis Martin S. Hirsch, Harvard University Medical School, Boston, Massachusetts Elliott Kieff, Harvard University and Brigham and Women's Hospital,Boston, Massachusetts Peter S. Kim, Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, Massachusetts Bernard Lo, University of California at San Francisco Program in Medical Ethics D. Grant Mcfadden, Robarts Research Institute, London, Ontario, Canada Bernard Moss, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland Richard W. Moyer, University of Florida College of Medicine, Gainesville Hidde L. Ploegh, Harvard University Medical School and Free University of Amsterdam, Netherlands Jack Schmidt, Merck Research Laboratories, Rahway, New Jersey Richard J. Whitley, University of Alabama at Birmingham Children's Hospital Flossie Wong-Staal, University of California at San Diego School of Medicine
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--> Staff Judith R. Bale, Director, Board on Global Health Rob Coppock, Study Consultant Stacey L. Knobler, Research/Administrative Assistant Stephanie Baxter-Parrott, Project Assistant Rona Briere, Editor
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--> Board On Global Health Barry R. Bloom (Cochair), Harvard University School of Public Health,Boston, Massachusetts Dean Jamison (Cochair), University of California at Los Angeles and the World Health Organization, Geneva, Switzerland Jacquelyn Campbell, Johns Hopkins University School of Nursing,Baltimore, Maryland Harvey V. Fineberg, Harvard University, Cambridge, Massachusetts Julio Frenk, World Health Organization, Geneva, Switzerland Eileen T. Kennedy, Research, Education, and Economics, U.S. Department of Agriculture, Washington, D.C. Arthur Kleinman, Harvard Medical School, Boston, Massachusetts Bernard Liese, The World Bank, Washington, D.C. William E. Paul, National Institute of Allergy and Infectious Diseases and Office of AIDS Research, National Institutes of Health, Bethesda, Maryland Allan Rosenfield, Columbia University School of Public Health, New York, New York Patricia L. Rosenfield, The Carnegie Corporation of New York, New York Thomas J. Ryan, Boston University School of Medicine and Boston University Medical Center, Massachusetts June E. Osborn (Institute of Medicine Liaison), Josiah Macy, Jr., Foundation, New York, New York David R. Challoner (Institute of Medicine Foreign Secretary), Institute for Science and Health Policy, University of Florida, Gainesville Staff Junith R. Bale, Director Stacey L. Knobler, Research/Administrative Assistant Stephanie Baxter-Parrott, Project Assistant Kay Harris, Financial Associate
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--> Preface The global eradication of smallpox stands as the most successful public health campaign in medical history. Smallpox was one of the most feared of plagues, the very epitome of the dread associated with rampant and devastating illness. Its eradication required the cooperation of dedicated physicians, public health officials, governments, and untold individuals around the world. Once that goal had been accomplished, known materials containing variola virus, the pathogen responsible for smallpox, were consolidated in two international repositories. It has been proposed by the World Health Organization that the two remaining stocks of variola be destroyed in June 1999. Advances in microbiology, however, now raise the question of the possible utility of retaining the only pathogenic virus humanity has been able to eradicate. The primary reason for the proposed destruction of the remaining known variola stocks is that, despite any medical advances that might result from studies using the live variola virus, the risks of retaining and working with the virus (ranging from accidental laboratory release to acquisition and use by terrorists) may outweigh the benefits. The U.S. Department of Defense, the U.S. Department of Energy, and the U.S. Department of Health and Human Services asked the Institute of Medicine to assess the scientific and medical information that might be lost were live variola virus no longer available for research purposes. The scientific and medical assessment presented in this report is but one of a number of efforts aimed at examining various aspects of the issue. The committee assembled to conduct this assessment includes not only those whose training and research gives them detailed knowledge of poxviruses, the class of organisms to which variola virus belongs, but also those whose background ensures consideration of broader
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--> medical and biological concerns. Also among the committee members are physicians who personally witnessed the devastation of smallpox prior to its eradication. It is important to note that the committee was not asked to assess the likelihood that an outbreak of smallpox might occur as the result of accidental or intentional action or biological terrorism. In assessing future scientific needs for variola virus, however, the committee addressed questions likely to be directed to scientists should this pathogen be used as a terrorist weapon. The committee assembled information from a variety of sources and in November 1998 conducted a public workshop attended by many of the nation's leading experts in fields related to the committee's charge. The workshop reviewed recent research on antiviral agents and vaccines, the status of detection and diagnosis technologies, and ways in which study of the variola virus might contribute to understanding of viral pathogenesis and the human immune system, and other research related to variola virus. This information was used by the committee to develop its findings and conclusions in meetings immediately following the November workshop and in January 1999. This final report is addressed to health policymakers, medical and biological researchers, and the public as the committee's assessment of the knowledge that might be lost if live variola virus were no longer available for research. CHARLES C. J. CARPENTER CHAIR
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--> Acknowledgments The committee appreciates the contributions of many individuals to this report. We express our gratitude to the experts who made presentations at the initial workshop: Mark Buller, Joseph Esposito, Donald A. Henderson, John Huggins, Peter Jahrling, Wolfgang Joklik, Sergei Shchelkunov, and Alan Zelicoff. We also thank the workshop participants who contributed their insights and raised important questions at the workshop. The following agencies and key staff provided funding and generated support within their institutions for this study: the U.S. Department of Defense (Michael Fitzgibbon, Sally Horn, Frank Miller, Stephen Morse), the U.S. Department of Energy (Page Stoutland), and the U.S. Department of Health and Human Services (Margaret Hamburg, Robert Knouss, William Raub, Kevin Tonat). Their willingness to sponsor this study on variola virus is a significant commitment, given the sensitive and controversial nature of policy discussions surrounding broader issues involving the variola virus stocks. Kenneth Bernard, National Security Council staff, provided useful information on the broader context in which the report findings would be used. The committee also thanks Stacey Knobler and Stephanie Baxter-Parrott for their excellent coordination of the committee's meetings and of the production this report, Rob Coppock for providing text for the committee's consideration, Rona Briere for editing the report, and Judith Bale for overall organization and execution of the effort. This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council's Report Review Committee. The purpose of this independent review is to provide candid and critical comments
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--> that will assist the Institute of Medicine in making the published report as sound as possible, and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remains confidential to protect the integrity of the deliberative process. The committee wishes to thank the following individuals for their participation in the review of this report: Reviewers Rafi Ahmed, Emory University Vaccine Center, Atlanta, Georgia Enriqueta Bond, Burroughs Wellcome Fund, Durham, North Carolina Mark Buller, St. Louis University Medical School, Missouri Erik De Clercq, Rega Institute for Medical Research, Leuven, Belgium Keith Dumbell, University of London, United Kingdom Joseph Esposito, Centers for Disease Control and Prevention, Atlanta,Georgia Frank Fenner, John Curtain School of Medical Research, Australian National University, Canberra Don Ganem, University of California at San Francisco Anne Gershon, Columbia University College of Physicians and Surgeons,New York, New York Donald A. Henderson, Center for Civilian Biodefense Studies, The Johns Hopkins University, Baltimore, Maryland Woflgang Joklik, Duke University, Durham, North Carolina Joshua Lederberg, Rockefeller University, New York, New York June Osborn, Josiah Macy, Jr., Foundation, New York, New York Bernard Roizman, The University of Chicago, Illinois Sir John Skehel, National Institute for Medical Research, London, United Kingdom Geoffrey Smith, Oxford University, Oxford, United Kingdom Patricia Spear, Northwestern University Medical School, Chicago, Illinois Imorton Swartz, Massachusetts General Hospital, Boston, Massachusetts Rolf Zinkernagel, University Hospital of Zurich and the Institute of Experimental Immunology, Zurich, Switzerland We also wish to thank the following individuals for their review of technical portions of the report: John Becher and Joseph Esposito, Centers for Disease Control and Prevention, Atlanta; and John Huggins and Peter Jahrling, United States Army Medical Research Institute of Infectious Diseases, Fort Derrick, Maryland.
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--> While the individuals listed above have provided constructive comments and suggestions, it must be emphasized that responsibility for the final content of this report rests entirely with the authoring committee and the Institute of Medicine.
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--> Contents Executive Summary 1 Part I Introduction 1 Introduction 7 Background 8 Contemporary Context 10 Scope 11 Scientific Needs for Variola Virus 11 Organization of This Report 13 Part II Smallpox And its control 2 Variola Virus and Other Orthopoxviruses 17 General Attributes of Orthopoxviruses 18 Poxvirus Replication 19 Properties of Specific Orthopoxviruses 20 3 Clinical Features of Smallpox 25 Entry and Infection 25 Dissemination 26 The Rash 27 Lesions of the Mucous Membranes 27 Effects on Other Organs 28 Immune Response 28 Immunity Against Smallpox 30
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--> 4 Epidemiology 33 Characteristics of Historical Outbreaks 33 Likely Characteristics of Future Smallpox Outbreaks 34 Control Strategies 35 5 Variola Virus Stocks Following Eradication of Smallpox 37 Establishment of International Repositories 38 Decision by the World Health Assembly to Destroy Variola Virus Stocks 40 U.S. Research on Smallpox 41 Research at CDC and USAMRIID 42 Part III Scientific Needs For Variola Virus 6 Development of Antiviral Agents 47 In Vitro Assays 48 Animal Models 50 7 Development of Vaccines 53 Current Status of Vaccinia Vaccine Preparations 54 Evaluation of Vaccinia Vaccine Derived from Tissue Culture 55 Evaluation of Novel Vaccines 57 8 Detection and Diagnosis 59 Environmental Detection 60 Diagnosis of Infection 61 Alternatives to Live Virus 62 9 Bioinformatics 63 Variability of Variola Virus 64 Potential Developments 66 10 Understanding of the Biology of Variola Virus 69 Virus-Cell Interactions 69 Virus-Host Interactions 70 11 Research on the Expressed Protein Products of Variola 73 Synthesis of Variola Proteins 74 Potential Utility of Variola Proteins 75
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--> Part IV Findings 12 Summary and Conclusions 79 The Broader Context 80 Scientific Needs for Live Variola Virus 81 Overall Conclusions 85 References 87 Appendixes A Glossary 93 B Acronyms 99 C Committee and Staff Biographies 101
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Assessment of Future Scientific Needs for Live Variola Virus
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