Appendix C
Anthrax Vaccine Safety & Efficacy Research Plan

Centers for Disease Control and Prevention (CDC) Department of Health and Human Services

February 21, 2002



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Appendix C Anthrax Vaccine Safety & Efficacy Research Plan Centers for Disease Control and Prevention (CDC) Department of Health and Human Services February 21, 2002

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Preface The CDC Anthrax Vaccine Safety & Efficacy Research Plan (The Plan) outlines studies and activities developed by CDC to address recent concerns that have been raised about the efficacy, safety, and to some extent, the acceptability of Anthrax Vaccine Adsorbed (AVA). The development and implementation of this plan is a direct response to U.S. House/Senate Conference Appropriations Language for FY001 and FY01.2 The Plan describes how CDC and its collaborators, including National Institutes of Health (NIH), Department of Defense (DoD), academic research centers, nongovernmental organizations, and private sector research organizations are responding to the Congressional charge to evaluate and improve the safety and efficacy of AVA. In one major component of this research, CDC’s National Center for Infectious Diseases (NCID) and National Immunization Program (NIP) are collaborating on an AVA clinical trial due to begin enrollment in March 2002. The interim results of data collected through subjects’ first 7 months of the study will be presented to the FDA for consideration of changing the route of AVA administration from SQ to IM, and elimination of the 2-week vaccine dose. At the end of the study, the entire results will be submitted to FDA for consideration of elimination of additional doses from the licensed AVA schedule. At that time, CDC will also supplement these data with results from parallel non-human primate challenge studies and additional research on immunologic correlates of protection. The CDC investigators will also evaluate the occurrence of local adverse events following AVA administration and the effect of selected risk factors, including gender on vaccine safety. CDC also is coordinating several activities to evaluate and improve adverse event reporting, evaluation, and management. As part of this activity, CDC and DoD are establishing a network of Vaccine Healthcare Centers (VHCs) of excellence within the military that will serve as a platform from which to conduct AVA safety research studies to enhance AVA’s safety, efficacy and acceptability. The DoD role is to focus on the clinical management and follow-up of service personnel with vaccine associated adverse events and the CDC role is to evaluate the VHC network’s impact, assess interventions and conduct vaccine safety-related research through these centers. This CDC Anthrax Vaccine Safety & Efficacy Research Plan proposes in greater detail several AVA research studies and activities that address the U.S. Congressional mandate to investigate the safety, efficacy and acceptability of AVA among military and civilian populations. 1   The FY2000 House/Senate Conference Appropriations Language specified that the funds be used to address “1) the risk factors for anthrax vaccine adverse events, including differences in rates of adverse events between men and women; 2) determining immunological correlates of protection and documenting anthrax vaccine efficacy; and 3) optimizing the anthrax vaccination schedule and administration to assure efficacy while minimizing the number of doses required and the occurrence of adverse events.” 2   The FY 2001 House/Senate Conference Appropriations Language states “Regarding the anthrax vaccine study, the conferees understand that clinical studies will be greatly facilitated by the establishment of the vaccine healthcare network, with the first site located at Walter Reed Army Medical Center.”

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TABLE OF CONTENTS     I.INTRODUCTION   3     II.BACKGROUND   3     HISTORY OF THE VACCINE:   4     CURRENT USE OF AVA:   5     III.LIST OF APPROVED AND PROPOSED RESEARCH STUDIES WITH PRIORITIZATION   5     IV.OBJECTIVES   9     1.EFFICACY   9     Rationale:   9     Regulatory considerations:   9     Summary of Objectives for Efficacy   10     Human clinical trials:   10     Non-human primate studies:   10     2.SAFETY   10     Rationale:   10     Vaccine Health Center (VHC) Network:   11     Summary of Objectives for Safety   11     Human clinical trial:   11     Other safety studies:   12     3.ACCEPTABILITY   13     Rationale:   13     Summary of Objectives for Acceptability   14     V.SCIENTIFIC BENEFITS   14     VI.PARTNERSHIPS   15     NATIONAL INSTITUTES OF HEALTH:   15     DEPARTMENT OF DEFENSE:   15     THE FOOD AND DRUG ADMINISTRATION:   16     UNIVERSITIES AND MEDICAL CENTERS:   16     PRIVATE SECTOR ORGANIZATIONS:   16     VII.EXPERT REVIEW AND OVERSIGHT   16     INSTITUTE OF MEDICINE:   16     EXPERT CONSULTATION PANELS:   17     VIII.ANTICIPATED OUTCOMES   18     IX.DISCONTINUED PREVIOUSLY PROPOSED STUDIES   18     X.ACKNOWLEDGEMENTS   19     APPENDIX A.EXPERT CONSULTATION PANELS   19

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I.Introduction The terrorist events of September 11, 2001 and the subsequent releases of B. anthracis spores in Florida, New York City, and Washington, D.C. have magnified the importance of the CDC anthrax vaccine safety and efficacy research agenda. In 1998, concerns about bioweapons led Secretary of Defense William S. Cohen to initiate a controversial program to immunize all U.S. military personnel against inhalational anthrax. In recent years, questions have been raised by members of the military, the scientific community, and Congress about Anthrax Vaccine Adsorbed’s (AVA) effectiveness, reactogenicity, and possible association with long-term sequelae such as infertility, Chronic Fatigue Syndrome, and Gulf War Illnesses. This document outlines studies and activities developed by CDC to evaluate the efficacy and safety of AVA, as requested in U.S. House/Senate Conference Appropriations Language for FY00 and FY01. In particular, it describes how CDC and its collaborators including NIH, DoD, academic research centers, and nongovernmental organizations will conduct a range of investigations to evaluate vaccine immunogenicity and correlates of protection; assess alternate vaccination schedules and routes of administration to enhance vaccine safety; and enhance reporting of adverse events after vaccination. In addition to evaluating the efficacy and short and long-term safety of AVA, CDC and its partners will use a variety of approaches to improve the acceptance of AVA amongst military personnel. The implementation of the CDC Anthrax Vaccine Safety & Efficacy Research Plan will provide scientific benefits for researchers in several disciplines e.g., the identification of measurable markers of protective immunity to anthrax infection will facilitate ongoing efforts by DoD, NIH, and others to design and validate a new generation of technologically advanced vaccines that will be more effective, less reactogenic, and easier to administer than AVA. II.Background The bacterium Bacillus anthracis (anthrax) is a “Category A” biologic agent,3 and, as the U.S. has already witnessed, a potential weapon of choice for both terrorists and rogue nations. It is relatively easy to obtain, grow, store and disseminate, and the inhalational form is nearly always fatal if untreated. During the 1980s, anthrax spores were engineered for mass dissemination at bioweapons factories in at least two nations: Iraq4 and the former Soviet Union4. In 1991, concerned that weaponized anthrax might be deployed by Iraq, DoD vaccinated 150,000 troops serving in the Persian Gulf, using AVA, the only FDA-licensed human anthrax vaccine. In the years after the Gulf War, DoD continued to use AVA to immunize selected military personnel to ensure their readiness for immediate worldwide deployment. In 1998, DoD established the Anthrax Vaccine Immunization Program (AVIP), whose 3   http://www.bt.cdc.gov/Agent/Agentlist.asp 4   http://www.anthrax.osd.mil/Flash_interface/default.html

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goal is to immunize all 2.4 million active duty and reservist military personnel. History of the Vaccine: AVA was developed during the 1950s as a specialized vaccine to protect mill workers, livestock handlers, veterinarians, and others at risk for cutaneous anthrax through contact with anthrax-infected animals or with contaminated animal products. It consists of the noninfectious filtrate from the culture of a heat-attenuated strain of B anthracis adsorbed to aluminum hydroxide adjuvant. AVA is poorly suited for mass immunization, because it requires a priming series of 6 subcutaneous injections (at 0, 2, and 4 weeks, and 6, 12, and 18 months), plus annual boosters. Moreover, subcutaneous administration of the vaccine (as well as the large number of injections) may increase the incidence of short-term side effects such as pain and swelling at the site of injection. FDA licensed AVA in 1970.5 Evidence for its efficacy is based on data from both human and animal models. A human clinical trial of AVA was conducted from 1955 to 1959, using a slightly different formulation than the one used in the1990s.6 The subjects were New Hampshire mill workers who processed goat hair from animals raised in anthrax-endemic areas. Several months after the trial began, there was an outbreak of inhalational anthrax in the study population, providing an unexpected opportunity to investigate AVA’s ability to provide protection against inhalational as well as cutaneous infection. The researchers documented a statistically significant reduction in the incidence of anthrax among the vaccinated group (3 cutaneous cases), as compared to the control group (18 cutaneous and 5 inhalational cases). In addition, four different AVA efficacy studies conducted in nonhuman primates indicated that the vaccine provides protection against challenge with aerosolized anthrax spores.7,8,9,10 Animal studies suggest that AVA’s efficacy is based on a protective immune response to a protein called Protective Antigen (PA).11 The nature of that response, however, is poorly understood. PA is one of three Bacillus anthracis proteins that combine to produce two highly dangerous exotoxins, one that causes cardiovascular collapse and the other causes pulmonary edema. The heat-attenuation process used to produce AVA apparently denatures the portions of PA that contribute to toxin 5   Department of Health Education and Welfare. Investigational New Drug Application for AVA DBS-IND 180. Washington DC: Centers for Disease Control and Prevention; 1966. 6   Brachman P, Gold H, Plotkin SA, Fekety FR, Werrin M, Ingraham NR. Field evaluation of a human anthrax vaccine. Am J Public Health. 1962;52:632-645. 7   Turnbull PC, Broster MG, Carman JA, Manchee RJ, Melling J. Development of antibodies to protective antigen and lethal factor components of anthrax toxin in humans and guinea pigs and their relevance to protective immunity. Infect Immun. 1986;52:356-63. 8   Ivins BE, Fellows PF, Pitt MLM, et al. Efficacy of a standard human anthrax vaccine against Bacillus anthracis aerosol spore challenge in rhesus monkeys. Salisbury Medical Journal Suppl. 1995;87:125-126. 9   Pitt MLM, Ivins BE, Estep JE, Farchaus J, Friedlander AM. Comparison of the efficacy of purified protective antigen and MDPH [AVA] to protect non-human primates from inhalation anthr. Salisbury Medical Journal Suppl. 1995;87:130. 10   Wright GG, Green TW, Kanode J, R.G. Studies on immunity in anthrax, V: Immunizing activity of alum-precipitated protective antigen. Journal of Immunology. 1954;73:387-391. 11   Reuveny S, White MD, Adar YY, et al. Search for correlates of protective immunity conferred by anthrax vaccine. Infect Immun. 2001;69:2888-2893.

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formation and cell death, while preserving the portions that elicit protective immune responses. Current use of AVA: AVA continues to be recommended by AVIP, for administration to military personnel serving in threat areas. However, because of limited current vaccine supply, the implementation of this policy has been limited. In addition, the Advisory Committee on Immunization Practices (ACIP), with CDC concurrence, has recently issued supplemental recommendations for the prevention of anthrax (unpublished ACIP). The supplemental recommendations reaffirm the principle of pre-exposure use of AVA based on a calculable risk assessment.12 In the current situation of limited AVA availability, ACIP recommends that AVA be prioritized for pre-exposure vaccination of groups with high risk of repeated exposures to B. anthracis spores. At present, these groups include laboratory personnel handling environmental specimens (especially powders) and performing confirmatory testing for B. anthracis in Level B and C laboratories, and those individuals involved in environmental B. anthracis clean-up at multiple contaminated sites in succession. Factors increasing risk in Level B and C laboratories include the type of specimens handled (powders presenting the highest risk) and the volume of specimens handled that are positive for B. anthracis. In addition, in December 2001, CDC received approval from FDA to implement emergency post-exposure prophylaxis using vaccine and antibiotics for individuals exposed to B. anthracis spores through letters sent through the U.S. mail system. Although DoD has rights to the current supply of AVA, which was produced through a DoD contract with the BioPort Corporation, emergency workers and first responders in the civilian community have expressed interest in the anthrax vaccine, an interest that is likely to grow in view of the terrorist attacks on New York City and Washington, D.C. and the releases of B. anthracis in Florida, New York City, and Washington D.C. Given the current circumstances, information about the efficacy and safety of AVA is extremely important to both military personnel and civilians. III.List of Approved and Proposed Research Studies with Prioritization Each of CDC’s approved and proposed AVA research studies are listed below. Included in the list are the studies’ prioritization and an explanation for the basis of their prioritization. An integrated timeline of all CDC’s AVA research studies is included in Section 2 of the binder and a table that outlines the critical AVA safety and efficacy research questions that are addressed by each study is included in Section 3 of the binder. Study 1. AVA Human Reactogenicity and Immunogenicity Trial to Address Change in Route of Administration and Dose Reduction (See Section 6 in the binder for study summary) 12   Ashford D.A., Rotz L.D., Perkins B.A. Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practice (ACIP). MMWR 2000;49 (no. RR-15).

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  Priority: Level 1 Basis: The human clinical trial is expected to serve as the principal scientific basis for decisions regarding changes in route of vaccine administration and reduction in number of doses in the vaccination series. In combination with the other studies, this trial will provide new understanding about anthrax pathogenesis and immunologic correlates for protection against inhalational anthrax in humans. This work is expected to serve as the scientific foundation for development and licensing of the next generation of anthrax vaccines. Study 2. Non-human Primate Vaccine Dose Ranging, Immunogenicity and Challenge Trial (See Section 7 in the binder for study summary)   Priority: Level 1 Basis: The Food and Drug Administration (FDA) supports use of animal studies to evaluate AVA efficacy in protecting against aerosol B. anthracis spore challenge; data from these studies will be used to support conclusions from the human clinical study. The non-human primate studies were therefore planned with the primary objective being use of anthrax aerosol challenge of AVA vaccinated animals to generate data about protection of animals at various points in the immunization process. This data will be used as evidence to support the objective of dose reduction in the licensed AVA schedule for humans. The immune response data collected from immunizing and challenging animals will be used to identify correlates of protection induced by AVA vaccination. Study 3. Correlates of Protection Study (See Section 8 in the binder for study summary)   Priority: Level 1 Basis: Despite the extensive research on anthrax pathogenesis and vaccines over the past 20 years the existence of a correlation between survival from virulent anthrax challenge and a defined immune response to anthrax vaccine components, and to PA in particular, remains unresolved. In the case of human vaccinees, where clinical trials of efficacy are untenable, it is clearly expedient to have an accessible and reliable surrogate marker of immune protection. The overall purpose of this study is to determine in NHPs an immunologic correlate of protection against anthrax and correlate these data with information from the human clinical trial to test the hypothesis that   ‘One or more measurable immunological markers of protection can be identified in a NHP model of inhalation infection withB. anthracisand that one or more of these measurable markers are identifiable or present in AVA-vaccinated humans.’   The objective of the Immune Correlates of Protection studies is to establish an immunologic

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  marker that endorses the human clinical trial endpoint, confirms human vaccinee protection, identifies when protection is achieved and determines how long protection lasts. Study 4. National Survey of Knowledge, Attitudes, and Beliefs Regarding the Anthrax Vaccine Among Military Personnel (See Section 9 in the binder for study summary)   Priority: Level 1 Basis: This is the only nationally representative survey that is designed to measure the KAB’s and the level of concern regarding AVA. This study will yield the most valid estimate of acceptability of AVA among military personnel. A contract has been established with RTI and the draft protocol has been submitted for regulatory approval. Study 5. Survey of Civilian and Military Healthcare Providers regarding the Anthrax Vaccine and the Reporting of Possible Vaccine-Associated Adverse Events (See Section 10 in the binder for study summary)   Priority: Level 1 Basis: This is the only nationally representative survey to obtain data on the knowledge and awareness of VAERS, and the attitudes and practices of both military and civilian healthcare providers regarding the reporting of adverse events following AVA immunization. A contract has been established with RTI and a draft protocol is being developed. Study 6. Study Protocol of Long-term Adverse Effects from Anthrax Vaccination Among Civilian Workers (See Section 11 in the binder for study summary)   Priority: Level 1 Basis: This will be the first long-term (>10 years) health effects study of a nonmilitary population previously vaccinated with AVA. An interagency agreement with the Social Security Administration has been established and a draft protocol has been completed and internally reviewed. Study 7. The VHC Platform for AVA Related Research (See Section 12b in the binder for study summary)   a. Effects of Route of Administration on the Occurrence of Local Adverse Events Following Immunization with AVA   b. Effects of Hormonal Phase in the Female Population on the Occurrence of Adverse Events Following Immunization with AVA

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  c. Comparative Evaluation of the Effect of AVA on Health Related Quality of Life   Priority: Level 1 Basis: The research questions being addressed in this series of VHC proposed studies are of primary importance and mandated in the congressional language. A draft protocol has been completed and is being reviewed by DoD for their comment and support. The lead and first regional VHC held their open house on Sept. 6, 2001. Study 8. Enhanced Signal Detection and Hypothesis Testing for Adverse Events Following Anthrax Vaccination & MOU Between AVSA/NIP and AMSA/DoD (See Section 13 in the binder for study summary)   Priority: Level 1 Basis: In 2000, CDC received congressional funding to perform studies to evaluate and enhance the safety and efficacy of anthrax vaccination. A key part of this program is to improve surveillance to detect adverse events and to investigate those events for association with vaccination. Collaboration with AMSA, and the use of DMSS for hypothesis testing studies is an important component in a system that will allow detection and evaluation of AVA AEs, fulfilling the congressional mandate to CDC. An MOU has been drafted and has been submitted for DoD review, comment and approval. Study 9. Proposed Evaluation of the Anthrax Vaccine and Antibiotics Availability Program (Draft protocol available on request)   Priority: Level 2 Basis: In recent years, there has been increasing public concern about vaccine safety. Subsequently, there is a growing need to better understand information needs and public perceptions of vaccine risks and benefits in order to improve vaccine risk communication efforts. The availability of AVA to persons of varying races and socioeconomic backgrounds who were exposed to inhalation anthrax will allow us to gain insight into vaccination decision-making in a context in which disease and vaccination risks are uncertain and strong recommendations by government agencies are absent. Information gained through this study will help guide future educational efforts associated with vaccination programs and to frame educational materials. A draft protocol has been completed. Study 10. Proposed Pediatric Study – Evaluation of Post-exposure Regimens, Using a Dose Escalation Approach (Protocol to be developed depending on availability of funding.)   Priority: Level 1

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  Basis: The importance of this proposed study is demonstrated by the recent anthrax terrorist events. AVA is currently licensed only for use in adults. The results of this proposed evaluation would enable modified use for children in a post-exposure setting. Study 11. Possible Role of Aluminum Hydroxide Adjuvant in AVA-Associated Adverse Events, Potential Areas for Future Research (See Section 14 in the binder for proposed study summary)   Priority: Level 2 Basis: AVA contains greater amounts of aluminum hydroxide adjuvant than other vaccines. There are no human studies that evaluate the clearance of aluminum hydroxide adjuvant from the site of injection. This adjuvant may have a role in the development of local adverse events. This study is currently in development. IV.Objectives The CDC Anthrax Vaccine Safety & Efficacy Research Plan focuses on three main objectives: 1.Efficacy Rationale: Because AVA’s efficacy in providing protection against inhalational anthrax cannot be ethically evaluated in human subjects, the efficacy studies will involve concurrent trials in humans and non-human primates. The animal studies will include a dose-ranging study whose aim is to induce a graded series of humoral and cell-mediated immune responses in animals vaccinated with different dilutions of AVA, using 3 priming shots of each dilution in each trial group. Immune responses will be compared in vaccinated animals that survive or succumb to infection upon challenge with live, inhaled anthrax spores. The goal is to identify one or more immunological markers of protection in the non-human primates that can be measured in AVA-vaccinated humans and to use these data to support a labeling change for AVA. Regulatory considerations: The efficacy data, along with safety data, will be used to support an application to FDA to change the labeling of AVA to allow administration by intramuscular injection and a reduction in the number of priming shots. According to a rule proposed by FDA on October 5, 1999,13 it is permissible to substitute animal data along with human safety and immunogenicity data in situations in which efficacy studies in humans are not ethically permissible. 13   Federal Register 64:53960-70, 1999. Evidence needed to demonstrate efficacy of new drugs for use against lethal or permanently disabling toxic substances when efficacy studies in humans ethically cannot be conducted. URL: http://www.fda.gov/cber/rules.htm

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Summary of Objectives for Efficacy Human clinical trials: Assess AVA efficacy in humans immunized with AVA [Study 1], by measuring immune responses identified as protective in efficacy objective B. Immune markers of protection will be evaluated under these conditions: When the number of priming shots is 3, 4, 5, or 6 and the vaccine is administered by intramuscular injection, and with boosters at varying intervals; and When the number of priming shots is 6 and the vaccine is administered by subcutaneous injection with an annual booster (standard conditions) Non-human primate studies: Assess AVA efficacy in animals immunized with serial dilutions of AVA and challenged with live, inhaled anthrax spores [Studies 2 and 3] Use blood samples from the subjects in the clinical trial [Study 1] and in animal studies [Studies 2 and 3] to identify immune correlates of protection and validate laboratory assays to measure them [Study 4]. 2.Safety Rationale: In 1998, a program to vaccinate all U.S. active and reservist service personnel with AVA was initiated by Secretary of Defense William S. Cohen. The program has elicited some opposition among service personnel and allegations have been made regarding the health effects associated with the vaccine including high rates of local adverse events, and possible linkage with Gulf War Illness, Chronic Fatigue Syndrome, and reproductive toxicity. These concerns led the U.S. Congress to appropriate funds for a collaborative effort by the CDC, NIH, and DoD to study the safety and efficacy of vaccines used against B. anthracis. Under CDC’s mandate, evaluation of the potential link between AVA vaccination and adverse events (AEs) is of primary importance. CDC’s safety research agenda includes the following objectives: To investigate potential long-term sequelae of AVA. To gain a better understanding about the type, frequency, and gender differences of vaccine AEs associated with AVA. To evaluate the completeness and accuracy of reporting of AVA AEs in the military and to develop and implement interventions to improve AVA AE reporting and surveillance.

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reduce local AVA-associated AEs in persons who exhibit moderate to severe symptoms after the first or second priming dose. Conducting clinical evaluations and retrospective studies of individuals with rare AVA associated AEs. Identification methods for these individuals will occur through VHC Network and/or VAERS reports (including as a result of enhanced signal detection methods) [Study 8]. Testing hypotheses about possible AVA-associated AEs in large, linked database such as DMSS [Safety Objective D and Study 8]. Retrospective chart reviews by VHC personnel and others would be conducted as part of hypothesis testing. Evaluating types and rates of occurrence of AEs associated with AVA vaccination. Monitoring and comparing the types and rates of occurrence of AVA-associated AEs before and after any changes in route and dosing regimen that is approved by FDA (this will be a continued assessment of any changes in route and dosing schedule as a result of the human clinical trial) [Study 1]. Assessing possible differences in risk factors between men and women for AVA-associated AEs including the hormonal status of female vaccine recipients [Study 7b]. This is related to the study of differences in rates of AVA-associated AEs between men and women conducted in the AVA Clinical Trial [Study 1]. Evaluating the impact of AVA vaccination on quality of life in military personnel using the SF-36 Health Survey [Study 7c] and comparing to similar data from civilian personnel from the Clinical Trial [Study 1]. 3.Acceptability Rationale: Critics of the DoD’s mandatory program for AVA vaccination have alleged that underreporting of AVA associated AEs has occurred. There also have been some well-publicized instances of service personnel who refused the immunization, some on the basis of alleged severe adverse health effects. Through the AVIP, the DoD has 1) conducted an intensive review of currently available data on the efficacy and safety of AVA including the establishment of the AVEC to review all AVA-associated VAERS reports, and contracting with a Committee of the Institute of Medicine (IOM) to review safety and efficacy of the vaccine, 2) conducted additional surveys and epidemiologic studies of service personnel receiving AVA to identify potential severe adverse health effects, and 3) established specific educational interventions including a quadfold information brochure on AVA, a hotline, a website, and other training materials and development of an expert model to identify barriers to risk communication and further direct educational efforts. However, no nationally representative survey of service personnel has been

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conducted to gauge the nature and extent of their concerns about AVA and the extent of underreporting of AEs to VAERS. Summary of Objectives for Acceptability KAB surveys [Study 4], patient satisfaction survey, and other assessment tools will be developed and used to identify concerns about anthrax vaccination among military vaccine recipients. Research partners will include the DoD, the VHC Network, and the Research Triangle Institute (RTI). In collaboration with AVIP, VHC Network, and others, knowledge gained from the KAB surveys and the efficacy and safety studies will be used to: Develop, promote, and provide training that will optimize and standardize procedures and quality assurance practices for the administration of AVA. Develop strategies and training materials to help improve the acceptability of AVA and military immune readiness, in general. Train NIP Hotline and other CDC Hotline personnel to respond effectively to military and public questions and concerns about AVA. A repeat KAB survey and other assessment tools will be used after education and training interventions to measure changes in KABs and impact of interventions. V.Scientific Benefits The implementation of the CDC Anthrax Vaccine Safety & Efficacy Research Plan will have significant future benefits beyond the immediate ones of evaluating the safety, efficacy, and acceptability of AVA. For example, the identification of the immune correlates of protection against anthrax infection, as well as the standardization of relevant immunologic assays will speed the development, laboratory evaluation, and clinical testing of the next generation of anthrax vaccines. For example, U.S Army Research Institute for Infectious Diseases (USAMRIID) and NIH/NIAID, are working to produce a vaccine that uses purified PA expressed from a cloned copy of the PA gene (the recombinant PA [rPA] vaccine). These efforts will be greatly assisted by CDC testing of the blood samples taken from participants in the planned NIH Phase 1 safety study of an rPA vaccine, using the same assays as planned for the CDC correlates of protection studies. In light of recent terrorist events in New York City, Washington D.C., Florida and New Jersey, there has been a heightened awareness that CDC should play a major role in enhancing public health preparedness in the event of future attacks. Because of the clinical centers, data management, and laboratory infrastructure that has been developed to date, CDC is now in a position (using separate funding) to initiate studies to evaluate post-exposure AVA regimens in pediatric populations, alternative

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therapeutic strategies such as immune globulin and to vaccinate civilians at high risk for exposure to anthrax under an emergency Investigational New Drug (IND) application filed in October 2001. VI.Partnerships The human clinical trial of AVA efficacy and safety as well as complementary animal studies [Study 1] was designed in partnership with NIH, DoD, and FDA. Implementation of this trial and of the other components of the CDC Anthrax Vaccine Safety & Efficacy Research Plan will require ongoing collaboration and technical assistance from these agencies, as well as from other partners in the public and private sectors. National Institutes of Health: NIH’s National Institute of Allergy and Infectious Diseases (NIAID/NIH) will continue to provide expert consultation through the Interagency Scientific Working Group on Anthrax Vaccine Research, which will meet every three months by phone or in person to monitor the progress of these studies. In addition, NIAID/NIH scientists will: Supply rPA and lethal factor for use in developing and standardizing immunologic assays. Perform plasmapheresis at the NIH Clinical Center on anthrax vaccinees from USAMRIID who donate plasma for use in testing of immunologic response. Department of Defense: CDC will continue to partner with DoD and expand the VHC network, which will serve as a platform from which to conduct AVA safety and acceptability research among military personnel. DoD centers and divisions involved in the partnership thus far include: Walter Reed Army Medical Center (WRAMC), which will serve as the lead VHC site and first regional site. North Atlantic Medical Research Command (NAMRC). Walter Reed Army Institute of Research (WRAIR), which is one of the five sites participating in the clinical trial. Army Medical Surveillance Activity (AMSA), receives medical surveillance data (including data on AEs associated with vaccination) from each of the services and maintains it in the DMSS. USAMRIID, which will recruit anthrax vaccinees to donate plasma for use as a reference standard in developing assays that measure protective immune responses. USAMRIID and AVIP will also participate (along with NIH/NIAID) in the Interagency Working Group on Anthrax Vaccine Research.

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The Food and Drug Administration: CDC is working with FDA to improve the completeness and accuracy of reporting to VAERS (Safety Objective F), which is jointly administered by the two agencies. Input from FDA has been essential in developing research protocols (see Appendix A) to generate data that may help support an application to change the labeling of AVA that would allow administration by intramuscular injection and fewer doses in the vaccination regimen. Universities and medical centers: The human clinical trial is being performed in collaboration with scientists and physicians at Emory University School of Medicine, Baylor College of Medicine, Mayo Clinic and Foundation, Walter Reed Army Institute of Research and University of Alabama at Birmingham. Additionally, Emory University Vaccine Center will also conduct correlates of protection studies. Academic scientists also participate in: Expert panels that review CDC’s research protocols and the NIP’s research agenda for investigating the safety of AVA. The AVEC, a group of civilian physicians and epidemiologists convened by the Department of Health and Human Services at the request of DoD to review cases of AVA-associated AEs reported to VAERS. The “Brighton Collaboration” a web-based group of U.S. and international scientists whose goal is to develop standard case definitions for AEs. Private sector organizations: CDC’s nongovernmental collaborators include individuals from: The RTI, a non-profit contract research organization, that has been contracted to implement the two KAB surveys among military and civilian vaccine recipients (Acceptability Objective B). Battelle Memorial Institute, a non-profit organization that will conduct the non-human primate challenge studies and correlates of protection studies [Study 1]. The Medical Outcomes Trust, a non-profit organization that developed and validated the SF-36 Health Survey, an assessment tool that measures health status and outcomes from the patient’s perspective (Safety Objective C). VII.Expert Review and Oversight Due to the scientific complexity of the issues involved in vaccine evaluation, as well as the increased need for transparency when addressing politically sensitive issues, CDC has arranged for oversight of all aspects of the AVA studies from recognized experts in vaccine research, medicine, microbiology, and statistics. Institute of Medicine: At CDC’s request, the IOM has established an expert scientific panel to meet on a periodic basis to review the completeness and appropriateness of the activities described in this plan.

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Expert Consultation Panels: To date, seven issue-specific scientific panels have been convened at CDC to review the various components of the CDC Anthrax Vaccine Safety & Efficacy Research Plan (See Appendix A for a list of panel members). They include: The Human Clinical Trial Data Safety Monitoring Board, which met in September, 2001, and which will meet on a quarterly basis throughout the clinical trial, to review all aspects of human clinical trial design, including Studies 1 through 3. The Laboratory Issues Panel, which met in September, 2001, to review the laboratory assays in Studies 1 through 3, and which will meet on a semi-annual basis to confirm that the assays are adequate for identifying and measuring immunologic markers of immune protection in animals and humans. The Statistics Panel, which met in October, 2001, and which will meet on a semi-annual basis to consider how to perform multiple imputations of the clinical trial data set to properly account for missing data from non-compliance or loss to follow-up, and to consider how the correlates of protection data (Study 3) might be pooled and analyzed to make inferences about how long protection lasts, when protection is achieved and whether a reduced number of priming shots will provide adequate protection in humans. The Nonhuman Studies Evaluation Panel, which met in October 2001, and which will meet on a semi-annual basis to consider whether Study 3 are adequately designed to help answer the question of whether AVA can protect humans from inhalational anthrax. The Ad hoc Panel for Review of the National Immunization Program’s Research Agenda for Investigating the Safety of AVA, which met in October, 2001, the panel was asked to offer comments on the overall focus and design of NIP’s AVA-related research agenda, and to offer recommendations on improvements and/or enhancements to the research agenda. The Ad hoc Panel for Review of the National Immunization Program’s KAB Survey Protocol, which met in December, 2001, to review the research protocol for the national survey of knowledge, attitudes and beliefs regarding the anthrax vaccine among military personnel and to offer recommendations on improvements and/or enhancements to the research protocol. The CDC Internal Panel to Review the Draft Protocol for a Long-term Follow up Study of Civilian Recipients of AVA, which met October, 2001, to review the draft research protocol for evaluating the mortality experience and current functional

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status of persons who were vaccinated with AVA more than 10 years ago. In addition to providing insights into the potential association of AVA with long-term AEs, the results of this study may suggest plausible areas for follow up research into the causal pathways of any long-term AEs that may be attributable to AVA. The panel made recommendations for improvements to the draft research protocol. The CDC External Panel to Review the Draft Protocol for a Long -term Follow up Study of Civilian Recipients of AVA is proposed for second quarter 2002. The members of the scientific panels are listed in Appendix A. They represent universities, medical centers, private companies, and other nongovernmental institutions. VIII.Anticipated Outcomes The comprehensive research plan detailed in this document should provide the following important outcomes: Optimization of the AVA vaccination schedule and route of administration to ensure efficacy while minimizing the occurrence of AEs. Identification of the immune correlates of protection against anthrax infection. Documentation of the efficacy of AVA in humans. Elucidation of the safety profile of AVA and identification of any long-term sequelae associated with AVA. Identification of risk factors for AEs among men and women. Adoption of optimized vaccination procedures and quality assurance practices. Improved acceptance of AVA among military personnel and civilians. Standardization of immunologic assays for use in developing and validating the next generation of anthrax vaccines. IX.Discontinued Previously Proposed Studies Meta-Analysis Study: Difficulties involved in combining information from different studies for the purpose of determining a single index of risk in a meta-analytic frame-work are well known. The problems of combining data from anthrax studies are even more challenging because of the following

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reasons: 1) the studies were conducted using different versions of vaccine over time, 2) the definitions of safety data elements were not necessarily uniform among different studies, 3) the method of data collection across different studies was not same, (passive versus active, self reported versus clinical observation and/or assessment), 4) the populations studied varied in risk of developing reactions and/or disease when exposed to anthrax antigen (factory workers versus DOD servicemen). Since it was not possible to combine data from published studies without substantially reducing the confidence that could be placed on the results from these analyses, CDC made the decision to discontinue the Meta-Analysis Study. X.Acknowledgements CDC acknowledges the contributions of Ms. Alexandra Levitt, as well as staff of the NCID Anthrax Vaccine Research Program (AVRP) and the NIP Anthrax Vaccine Safety Activity (AVSA) in the preparation of this document. Appendix A.Expert Consultation Panels Data Safety Monitoring Board Date: Sept 28, 2001 Charge: To review all aspects of human clinical trial design, including Studies 1 through 3. Panel Members: Stanley Plotkin, M.D. Aventis Pasteur William Schaffner, M.D. Vanderbilt University John Sever, M.D. National Childrens Medical Center Lisa Jackson, M.D., M.PH. University of Washington Larry Moulton, Ph.D. Johns Hopkins University Neal Halsey, M.D., Johns Hopkins University Robert Levine, M.D. Yale University

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Laboratory Issues Panel Date: September 24-25, 2001 Charge: To review the laboratory assays in Studies 1 through 3, and confirm that they are adequate for identifying and measuring immunologic markers of immune protection in humans and animals. Panel Members: Timothy Hirst, Ph.D. University of Bristol Steve McDougal, M.D., Ph.D. CDC Julie Westerink, M.D. Medical College of Ohio Stephen Hildreth, D. Ph. Wyeth-Lederle Vaccines Statistics Panel Date: October 1-2, 2001 Charge: to consider how to perform multiple imputations of the clinical trial data set to properly account for missing data from non-compliance or loss to follow-up, and to consider how the correlates of protection data (Study 3) might be pooled and analyzed to make inferences about how long protection lasts, when it is achieved and whether a reduced number of priming doses will provide adequate protection in humans. Panel Members: Steven Self, Ph.D. Scharp Organization Gregory Ridgeway, Ph.D. Rand Corporation Donald Rubin, Ph.D. Harvard University Nonhuman Studies Evaluation Panel Date: October 4-5, 2001 Charge: To consider whether the design of the nonhuman primate studies (Study 2 and 3) is adequate to determine whether AVA will protect humans from inhalational anthrax. Panel Members: Porter Anderson, Ph.D. University of Rochester Medical Center

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Dr. Scott Giebink, M.D. University of Minnesota The Ad hoc Panel for Review of the National Immunization Program’s Research Agenda for Investigating the Safety of AVA Date: October 19, 2001 Charge: To offer comments on the overall focus and design of NIP’s AVA-related research agenda, and to offer recommendations on improvements and/or enhancements to the current research agenda. Panel Members: Col. Denise Baken, Office of Health Affairs, Secretary of Defense Robert Chen, M.D., M.A., Chief, Vaccine Safety and Development Activity, ESD, NIP, CDC Dennis M. Dixon, Ph.D. Chief, Bacteriology and Mycology Branch, Division of Microbiology and Infectious Diseases, NIH/NIAID Lt. Col. John Grabenstein, Ph.D., R.Ph. Deputy Director, Anthrax Vaccine Immunization Program, Office of the Surgeon General, US Army Charles M. Helms, M.D., Ph.D. Professsor of Medicine, University of Iowa Hospital and Clinics Nina Marano, D.V.M., M.P.H. Coordinator, Anthrax Vaccine Research Program, Meningitis and Special Pathogens Branch, NCID, CDC Col. Bryan Martin, D.O. Deputy Chief, Department of Allergy and Immunology, Walter Reed Army Medical Center Lt. Col. Phillip Pittman, M.D., M.P.H. Senior Scientist, USAMRIID The CDC Internal Panel to Review the Draft Protocol for a Long-term Follow up Study of Civilian Recipients of AVA Date: October 4, 2001 Charge: To review the draft research protocol for evaluating the mortality experience and current functional status of persons who were vaccinated with AVA more than 10 years ago. In addition to

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providing insights into the potential association of AVA with long-term adverse effects, the results of this study may suggest plausible areas for follow up research into the causal pathways of any long-term adverse events that may be attributable to receipt of AVA. The panel also made recommendations for improvements and/or enhancements to the draft research protocol. Panel Members: Bill Thompson, Ph.D. Biostatistician, VSDA, ESD, NIP, CDC, Atlanta Colleen Boyle Acting Assoc for SPP NCBDDD Teresa M. Schnorr, Ph.D Assistant Chief, Industry Wide Studies Branch Div Surveillance, Hazard Evaluations, and Field Studies (DSHEFS) NIOSH, CDC, Cincinnati Matthew Zack, M.D. Medical Epidemiologist Health Care and Aging Studies Branch DACH, NCCDPHP, CDC Alison Mawle, M.D. Research Biologist NCID, OD, CDC, Atlanta Ralf Coates, Ph.D. Assoc Dir for Science NCCDPHP, CDC, Atlanta Drue Barrett, Ph.D., M.S., M.A. Medical Epidemiologist DEHHE,OD NCEH, CDC, Atlanta The Ad hoc Panel for Review of the National Immunization Program’s KAB Survey Protocol Date: December 4, 2001 Charge: To review the draft study protocol for the national survey of knowledge, attitudes and beliefs (KABs) regarding the anthrax vaccine among military personnel and to offer recommendations on improvements and/or enhancements. In particular recommendations concerning the soundness of study design, and strategies to ensure the methods proposed answer the aims of the KAB survey in each of

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the following areas: Does the study design appear feasible? Will the methods proposed answer the aims outlined for the KAB study? Are the sampling strategies adequate and effective? Is the longitudinal component well planned? Are the components of cognitive testing, social desirability, and psychometric analysis sound? Panel Members: Col. Gary D. Gackstetter, D.V.M., M.P.H., Ph.D. Assistant Professor and Deputy Director Uniformed Services University of the Health Sciences Donald Hedeker, Ph.D. Professor of Biostatistics, School of Public Health University of Illinois at Chicago Michael Puma, Ph.D. Principal Research Associate The Urban Institute, Washington DC Michael Schwerin, Ph.D. Navy Personnel Research Studies & Technology Dept Institute for Organizational Assessment, Millington TN Paul Levy, Sc.D. Professor of Biostatistics & Epidemiology School of Public Health University of Illinois at Chicago