Executive Summary

Anthrax is a potentially fatal disease caused by Bacillus anthracis, a bacterium that produces spores that are resistant to many environmental conditions and can persist in soils. It is primarily a disease of livestock, and humans have generally become infected through contact with infected animals or contaminated animal products. A vaccine against anthrax, Anthrax Vaccine Adsorbed (AVA),1 was licensed by the U.S. Food and Drug Administration in 1970. It is currently administered in a series of six subcutaneous doses over an 18-month period and requires annual booster doses.

The stability and availability of B. anthracis spores make them a feasible agent for biological warfare, and programs to produce anthrax-based bioweapons are known to exist. In 1998, the Department of Defense (DoD) began a program of mandatory immunization against anthrax for all military personnel. As the program proceeded, however, some military personnel and their families raised concerns about the safety and efficacy of AVA.

Acknowledging both the need to protect military personnel and the concerns about AVA, Congress directed the Centers for Disease Control and Prevention (CDC) to carry out a research program on the safety and efficacy of the anthrax vaccine. The congressional mandate in appropriations legislation for fiscal year 2000 specified that CDC was to address “(1) the risk factors for adverse events, including differences between men and women; (2) determining immunological correlates of protection and documenting vaccine efficacy; and (3) optimizing the vaccination schedule and routes of administration to assure efficacy while minimizing the number of doses required and the occurrence of adverse events.”2 The program has been funded at $18 million annually for fiscal years 2000, 2001, and 2002.3 In this report, the Institute of Medicine (IOM) Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program reviews the completeness and appropriateness of the research program developed by CDC.

The distribution of anthrax spores through the U.S. postal system in fall 2001 altered perspectives on the risks posed by anthrax and on the need for an anthrax vaccine. This change in context necessarily affected CDC and the committee, which had begun work in October 2000. For example, the domestic bioterrorist events stimulated vigorous government efforts to accelerate the development and licensure of a

1  

As of January 31, 2002, AVA is being manufactured under the name Biothrax.

2  

Conference Report 106-479 to Accompany an Act Making Consolidated Appropriations for the Fiscal Year Ending September 30, 2000, and for Other Purposes, Public Law No. 106-113 (1999).

3  

Conference Report 106-479 to Accompany an Act Making Consolidated Appropriations for the Fiscal Year Ending September 30, 2000, and for Other Purposes, P. L. No. 106-113 (1999); Conference Report 106-645 to Accompany an Act Making Appropriations for the Departments of Labor, Health and Human Services, and Education, and Related Agencies for the Fiscal Year Ending September 30, 2001, and for Other Purposes, P. L. No. 106-554 (2000).



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Executive Summary Anthrax is a potentially fatal disease caused by Bacillus anthracis, a bacterium that produces spores that are resistant to many environmental conditions and can persist in soils. It is primarily a disease of livestock, and humans have generally become infected through contact with infected animals or contaminated animal products. A vaccine against anthrax, Anthrax Vaccine Adsorbed (AVA),1 was licensed by the U.S. Food and Drug Administration in 1970. It is currently administered in a series of six subcutaneous doses over an 18-month period and requires annual booster doses. The stability and availability of B. anthracis spores make them a feasible agent for biological warfare, and programs to produce anthrax-based bioweapons are known to exist. In 1998, the Department of Defense (DoD) began a program of mandatory immunization against anthrax for all military personnel. As the program proceeded, however, some military personnel and their families raised concerns about the safety and efficacy of AVA. Acknowledging both the need to protect military personnel and the concerns about AVA, Congress directed the Centers for Disease Control and Prevention (CDC) to carry out a research program on the safety and efficacy of the anthrax vaccine. The congressional mandate in appropriations legislation for fiscal year 2000 specified that CDC was to address “(1) the risk factors for adverse events, including differences between men and women; (2) determining immunological correlates of protection and documenting vaccine efficacy; and (3) optimizing the vaccination schedule and routes of administration to assure efficacy while minimizing the number of doses required and the occurrence of adverse events.”2 The program has been funded at $18 million annually for fiscal years 2000, 2001, and 2002.3 In this report, the Institute of Medicine (IOM) Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program reviews the completeness and appropriateness of the research program developed by CDC. The distribution of anthrax spores through the U.S. postal system in fall 2001 altered perspectives on the risks posed by anthrax and on the need for an anthrax vaccine. This change in context necessarily affected CDC and the committee, which had begun work in October 2000. For example, the domestic bioterrorist events stimulated vigorous government efforts to accelerate the development and licensure of a 1   As of January 31, 2002, AVA is being manufactured under the name Biothrax. 2   Conference Report 106-479 to Accompany an Act Making Consolidated Appropriations for the Fiscal Year Ending September 30, 2000, and for Other Purposes, Public Law No. 106-113 (1999). 3   Conference Report 106-479 to Accompany an Act Making Consolidated Appropriations for the Fiscal Year Ending September 30, 2000, and for Other Purposes, P. L. No. 106-113 (1999); Conference Report 106-645 to Accompany an Act Making Appropriations for the Departments of Labor, Health and Human Services, and Education, and Related Agencies for the Fiscal Year Ending September 30, 2001, and for Other Purposes, P. L. No. 106-554 (2000).

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new anthrax vaccine, although it remains uncertain when a new vaccine will be available. In addition, some elements of the research program will be affected by DoD’s decision, announced in June 2002, to resume its anthrax vaccination program on a more limited basis than initially planned. Although beyond CDC’s control, some of these factors make the timeline for the CDC research more critical. The results of many of the planned studies will help guide the use of AVA, as well as provide information relevant for the development of a new anthrax vaccine. However, with the push for a new vaccine, some data on AVA could conceivably come too late to be useful. The committee strove to focus on the research questions that exist regardless of these circumstances. The committee also acknowledges that the bioterrorist events have put great demands upon CDC and hopes that this report will provide advice that will help optimize the usefulness of the research program. STUDY PROCESS In response to a request from CDC, IOM convened the Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program in fall 2000.4 The IOM committee members brought expertise in microbiology; infectious diseases; vaccine research, development, and evaluation; postmarketing surveillance of adverse events; regulatory and licensing procedures; epidemiology; biostatistics; survey research and design; immunology; differences in disease between men and women; and health surveillance (see Appendix A for biographical sketches of the committee members). The committee obtained information about CDC’s anthrax vaccine research program from written materials and oral presentations provided by CDC investigators. Military personnel and others with concerns about the safety or efficacy of AVA also made presentations and provided written materials. The committee issued an interim report in July 2001 (IOM, 2001). (See Appendix F for the interim findings and recommendations.) This final report is based primarily on the committee’s review of the materials provided by CDC in February 2002, supplemented by information gathered and discussed in the committee meetings. The materials provided in February 2002 describe the objectives and design of the proposed research studies and list critical research questions. (See Box ES-1 for a list of the proposed studies and Appendix C for a subset of the documents provided by CDC.) The committee made an overall assessment of the CDC research plan (Chapter 7) and reviewed the specific studies proposed by CDC in the three areas of efficacy, safety, and acceptability (Chapters 4, 5, and 6, respectively). The committee also noted additional research needs that became evident following the bioterrorist events of 2001 and expressed concerns about the leadership of the research program (Chapter 7). Key findings and recommendations appear below, and a complete listing appears in Boxes ES-2, ES-3, ES-4, and ES-5. OVERALL ASSESSMENT OF THE CDC RESEARCH PLAN CDC considered many of the findings and recommendations in the committee’s interim report in the further development of the studies comprising the anthrax vaccine safety and efficacy research program. After examining the components of the research program described in the February 2002 materials, the committee found the CDC response to the congressional mandate to be generally complete and appropriate. The clinical trial is appropriate and satisfactorily designed to address the congressionally mandated charge to optimize the vaccination schedule and the route of vaccine administration. The nonhuman primate (NHP) studies conducted in conjunction with the human clinical trial will largely address the challenge of determining immunologic correlates of protection (ICP) and documenting the efficacy of the vaccine. 4   The committee was not asked to evaluate the safety and efficacy of AVA. Another IOM committee asked to consider those issues found that AVA as currently administered should be effective against anthrax toxicity from all known strains of the bacterium, as well as from any potential bioengineered strains (IOM, 2002). AVA was also found to be reasonably safe, with reactions occurring soon after vaccination that are comparable to those observed with other vaccines regularly administered to adults. (See Appendix G for the findings and recommendations from that committee’s report.)

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BOX ES-1 Studies Proposed by CDC for the Anthrax Vaccine Safety and Efficacy Research Program Efficacy Anthrax Vaccine Adsorbed: Human Reactogenicity and Immunogenicity Trial to Address Change in Route of Administration and Dose Reduction Nonhuman Primate Vaccine Dose Ranging, Immunogenicity, and Challenge Trial Immune Correlates of Protection (ICP) Against Inhalational Anthrax Safety Anthrax Vaccine Adsorbed: Human Reactogenicity and Immunogenicity Trial to Address Change in Route of Administration and Dose Reduction Follow-up Study of Textile Mill Workers Vaccinated Against Anthrax Studies Based in the Vaccine Healthcare Center Network Effects of Change of Route of Administration on Local Adverse Events Following AVA Vaccination Effect of AVA Vaccination on Health-Related Quality of Life Effect of Hormonal Phase in the Female Population on the Occurrence of Adverse Events Following Immunization with AVA Enhanced Signal Detection and Hypothesis Testing for Adverse Events Following Anthrax Vaccination Possible Role of Aluminum Hydroxide Adjuvant in AVA-Associated Adverse Events Acceptability Survey of Knowledge, Attitudes, and Beliefs Regarding the Anthrax Vaccine Among Military Personnel Survey of Civilian and Military Health Care Providers Regarding the Anthrax Vaccine and the Reporting of Possible Vaccine-Associated Adverse Events The committee’s qualifications regarding the research plan arise from both the lack of passive protection studies in the determination of ICPs (discussed in Chapter 4 and reviewed briefly below) and potential constraints from small sample sizes in the investigation of differences between men and women in risk factors for adverse events that occur at the time of vaccination (described in Chapter 5 and recapitulated below). Although the research program lacks satisfactory plans for investigating possible adverse health effects that are rare or might become evident many years after vaccination, the committee has seen no evidence that such studies should be a high priority. These limitations do not alter the committee’s conclusion that the CDC research program as planned includes most of the studies needed to provide a strong and appropriate response to the congressional mandate. When considered in its entirety, however, the CDC anthrax vaccine research program also includes elements that the committee considers to be of lower priority and some that should not be carried out as planned. Findings: With respect to the tasks specifically outlined in the congressional mandate, CDC’s research response is generally complete and appropriate. When considered as a whole, however, the research program has elements that are of low priority and other elements that are inappropriate and should not be carried out as planned.

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PROPOSED STUDIES ON THE EFFICACY OF THE ANTHRAX VACCINE Anthrax Vaccine Adsorbed: Human Reactogenicity and Immunogenicity Trial to Address Change in Route of Administration and Dose Reduction (Human Clinical Trial) CDC is conducting a human clinical trial with 1,560 healthy civilian volunteers to compare the immunogenicity of subcutaneous (SQ) and intramuscular (IM) administration of AVA, and the immunogenicity of the licensed schedule of six SQ doses and annual boosters with regimens that use fewer doses administered IM. The committee found that the study, as described in the protocol, provides an appropriate basis for these intended comparisons, which will help optimize the administration of AVA. In conjunction with the NHP challenge studies, this study should also provide information on the kinetics of the antibody response, which is valuable for the development and licensure of new anthrax vaccines. These research needs were emphasized in another IOM report on AVA (IOM, 2002), and their importance has increased as a result of the bioterrorist incidents in fall 2001. Finding: As described in the study protocol, the human clinical trial is generally responsive to the congressional mandate and to important research needs for determining immunologic correlates of protection, documenting the immunogenicity of AVA, and optimizing the vaccination schedule and routes of administration of AVA. Nonhuman Primate Vaccine Dose Ranging, Immunogenicity, and Challenge Trial This study will test the efficacy of AVA in protecting NHPs (i.e., rhesus macaques) when they are exposed to aerosolized doses of anthrax spores. It is an appropriate and crucial aspect of the congressionally mandated research to document the efficacy of AVA and to determine immune correlates of protection. Because challenging humans with lethal agents such as B. anthracis is not ethical, animal experiments are necessary, and the rhesus macaque is an appropriate model for such studies (IOM, 2002). The current approach to the NHP study promises to meet the need for additional information about protective levels of antibody or other immune factors. Such information can be useful not only in optimizing the schedule of doses for AVA, but also in evaluating the efficacy of new anthrax vaccines under development. Finding: The committee finds that the nonhuman primate studies that have been proposed as a means to provide information about the efficacy of AVA are well designed and responsive to the congressional mandate and to important research needs. The information gathered will inform and influence the development and licensure of new protective antigen-based anthrax vaccines. The research protocols and other materials submitted to the committee for review do not, however, describe plans for passive protection studies. Passive protection studies are experiments in which serum from immunized animals or humans (i.e., immunoglobulin) is administered to naïve animals, who are then challenged (by exposure to anthrax spores in studies of AVA) to evaluate the level of protection provided by the circulating antibody in the immunized animal or human. The committee considers passive protection studies to be an essential component of a research program on AVA (see Chapter 4). Recommendation: CDC should conduct passive protection studies as part of its anthrax vaccine safety and efficacy research program. The bioterrorist incidents in fall 2001 made clear the need for additional information about the protection afforded by AVA against exposure to different amounts of B. anthracis spores. The committee urges CDC to help address this research gap. The recommended passive protection studies will help determine an optimal level of antibody or other component of immunity to achieve protection against a

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given dose of spores. Once a protective level of antibody (or other correlate of protection) has been established, the effect of varying the size of the challenge dose should be evaluated. Recommendation: CDC should support or conduct research on the effect of the size of the challenge dose on immunity provided by vaccination with AVA. Immune Correlates of Protection Against Inhalational Anthrax Studies While qualitative correlations between survival and the presence of antibodies to protective antigen (PA)—a protein produced by B. anthracis and the principal immunogen in AVA—have been established in animal models, quantitative correlations remain to be determined. In general, the committee found that the planned ICP studies should provide the additional information needed to make these quantitative correlations. This information can be useful for better understanding AVA’s mechanism of protection and also for licensing newer PA-based vaccines that are under development. However, CDC’s many goals for the ICP studies varied widely in scientific value. Quantifying and characterizing the humoral responses to PA and other anthrax antigens are important and necessary goals, but the committee considers it unlikely that the analyses in support of CDC’s other goals will provide important new insights regarding the mechanism by which AVA protects against anthrax infection. The committee also had concerns about the plans to carry out multiple lymph node biopsies, bone marrow biopsies, and bronchoalveolar lavage on a subset of rhesus macaques included in the NHP studies. Researchers hope to use those samples for tests to correlate immune responses occurring in tissues or organs of the macaques with the animals’ peripheral blood mononuclear cells. According to the protocol, the analysis may provide new guidelines for the minimum number of vaccinations necessary to generate long-term humoral immunity to anthrax. The committee questions the extent to which these studies can contribute to addressing this research question. In addition, the procedures do not appear to be adequately justified or even likely to be useful, since the frequent administration of anesthesia and the repeated biopsies may alter the responses of interest. The proposed research is descriptive, rather than hypothesis-driven, and should be a low priority. Recommendation: On the basis of the information provided to the committee for evaluation, the committee recommends that the NHP studies requiring multiple samplings from biopsies of lymph nodes and bone marrow and from bronchoalveolar lavage should not be continued in their current form. If such studies can be adequately justified, they should be modified to require fewer invasive procedures. Finding: With the exception of the biopsy and bronchoalveolar lavage studies noted above, the committee finds that the ICP studies that have been proposed as a means to provide information about the efficacy and immunogenicity of AVA are responsive to the congressional mandate and to important research needs. The information gathered will inform and influence the development and licensure of new PA-based anthrax vaccines. PROPOSED STUDIES ON THE SAFETY OF THE ANTHRAX VACCINE Human Clinical Trial The committee concluded that the human clinical trial should provide helpful information about the risk factors for common adverse reactions that occur soon after vaccination, including differences in reaction rates related to SQ versus IM administration of AVA. It should also be possible to examine differences between men and women in the occurrence of immediate-onset adverse events and to compare those results with findings from other studies (CDC, 2000; Hoffman et al., submitted for publication; Pittman et al., 2002). However, additional studies beyond those described by CDC would be needed to better understand the reasons for any differences between men and women in the occurrence of adverse

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events. The committee cautions that if used by itself, the SF-36 health status survey is unlikely to be a satisfactory tool for the proposed evaluation of changes in health-related quality of life associated with AVA vaccination. Finding: As described in the study protocol, the human clinical trial is generally responsive to the congressional mandate to evaluate the incidence of, risk factors for, and differences between men and women in local and systemic immediate-onset health effects associated with AVA and the effect of the route of vaccine administration on adverse events. The study will also provide a 42-month follow-up period during which to monitor the occurrence of later-onset health effects.5 Follow-up Study of Textile Mill Workers Vaccinated Against Anthrax The committee recommends against the retrospective cohort study intended to investigate potential chronic health effects or later-onset adverse events following anthrax vaccination. As proposed, the study of former textile mill workers is highly unlikely to be able to detect important later-onset health effects of anthrax vaccination that might exist and would carry the risk of producing spurious positive or negative associations. The study faces these problems because of the difficulty in finding truly comparable control groups and because of the relatively small size of the study population and the large number of variables in the planned analyses. Conducting the study poses the risk of generating unwarranted health concerns among the participants, without scientific benefit. Recommendation: CDC should not continue work on the proposed follow-up study of textile mill workers who received AVA. Studies Based in the Vaccine Healthcare Center Network The Vaccine Healthcare Center (VHC) Network is a collaboration between DoD and CDC to address issues of safety and acceptability of all types of vaccines administered within the military health care system. The VHC network is expected to serve as a base for research on AVA and other vaccines administered to military personnel. The committee reviewed draft proposals for studies of (1) the effect of route of AVA administration on the occurrence of adverse events soon after vaccination; (2) the effect of AVA on health-related quality of life; and (3) the effect of women’s hormonal phase on the occurrence of adverse events. The first of these proposed studies could provide useful postmarketing-type data to confirm the rates of adverse events observed in the human clinical trial, if the study population is comparable in size to that of the clinical trial. The study, however, is not suitable for monitoring a large study population (10,000 subjects) to detect the occurrence of less common, medically significant conditions that may not be seen during a clinical trial. Recommendation: A VHC-based study to verify reaction rates to AVA and the validity of self-reported data observed in the clinical trial should provide for intensive active surveillance of relatively small cohorts, similar in size to the study groups in the human clinical trial. Because of questions about its feasibility, the committee recommends against the second VHC study, designed to compare the effect of SQ versus IM administration of AVA on health-related quality of life using the SF-36 health survey. This study is likely to face the following difficulties: distinguishing differences between generally healthy populations with the SF-36, following study participants who have been 5   The committee has adopted the terminology used by the Committee to Assess the Safety and Efficacy of the Anthrax Vaccine (IOM, 2002). The phrases “short term” and “long term” were not used to characterize adverse events because of the potential for confusion. Instead, the duration of an adverse event is characterized as acute or chronic; the timing of the onset of an adverse event is characterized as immediate or later.

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deployed, and distinguishing any effects on health status related to receiving AVA from those related to deployment or to receiving other medications and vaccines in preparation for deployment. The proposed study about the effect of women’s hormonal phase on the occurrence of adverse events is likely to prove more complex than is suggested by the proposal because of the many potentially confounding factors (e.g., age, race, parity, and contraceptive use). The committee considers the study a low priority. The committee concluded that the complexities evident in the three draft proposals for VHC-based research studies indicate the need for regular consultation with a standing panel of outside scientific experts for guidance on matters ranging from study design to data analysis for all VHC-based research activities. Recommendation: An external scientific advisory group should be constituted to provide guidance to CDC and DoD on all research undertaken through the VHC network. Given the draft study proposals reviewed by the committee, the advisory group should include, among others, experts in biostatistics (propensity analysis), health care outcomes assessment, pharmacoepidemiology (postmarketing surveillance), and clinical epidemiology (medically unexplained symptoms). Enhanced Signal Detection and Hypothesis Testing for Adverse Events Following Anthrax Vaccination The committee is pleased to see that CDC has begun to give attention to the Defense Medical Surveillance System (DMSS)—a set of DoD-wide health-related databases covering military personnel on active duty—as a resource for generating and testing hypotheses concerning adverse events that might be associated with receipt of AVA. In particular, data from DMSS should be used to follow up hypotheses concerning AVA that have already been generated. To allow for analysis of health effects of AVA that might arise beyond the period of active duty, CDC should investigate ways to use DMSS data in conjunction with morbidity and mortality data from ongoing military cohort studies, such as the Millennium Cohort Study,6 and from the health system of the Department of Veterans Affairs. The committee is concerned, however, about the proposed use of data mining to screen data from the Vaccine Adverse Event Reporting System (VAERS), a spontaneous reporting system that is inherently incomplete and subject to often-unknown reporting biases. Such techniques must first be thoroughly evaluated in other, more complete data sets—possibly DMSS—and shown to be effective even in the face of the kinds of biases inherent in the VAERS data. The availability of data on health outcomes following exposure to AVA in both DMSS and VAERS may provide an opportunity to use associations identified in DMSS in efforts to validate the use of data mining in VAERS. Recommendation: Hypothesis generation using data mining and other statistical techniques for screening data should be tested and validated in DMSS or other structured data sets before being considered for use with VAERS. Only if these techniques can be validated with a structured data set and then with VAERS data should they be used to generate hypotheses from VAERS concerning adverse events and AVA. Despite indications of greater collaboration between CDC and DoD on the analysis of DMSS data, the committee is concerned that as of February 2002, these studies were still not receiving the appropriate attention, priority, and funding. The committee also sees a need for an overall plan to guide the hypothesis-generation and hypothesis-testing activities, with staff designated to provide overall management and an external panel to provide periodic advice on analyses. 6   The Millennium Cohort Study will monitor a total of 140,000 U.S. military personnel during and after their military service for up to 21 years to evaluate the health risks of military deployment, military occupations, and general military service (see http://www.millenniumcohort.org/about.html).

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Recommendation: Adequate resources (substantially more than can currently be identified from the CDC–DoD Memorandum of Understanding) should be made available to support the use of DMSS data for testing hypotheses regarding health effects related to AVA or other vaccine exposures. Possible Role of Aluminum Hydroxide Adjuvant in AVA-Associated Adverse Events The committee concluded that studying the possible role of aluminum hydroxide in adverse events would be difficult and is not of sufficient priority to pursue as part of the CDC anthrax vaccine research program. PROPOSED STUDIES ON THE ACCEPTABILITY OF THE ANTHRAX VACCINE Investigation of the acceptability of the anthrax vaccine was not directly specified in the congressional mandate to CDC, but acceptability issues are potentially important in the overall success of any vaccination program. The committee found the planned survey of knowledge, attitudes, and beliefs (KABs) regarding the anthrax vaccine among 17,000 members of the military to be unnecessary in its proposed form. However, information about attitudes in groups that are likely to be immunized can help guide the development of educational interventions intended to address concerns about the anthrax vaccine. Thus, the committee recommended against exhaustively detailing the level of concern among various segments of the military population. Instead, relevant information could be gathered using focus groups and smaller surveys and then applied to the development, refinement, and evaluation of educational interventions. Recommendation: In view of the study timeline and research needs, CDC should modify the design of the KAB study of military personnel to focus on more timely development of educational interventions and the evaluation of their impact on the acceptability of AVA and a broader range of vaccines, including a new anthrax vaccine. The committee also felt that the separate survey of health care providers could be of greater value if the focus was broadened from providers’ KABs about VAERS and AVA to their KABs about immunization and adverse events more generally. The committee advises including not only health care providers who administer vaccines, but also those who might see patients with concerns about adverse events. Thus, while the study as proposed is considered of low priority, it could make a more important contribution to the research effort if it were modified. Recommendation: In addition to gathering information on KABs about VAERS and the current anthrax vaccine, CDC should modify the survey of health care providers to study KABs about a new anthrax vaccine, other military vaccines, and vaccines in general, with a focus on information useful for timely development and testing of appropriate educational materials. The study population should include health care providers who may treat service members with adverse events following vaccination, as well as those who administer vaccines. RESEARCH GAPS The gaps in the CDC research program that were noted in the preceding discussion of the individual research studies are summarized in Table ES-1.

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TABLE ES-1 Additional Research Needs Concerning the Safety and Efficacy of the Anthrax Vaccine, Identified and Prioritized by the Committee Committee Priority Additional Research Needs Identified by the Committee High Passive protection studies in nonhuman primates (Chapter 4, p. 51)   Studies of the effect of the size of the challenge dose on protection (Chapter 4, p. 51) Linkage of the Defense Medical Surveillance System and other databases for longer-term follow-up of military personnel who received AVA (Chapter 5, p. 77) Medium Focused, small-scale surveys of knowledge, attitudes, and beliefs regarding the anthrax vaccine among military personnel to guide the design of information programs (Chapter 6, p. 87)   Survey of civilian and military health care providers regarding vaccination and the reporting of possible vaccine-associated adverse events (modification of a study proposed by CDC, Chapter 6, p. 89) BIOTERRORISM AND RESEARCH NEEDS CDC’s research program was mandated by Congress in 1999 and initiated before the distribution of anthrax spores in fall 2001 resulted in five deaths from inhalational anthrax and the possible exposure of more than 30,000 people to the risk of infection (CDC, 2001a,b). The nation’s experience of civilian bioterrorism confirmed the urgency of the research that CDC has already planned, and it also showed the need for studies related to the possible use of anthrax vaccine following exposure to anthrax spores and its use in the civilian population. With some additions to its research portfolio, CDC could help respond to these other research needs. In particular, the CDC research plan could benefit from the addition of studies using animal models to investigate the immunogenicity of AVA (or another anthrax vaccine) when it is administered following, rather than before, exposure to anthrax spores. Because it is not ethical to expose humans to anthrax spores for research purposes, studies of postexposure use of the anthrax vaccine must be conducted in animals. Only two such studies have been carried out in nonhuman primates. This research is also needed to establish the appropriate duration of antibiotic prophylaxis after vaccine administration (IOM, 2002). Recommendation: As part of its research plan, CDC should support studies in laboratory animals to establish an appropriate duration for antibiotic prophylaxis when administered with AVA followingB. anthracisspore challenge. The committee also notes that there is little information concerning the immunogenicity or adverse event profile for AVA when administered to children, the elderly, or persons with chronic illnesses. Current knowledge of the vaccine’s potential adverse health effects is derived from its use by a healthy adult population. While recognizing the challenges involved in conducting studies in vulnerable populations, the committee is persuaded that efforts to study the use of AVA in children, the elderly, and persons with chronic illnesses should be a high priority once the findings from the human clinical trial have established the optimal route (SQ versus IM) and number of AVA doses for young and middle-aged adults. The planning for future studies in vulnerable populations should be flexible enough to respond to changing circumstances, including the possible availability of a newer anthrax vaccine. Recommendation: Studies of the use of AVA (and any future anthrax vaccine) by children, the elderly, or persons with chronic illnesses should have a high priority once the findings from the clinical trial have established the optimal route and number of vaccine doses in

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young and middle-aged adults. The possible availability of newer-generation anthrax vaccines should be taken into account in planning these future studies in vulnerable populations. Although the congressional mandate might seem to confine CDC to studies of pre-exposure use of the current anthrax vaccine, the committee urges CDC to interpret the congressional mandate broadly in order to improve preparedness for the possibility of future bioterrorist events involving anthrax. The research program must be flexible enough to respond to changing circumstances by using both intramural and extramural resources, and to draw fully upon the expertise in vaccine development and testing available within NIH and DoD. A NEED FOR A SINGLE PROGRAM LEADER From its review, the committee sees evidence of a need for strong internal overall leadership of the CDC anthrax vaccine research plan to provide management and oversight. Although the research plan responds well to the specific elements of the congressional mandate, it currently includes studies that the committee concluded should have a low priority or should not be conducted, and it omits studies that the committee considers important. In the absence of authoritative centralized senior leadership, individual projects within programs can sometimes gain a momentum of their own and become difficult to modify or stop, even if they are no longer appropriate. Given the size of the task and the nature of the work, it is appropriate that the anthrax vaccine research program receive high-level attention and direction from the leadership at CDC. However, it does not appear that it has. Despite hard work from the two units involved in developing and improving the proposals and protocols for the individual studies that make up the research program, the research program still appears to lack a comprehensive plan to guide its continued overall development. The committee found two groups of studies being planned and carried out by two separate organizational units within CDC but drawing on a single ongoing source of funds. The committee is persuaded that effective coordination of the anthrax vaccine research program requires management by a single senior CDC biomedical scientist who has responsibility for the overall program. In addition to setting priorities and guiding strategic planning for the research program, a clearly defined leader can facilitate appropriate responses to changing circumstances and new opportunities that may arise. Recommendation: CDC should establish clearly defined senior leadership for the anthrax vaccine research program to articulate precise objectives for the research plan and to provide authority and accountability in the management of a coherent research plan. A single senior biomedical scientist should be given management authority for the entire program. A research program of this size and visibility can also benefit from ongoing guidance from a group of external scientific advisors who can assist in planning and setting priorities. This IOM committee has provided input for planning and prioritizing studies in the research plan, but it cannot continue in this role and moreover is not well suited to providing ongoing real-time advice. Although CDC responded to the committee’s prior recommendation to convene scientific advisory panels for individual studies, there is no indication that CDC will have a future source of external advice to the research program as a whole. The overall program should be overseen by an external advisory committee that will provide scientific recommendations to the program leadership on terminating studies or redirecting program resources. Recognizing that the administrative and procedural requirements related to such groups can be burdensome and time-consuming, the committee encourages CDC to seek the most efficient means of gaining access to ongoing expert scientific guidance. Recommendation: As soon as possible, CDC should convene an external advisory group for the overall anthrax vaccine research plan and its progress. This group should have an advisory role regarding the continuation or termination of studies that are under way, the initiation of new studies, and the direction of the entire program.

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Boxes ES-2, ES-3, ES-4, and ES-5 provide a complete listing of the findings and recommendations from this report. Subsequent chapters provide background for these findings and recommendations. BOX ES-2 CHAPTER 4 FINDINGS AND RECOMMENDATIONS Finding: As described in the study protocol, the human clinical trial is generally responsive to the congressional mandate and to important research needs for determining immunologic correlates of protection, documenting the immunogenicity of AVA, and optimizing the vaccination schedule and routes of administration of AVA. Finding: The HLA substudy experiments as described are not critical to resolving the concerns regarding the safety and efficacy of AVA. As part of the CDC anthrax vaccine safety and efficacy research program, the studies should be considered of low priority. Recommendation: CDC should consult with FDA and receive their approval regarding the type of analysis (according to protocol, intent to treat, or other) that will provide appropriate support for a change in the labeling of AVA regarding the route of administration and the number of doses required. Finding: The committee finds that the nonhuman primate studies that have been proposed as a means to provide information about the efficacy of AVA are well designed and responsive to the congressional mandate and to important research needs. The information gathered will inform and influence the development and licensure of new protective antigen-based anthrax vaccines. Recommendation: Careful characterization of the vaccine lots used in the clinical trial and nonhuman primate studies is crucial. Protocols for this work should undergo review by the expert consultative panel convened for laboratory issues. Recommendation: CDC should consult with the Statistics Panel for expert guidance on analyses of data from the nonhuman primate studies, including devising appropriate methods for handling missing data. Finding: Passive protection studies are important for improving understanding of the mechanism(s) of the efficacy of AVA and can help to address practical issues related to the management of anthrax disease. Recommendation: CDC should conduct passive protection studies as part of its anthrax vaccine safety and efficacy research program. Finding: Research is needed to understand better the effect of the size of the challenge dose on the protection afforded by AVA. Recommendation: CDC should support or conduct research on the effect of the size of the challenge dose on immunity provided by vaccination with AVA. Finding: The committee strongly supports the use of validated assays that can be standardized across the field of anthrax vaccine research. CDC’s development and validation of such assays will provide an important contribution in this regard. Recommendation: CDC should give high priority to standardization of assays that can be used across laboratories conducting research with anthrax vaccine. Finding: The biopsies of lymph nodes and bone marrow and the bronchoalveolar lavage planned as part of the Immune Correlates of Protection Study require multiple invasive procedures that do not appear to be adequately justified.

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Recommendation: On the basis of the information provided to the committee for evaluation, the committee recommends that the NHP studies requiring multiple samplings from biopsies of lymph nodes and bone marrow and from bronchoalveolar lavage should not be continued in their current form. If such studies can be adequately justified, they should be modified to require fewer invasive procedures. Finding: With the exception of the biopsy and bronchoalveolar lavage studies noted above, the committee finds that the ICP studies that have been proposed as a means to provide information about the efficacy and immunogenicity of AVA are responsive to the congressional mandate and to important research needs. The information gathered will inform and influence the development and licensure of new PA-based anthrax vaccines. BOX ES-3 CHAPTER 5 FINDINGS AND RECOMMENDATIONS Finding: As described in the study protocol, the human clinical trial is generally responsive to the congressional mandate to evaluate the incidence of, risk factors for, and differences between men and women in local and systemic immediate-onset health effects associated with AVA and the effect of the route of vaccine administration on adverse events. The study will also provide a 42-month follow-up period during which to monitor the occurrence of later-onset health effects. Recommendation: The analyses of reactogenicity in CDC’s human clinical trial of AVA should use two-sided statistical tests. Finding: The committee concludes that the preliminary exploration of a study of possible chronic or later-onset adverse events related to anthrax vaccination among goat-hair textile mill workers, with community and occupational comparison cohorts, was appropriate. That effort, however, has produced sufficient information to indicate that the study (1) poses the risk of generating spurious associations or masking real associations, in part because of the difficulty of identifying suitable comparison groups, and (2) would not have sufficient statistical power to detect conditions of interest. Furthermore, with these limitations, conducting the study poses the risk of generating unwarranted health concerns among the participants. Recommendation: CDC should not continue work on the proposed follow-up study of textile mill workers who received AVA. Finding: Postmarketing-type cohort studies of anthrax vaccine use are appropriate for two purposes: to confirm in a population not participating in a clinical trial the findings from the clinical trial regarding rates of adverse events commonly associated with receipt of AVA, differences between subcutaneous and intramuscular administration in rates of adverse events, and risk factors for adverse events, and to detect rare but medically significant adverse events that will be found only by observing a larger population over a longer period of time than is possible in the human clinical trial. Recommendation: A VHC-based study to verify reaction rates to AVA and the validity of self-reported data observed in the clinical trial should provide for intensive active surveillance of relatively small cohorts, similar in size to the study groups for the human clinical trial. Finding: Because of the anticipated labeling change that will specify intramuscular administration of AVA, a VHC-based study of adverse events must be initiated promptly if it is to follow a cohort of military personnel who receive AVA subcutaneously.

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Finding: A large cohort study intended to detect the occurrence of less common, medically significant adverse events following receipt of AVA would require the inclusion of a control group that has not received AVA and that is comparable in initial health status to the vaccinated cohorts. Because vaccination is related to deployment and deployment is related to health status, it would be challenging to assemble a suitable control group. Finding: The SF-36 is designed to detect large changes in health status. It is not suitable for distinguishing differences in health-related quality of life among basically healthy people such as the military personnel who will receive AVA. Furthermore, in the proposed study population, the confounding effects of exposure to other vaccines and particularly of the experience of deployment are likely to make it difficult to discern any unique effect associated with the receipt of AVA. Recommendation: CDC should not conduct the proposed VHC-based study of the effect of AVA vaccination on health-related quality of life. Finding: The VHC-based study of the effect of women’s hormonal phase on the occurrence of adverse events following receipt of AVA, would be addressing a complex subject with many potentially confounding factors (e.g., age, race, parity). Recommendation: As currently described, the VHC-based study of the relationship between women’s hormonal phase and the occurrence of adverse events following receipt of AVA should have a low priority in the CDC research program. Recommendation: An external scientific advisory group should be constituted to provide guidance to CDC and DoD on all research undertaken through the VHC network. Given the draft study proposals reviewed by the committee, the advisory group should include, among others, experts in biostatistics (propensity analysis), health care outcomes assessment, pharmacoepidemiology (postmarketing surveillance), and clinical epidemiology (medically unexplained symptoms). Finding: The application of data mining and other statistical analysis techniques to screen data from VAERS and from DMSS data sets is still experimental. Recommendation: Hypothesis generation using data mining and other statistical techniques for screening data should be tested and validated in DMSS or other structured data sets before being considered for use with VAERS. Only if these techniques can be validated with a structured data set and then with VAERS data should they be used to generate hypotheses from VAERS concerning adverse events and AVA. Finding: DMSS is a uniquely valuable resource for testing hypotheses regarding medically significant health effects, especially possible later-onset effects, of exposure to AVA or other vaccines, especially those that might arise several months after vaccination but within the period of active duty. Recommendation: CDC should work with DoD to follow up the signals regarding AVA that have already been generated by the review of VAERS reports and preliminary analyses of DMSS data on hospitalization and outpatient visits (see IOM, 2002). Recommendation: Analysis of DMSS data should be the primary approach for investigation of possible AVA-related health effects of medical significance that occur within the typical period of active duty following vaccination (perhaps as much as 3 to 4 years on average).

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Recommendation: To allow for analysis of health effects of AVA that might arise following the completion of active duty, CDC should investigate the use of DMSS data in conjunction with morbidity and mortality data from the Millennium Cohort Study and the health system of the Department of Veterans Affairs. Deaths of military personnel identified through DMSS could be tracked through resources such as the Beneficiary Identification and Records Locator Subsystem of the VA, the Social Security Administration, and the National Death Index. Recommendation: Adequate resources (substantially more than can currently be identified from the CDC–DoD Memorandum of Understanding) should be made available to support the use of DMSS data for testing hypotheses regarding health effects related to AVA or other vaccine exposures. Finding: An overall study plan or strategy is needed to guide CDC’s use of VAERS, DMSS data sets, and other data sources for hypothesis-generating and hypothesis-testing activities related to AVA. Recommendation: CDC, working with DoD, should establish a staff team with overall responsibility for the review and analysis of VAERS and DMSS data for both hypothesis generation and hypothesis testing related to AVA. Recommendation: A committee of nongovernmental experts should be established to periodically advise CDC on plans and priorities for the analyses of data from DMSS and other sources to test hypotheses regarding health effects related to AVA. Finding: Widespread environmental exposure to aluminum makes it difficult to conduct a study of potential adverse effects of exposure to the aluminum hydroxide adjuvant/adsorbant in AVA. Finding: The significance of the presence of aluminum in tissue biopsies of persons diagnosed with the condition called macrophagic myofasciitis has not been established. Recommendation: The study of the possible role of the aluminum hydroxide adjuvant in adverse events following receipt of AVA should be eliminated from the CDC research program.

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BOX ES-4 CHAPTER 6 FINDINGS AND RECOMMENDATIONS Finding: With its large sample size, the current design of the study of knowledge, attitude, and beliefs regarding AVA primarily addresses the acceptability of the vaccine among military personnel. Further documentation of the prevalence of attitudes and beliefs regarding the vaccine is unlikely to significantly advance the acceptability of the vaccine, which should be the major goal. Instead, qualitative research techniques such as focus groups and smaller-scale surveys can be used to determine the breadth, depth, and underlying reasons for the attitudes and beliefs regarding AVA. This information can serve as the basis for targeted interventions, the impact of which can be assessed with subsequent surveys. Recommendation: In view of the study timeline and research needs, CDC should modify the design of the KAB study of military personnel to focus on more timely development of educational interventions and the evaluation of their impact on the acceptability of AVA and a broader range of vaccines, including a new anthrax vaccine. Finding: Potential differences between racial and ethnic groups in knowledge, attitudes, and beliefs about AVA and military vaccines generally may be important. Recommendation: CDC should design the focus groups and preliminary survey to take into account different racial and ethnic groups. Finding: As proposed, the survey of civilian and military health care providers has a focus on knowledge, attitudes, and beliefs concerning VAERS and vaccination with AVA. Additional questions oriented toward the development of educational materials concerning AVA and other vaccines, immunization, and adverse events could broaden its usefulness. In addition, further articulation of links between the study and development of educational materials is needed. Recommendation: In addition to gathering information on KABs about VAERS and the current anthrax vaccine, CDC should modify the survey of health care providers to study KABs about a new anthrax vaccine, other military vaccines, and vaccines in general, with a focus on information useful for timely development and testing of appropriate educational materials. The study population should include health care providers who may treat service members with adverse events following vaccination, as well as those who administer vaccines.

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BOX ES-5 CHAPTER 7 FINDINGS AND RECOMMENDATIONS Finding: With respect to the tasks specifically outlined in the congressional mandate, CDC’s research response is generally complete and appropriate. When considered as a whole, however, the research program has elements that are of low priority and other elements that are inappropriate and should not be carried out as planned. Finding: Additional studies in laboratory animals of the efficacy of AVA in combination with antibiotics following inhalational exposure to anthrax spores are needed to establish an appropriate duration for antibiotic prophylaxis after vaccine administration (see IOM, 2002). Recommendation: As part of its research plan, CDC should support studies in laboratory animals to establish an appropriate duration for antibiotic prophylaxis when administered with AVA followingB. anthracisspore challenge. Finding: The exposure of members of the civilian population to anthrax spores in the bioterrorist incidents in the fall of 2001 demonstrates the importance of determining the immunogenicity and reactogenicity of AVA or any future anthrax vaccine when used by children, the elderly, and persons with chronic illnesses. Recommendation: Studies of the use of AVA (and any future anthrax vaccine) by children, the elderly, or persons with chronic illnesses should have a high priority once the findings from the clinical trial have established the optimal route and number of vaccine doses in young and middle-aged adults. The possible availability of newer-generation anthrax vaccines should be taken into account in planning these future studies in vulnerable populations. Finding: The CDC anthrax safety and efficacy research program lacks clearly defined senior leadership. It also lacks an ongoing external review committee that is independent of the consultative groups for individual studies. Recommendation: CDC should establish clearly defined senior leadership for the anthrax vaccine research program to articulate precise objectives for the research plan and to provide authority and accountability in the management of a coherent research plan. A single senior biomedical scientist should be given management authority for the entire program. Recommendation: As soon as possible, CDC should convene an external advisory group for the overall anthrax vaccine research plan and its progress. This group should have an advisory role regarding the continuation or termination of studies that are under way, the initiation of new studies, and the direction of the entire program. REFERENCES CDC (Centers for Disease Control and Prevention). 2000. Surveillance for adverse events associated with anthrax vaccination—U.S. Department of Defense, 1998–2000. MMWR (Morbidity and Mortality Weekly Report) 49(16):341–345. CDC. 2001a. Update: investigation of bioterrorism-related inhalational anthrax—Connecticut, 2001. MMWR (Morbidity and Mortality Weekly Report) 50(48):1077–1079. CDC. 2001b. Update: investigation of bioterrorism-related anthrax and adverse events from antimicrobial prophylaxis. MMWR (Morbidity and Mortality Weekly Report) 50(44):973–976. Hoffman K, Costello C, Engler RJM, Grabenstein J. Submitted for publication. Using a patient-centered structured medical note for aggregate analysis: determining the side-effect profile of anthrax vaccine at a mass immunization site.

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IOM (Institute of Medicine). 2001. CDC Anthrax Vaccine Safety & Efficacy Research Program. Interim Report. Washington, D.C.: National Academy Press. IOM. 2002. Joellenbeck LM, Zwanziger LL, Durch JS, Strom BL, eds. The Anthrax Vaccine: Is It Safe? Does It Work?Washington, D.C.: National Academy Press. Pittman PR, Kim-Ahn G, Pifat DY, Coonan K, Gibbs P, Little S, Pace-Templeton JG, Myers R, Parker GW, Friedlander AM. 2002. Anthrax vaccine: immunogenicity and safety of a dose-reduction, route-change comparison study in humans. Vaccine 20(9–10):1412–1420.