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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
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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. 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
Engineering, 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,
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(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.
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“Knowing is not enough; we must apply.
Willing is not enough; we must do.”
— Goethe
Advising the Nation. Improving Health.
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The National Academy of Sciences is a private, nonprofit, self-perpetuating society
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and recognizes the superior achievements of engineers. Dr. Charles M. Vest is presi-
dent of the National Academy of Engineering.
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of the National Research Council.
www.national-academies.org
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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
v
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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 Council’s 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
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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.
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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
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x PREFACE
This committee’s 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 committee’s 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 counterpart, 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
public 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
topics relevant to the committee’s 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,
Director-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 others
under which it would be useful for research or public health purposes, as
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xi
PREFACE
presented in this report. The report is intended to provide information
about what has been accomplished since the 1999 IOM committee’s 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
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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 Hojvat,
Dennis Hruby, Peter Jahrling, Kevin Karem, Daniel Lavanchy, Grant
McFadden, 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, Director-General,
Head, WHOCC for Orthopoxvirus Diagnosis and Repository for Variola
Virus Strains and DNA, for his detailed response to its inquiries concerning
the variola-associated work that has been conducted at VECTOR.
The committee’s 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
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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
Host–Pathogen Interactions, 38
References, 42
xv
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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
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xvii
CONTENTS
10 CONCLUSIONS AND RECOMMENDATIONS 131
Conclusions, 132
Recommendations, 136
APPENDIX
Variola Strains Used to Validate Diagnostic and Detection Assays 139
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