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Committee on the Assessment of Studies of Health Outcomes Related to
the Recommended Childhood Immunization Schedule
Board on Population Health and Public Health Practice
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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001
NOTICE: The project that is the subject of this report was approved by the Govern-
ing Board of the National Research Council, whose members are drawn from the
councils of the National Academy of Sciences, the National Academy of Engineer-
ing, and the Institute of Medicine. The members of the committee responsible for
the report were chosen for their special competences and with regard for appropri-
ate balance.
This study was supported by Contract No. HHSP23337025T, Mod 2, between
the National Academy of Sciences and 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 views of the
organizations or agencies that provided support for this project.
International Standard Book Number-13: 978-0-309-26702-1
International Standard Book Number-10: 0-309-26702-1
Additional copies of this report are available from the National Academies Press,
500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202)
334-3313; http://www.nap.edu.
For more information about the Institute of Medicine, visit the IOM home page at:
www.iom.edu.
Copyright © 2013 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 ad-
opted 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). 2013. The childhood immunization
schedule and safety: Stakeholder concerns, scientific evidence, and future studies.
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
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 Acad-
emy 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 en-
gineers. 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 Sci-
ences 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 Coun-
cil 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
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COMMITTEE ON THE ASSESSMENT OF STUDIES OF
HEALTH OUTCOMES RELATED TO THE RECOMMENDED
CHILDHOOD IMMUNIZATION SCHEDULE
ADA SUE HINSHAW (Chair), Uniformed Services University of the
Health Sciences, Bethesda, MD
TOMÁS J. ARAGÓN, San Francisco Department of Public Health, CA
ALFRED BERG, University of Washington School of Medicine, Seattle
STEPHEN L. BUKA, Brown University, Providence, RI
R. ALTA CHARO,* University of Wisconsin Law School, Madison
GERRY FAIRBROTHER, AcademyHealth, Washington, DC
ELENA FUENTES-AFFLICK, University of California School of
Medicine, San Francisco, CA
SIDNEY M. GOSPE, JR., University of Washington School of Medicine,
Seattle
PAUL A. GREENBERGER, Northwestern University Feinberg School of
Medicine, Chicago, IL
DANIEL F. HEITJAN, University of Pennsylvania Perelman School of
Medicine, Philadelphia
ANNETTE C. LELAND, Independent, Washington, DC
PEJMAN ROHANI, University of Michigan, Ann Arbor
LAINIE FRIEDMAN ROSS, University of Chicago, IL
PAULINE A. THOMAS, New Jersey Medical School, Newark
Study Staff
KAREN HELSING, Study Director
SUZANNE LANDI, Research Associate
CHELSEA FRAKES, Research Assistant
HOPE HARE, Administrative Assistant
ROSE MARIE MARTINEZ, Director, Board on Population Health and
Public Health Practice
*Until August 2012.
v
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Reviewers
This report has been reviewed in draft form by persons 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 confidential to protect the integrity
of the deliberative process. We wish to thank the following individuals for
their review of this report:
Ann Bostrom, University of Washington
Doug Campos-Outcalt, University of Arizona, Phoenix
Louis Z. Cooper, Columbia University
Rebecca Fleischauer, Steege Thomson Communications
Gary L. Freed, University of Michigan Health System
Sean Hennessy, University of Pennsylvania
S. Claiborne Johnston, University of California, San Francisco
Stanley Lemeshow, Ohio State University
Tracy Lieu, Kaiser Permanente Northern California
Kenneth McIntosh, Harvard University
Arthur Reingold, University of California, Berkeley
Although the reviewers listed above have provided many constructive
comments and suggestions, they were not asked to endorse the conclusions
vii
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viii REVIEWERS
or recommendations nor did they see the final draft of the report before
its release. The review of this report was overseen by Bradford H. Gray,
the Milbank Quarterly, the Urban Institute, and Donald M. Steinwachs,
Johns Hopkins University. Appointed by the National Research Council
and the 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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Acknowledgments
The committee thanks colleagues both within and outside the National
Academies who provided expertise and time to inform the committee and
enhanced the quality of the report. Numerous individuals and organiza-
tions shared their knowledge and expertise with the committee during
information-gathering sessions held on February 9, March 8, and May 29,
2012. These sessions were intended to assist the committee in collecting
information on the safety and study of current and past vaccine schedules in
the United States and abroad to inform the committee’s understanding and
vision in completing its task. These individuals are listed in Appendix E.
Of particular note, Martin Kulldorff provided a commissioned paper
on study designs that could be considered to assess the safety of the im-
munization schedule (see Appendix D). Both draft and revised versions of
the paper were posted on the study’s website to receive public comments
to inform the committee’s work. In total, the committee reviewed more
than 900 public comments. The commissioned paper and public submis-
sions were critical to ensuring fruitful discussions among the members of
the committee.
Committee members Alfred Berg and Elena Fuentes-Afflick graciously
hosted committee meetings near their respective institutions. The commit-
tee thanks the numerous staff members of the Institute of Medicine (IOM),
the National Research Council, and the National Academies Press who
contributed to the development, production, and dissemination of the re-
port, including study staff Karen Helsing, Suzanne Landi, Chelsea Frakes,
Rose Marie Martinez, and Hope Hare. In addition, the study received
valuable contributions from Christine Stencel (Office of News and Public
ix
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x ACKNOWLEDGMENTS
Information), Daniel Bethea, Marton Cavani, Laura Harbold DeStefano,
and Diedtra Henderson (IOM Office of Reports and Communication), and
Doris Romero (IOM Office of Financial Administration). Clyde Behney,
Katharine Bothner, and Sarah Ziegenhorn (IOM Deputy Executive Office)
provided guidance on best practices throughout the study. Michael Hayes
served as the editor for the report.
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Contents
ABSTRACT xiv
SUMMARY 1
1 INTRODUCTION 17
Study Background, 20
Committee on the Assessment of Studies of Health Outcomes
Related to the Recommended Childhood Immunization
Schedule, 20
Committee Process, 21
Previous IOM Vaccine Studies, 22
Organization of the Report, 23
References, 23
2 DETERMINATION OF THE IMMUNIZATION SCHEDULE 25
Immune System Responses, 25
Immunization at the Population Level, 28
Immunization Policy, 30
Vaccine Development and Approval Specifics, 31
Past and Present Immunization Schedules, 34
References, 37
3 EXISTING DATA SOURCES AND SYSTEMS 39
Immunization Safety Surveillance, 39
Databases Used to Assess Coverage, 46
xi
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xii CONTENTS
Databases Examining Adverse Events After Immunization for
Vaccine-Preventable Diseases, 48
Immunization Data Systems in Other Countries, 50
References, 54
4
STAKEHOLDER CONCERNS RELATED TO THE SAFETY OF
THE IMMUNIZATION SCHEDULE 59
Identification of Stakeholders, 60
Information Gathering, 61
Literature Search, 61
Parental Concerns in the Scientific Literature, 62
Public Concerns Presented to the Committee, 65
Patient-Provider Communication, 66
Conclusions, 68
References, 72
5 REVIEW OF SCIENTIFIC FINDINGS 75
Literature Search Methods, 76
Literature Summary, 78
Conclusions, 94
References, 95
6 METHODOLOGICAL APPROACHES TO STUDYING
HEALTH OUTCOMES ASSOCIATED WITH THE CURRENT
IMMUNIZATION SCHEDULE: OPTIONS, FEASIBILITY,
ETHICAL ISSUES, AND PRIORITIES 99
Considerations to Determine Need for Initiation of
New Studies, 100
Potential Research Questions of Interest, 103
General Research Approaches to Address Primary Research
Questions of Interest, 105
Methods to Monitor Community Immunity and Measure
Population-Level Impacts of Studies of the Immunization
Schedule, 119
Conclusions, 122
References, 123
7 CONCLUSIONS AND RECOMMENDATIONS 127
Committee Response to Its Statement of Task, 127
Concluding Observations, 135
References, 136
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CONTENTS xiii
APPENDIXES
A 2012 Advisory Committee on Immunization Practices’
Recommended Immunization Schedule for Children 137
B Glossary 145
C Acronyms 157
D Study Designs for the Safety Evaluation of Different Childhood
Immunization Schedules, Martin Kulldorff 161
E Agendas of Public Meetings Held by the Committee 201
F Biographical Sketches of Committee Members 207
G Institute of Medicine Publications on Vaccines 217
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Abstract
The charge to the Committee on the Assessment of Studies of Health
Outcomes Related to the Recommended Childhood Immunization Schedule
was to (1) review scientific findings and stakeholder concerns related to the
safety of the recommended childhood immunization schedule and (2) iden-
tify potential research approaches, methodologies, and study designs that
could inform this question, considering strengths, weaknesses, as well as
the ethical and financial feasibility of each approach. As reviewed by prior
Institute of Medicine studies, a substantial literature exists on adverse ef-
fects of individual vaccines, but few studies have focused on elements of or
the recommended childhood immunization schedule as a whole. The lack
of conclusive evidence linking adverse events to multiple immunizations
or other “schedule” exposures suggests that the recommended schedule
is safe. There are concerns from some stakeholders that merit exploration
through research if epidemiological signals are detected and an indication of
biological plausibility is available. However, the committee concludes that
it is not ethical to implement any study requiring that some children receive
fewer vaccines than recommended as part of the childhood immunization
schedule because this would needlessly endanger children’s lives. The com-
mittee concludes that data from existing surveillance systems, such as the
Vaccine Safety Datalink, could be used and offer the best means for ongoing
research efforts regarding the safety of the schedule. In recognition of this,
future federal research approaches should
• collect and assess evidence regarding public confidence in and con-
cerns about the entire childhood immunization schedule, with the
xiv
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ABSTRACT xv
goal to improve communication with health care professionals, and
between health care professionals and the public regarding safety;
• standardize definitions of key elements of the schedule, and rel-
evant health outcomes;
• establish research priorities on the basis of epidemiological evi-
dence, biological plausibility, and feasibility; and
• continue to fund and support the Vaccine Safety Datalink project
to study the safety of the recommended immunization schedule.
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