THE ANTHRAX VACCINE

Is It Safe? Does It Work?

Lois M. Joellenbeck, Lee L. Zwanziger, Jane S. Durch, and Brian L. Strom, Editors

Committee to Assess the Safety and Efficacy of the Anthrax Vaccine

Medical Follow-up Agency

INSTITUTE OF MEDICINE

NATIONAL ACADEMY PRESS
Washington, D.C.



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The Anthrax Vaccine: Is it Safe? Does it Work? THE ANTHRAX VACCINE Is It Safe? Does It Work? Lois M. Joellenbeck, Lee L. Zwanziger, Jane S. Durch, and Brian L. Strom, Editors Committee to Assess the Safety and Efficacy of the Anthrax Vaccine Medical Follow-up Agency INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C.

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The Anthrax Vaccine: Is it Safe? Does it Work? NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, DC 20418 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. International Standard Book Number 0-309-08309-5 Library of Congress Control Number 2002104241 Additional copies of this report are available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, DC 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP’s home page at www.nap.edu. The full text of this report is available at www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at www.iom.edu. Copyright 2002 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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The Anthrax Vaccine: Is it Safe? Does it Work? “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE Shaping the Future for Health

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The Anthrax Vaccine: Is it Safe? Does it Work? THE NATIONAL ACADEMIES National Academy of Sciences National Academy of Engineering Institute of Medicine National Research Council 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. Kenneth I. Shine 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 chairman and vice chairman, respectively, of the National Research Council.

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The Anthrax Vaccine: Is it Safe? Does it Work? 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 Research Professor, 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 Director, 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 Consultants 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, Wyeth-Ayerst Pharmaceuticals Staff 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

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The Anthrax Vaccine: Is it Safe? Does it Work? Preface 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

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The Anthrax Vaccine: Is it Safe? Does it Work? 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 Chair

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The Anthrax Vaccine: Is it Safe? Does it Work? Acknowledgments 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

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The Anthrax Vaccine: Is it Safe? Does it Work? 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.

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The Anthrax Vaccine: Is it Safe? Does it Work? Reviewers 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

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The Anthrax Vaccine: Is it Safe? Does it Work? 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.

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The Anthrax Vaccine: Is it Safe? Does it Work? Contents     EXECUTIVE SUMMARY   1     Abstract,   1     Study Process and Information Sources,   3     Anthrax and Anthrax Vaccine,   5     Anthrax Vaccine Efficacy,   5     Anthrax Vaccine Safety,   10     Anthrax Vaccine Manufacture,   14     Future Needs,   15     References,   28 1   INTRODUCTION   33     Study Process and Information Sources,   34     Related Reports,   35     General Principles Regarding Use of Vaccines,   37     Organization of the Report,   38     References,   39 2   BACKGROUND   40     The Disease,   41     Anthrax Vaccine Development,   48     Use of Anthrax Vaccine,   49     Concerns About Use of AVA,   50     Available Data on AVA,   51     References,   53

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The Anthrax Vaccine: Is it Safe? Does it Work? 3   ANTHRAX VACCINE EFFICACY   56     Evaluating Efficacy of AVA for Inhalational Anthrax,   57     Efficacy of AVA Against All Known B. anthracis Strains,   69     Correlation of Protection: Animal Models and Human Immunity,   72     Postexposure Use of Anthrax Vaccine,   75     Conclusions Regarding Efficacy,   76     References,   78 4   SAFETY: INTRODUCTION   83     Safety Concerns About the Anthrax Vaccine,   84     Identifying Vaccine-Related Adverse Events,   85     Gaining Perspective on Adverse Events Following Vaccination,   88     Sources of Information Regarding the Safety of AVA,   93     Testing for Vaccine Contamination,   95     References,   97 5   SAFETY: CASE REPORTS   102     Vaccine Adverse Event Reporting System,   102     DoD and VAERS,   107     Reports to VAERS Related to AVA,   112     References,   115 6   SAFETY: EPIDEMIOLOGIC STUDIES   118     Ad Hoc Studies,   119     Record-Linkage Studies,   155     Preliminary Information on Analysis of Data on Birth Defects,   171     Conclusions Regarding AVA Vaccination and Adverse Events,   172     Findings and Recommendations,   175     References,   176 7   ANTHRAX VACCINE MANUFACTURE   180     Committee’s Interpretation of the Charge,   180     Regulatory Oversight of Vaccine Manufacture,   181     Anthrax Vaccine Development,   183     Regulatory Actions Concerning AVA Manufacture,   190     Findings and Recommendations,   194     References,   195

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The Anthrax Vaccine: Is it Safe? Does it Work? 8   FUTURE NEEDS   198     Future Use of AVA,   199     Surveillance for Adverse Events,   201     New Anthrax Vaccine Development,   207     References,   210     APPENDIXES         A Statement of Task,   213     B Biographical Sketches,   214     C Information-Gathering Meeting Agendas,   218     D Anthrax Vaccine Adsorbed Package Inserts,   227     E Vaccine Adverse Event Reporting System (VAERS) Form,   239     F Anthrax Vaccine Expert Committee (AVEC) Case Assessment Form,   243     G DMSS Analyses Requested by the IOM Committee to Assess the Safety and Efficacy of the Anthrax Vaccine,   245     H An Assessment of the Safety of the Anthrax Vaccine: A Letter Report,   251

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The Anthrax Vaccine: Is it Safe? Does it Work? Figures, Tables, and Boxes FIGURES ES-1   Model of anthrax toxin action,   8 2-1   Cutaneous anthrax lesion,   43 2-2   Chest radiograph characteristic of inhalational anthrax,   45 2-3   Hemorrhagic meningitis caused by anthrax,   45 2-4   Model of anthrax toxin action,   47 5-1   VAERS information flowchart. AVEC is unique to the anthrax vaccine,   104 7-1   Changes to parameters of the Anthrax Vaccine Adsorbed manufacturing process,   191 TABLES 4-1   Local and Systemic Event Rates Reported in Selected Prospective Vaccine Trials,   90 5-1   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,   113

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The Anthrax Vaccine: Is it Safe? Does it Work? 5-2   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,   114 6-1   Ad Hoc Studies of Immediate-Onset Adverse Events Following Anthrax Vaccination: Local Events,   120 6-2   Ad Hoc Studies of Immediate-Onset Adverse Events Following Anthrax Vaccination: Systemic Events,   128 6-3   Ad Hoc Studies of Later-Onset Adverse Events Following Anthrax Vaccination,   134 6-4   Record-Linkage Studies of Adverse Events Following Anthrax Vaccination,   136 7-1   Events in AVA Development and Manufacture,   184 7-2   Comparison of AVA and Merck Vaccine,   185 7-3   Timeline for Production of AVA,   189 8-1   Functions of AVEC and Post-AVEC Panels,   203 BOXES ES-1   Chapter 3 Findings and Recommendations,   22 ES-2   Chapter 5 Findings and Recommendations,   23 ES-3   Chapter 6 Findings and Recommendations,   24 ES-4   Chapter 7 Findings,   25 ES-5   Chapter 8 Findings,   26 ES-6   Chapter 8 Recommendations,   27 8-1   Goals of Anthrax Vaccine Development,   209

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The Anthrax Vaccine: Is it Safe? Does it Work? Abbreviations and Acronyms ACCA Advisory Committee on Causality Assessment ACIP Advisory Committee on Immunization Practices AMSA Army Medical Surveillance Activity ATR anthrax toxin receptor AVA Anthrax Vaccine Adsorbed AVEC Anthrax Vaccine Expert Committee AVIP Anthrax Vaccine Immunization Program BLA Biologics License Application CBER Center for Biologics Evaluation and Research CDC Centers for Disease Control and Prevention C.F.R. Code of Federal Regulations CI confidence interval cm centimeter DBS Division of Biologics Standards, National Institutes of Health DEERS Defense Enrollment Eligibility Reporting System DHHS Department of Health and Human Services DMSS Defense Medical Surveillance System DNA deoxyribonucleic acid DoD Department of Defense DTaP diphtheria and tetanus toxoid and acellular pertussis

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The Anthrax Vaccine: Is it Safe? Does it Work? EF edema factor E/I erythema and/or induration EIR Establishment Inspection Report ELISA enzyme-linked immunosorbent assay FDA Food and Drug Administration GAO General Accounting Office GMPs good manufacturing practices ICD-9-CM International Classification of Diseases, Ninth Revision, Clinical Modification IgG immunoglobulin G IND Investigational New Drug IOM Institute of Medicine kDa kilodalton LF lethal factor MBPI Michigan Biologic Products Institute MDPH Michigan Department of Public Health ml milliliter NCDC National Communicable Disease Center NIH National Institutes of Health NOIR Notice of Intent to Revoke OR odds ratio PA protective antigen PBT pentavalent botulinum toxoid PCR polymerase chain reaction ROTC Reserve Officer Training Corps SDS-PAGE sodium dodecyl sulfate-polyacrylamide gel electrophoresis SWA Southwest Asia Td tetanus and diphtheria toxoid TNA toxin neutralizing antibody µg microgram

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The Anthrax Vaccine: Is it Safe? Does it Work? µm micrometer USAMRIID U.S. Army Medical Research Institute of Infectious Diseases VA Department of Veterans Affairs VAERS Vaccine Adverse Event Reporting System VNTR variable-nucleotide tandem repeat

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