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Committee on the Assessment of Future Scientific Needs for Live Variola Virus Board on Global Health Ann M. Arvin and Deepali M. Patel, Editors
THE NATIONAL ACADEMIES PRESSâ 500 Fifth Street, N.W.â Washington, DC 20001 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 E Â ngineering, and the Institute of Medicine. The members of the committee respon- sible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract No. BOGH-H-07-05-A between the National Academy of Sciences and the Centers for Disease Control and Prevention. Funds originated with both the Centers for Disease Control and Prevention and the Office of the Biomedical Advanced Research and Development Authority of the U.S. Department of Health and Human Services. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-13690-7 International Standard Book Number-10: 0-309-13690-3 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2009 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Front cover: Reprinted with Permission by Luke Jerram, Artist in Residence at FACT, Liverpool for European Capital of Culture 2008. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2009. Live Variola Virus: Consider- ations for Continuing Research. Washington, DC: The National Academies Press.
âKnowing is not enough; we must apply. Willing is not enough; we must do.â âGoethe Advising the Nation. Improving Health.
The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general wel- fare. Upon the authority of the charter granted to it by the Congress in 1863, the Â Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding e Â ngineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is presi- dent of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Insti- tute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of ÂSciences in 1916 to associate the broad community of science and technology with the Academyâs purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The C Â ouncil is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org
COMMITTEE ON THE ASSESSMENT OF FUTURE SCIENTIFIC NEEDS FOR LIVE VARIOLA VIRUS Ann M. Arvin (Chair), Lucile Packard Professor of Pediatrics and Microbiology and Immunology, Stanford University School of Medicine Donald Burke, Dean, Graduate School of Public Health, University of Pittsburgh Liang Deng, Assistant Member, Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York Diane E. Griffin, Professor and Chair in Molecular Microbiology and Immunology, Johns Hopkins School of Public Health Stephen Ostroff, Director, Pennsylvania Department of Health, Bureau of Epidemiology, Harrisburg Peter A. Patriarca, Senior Clinical Consultant, Biologics Consulting Group, Inc., Bethesda Clarence J. Peters, Professor, Department of Microbiology and Immunology and Pathology, University of Texas Medical Branch at Galveston David A. Relman, Thomas C. and Joan M. Merigan Professor of Medicine, and of Microbiology and Immunology, Stanford University; Chief, Infectious Diseases, VA Palo Alto Health Care System Maria Salvato, Professor, Institute of Human Virology, University of Maryland School of Medicine Mark Slifka, Associate Scientist, Vaccine and Gene Therapy Institute, Oregon Health and Sciences University Holly Taylor, Assistant Professor, Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health Paula Traktman, Professor, Department of Microbiology and Molecular Genetics, Medical College of Wisconsin David Ulaeto, Principal Scientist, Department of Biomedical Sciences, Defense Science and Technology Laboratory, Salisbury, UK Study Staff Deepali Patel, Program Officer Katherine McClure, Senior Program Associate Allison Brantley, Senior Program Assistant Patrick Kelley, Director, Board on Global Health Carly Langlais, Consultant Julie Wiltshire, Financial Associate
Reviewers T his 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 Councilâs Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its 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 remain confiden- tial to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Kenneth I. Berns, University of Florida Genetics Institute R. Mark L. Buller, Department of Molecular Microbiology and Immunology, St. Louis University Health Sciences Center R. Alta Charo, University of Wisconsin Law School Lawrence Corey, Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center and Virology Department, University of Washington Kathryn M. Edwards, Department of Pediatrics, Vanderbilt University School of Medicine William M. Egan, PharmaNet Consulting Joseph J. Esposito, JGL Tech-consult Thomas Inglesby, Center for Biosecurity, University of Pittsburgh Medical Center vii
viii REVIEWERS W. Ian Lipkin, Center for Infection and Immunity, Mailman School of Public Health, Columbia University D. Grant McFadden, Department of Molecular Genetics and Microbiology, University of Florida College of Medicine Philip K. Russell, Major General (retired) USA, Professor Emeritus, Johns Hopkins School of Public Health Ronald K. St. John, St. John Public Heath Consulting International Inc., Ontario Robert Swanepoel, Special Pathogens Unit, National Institute for Communicable Diseases, South Africa Richard Whitley, Department of Pediatrics and Microbiology, University of Alabama Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations nor did they see the final draft of the report before its release. The review of this report was overseen by Dr. Floyd E. Bloom, Pro- fessor Emeritus, Department of Molecular and Integrative, Neuroscience, The Scripps Research Institute, and Dr. Adel A.F. Mahmoud, Woodrow Wilson School and Department of Molecular Biology, Princeton University. Appointed by the National Research Council and Institute of Medicine, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.
Preface S mallpox is caused by variola virus, which modern genomics reveals to be very closely related to vaccinia and other orthopoxviruses. These similarities mean that vaccination protects against smallpox, as Edward Jenner observed in the late eighteenth century. Transmission of variola in the human population, its only natural host, was halted in the twentieth century through the dedicated efforts of public health workers and volunteers on every continent. Smallpox was declared eradicated by the World Health Assembly in 1980, a moment that is recognized as one of the most important achievements of mankind. In the course of the smallpox eradication campaign, laboratories that held variola virus isolates or clinical specimens that might contain infectious virus destroyed the materials or sent them to one of two repositories that were established in the United States and Russia under the direction of the World Health Organization (WHO). Since then, the World Health Assem- bly has debated whether the live variola virus stocks or other potentially infectious materials collected at these two repositories should be destroyed. The World Health Assembly will take up the issue of the retention or destruction of live variola virus stocks in 2010. Therefore, the Institute of Medicine (IOM) was asked by the Centers for Disease Control and Preven- tion and the Office of the Biomedical Advanced Research and Development Authority of the U.S. Department of Health and Human Services to form a committee that would conduct a study on the continued use of live variola virus for research and public health purposes. ix
PREFACE This committeeâs work follows upon that of an earlier IOM committee that was formed in 1998 to assess future scientific needs for live variola virus. The previous committeeâs deliberations were undertaken in prepara- tion for the 1999 meeting of the World Health Assembly, which was to address what should be done with the variola stocks being maintained at the Centers for Disease Control and Prevention in the United States and at the State Centre for Research of Virology and Biotechnology (VECTOR) in Russia. In 1999, the IOM committee released its report, Assessment of Future Scientific Needs for Live Variola Virus, in which it offered a number of consensus conclusions. These conclusions focused particularly on the uses of live variola virus for developing medical countermeasures against smallpox. At that time, the World Health Assembly chose to defer its deci- sion on destroying the variola stocks until such research could be conducted in the future. In the interim, WHO has been responsible for overseeing all research involving live variola virus, which has been allowed only under the highest level of biosafety containment at the two WHO Collaborating Centers for Smallpox and Other Poxviruses. In this context, the present committee undertook an examination of the scientific needs for live variola virus, based on a critical assessment of the research that has been reported in the decade since the first IOM report was published. It is important to note that this committee, like its 1999 counterÂpart, was not asked to consider whether the stocks should be retained or destroyed, nor was it charged with evaluating the risks of an accidental or intentional release of variola virus. To address its charge, the committee organized two workshops for p Â ublic presentations by leading experts, including those with experience from the smallpox eradication campaign, investigators who have done basic and applied research with live variola virus, and others who addressed t Â opics relevant to the committeeâs task. The committee members also reviewed the scientific literature related to variola and other poxviruses in their specific areas of expertise and summarized their findings for the com- mittee. The committee formally requested from VECTOR information on a range of aspects of their variola-related research. Professor Ilya G. Drozdov, D Â irector-General, Head, WHOCC for Orthopoxvirus Diagnosis and Repos- itory for Variola Virus Strains and DNA, provided extensive information on accomplishments at VECTOR over the past decade that have been cited in the report. The workshops and the analysis of the literature served as the background for extensive discussions and the development of conclusions by the committee in the course of three convened meetings. Through its deliberations, the committee reached consensus on the circumstances under which live variola virus would be essential and Âothers under which it would be useful for research or public health purposes, as
PREFACE xi presented in this report. The report is intended to provide information about what has been accomplished since the 1999 IOM committeeâs assess- ment and to offer recommendations to basic and clinical researchers, policy makers, and the public regarding the scientific uses of live variola virus in the contemporary context. Ann M. Arvin, Chair Committee on the Assessment of Future Scientific Needs for Live Variola Virus
Acknowledgments T he committee and the Institute of Medicine wish to express their appreciation to the many individuals who took the time to share their expert knowledge and perspectives with the committee in the course of its work and to the organizations that provided necessary information. The committee would like to thank the following individuals for their presentations at the public workshops: Kenneth Berns, Paul Chaplin, Inger Damon, Joseph Esposito, Donald Henderson, Lisa Hensley, Sally ÂHojvat, Dennis Hruby, Peter Jahrling, Kevin Karem, Daniel Lavanchy, Grant M Â cFadden, Michael Merchlinsky, Hermann Meyer, Bernard Moss, Gerald Parker, Anne Rimoin, Kate Rubins, Barbara Styrt, and Richard Whitley. The committee would like to thank Professor Ilya G. Drozdov, ÂDirector-General, Head, WHOCC for Orthopoxvirus Diagnosis and Repository for Variola Virus Strains and DNA, for his detailed response to its Âinquiries concerning the variola-associated work that has been conducted at VECTOR. The committeeâs work could not have been completed without the skilled professional support of the Institute of Medicine staff. We are grate- ful to Allison Brantley, Patrick Kelley, Carly Langlais, Katherine McClure, and Deepali Patel. xiii
Contents SUMMARY 1 1 INTRODUCTION 9 Overview of Scientific Needs for Live Variola Virus, 10 Current Status of Variola Virus and Materials, 12 Regulations and Other Guidance Pertaining to Countermeasures for Smallpox, 14 Study Charge and Approach, 15 Organization of the Report, 17 References, 17 2 OVERVIEW OF SMALLPOX AND ITS SURVEILLANCE AND CONTROL 19 Epidemiology, 19 Surveillance and Control, 21 References, 23 3 COMPARATIVE POXVIROLOGY 27 Poxvirus Taxonomy, 27 Poxvirus Structure, 28 Poxvirus Genomics, 28 Viral Life Cycle, 32 Host Specificity and Range, 36 HostâPathogen Interactions, 38 References, 42 xv
xvi CONTENTS 4 ANIMAL MODELS USING VARIOLA AND OTHER ORTHOPOXVIRUSES 49 Variola, 49 Vaccinia, Cowpox, and Mousepox, 51 Monkeypox, 52 Myxoma Virus, 53 Chimeric Viruses, 53 Usefulness of Various Models, 55 References, 55 5 GENOMIC ANALYSIS 59 Sequence Analysis, 60 Beyond Genomic Analysis, 63 Need for Live Variola Virus, 64 References, 64 6 DEVELOPMENT OF THERAPEUTICS 67 Potential Therapeutics for Smallpox, 68 Regulatory Requirements, 78 Need for Live Variola Virus, 80 References, 81 7 DEVELOPMENT OF VACCINES 87 History of Smallpox Vaccine Development, 88 Current Status of Smallpox Vaccine Development, 91 The Scientific Pathway to Development, 99 Regulatory Requirements, 100 Need for Live Variola Virus, 102 References, 103 8 METHODS FOR DETECTION AND DIAGNOSIS 111 Current Status of Detection and Diagnostic Methods, 112 Regulatory Requirements, 118 Need for Live Variola Virus, 119 References, 120 9 DISCOVERY RESEARCH 123 Systems Biology and Smallpox Pathogenesis, 124 Subversion and Modulation of Human Immune Responses, 125 Novel Variola-Based Therapeutics, 128 Need for Live Variola Virus, 128 References, 129
CONTENTS xvii 10 CONCLUSIONS AND RECOMMENDATIONS 131 Conclusions, 132 Recommendations, 136 APPENDIX Variola Strains Used to Validate Diagnostic and Detection Assays 139