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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.
Support for this project was provided by the Department of Defense (Contract No. DASW01-00-6-3045). The views presented in this report are those of the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine and are not necessarily those of the funding agency.
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COMMITTEE TO ASSESS THE SAFETY AND EFFICACY OF THE ANTHRAX VACCINE
BRIAN L. STROM (Chair), Professor and Chair,
Biostatistics & Epidemiology, University of Pennsylvania School of Medicine
WILLIAM E. BARLOW, Senior Scientific Investigator,
Center for Health Studies, Group Health Cooperative, and
Biostatistics Department, University of Washington
DAN G. BLAZER II, J. P. Gibbons Professor of Psychiatry,
Duke University Medical Center
LINDA D. COWAN, Professor of Biostatistics and Epidemiology,
University of Oklahoma College of Public Health
KATHRYN M. EDWARDS, Professor of Pediatrics,
Division of Infectious Diseases, Vanderbilt University School of Medicine
DENISE L. FAUSTMAN, Associate Professor of Medicine,
Harvard Medical School, and
Immunobiology Laboratory, Massachusetts General Hospital
EMIL C. GOTSCHLICH, Vice President for Medical Sciences and R. Gwin Follis-Chevron Professor,
The Rockefeller University
DENNIS L. KASPER, Executive Dean for Academic Programs, William Ellery Channing Professor of Medicine, and Professor of Microbiology and Molecular Genetics,
Harvard Medical School
DON P. METZGAR, Scientific Consultant
HUGH H. TILSON, Clinical Professor of Epidemiology and Health Policy and Senior Adviser to the Dean,
University of North Carolina School of Public Health
STANLEY A. PLOTKIN, Medical and Scientific Consultant, Aventis Pasteur, and Emeritus Professor of Pediatrics,
University of Pennsylvania
GEORGE A. ROBERTSON, Senior Manager of Biological Quality Control,
LOIS JOELLENBECK, Senior Program Officer (Study Director)
LEE ZWANZIGER, Senior Program Officer (until January 2002)
JANE DURCH, Freelance Writer and Editor
KAREN KAZMERZAK, Research Assistant
PHILLIP BAILEY, Project Assistant
RICHARD MILLER, Director,
Medical Follow-up Agency
The Institute of Medicine convened the Committee to Assess the Safety and Efficacy of the Anthrax Vaccine in October 2000 to prepare a congressionally mandated report for the Department of Defense. The committee was charged with reviewing data regarding the efficacy and safety of the currently licensed anthrax vaccine—Anthrax Vaccine Adsorbed (AVA)—and assessing the efforts to resolve manufacturing issues and resume production and distribution of the vaccine. This report is a summary of the committee’s deliberations.
As the committee completed its work, the nation experienced the traumas of not only the attacks of September 11, 2001, but also the distribution of potent anthrax spores through the U.S. mail, which resulted in 5 deaths, at least 13 nonfatal confirmed cases, and the exposure of more than 30,000 other people. The nation and public health and health care professionals found themselves with much new but hard-won knowledge about anthrax, as well as many new questions about the disease and its prevention and treatment, including the merits of vaccination following exposure.
These events lent urgency to the committee’s work. However, the study charge already reflected concerns that arose in the context of discussions of the risk of exposure to anthrax spores and the merits of vaccination for military personnel, given the perceived threat of battlefield exposure to anthrax. The Department of Defense had begun to implement a plan to vaccinate all military personnel, but some service members were sufficiently concerned about the efficacy or safety of AVA that they chose to resign or even undergo court-martial to avoid vaccination. Some have also questioned whether the vaccine might be related to the health problems experienced by some Gulf War veterans. In addition, the manufacturing plant
producing the vaccine failed to pass Food and Drug Administration inspection until very recently. As a result of the limited supply of the vaccine, the Department of Defense’s Anthrax Vaccine Immunization Program was proceeding at a very reduced rate. These manufacturing issues further accentuated the questions about the vaccine.
Vaccines are critically important tools for the prevention of serious infectious diseases. As with any pharmaceutical product or medical procedure, however, the use of vaccines carries a risk of adverse health effects, which must be weighed against the expected health benefit. Safety expectations for vaccines are especially high because they are usually given to healthy people to protect them against a disease that they may not be exposed to in the future.
In approaching its task, the committee recognized that it was dealing with difficult issues, both scientifically and politically. Scientifically, it was dealing with a series of questions on which the published data were limited. Politically, it was operating in a charged arena, where strong positions had been taken and strong emotions expressed, even in the absence of convincing data. In response, the committee chose to embark on a process that would be as open as possible while maintaining maximum scientific rigor. It elected to hear from all who had anything to contribute, whether the contributions were concerns, complaints, or data. All available data were sought and reviewed and were then weighed in the committee’s scientific assessment. Through its questions and initiatives the committee even triggered the development of significant new data on these questions.
Of course, upon starting its work, the committee never foresaw how timely its efforts would be. In the wake of the attacks of September 11 and especially the subsequent use of anthrax as a bioterrorist weapon, the committee debated how and when to accelerate the release of its findings and recommendations, whether through an abbreviated interim report or through normal channels. In the end, it chose to complete its full report but to accelerate the timetable. We are grateful to the Institute of Medicine for providing us the extra staff support necessary to achieve this.
Recent events, including the deployment of U.S. troops to Afghanistan and surrounding areas and contamination of the U.S. mail with items containing anthrax spores, all strongly suggest not only the possibility of resumption of anthrax vaccination for military personnel but also the possibility of expanding vaccination to newly recognized high-risk persons in the civilian population. To the degree that our efforts will assist in these future decisions, we are grateful for having had the opportunity to help.
Brian L. Strom
The committee has been honored and privileged to be able to contribute to this important effort and wishes to acknowledge the valuable contributions and assistance from many individuals who shared their experiences and their expertise. We are especially grateful for the perspectives provided by individuals who took their own time to provide information to the committee through presentations or testimony. Personal and written testimony from members of the military, former members of the military, and family members of those who had been vaccinated with Anthrax Vaccine Adsorbed (AVA) provided important information to the committee. The committee also appreciates the extra work and efforts of many scientific investigators, both military and civilian, who shared their work with the committee both through scientific presentations and through their manuscripts. (Agendas for the committee’s information-gathering sessions are found in Appendix C, which also includes the names of the many individuals who generously provided testimony and presentations.) The Department of Defense (particularly the Anthrax Vaccine Immunization Program Agency, the Army Medical Surveillance Activity, and the U.S. Army Medical Research Institute of Infectious Diseases) and the Department of Health and Human Services (particularly the Food and Drug Administration and the Centers for Disease Control and Prevention) provided valuable information throughout the study, as well as technical review of some background portions of the report. As our study contact with the Department of Defense, LTC John Grabenstein was very helpful and responsive in his efforts to provide information to the committee. BioPort Corporation also
provided a tremendous amount of information to the committee in the form of reports and correspondence relevant to its product, AVA; technical review of some background information for the report; and last-minute information about the newly approved license supplement.
The committee also appreciates the valuable contributions of two unpaid consultants. Stanley Plotkin shared some of his wisdom and experience in vaccinology with the group, and George Robertson provided useful expertise in the area of biologics manufacture. We are also grateful to John Treanor who furthered our study with a very helpful commissioned paper on adverse events associated with adult vaccines.
We also would like to thank our tireless staff, who made this possible. Lois Joellenbeck was terrific to work with as our project director, providing guidance and assistance as we gathered data and then enormous assistance as we crafted our final language. We were particularly delighted, as well, when our committee’s family was increased in size with the arrival of her first child. Lee Zwanziger was generous as she stepped in while Lois was on maternity leave, taking on our work along with that of our sister committee, the Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program. We also appreciated her continued assistance, along with the skilled assistance of Jane Durch, as we moved to accelerate our timetable. Karen Kazmerzak was extremely helpful in gathering and keeping track of the array of references, handouts, and other materials used during the study. Phillip Bailey was always a great help, assisting with the myriad logistical arrangements needed for the committee’s meetings. In addition, IOM staff Andrea Cohen, Bronwyn Schrecker, Paige Baldwin, Jennifer Otten, Hallie Wilfert, and Clyde Behney provided important assistance in the report review, preproduction, and dissemination processes. Finally, we would like to thank our peer reviewers and our review coordinator and monitor for their useful and constructive suggestions.
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 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:
KEN ALIBEK, President, Advanced Biosystems, Inc.
R. JOHN COLLIER, Presley Professor of Microbiology and Molecular Genetics, Department of Microbiology and Molecular Genetics, Harvard Medical School
DOUGLAS T. GOLENBOCK, Chief, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School
HARRY A. GUESS, Vice President, Epidemiology, Merck Research Laboratories
FLORENCE P. HASELTINE, Director, Center for Population Research, National Institute of Child Health and Human Development, National Institutes of Health
SAMUEL L. KATZ, Wilburt C. Davison Professor Emeritus, Department of Pediatrics, Duke University Medical Center
MYRON M. LEVINE, Professor and Director, Center for Vaccine Development, School of Medicine, University of Maryland at Baltimore
PAUL PARKMAN, Parkman Associates
RICHARD PLATT, Professor of Ambulatory Care and Prevention, Harvard Medical School and Harvard Pilgrim Health Care
ART REINGOLD, Epidemiology Department, University of California, Berkeley
RONALD J. SALDARINI, President, Wyeth Lederle Vaccines and Pediatrics (Retired)
FRANKLIN H. TOP, JR., Executive Vice President and Medical Director, MedImmune, Inc.
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 Leslie Z. Benet, professor, Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, and Enriqueta C. Bond, Burroughs Wellcome Fund. 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.
Figures, Tables, and Boxes
Model of anthrax toxin action,
Cutaneous anthrax lesion,
Chest radiograph characteristic of inhalational anthrax,
Hemorrhagic meningitis caused by anthrax,
Model of anthrax toxin action,
VAERS information flowchart. AVEC is unique to the anthrax vaccine,
Changes to parameters of the Anthrax Vaccine Adsorbed manufacturing process,
Local and Systemic Event Rates Reported in Selected Prospective Vaccine Trials,
AVEC Classification of Hospitalizations Reported to VAERS (as of October 2, 2001) Following Anthrax Vaccination and Not Classified as “Very Likely/Certainly” or “Probably” Caused by Anthrax Vaccine Adsorbed,
Adverse Events Reported to VAERS (as of October 2, 2001) Involving Loss of Time from Duty of 24 Hours or More and Considered by AVEC as Certainly or Probably Caused by Anthrax Vaccine Adsorbed,
Ad Hoc Studies of Immediate-Onset Adverse Events Following Anthrax Vaccination: Local Events,
Ad Hoc Studies of Immediate-Onset Adverse Events Following Anthrax Vaccination: Systemic Events,
Ad Hoc Studies of Later-Onset Adverse Events Following Anthrax Vaccination,
Record-Linkage Studies of Adverse Events Following Anthrax Vaccination,
Events in AVA Development and Manufacture,
Comparison of AVA and Merck Vaccine,
Timeline for Production of AVA,
Functions of AVEC and Post-AVEC Panels,
Abbreviations and Acronyms
Advisory Committee on Causality Assessment
Advisory Committee on Immunization Practices
Army Medical Surveillance Activity
anthrax toxin receptor
Anthrax Vaccine Adsorbed
Anthrax Vaccine Expert Committee
Anthrax Vaccine Immunization Program
Biologics License Application
Center for Biologics Evaluation and Research
Centers for Disease Control and Prevention
Code of Federal Regulations
Division of Biologics Standards, National Institutes of Health
Defense Enrollment Eligibility Reporting System
Department of Health and Human Services
Defense Medical Surveillance System
Department of Defense
diphtheria and tetanus toxoid and acellular pertussis
erythema and/or induration
Establishment Inspection Report
enzyme-linked immunosorbent assay
Food and Drug Administration
General Accounting Office
good manufacturing practices
International Classification of Diseases, Ninth Revision, Clinical Modification
Investigational New Drug
Institute of Medicine
Michigan Biologic Products Institute
Michigan Department of Public Health
National Communicable Disease Center
National Institutes of Health
Notice of Intent to Revoke
pentavalent botulinum toxoid
polymerase chain reaction
Reserve Officer Training Corps
sodium dodecyl sulfate-polyacrylamide gel electrophoresis
tetanus and diphtheria toxoid
toxin neutralizing antibody