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7 Summary Assessment of the CDC Anthrax Vaccine Research Plan The charge to this Institute of Medicine (IOM) committee was to advise the Centers for Disease Control and Prevention (CDC) on the completeness and appropriateness of its response to a congressional mandate to study the safety and efficacy of the anthrax vaccine. The vaccine currently licensed for human use is Anthrax Vaccine Adsorbed (AVA). The congressional mandate (included in Public Law No. 106-113) specified that CDC was to address “(1) 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.” Over the course of the committee’s five open meetings, CDC provided written information and oral presentations about its developing anthrax vaccine research program. The committee also heard oral presentations and received written materials from service members and others with concerns about the safety or efficacy of the anthrax vaccine. The committee issued an interim report in July 2001, 8 months into its work (IOM, 2001). Meanwhile, the CDC research program and plans for individual studies continued to evolve over the course of the committee’s work. To make its final assessment, the committee requested written materials from CDC that would provide a comprehensive description of the objectives and design of the proposed research studies as of February 2002. The committee also requested that CDC identify critical research questions related to the efficacy, safety, and acceptability of the anthrax vaccine. This final report is based on the committee’s deliberations, with significant emphasis on its review of the materials provided by CDC in February 2002. A subset of these key documents is found in Appendix C. CDC RESEARCH PLAN Responsiveness to the Congressional Mandate After examining the components of the CDC anthrax vaccine safety and efficacy research program specifically in terms of the congressional mandate, the committee finds the CDC response 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 studies conducted in conjunction with the human clinical trial should largely address the challenge of determining immunological correlates of protection and documenting the efficacy of the vaccine. The committee’s qualifications regarding the research plan arise from the lack of passive protection studies in the determination of immunological correlates of protection (discussed in Chapter 4 and re
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viewed briefly below) and potential constraints from small sample sizes on 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 also lacks satisfactory plans for investigating adverse health effects that might be rare or 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 includes elements that the committee considers to be of lower priority, and some that should not be carried out as planned (see Table 7-1). These concerns have been detailed in chapters 4, 5, and 6 and are summarized below. 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. Research Studies and Priorities Since the release of the interim report from this committee, CDC has devoted considerable and commendable effort to the development of the studies that make up the research plan. CDC grouped these studies into the categories of efficacy, safety, and acceptability. The committee’s assessments of the research objectives and studies planned in each of these categories are discussed in detail in the preceding chapters and are summarized below and in Table 7-1. In making its assessments, the committee also considered the priority to be given to individual studies within the overall research program. While CDC designated all of the proposed studies as of high priority, the committee concluded that two efforts should be considered of the highest priority. One is the clinical trial and its related studies, which are aimed at identifying correlates of protection and establishing the optimal vaccination schedule and route of vaccine administration in terms of achieving a satisfactory immune response and minimizing the occurrence of adverse events. The other studies of highest priority are those exploiting the resource provided by the Defense Medical Surveillance System (DMSS) for generating and testing hypotheses about medically significant adverse events that might be associated with the anthrax vaccine. The committee also concluded that several studies had a low priority or should not be conducted at all. Efficacy Overall, the efficacy research program includes a strong set of studies (Human Clinical Trial, Nonhuman Primate Studies, Immune Correlates of Protection Studies) that are of high priority and are well designed to address many of the most important critical research questions and the congressional mandate. Aspects of the efficacy program pertaining to correlates of protection were viewed as particularly relevant, given that new anthrax vaccines are in development. Yet, the committee also notes important limitations of the research on the efficacy of AVA. Most importantly, the program lacks studies of passive protection in rhesus macaques. The committee views these studies as a high priority. They are necessary to determine the level of antibody required to achieve protection from disease caused by anthrax spores (see Chapter 4). The committee also notes the need for studies to evaluate the effect of inoculum size on the protection afforded by AVA. Such studies would be a natural follow-up to studies of passive protection that determined protective levels of antibodies. Their importance was made clear by the bioterrorist actions in the fall of 2001.
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TABLE 7-1 Committee Prioritization of Studies in the CDC Research Program on the Safety and Efficacy of the Anthrax Vaccine Committee Priority Studies Proposed by CDC High Human Clinical Trial (Chapter 4, p. 47, and Chapter 5, p. 61) Nonhuman primate vaccine dose ranging, immunogenicity and challenge trial (Chapter 4, p. 50) Immune correlates of protection studies (antibodies only) (Chapter 4, p. 52) Hypothesis testing using data from the Defense Medical Surveillance System (Chapter 5, p. 76) Medium Vaccine Healthcare Center (VHC) study of adverse events occurring soon after receipt of AVA (Chapter 5, p. 68) Low Human leukocyte antigen substudy (Chapter 4, p. 48) Immune correlates of protection studies (other than antibody-based) (Chapter 4, p. 53) VHC-based study of the effect of women’s hormonal phase on the occurrence of adverse events following immunization with AVA (Chapter 5, p. 72) Hypothesis generation from use of data mining and other statistical techniques to screen data from the Defense Medical Surveillance System (Chapter 5, p. 76) Not Recommended Nonhuman primate-immune correlates of protection substudy involving multiple invasive procedures (e.g., biopsies) (Chapter 4, p. 54) Textile mill worker follow-up study (Chapter 5, p. 66) VHC-based study of the effect of AVA vaccination on health-related quality of life (Chapter 5, p. 71) Hypothesis generation from use of data mining and other statistical techniques to screen data from the Vaccine Adverse Event Reporting System (Chapter 5, p. 76) Possible role of aluminum hydroxide adjuvant in AVA-associated adverse events (Chapter 5, p. 80) Not Recommended; Committee recommends a related study (see text and Table 7-2) Survey of knowledge, attitudes, and beliefs regarding the anthrax vaccine among military personnel (as proposed by CDC) (Chapter 6, p. 87) Survey of civilian and military health care providers regarding the anthrax vaccine and the reporting of possible vaccine-associated adverse events (as proposed by CDC) (Chapter 6, p. 89) In contrast, the committee concluded that other proposed studies have a relatively low priority. These studies include the analysis of genetic polymorphisms of the human leukocyte antigen system as well as many of the assays that focus on cellular aspects of immunity as part of the proposed studies of the immune correlates of protection. The committee questions the usefulness of the multiple lymph node biopsies, bone marrow biopsies, and bronchoalveolar lavage planned for a subset of the animals in the nonhuman primate study since the repeated procedures and the accompanying need for anesthesia may alter the observed responses. The committee recommends that these studies not be continued in their current form.
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Safety Regarding the studies related to the safety of the anthrax vaccine, the committee found that the human clinical trial should provide important information about the risk factors for common adverse reactions that occur soon after vaccination, including differences in reaction rates related to subcutaneous (SQ) versus intramuscular (IM) administration of the vaccine. With data from the clinical trial 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). The clinical trial will include an investigation of the effect of women’s hormonal phase on the risk of adverse events, but additional studies beyond those described by CDC would be needed to better understand the reasons for any differences that might be found between men and women in the occurrence of adverse events. The committee also cautions that the SF-36 health status survey, if used by itself, is unlikely to be a satisfactory tool for the proposed evaluation of the association between receipt of AVA and changes in health-related quality of life in the clinical trial. 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 any important later-onset health effects that might be associated with anthrax vaccination 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 medical or scientific benefit. One of the proposed cohort studies to be conducted through the Vaccine Healthcare Center (VHC) Network could, with a study population comparable in size to that of the clinical trial, provide useful postmarketing-type data to confirm the rates observed in the human clinical trial of common adverse events that occur soon after vaccination. With the plans to seek approval from the Food and Drug Administration for a change from SQ to IM administration of AVA, the study must be initiated promptly to include the planned comparisons of rates of adverse events with SQ and IM administration. The committee notes that the proposed study is not well suited to monitoring the occurrence of less common, medically significant conditions that may not be seen during a clinical trial. Monitoring the occurrence of these events would require use of a much larger study population (10,000 or more participants). It would also require a control group whose members have not received AVA and who are comparable in initial health status to the population that received AVA. Identifying a suitable control group would be challenging because receipt of AVA will generally be related to deployment (Wolfowitz, 2002). Deployed personnel are likely to be healthier on average than nondeployed personnel because health problems may disqualify an individual from deployment. For several reasons, the plans for a VHC-based study to assess the effect of AVA vaccination on health-related quality of life using the SF-36 health survey do not appear feasible. When used by itself, the SF-36 has limitations in distinguishing differences between generally healthy populations. It will also be challenging to follow study participants who are likely to have been deployed. In addition, it may be difficult to distinguish any changes in health status related to AVA from those related to deployment. Health status might also be affected by various other medications and vaccines received in preparation for deployment. The VHC-based study of 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 and is considered a low priority by the committee. The committee is pleased to see that CDC has begun to give attention to DMSS as a resource for generating and testing hypotheses concerning adverse events that might be associated with receipt of AVA. The committee is concerned, however, about the proposed use of data mining to screen data from the Vaccine Adverse Event Reporting System (VAERS) for hypothesis generation. VAERS is a spontaneous reporting system that is inherently incomplete and subject to often-unknown reporting biases. Therefore
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the committee considers it inappropriate to apply data mining techniques to VAERS data unless those techniques are thoroughly evaluated in other, more complete data sets and are shown to be effective even in the face of the kinds of biases inherent in the VAERS data. It might be possible to conduct such validation studies using DMSS data. In addition, the availability of data from both DMSS and VAERS on health outcomes following exposure to AVA provides an unprecedented opportunity to use associations that might be found in DMSS in subsequent efforts to validate the use of data mining in VAERS. Resources for generating and testing hypotheses about adverse events and the anthrax vaccine might be better expended in the effort to use data from DMSS to their fullest potential. The committee is concerned that despite movement toward collaboration between CDC and the Department of Defense (DoD) to permit work with the DMSS databases, as of February 2002 these studies were still not receiving the appropriate attention, priority, and funding. Hypothesis testing with DMSS should be one of CDC’s highest priorities, but the research plan does not reflect that. Finally, the committee believes the proposed study of the possible role of aluminum hydroxide in adverse events would be difficult to conduct and is not of sufficient priority to pursue as part of the CDC anthrax vaccine research program. Acceptability Investigation of the acceptability of the anthrax vaccine was not directly specified in the congressional mandate to CDC; however, the committee recognizes the potential importance of acceptability issues to the overall success of any vaccination program. The committee found that the planned study of knowledge, attitudes, and beliefs (KABs) regarding the anthrax vaccine among members of the military was unnecessary in its proposed form. However, information about attitudes in groups that are likely to be immunized can be useful in guiding the development of interventions intended to address concerns about the anthrax vaccine. Thus, the committee recommended against exhaustively detailing the current level of concern among various categories of service members. Instead, relevant information could be gathered using focus groups and smaller surveys and then usefully applied to the development, refinement, and evaluation of the interventions. The committee also felt that the separate survey of health care providers could be of greater value if the focus were 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 modifications were made. Research Gaps In its review of the studies proposed by CDC, the committee identified gaps in the research plan. These needed studies are noted in Chapters 4, 5, and 6; in the text above; and in Table 7-2. The committee feels that the clearest gap in the research plan as mandated by Congress is the absence of passive protection studies—studies to determine the amount of human antibody against protective antigen needed to protect rhesus monkeys from aerosol anthrax spore challenge. Studies that evaluate the impact of different challenge doses of spores on correlates of protection are also needed. Such studies would appropriately follow determinations from passive protection studies of the appropriate level of antibody needed to provide protection at a given dose. This information may have a bearing on the possible use of immune serum globulin as a prophylactic agent after exposure to anthrax spores. The committee also perceives a gap in the efforts to link data available from the Defense Medical Surveillance System with databases that could provide additional years of follow-up among military personnel who have received AVA. Linkages with data from sources such as the Millennium Cohort Study or the Department of Veterans Affairs health system hold the potential for evaluating whether the vaccine is associated with health effects that arise in the longer term.
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TABLE 7-2 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) Another research gap is suggested by the planned studies regarding acceptability. The most pressing need in that area is for studies that can help guide the design of materials and interventions to improve the acceptability of the vaccine and the design of materials and strategies to better inform health care providers who see vaccinees about the potential adverse events associated with the licensed anthrax vaccine and with vaccines more generally. BIOTERRORISM AND RESEARCH NEEDS CDC’s research program was mandated by Congress in 1999 and initiated before the bioterrorist use of anthrax spores in 2001. The nation’s experience of civilian bioterrorism confirmed the urgency of the research that CDC has already planned, but also made clear the need for studies related to the possible use of the anthrax vaccine following exposure to anthrax spores and the use of the vaccine in the civilian population. With some additions to its research portfolio, CDC could make further contributions to understanding of the safety and efficacy of AVA as it is currently used or of new uses of AVA or a new anthrax vaccine. 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 prior to, exposure to anthrax spores. Antibiotics are also provided in such a situation to provide protection until immunity is established in response to the vaccine. AVA was offered to postal workers and Senate staff members in late 2001 following their potential exposure to anthrax spores, and such postexposure use is a likely scenario for future civilian use of an anthrax vaccine following a bioterrorist event. 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, such as nonhuman primates. As noted by an earlier IOM committee, only two such studies have been carried out in nonhuman primates (Friedlander et al., 1993; Henderson et al., 1956). This research is also needed to establish the appropriate duration for antibiotic prophylaxis after vaccine administration (IOM, 2002). 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).
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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. In fact, the newest data come from the vaccination of military personnel subject to deployment to areas considered to be at risk for exposure to military bioweapons. Analysis of data from DMSS suggests that on average, the recipients of AVA were healthier than the general military population (IOM, 2002). In the materials provided to the committee, CDC gave the research questions concerning postexposure vaccine use by children and the elderly a lower priority than other topics, and no mention was made of persons with chronic illnesses as a population of special concern. The CDC materials included mention of a proposed pediatric study, but indicated that the development of a study protocol depended on the availability of funding. 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 also be flexible enough to respond to changing circumstances, including the possible availability of a newer anthrax vaccine. 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. The bioterrorist events of 2001 also made clear the potential need to administer an anthrax vaccine following exposure to anthrax spores. 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 to improve preparedness for the possibility of future bioterrorist events involving anthrax. The research program must be flexible enough to respond to changing circumstances using both intramural and extramural resources, and to draw fully upon the expertise in vaccine development and testing available within the National Institutes of Health and DoD as it does so. A NEED FOR A SINGLE PROGRAM LEADER From its review, the committee sees evidence of a need for strong 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.
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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. The interim report from this committee noted a concern that CDC had not described a comprehensive plan explaining how the array of projects it was planning fit the overall goals for the research program (IOM, 2001). Following CDC’s final presentations to the committee in January 2002, the committee still did not have an understanding of the guiding plan for the research program. As a result, the committee requested that CDC provide a comprehensive written description of the research plan as of February 2002. The committee also requested a listing of the critical research questions relating to anthrax vaccine safety and efficacy, with an indication as to which studies were addressing these questions, what priority was assigned to the studies, and where research gaps remained. After reviewing these materials, the committee concluded that despite evident 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, there still does not appear to be a comprehensive plan guiding the continued overall development of the research program. The description of the research plan provided to the committee was developed only after repeated requests, and it did not provide a compelling rationale for the array of studies or justify CDC’s prioritizations of the studies. Rather than constituting a coherent research plan, the work planned by CDC falls into two groups of studies drawing on a single ongoing source of funds but being planned and carried out by two separate organizational units within CDC. The committee concluded that centralized senior leadership would aid in the development of a single integrated plan that will make the most effective use of the total resources available to CDC. 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 and, in any case, is not well suited to providing ongoing real-time advice. CDC has responded vigorously to the IOM committee’s recommendation to convene scientific advisory panels for individual studies, but there is no indication that CDC will have a future source of external advice to the research program as a whole. The timelines for the studies that make up the research plan are also an important consideration. The timetable for the entire program must be viewed in the context of the urgent efforts to develop an alternative anthrax vaccine (Enserink and Marshall, 2002; NIH, 2002). The narrow focus and extended timelines for several of the studies might limit the usefulness of the data obtained, except to the extent that those data can inform the licensing and acceptability of new vaccines. Anticipated changes to improve the use of the current vaccine (AVA) in terms of the route of administration or the number of doses are needed as soon as possible, but will also affect plans for some of the studies. Without strong leadership to hasten some of the studies or extend their scope (e.g., the KAB studies), some of the studies may extend into irrelevancy. 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. The committee is persuaded that effective coordination of a research program distributed across two separate organizational units of CDC requires management by a single senior CDC biomedical scientist with responsibility for the overall program. In addition to monitoring timelines and providing prioritization and strategic planning for the research program, a clearly defined leader can facilitate appropriate responses to changing circumstances and new opportunities that may arise. Furthermore, 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. This group can also provide advice about the membership of the consultative groups that were convened by CDC to provide real-time input on study design. Recognizing that the administrative and procedural requirements related to such groups can be burdensome and time-consuming, the com-
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mittee encourages CDC to seek the most efficient means of gaining access to ongoing expert scientific guidance. The CDC program leader should be responsible for all aspects of the anthrax vaccine research program and have the authority to initiate, redirect, or terminate research studies, with advice from the external committee. 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. Enserink M, Marshall E. 2002. Biodefense: new anthrax vaccine gets a green light. Science 296(5568):639–640. Friedlander AM, Welkos SL, Pitt ML, Ezzell JW, Worsham PL, Rose KJ, Ivins BE, Lowe JR, Howe GB, Mikesell P, Lawrence WB. 1993. Postexposure prophylaxis against experimental inhalation anthrax. Journal of Infectious Diseases 167(5):1239–1243. Henderson DW, Peacock S, Belton FC. 1956. Observations on the prophylaxis of experimental pulmonary anthrax in the monkey. Journal of Hygiene 54:28–36. 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. 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. NIH (National Institutes of Health). 2002. Request for Proposal: Development and Testing of Vaccines Against Anthrax. RFP-NIH-NIAID-DMID-02-26. Bethesda, Md.: NIH. 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. Wolfowitz P. 2002. Reintroduction of the Anthrax Vaccine Immunization Program (AVIP). Memorandum for Secretaries of the Military Departments, Chairman of the Joint Chiefs of Staff, Under Secretaries of Defense, Assistant Secretaries of Defense, General Counsel, DoD, Inspector General, DoD, Directors of Defense Agencies, and Commandant of the U.S. Coast Guard. Department of Defense, Washington, D.C.
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