An Assessment of the CDC Anthrax Vaccine Safety and Efficacy Research Program

Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program

Medical Follow-up Agency

OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
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An Assessment of the CDC Anthrax Vaccine Safety and Efficacy Research Program Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program Medical Follow-up Agency 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, DC20001 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 Centers for Disease Control and Prevention, Department of Health and Human Services (Contract No. 200-2000-00629). The views presented in this report are those of the Institute of Medicine Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program and are not necessarily those of the funding agencies. International Standard Book Number 0-309-08626-4 Additional copies of this report are available for sale from the National Academies Press, 500 Fifth Street, NW, Lockbox 285, Washington, DC20055; (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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“Knowing is not enough; we must apply. Willing is not enough; we must do.” —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.national-academies.org

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COMMITTEE TO REVIEW THE CDC ANTHRAX VACCINE SAFETY AND EFFICACY RESEARCH PROGRAM PHILIP S. BRACHMAN (Chair), Professor, Department of International Health, Rollins School of Public Health, Emory University ADAORA ALISE ADIMORA, Assistant Professor of Medicine and Clinical Assistant Professor of Epidemiology, University of North Carolina School of Medicine SANDRA H. BERRY, Senior Behavioral Scientist and Director, RAND Survey Research Group TRUDY BUSH,* Professor and Director of the Graduate Program in the Department of Epidemiology and Preventive Medicine at the University of Maryland School of Medicine THEODORE C. EICKHOFF, Professor of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center PATRICIA FERRIERI, Professor of Laboratory Medicine and Pathology and Pediatrics, University of Minnesota Medical School, and Director of the Clinical Microbiology Laboratory at Fairview-University Medical Center EMIL C. GOTSCHLICH, Vice President for Medical Sciences and R. Gwin Follis-Chevron Professor, The Rockefeller University MAURICE HILLEMAN, Director, Merck Institute for Vaccinology DENNIS L. KASPER, Executive Dean for Academic Programs, William Ellery Channing Professor of Medicine, and Professor of Microbiology and Molecular Genetics, Harvard Medical School MICHAEL D. LOCKSHIN, Director, Barbara Volcker Center for Women and Rheumatic Disease, and Professor of Medicine and Obstetrics-Gynecology, Joan and Sanford I. Weill Medical College of Cornell University DAVID MADIGAN, Professor of Statistics, Rutgers University KATHLEEN M. NEUZIL, Assistant Professor of Medicine, Division of Infectious Diseases, University of Washington School of Medicine N. REGINA RABINOVICH, Director, Malaria Vaccine Initiative, Program for Appropriate Technology in Health (PATH) BRIAN L. STROM, Professor and Chair, Biostatistics & Epidemiology, University of Pennsylvania School of Medicine HUGH H. TILSON, Clinical Professor of Epidemiology and Health Policy and Senior Adviser to the Dean, University of North Carolina School of Public Health Staff LOIS JOELLENBECK, Senior Program Officer (Study Director since January 2002) LEE ZWANZIGER, Senior Program Officer (Study Director until January 2002) JANE DURCH, Consultant (January to May 2002), Senior Program Officer (since June 2002) KAREN KAZMERZAK, Research Associate PHILLIP BAILEY, Senior Project Assistant RICHARD MILLER, Director, Medical Follow-up Agency *   Through March 2001.

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Preface Anthrax is a deadly disease, and the organism that causes it, Bacillus anthracis, has long been considered a prime agent for biological warfare and bioterrorism. The United States saw its dangers first hand in 2001 when letters containing anthrax spores were mailed to media organizations and to two U.S. senators, resulting in five deaths from inhalational anthrax. Unlike some biological warfare agents, though, a vaccine is available to prevent anthrax. Anthrax Vaccine Adsorbed (AVA) was licensed in 1970, and until the 1990s it was used primarily to protect veterinarians, textile mill workers who processed imported goat hair, and others with a high risk of occupational exposure to anthrax. Since the Gulf War, however, there has been great concern that U.S. troops deployed to certain parts of the world faced the threat of exposure to biological weapons. In 1998, the Department of Defense began a mandatory anthrax vaccination program intended to protect U.S. forces. Some members of the armed forces have been concerned that the vaccine itself might be responsible for health problems and that the mandatory vaccination program put them at unnecessary risk. Facing concerns over both the need to protect military personnel against the threat of biological weapons and the fears of some about the vaccine, the U.S. Congress directed the Centers for Disease Control and Prevention (CDC) to develop a research program to study the safety and efficacy of the currently available anthrax vaccine. In turn, CDC asked the Institute of Medicine to establish a panel of experts to review the completeness and appropriateness of its research program. The committee appointed by the Institute of Medicine represented a comprehensive range of professional competencies to be able to successfully evaluate the full scope of the CDC research proposals. CDC provided written materials describing its research program. Over the course of several meetings, the committee also had the opportunity to hear about the evolving research program from CDC investigators and other participating researchers. The committee also heard from military personnel and others with concerns about the safety and efficacy of AVA. The committee’s initial findings and recommendations regarding the CDC research program were presented in an interim report, issued in July 2001. The present report reflects the final results of the committee’s detailed deliberations that took into account a final written document describing the entire research program, which was provided to the committee in late February 2002. The committee strongly endorsed certain aspects of the CDC research program, made suggestions for changes in some proposals, and recommended that other planned research activities not be pursued. The committee also found that the bioterrorist events in the autumn of 2001 raised new questions beyond the scope of the original congressional charge and has encouraged CDC to incorporate some additional research into its program.

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The committee is aware that the currently licensed vaccine, AVA, could be improved upon and strongly encourages the efforts already under way to develop a new anthrax vaccine. Another Institute of Medicine committee, the Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, has also emphasized the need for a more modern anthrax vaccine and recommended in its March 2002 report that the Department of Defense expedite its work in this area. While reviewing the CDC research program, our committee was alert to the need to address questions concerning the present anthrax vaccine and to consider the contribution that CDC’s research might make in support of the evaluation of a newer vaccine. The committee would like to thank staff members from the Centers for Disease Control and Prevention and their collaborators who prepared reports and presentations for the committee and responded to our questions throughout our deliberations. We especially acknowledge the efforts of Randy Louchart, R.N., M.P.H., who served graciously as the primary contact for the study, and David Ashford, D.V.M., M.P.H., D.Sc.; Deborah Gust, Ph.D.; Laurie Kamimoto, M.D.; Jairam Lingappa, M.D., Ph.D.; Nina Marano, D.V.M., M.P.H.; Stacey Martin, M.Sc.; Michael McNeil, M.D., M.P.H.; Bradley Perkins, M.D.; Conrad Quinn, Ph.D.; and Benjamin Schwartz, M.D. In addition, the committee extends its thanks to those who provided personal and written testimony to the committee regarding concerns about AVA and the military immunization program. The early work of the committee was also aided by the contributions of committee member Trudy Bush, Ph.D., M.H.S., of the University of Maryland School of Medicine, who died suddenly in April 2001. Her valuable insights have been missed. The committee is greatly appreciative of the strong and constant support provided by the study staff from the Institute of Medicine, who worked diligently over the many months of our deliberations and report preparation. Without their excellent and unending support we would never have been able to complete our task. We specifically wish to thank Richard Miller, Lee Zwanziger (study director until January 2002), Lois Joellenbeck, Karen Kazmerzak, Jane Durch, Phillip Bailey, and Pamela Ramey-McCray from the staff of the Medical Follow-up Agency. Other members of the Institute of Medicine and National Academies staff who aided the study include Andrea Cohen, Linda Kilroy, Bronwyn Schrecker, Jennifer Bitticks, Janice Mehler, Sally Stanfield, and Christine Stencel. Jill Shuman assisted in copy editing the report. Philip S. Brachman Chair

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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 approved by the NRC'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: R. JOHN COLLIER, Harvard Medical School JAMES W. CURRAN, Rollins School of Public Health, Emory University BRADLEY N. DOEBBELING, University of Iowa Colleges of Medicine and Public Health THOMAS R. FLEMING, University of Washington DOUGLAS T. GOLENBOCK, University of Massachusetts Medical School MARY GRACE KOVAR, National Opinion Research Center, University of Chicago MYRON M. LEVINE, School of Medicine, University of Maryland at Baltimore GEORGES PETER, Brown University School of Medicine ALEXANDER WALKER, Harvard School of Public Health 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 Morton Swartz, Massachusetts General Hospital, and Paul D. Stolley, School of Medicine, University of Maryland at Baltimore. 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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Contents     EXECUTIVE SUMMARY   1     Study Process,   2     Overall Assessment of the CDC Research Plan,   2     Proposed Studies on the Efficacy of the Anthrax Vaccine,   4     Proposed Studies on the Safety of the Anthrax Vaccine,   5     Proposed Studies on the Acceptability of the Anthrax Vaccine,   8     Research Gaps,   8     Bioterrorism and Research Needs,   9     A Need for a Single Program Leader,   10     References,   16 1   INTRODUCTION   18     Origin of the Study,   18     Study Process and Information Sources,   20     Interim Report,   20     Related Reports,   21     Organization of the Report,   22     References,   22 2   BACKGROUND   23     Anthrax Disease,   24     Anthrax Vaccine,   25     Immunogenicity and Efficacy Issues,   26     Regulatory Considerations,   26     Safety Concerns About the Anthrax Vaccine,   27     Vaccine Adverse Event Reporting System,   28     Defense Medical Surveillance System,   29     References,   30

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3   THE CDC ANTHRAX VACCINE RESEARCH PLAN   33     Efficacy,   34     Safety,   39     Acceptability,   41     References,   42 4   PROPOSED STUDIES ON THE EFFICACY OF THE ANTHRAX VACCINE   43     Objectives and Critical Research Questions for CDC Research on the Efficacy of the Anthrax Vaccine,   43     Anthrax Vaccine Adsorbed: Human Reactogenicity and Immunogenicity Trial to Address Change in Route of Administration and Dose Reduction (Human Clinical Trial),   45     Nonhuman Primate Vaccine Dose Ranging, Immunogenicity, and Challenge Trial,   49     Immune Correlates of Protection Against Inhalational Anthrax Studies,   52     References,   55 5   PROPOSED STUDIES ON THE SAFETY OF THE ANTHRAX VACCINE   56     Objectives and Critical Research Questions for CDC Research on the Safety of the Anthrax Vaccine,   57     Anthrax Vaccine Adsorbed: Human Reactogenicity and Immunogenicity Trial to Address Change in Route of Administration and Dose Reduction,   58     Follow-up Study of Textile Mill Workers Vaccinated Against Anthrax,   63     Studies Based in the Vaccine Healthcare Center Network,   66     Enhanced Signal Detection and Hypothesis Testing for Adverse Events Following Anthrax Vaccination,   73     Possible Role of Aluminum Hydroxide Adjuvant in AVA-Associated Adverse Events,   79     Reproductive Health,   80     References,   80 6   PROPOSED STUDIES ON THE ACCEPTABILITY OF THE ANTHRAX VACCINE   82     Objectives and Critical Research Questions for CDC Research on the Acceptability of the Anthrax Vaccine,   82     Survey of Knowledge, Attitudes, and Beliefs Regarding the Anthrax Vaccine Among Military Personnel,   84     Survey of Civilian and Military Health Care Providers Regarding the Anthrax Vaccine and the Reporting of Possible Vaccine-Associated Adverse Events,   88     References,   89 7   SUMMARY ASSESSMENT OF THE CDC ANTHRAX VACCINE RESEARCH PLAN   91     CDC Research Plan,   91     Bioterrorism and Research Needs,   96     A Need for a Single Program Leader,   97     References,   99     APPENDIXES     A   Biographical Sketches,   101 B   Information-Gathering Meeting Agendas,   105 C   CDC Anthrax Vaccine Safety and Efficacy Research Plan,   113

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D   Food and Drug Administration Final Rule: New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible,   137 E   Department of Defense Memorandum: Reintroduction of the Anthrax Vaccine Immunization Program,   149 F   Institute of Medicine: CDC Anthrax Vaccine Safety & Efficacy Research Program: Interim Report Findings and Recommendations,   153 G   Institute of Medicine: The Anthrax Vaccine: Is It Safe? Does It Work? Findings and Recommendations,   155

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Figures, Tables, and Boxes FIGURES 6-1   Proposed components and estimated timeline for the KAB survey of military personnel regarding the anthrax vaccine,   85 TABLES ES-1   Additional Research Needs Concerning the Safety and Efficacy of the Anthrax Vaccine, Identified and Prioritized by the Committee,   9 3-1   CDC Efficacy Research Questions,   35 3-2   CDC Safety Research Questions,   36 3-3   CDC Acceptability Research Questions,   37 4-1   Schedule of Injections for Study Groups in the Human Clinical Trial of Alternative Routes of Vaccine Administration and Schedules of Vaccine Doses,   46 7-1   Committee Prioritization of Studies in the CDC Research Program on the Safety and Efficacy of the Anthrax Vaccine,   93 7-2   Additional Research Needs Concerning the Safety and Efficacy of the Anthrax Vaccine, Identified and Prioritized by the Committee,   96 BOXES ES-1   Studies Proposed by CDC for the Anthrax Vaccine Safety and Efficacy Research Program,   3 ES-2   Chapter 4 Findings and Recommendations,   11 ES-3   Chapter 5 Findings and Recommendations,   12 ES-4   Chapter 6 Findings and Recommendations,   15 ES-5   Chapter 7 Findings and Recommendations,   16 1-1   Congressional Request for CDC Anthrax Vaccine Research, FY 2000–1,   19

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1-2   Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program Statement of Task,   19 3-1   CDC Objectives for Research on the Efficacy of the Anthrax Vaccine,   34 3-2   CDC Objectives for Research on the Safety of the Anthrax Vaccine,   40 3-3   CDC Objectives for Research on the Acceptability of the Anthrax Vaccine,   41 4-1   CDC Objectives for Research on the Efficacy of the Anthrax Vaccine,   44 4-2   Critical Research Questions Regarding the Efficacy of the Anthrax Vaccine, as Identified by CDC,   44 4-3   Goals of Assays of Immune Correlates of Protection, as Specified by CDC,   53 5-1   CDC Objectives for Research on the Safety of the Anthrax Vaccine,   57 5-2   Critical Research Questions Regarding the Safety of the Anthrax Vaccine, as Identified by CDC,   57 5-3   Categories of Adverse Events to Be Identified During the Human Clinical Trial,   60 6-1   CDC Objectives for Research on the Acceptability of the Anthrax Vaccine,   83 6-2   Critical Research Questions Regarding the Acceptability of the Anthrax Vaccine, as Identified by CDC,   83 6-3   Specific Aims of the Survey of Knowledge, Attitudes, and Beliefs Regarding the Anthrax Vaccine Among Military Personnel, as Identified by CDC,   84

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Abbreviations and Acronyms ACIP Advisory Committee on Immunization Practices AMSA Army Medical Surveillance Activity AVA Anthrax Vaccine Adsorbed AVIP Anthrax Vaccine Immunization Program B. anthracis Bacillus anthracis BIDR balanced inventory of desirable responding BMI Battelle Memorial Institute CAMR Centre for Applied Microbiology and Research CD4+ T cell cluster of differentiation antigen 4 T cell CDC Centers for Disease Control and Prevention CFR Code of Federal Regulations CMI cell-mediated immune response COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms DMSS Defense Medical Surveillance System DNA deoxyribonucleic acid DoD Department of Defense DTP diphtheria and tetanus toxoids and pertussis vaccine EF edema factor ELISA enzyme-linked immunosorbent assay ELISPOT enzyme-linked immunospot FDA Food and Drug Administration GMC geometric mean concentration HLA human leukocyte antigen HRQoL health-related quality of life

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ICD-9-CM International Classification of Diseases, Ninth Revision, Clinical Modification ICP immune correlates of protection IgG immunoglobulin gamma IM intramuscular IOM Institute of Medicine KAB(s) knowledge, attitudes, and beliefs LF lethal factor MBPI Michigan Biologic Products Institute MDPH Michigan Department of Public Health MMF macrophagic myofasciitis NCID National Center for Infectious Diseases, CDC NHP nonhuman primate NIOSH National Institute for Occupational Safety and Health NIP National Immunization Program, CDC PA protective antigen PBMC(s) peripheral blood mononuclear cells pXO1 plasmid XO1 pXO2 plasmid XO2 RTI Research Triangle Institute SF-36 36-item short-form health survey SMR standardized mortality ratio SQ subcutaneous SSA Social Security Administration TNA toxin neutralizing antibody U.S. United States VAERS Vaccine Adverse Event Reporting System VHC Vaccine Healthcare Center VSD Vaccine Safety Datalink

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