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SRFETY
,
1
~RCC
TH
Kathleen Stratton, Donna A. Almario, Theresa M. Wizemann,
and Marie C. McCormick, Eclitors
Immunization Safety Review Committee
Board on Health Promotion and Disease Prevention
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
THE NATIONAL ACADEMIES PRESS
Washington, D.C.
www.nap.edu
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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 Insti-
tute of Medicine. The members of the committee responsible for the report were chosen
for their special competences and with regard for appropriate balance.
Support for this project was provided by the Centers for Disease Control and Prevention
and the National Institute of Allergy and Infectious Diseases of the National Institutes of
Health as part of a National Institutes of Health Task Order No.74. The views presented in
this report are those of the Institute of Medicine Immunization Safety Review Committee
and are not necessarily those of the funding agencies.
International Standard Book Number 0-309-08886-0 (Book)
International Standard Book Number 0-309-52317-6 (PDF)
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 2003 by the National Academy of Sciences. All rights reserved.
Printed in the United States of America.
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.
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"I~nowin,g is not enough; we finest apply.
Willin,g is not enough; we must dlo. "
Goethe
. .
INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES
Shaping the Future for Health
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THE NATIONAL ACADEMIES
Advisers to the Nation on Science, Engineering, and Medicine
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 welfare. Upon the
authority of the charter granted to it by the Congress in 1863, the Academy has a mandate
that requires it to advise the federal government on scientific and technical matters. Dr.
Bruce M. Alberts 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 engineers. 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 engineering programs aimed at
meeting national needs, encourages education and research, and recognizes the superior
achievements of engineers. Dr. Wm. A. Wulf is president 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 Institute 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 Sciences in
1916 to associate the broad community of science and technology with the Academy's
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 Council is administered jointly by both
Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. Wm. A. Wulf are
chair and vice chair, respectively, of the National Research Council.
www. nationa l-academies.org
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IMMUNIZATION SAFETY REVIEW COMMITTEE
MARIE C. McCORMICK, M.D., Sc.D. (Chair), Professor and Chair,
Department of Maternal and Child Health, Harvard School of Public
Health
ALFRED BERG, M.D., M.P.H., Professor and Chair, Department of Family
Medicine, University of Washington School of Medicine
ROSEMARY CASEY, M.D., Associate Professor of Pediatrics, Jefferson
Medical College and Director, Lankenau Faculty Pediatrics, Wynnewood
Pennsylvania
JOSHUA COHEN, Ph.D., Senior Research Associate, Harvard Center for
Risk Analysis, Harvard School of Public Health
BETSY FOXMAN, Ph.D., Professor, Department of Epidemiology, School of
Public Health, University of Michigan
CONSTANTINE GATSONIS, Ph.D., Professor of Medical Science and
Applied Math, and Director, Center for Statistical Sciences, Brown
University
ELLEN HORAK, M.S.N., Education and Nurse Consultant, Public
Management Center, University of Kansas
MICHAEL KABACK, M.D., Professor, Pediatrics and Reproductive
Medicine, University of California, San Diego
GERALD MEDOFF, M.D., Professor, Department of Internal Medicine,
Washington University School of Medicine, St. Louis
REBECCA PARKIN, Ph.D., Associate Research Professor, Department of
Occupational and Environmental Health, School of Public Health and
Health Services, George Washington University
BENNETT SHAYWITZ, M.D., Professor of Pediatrics and Neurology, Co-
Director, Yale Center for the Study of Learning and Attention
CHRISTOPHER B. WILSON, M.D., Professor and Chair, Department of
Immunology, University of Washington
The following individuals are members of the Immunization Safety
Review Committee but were unable to attend the meeting on the topic of
this report:
RONALD BAYER, Ph.D., Professor, Division of Sociomedical Sciences,
School of Public Health, Columbia University
STEVEN GOODMAN, M.D., M.H.S., Ph.D., Associate Professor,
Department of Oncology, Division of Biostatistics, Johns Hopkins School
of Medicine
v
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Health Promotion and Disease Prevention Board Liaison
RICHARD B. JOHNSTON, fir., M.D., Professor of Pediatrics, Associate
Dean for Research Development, University of Colorado School of
Medicine and National Jewish Medical and Research Center
Study Staff
KATHLEEN STRATTON, Ph.D., Study Director
THERESA M. WIZEMANN, Ph.D., Senior Program Officer
JANE DURCH, M.A., Senior Program Officer
DONNA ALMARIO, M.P.H., Research Associate
KYSA CHRISTIE, Research Assistant
KATRINA ,1. LAWRENCE, M.S., Research Assistant
AMY GROSSMAN, Senior Project Assistant
ROSE MARIE MARTINEZ, Sc.D., Director, Board on Health Promotion and
Disease Prevention
Contract Editor
STEVEN J. MARCUS, Ph.D.
vim
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Reviewers
This report has been reviewed in draft form by individuals chosen for their
diverse perspectives and technical expertise, in accordance with procedures ap-
proved by the NRC's Report Review Committee. The purpose of this indepen-
dent review is to provide candid and critical comments that will assist the institu-
tion 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:
Ann Bostrom, Ph.D., Georgia Institute of Technology
Aurore Cote, M.D., Montreal Children's Hospital
Linda D. Cowan, Ph.D., University of Oklahoma
Enid Gilbert-Barness, M.D., Tampa General Hospital
Samuel L. Katz, M.D., Duke University Medical Center
Hannah Kinney, M.D., Children's Hospital, Boston
Linda Linville, M.S., R.N., Texas Department of Health
Martin Ward Platt, M.D., F.R.C.P, Royal Victoria Infirmary
Richard Rheingans, Ph.D., Emory University
Frank M. Sullivan, B.Sc.(Hons), Consultant Toxicologist
Brian ,1. Ward, M.D., Montreal General Hospital
Although the reviewers listed above have provided many constructive com-
ments and suggestions, they were not asked to endorse the conclusions or recom-
. .
via
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vit!
REVIEWERS
mendations nor did they see the final draft of the report before its release. The
review of this report was overseen by Robert Lawrence, M.D., The Johns
Hopkins University. Appointed by the National Research Council and Institute of
Medicine, he was responsible for making certain that an independent examina-
tion 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 institu-
tion.
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Foreword
Vaccines are among the greatest public health accomplishments of the past
century. In recent years, however, a number of concerns have been raised about
both the safety of and the need for certain immunizations. Indeed, immunization
safety is a contentious area of public health policy, with discourse around it
having become increasingly polarized and exceedingly difficult. The numerous
controversies and allegations surrounding immunization safety signify an erosion
of public trust in those responsible for vaccine research, development, licensure,
schedules, and policy making. Because vaccines are so widely used and be-
cause state laws require that children be vaccinated to enter daycare and school,
in part to protect others immunization safety concerns should be vigorously
pursued in order to restore this trust.
It is in this context that the Institute of Medicine (IOM) was approached
more than a year ago by the Centers for Disease Control and Prevention and the
National Institutes of Health to convene an independent committee that could
provide timely and objective assistance to the Department of Health and Human
Services in reviewing emerging immunization safety concerns.
The IOM was chartered by the National Academy of Sciences in 1970 to
serve as an adviser to the federal government on issues affecting the public's
health, as well as to act independently in identifying important issues of medical
care, research, and education. The IOM thus brings to this mission three decades
of experience in conducting independent analyses of significant public health
policy issues. In particular, as described in more detail in this report, the IOM has
a long history of involvement in vaccine safety. The IOM published its first major
vaccine safety report in 1977, followed by a subsequent report in 1988; both
Six
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x
FOREWORD
focused on the safety of polio vaccines. Two subsequent major reports, published
in 1991 and 1994, examined the adverse events of childhood vaccines. Since
then, the IOM has conducted several smaller studies and workshops focused on
various vaccine safety topics. These studies were all well received by both the
public and policy makers, and previous IOM committees on vaccine safety issues
have been viewed as objective and credible.
Given the sensitive nature of the present immunization safety review study,
the IOM felt it was especially critical to establish strict criteria for committee
membership. These criteria prevented participation by anyone with financial ties
to vaccine manufacturers or their parent companies, previous service on major
vaccine advisory committees, or prior expert testimony or publications on issues
of vaccine safety.
The rationale for imposing these stringent criteria was twofold. First, given
growing public concern about vaccine safety and the public scrutiny surrounding
this committee's work, it was important to establish standards that would pre-
clude any real or perceived conflict of interest or bias on the part of the committee
members. While the committee members all share a belief in the benefits of
vaccines to the public health, none of them has any vested interest in any of the
vaccine safety issues that will come before them. Second, the IOM wanted to
ensure consistency in the committee membership and to avoid having members
recuse themselves from the deliberations because they had participated in the
development or evaluation of a vaccine under study.
Thus, the IOM has convened a distinguished panel of 15 members who
possess significant breadth and depth of expertise in a number of fields, including
pediatrics, neurology, immunology, internal medicine, infectious diseases, genet-
ics, epidemiology, biostatistics, risk perception and communication, decision
analysis, public health, nursing, and ethics. The committee members were chosen
because they are leading authorities in their respective fields, are well respected
by their colleagues, and have no conflicts of interest. This committee brought a
fresh perspective to these critically important issues and approached its charge
with impartiality and scientific rigor.
The IOM does not propose the use of the criteria it has laid out above in
selecting members for federal vaccine advisory committees. The IOM committee
was convened for a very different purpose from the usual federal vaccine advi-
sory committees and, as such, required different standards.
As with all reports from the IOM, the committee' s work was reviewed by an
independent panel of experts. The purpose of the review process is to enhance the
clarity, cogency, and accuracy of the final report and to ensure that the authors
and the IOM are creditably represented by the report published in their names.
The report review process is overseen by the National Research Council's (NRC)
Report Review Committee (RRC), comprised of approximately 30 members of
the National Academy of Sciences, National Academy of Engineering, and IOM.
The IOM, in conjunction with the RRC, appoints a panel of reviewers with a
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FOREWORD
Xt
diverse set of perspectives on key issues considered in the report. Unlike the
selection criteria for committee membership (discussed above), many reviewers
will have strong opinions and biases about the report topic. The composition of
the review panel is not disclosed to the committee until after the report is ap-
proved for release. While the committee must consider and evaluate all com-
ments from reviewers, it is not obligated to change its report in response to the
reviewers' comments. The committee must, however, justify its responses to the
reviewers' comments to the satisfaction of the RRC's review monitor and the
IOM's review coordinator. A report may not be released to the sponsors or the
public, nor may its findings be disclosed, until after the review process has been
satisfactorily completed and all authors have approved the revised draft.
This report represents the unanimous conclusions and recommendations of
that dedicated committee whose members deliberated a critical health issue. The
report's conclusions and recommendations should be of value to all concerned
about these important matters.
Harvey V. Fineberg
President, Institute of Medicine
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Acknowledgments
The committee would like to acknowledge the many speakers and attendees
at its open meeting held on October 28, 2002, at the Beckman Center in Irvine,
CA. The discussions were informative and helpful. The committee would also
like to thank those people who submitted information to the committee through
the mail or via e-mail. Finally, the committee would like to thank the IOM staff
for their dedication to this project. Without their commitment, attention to detail,
creativity, sensitivity, and hard work, this project would be unworkable.
. .
x~
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Contents
Executive Summary ..........................................................................................
Immunization Safety Review:
Vaccinations and Sudden Unexpected Death in Infancy
The Charge to the Committee .....
The StudY Process ......
The Framework for Scientific Assessment...................
.17
.17
.19
21
Under Review: Vaccinations and Sudden Unexpected Death in Infancy 25
Scientific Assessment 34
Significance Assessment 69
Recommendations for Public Health Response
References
.71
.78
85
96
.98
103
Appendix A
Appendix B
Appendix C
Appendix D
. . .
x~
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