Executive Summary

ABSTRACT

Anthrax Vaccine Adsorbed (AVA) was licensed in 1970 to provide protection against infection with Bacillus anthracis. AVA was initially administered on a limited basis, primarily to protect veterinarians and workers processing animal products such as hair or hides that could be contaminated with anthrax spores. In the 1990s, with growing concerns about the possible use of anthrax as a biological weapon, use of the vaccine was substantially expanded. The Department of Defense (DoD) vaccinated some of the military personnel deployed for the Gulf War in 1991 and in 1998 initiated the Anthrax Vaccine Immunization Program, calling for mandatory vaccination of all U.S. service members. By late 2001, roughly 2.1 million doses of AVA had been administered. Production of AVA was suspended in 1998 when the facility manufacturing the vaccine was closed for renovations, which were undertaken to meet regulatory requirements of the Food and Drug Administration (FDA).

Concerns about the efficacy and safety of AVA, and about vaccine production, led Congress to direct the DoD to support an independent examination of AVA by the Institute of Medicine. In October 2000, the Institute of Medicine convened the Committee to Assess the Safety and Efficacy of the Anthrax Vaccine. The committee reviewed all available data, both published and unpub-



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The Anthrax Vaccine: Is it Safe? Does it Work? Executive Summary ABSTRACT Anthrax Vaccine Adsorbed (AVA) was licensed in 1970 to provide protection against infection with Bacillus anthracis. AVA was initially administered on a limited basis, primarily to protect veterinarians and workers processing animal products such as hair or hides that could be contaminated with anthrax spores. In the 1990s, with growing concerns about the possible use of anthrax as a biological weapon, use of the vaccine was substantially expanded. The Department of Defense (DoD) vaccinated some of the military personnel deployed for the Gulf War in 1991 and in 1998 initiated the Anthrax Vaccine Immunization Program, calling for mandatory vaccination of all U.S. service members. By late 2001, roughly 2.1 million doses of AVA had been administered. Production of AVA was suspended in 1998 when the facility manufacturing the vaccine was closed for renovations, which were undertaken to meet regulatory requirements of the Food and Drug Administration (FDA). Concerns about the efficacy and safety of AVA, and about vaccine production, led Congress to direct the DoD to support an independent examination of AVA by the Institute of Medicine. In October 2000, the Institute of Medicine convened the Committee to Assess the Safety and Efficacy of the Anthrax Vaccine. The committee reviewed all available data, both published and unpub-

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The Anthrax Vaccine: Is it Safe? Does it Work? lished, and heard from representatives of DoD, FDA, and other federal agencies; from the vaccine manufacturer BioPort; from researchers studying the efficacy and safety of the vaccine; and from service members and others with concerns about the safety or efficacy of the vaccine. After the bioterrorism of fall 2001, the committee accelerated its original timetable for its review. As indicated by evidence from studies in both humans and animals, the committee concluded that AVA, as licensed, is an effective vaccine to protect humans against anthrax, including inhalational anthrax. Moreover, because the vaccine exerts its protection via an antigen crucial to the action of the bacterium’s toxins, AVA should be effective against anthrax toxicity from all known strains of B. anthracis, as well as from any potential bioengineered strains. After examining data from numerous case reports and especially epidemiologic studies, the committee also concluded that AVA is reasonably safe. Within hours or days following vaccination, it is fairly common for recipients to experience some local events (e.g., redness, itching, swelling, or tenderness at the injection site), while a smaller number of vaccine recipients experience some systemic events (e.g., fever and malaise). But these immediate reactions, and the rates at which they occur, are comparable to those observed with other vaccines regularly administered to adults. The committee found no evidence that vaccine recipients face an increased risk of experiencing life-threatening or permanently disabling adverse events immediately after receiving AVA, when compared with the general population. Nor did it find any convincing evidence that vaccine recipients face elevated risk of developing adverse health effects over the longer term, although data are limited in this regard (as they are for all vaccines). Regarding manufacture of AVA, the committee reviewed and evaluated the steps taken by BioPort to win FDA approval of its production process. With the newly validated manufacturing process being used in a renovated facility, AVA will be produced under strict controls according to current FDA requirements. The newly produced vaccine is expected to have greater assurance of consistency than the vaccine produced at the time of its original licensure. It remains important to continue and improve monitoring efforts to detect any adverse health effects caused by AVA and other vaccines. Also needed are studies to establish a quantitative correlation of protective levels of antibodies in animals with antibody levels in humans after full immunization. Direct tests of the efficacy of AVA are neither feasible nor ethical in humans. However, corre-

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The Anthrax Vaccine: Is it Safe? Does it Work? lates of protection in animal models can be used to test the efficacy of AVA, as well as new vaccines against anthrax. The production, testing, and licensure of a new vaccine requiring fewer doses and producing fewer local reactions are needed. Anthrax Vaccine Adsorbed1 (AVA) was licensed in 1970. More than 2 million doses have been administered, and most of those doses have been given since 1998 to U.S. military personnel to protect them against possible exposure to anthrax spores used as biological weapons. The terrorist attacks of September 11, 2001, and the subsequent distribution through the U.S. mail of potent doses of anthrax spores drew new attention to the risks of anthrax exposure and to questions about the anthrax vaccine. Until the 1990s, AVA had primarily been used by a small population with a risk of occupational exposure to anthrax (e.g., textile mill workers and veterinarians). In 1990, concerns that Iraq had biological weapons containing anthrax spores motivated the U.S. military to administer AVA to an estimated 150,000 service members deployed for the Gulf War. The existence of an Iraqi biological weapons program was confirmed in the mid-1990s (Henderson, 1999; Zilinskas, 1997), and in 1997 the Department of Defense (DoD) announced a plan to vaccinate all U.S. service members with the licensed anthrax vaccine. DoD’s Anthrax Vaccine Immunization Program (AVIP) began in March 1998 with personnel scheduled for deployment to higher-risk areas (e.g., Korea and Southwest Asia). In 2000 a limited vaccine supply, the result of delays in federal approval for release of newly manufactured vaccine lots, began slowing plans to vaccinate all military personnel. As more service members were vaccinated under the mandatory AVIP, some raised concerns about the safety or the efficacy of AVA, and more than 400 personnel refused vaccination (Weiss, 2001). Some had also suggested a link between vaccination with AVA and illnesses in Gulf War veterans. STUDY PROCESS AND INFORMATION SOURCES Responding to the concerns about the anthrax vaccine and AVIP, the U.S. Congress directed DoD to enter into a contract with the National Research Council for a study of the vaccine’s efficacy and safety.2 In October 2000 the Institute of Medicine (IOM) convened the Committee to 1   As of January 31, 2002, AVA will be manufactured under the name Biothrax. 2   The study was called for in the conference report accompanying the 2000 DoD appropriations act P. L. No. 106-79 (1999).

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The Anthrax Vaccine: Is it Safe? Does it Work? Assess the Safety and Efficacy of the Anthrax Vaccine to carry out that study. Committee members were selected for their expertise in microbiology; vaccine research, development, manufacture, and evaluation; post-marketing surveillance of adverse events; regulatory and licensing procedures; epidemiology; biostatistics; immunology; and health surveillance. The charge to the committee included consideration of the types and severity of adverse reactions, sex differences in adverse reactions, long-term health implications, the efficacy of AVA against inhalational exposure to all known anthrax strains, and the correlation of the safety and efficacy of the vaccine in animal models to its safety and efficacy in humans. The study was also to address the issue of validation of the manufacturing process, with consideration of discrepancies identified by the Food and Drug Administration (FDA) in February 1998, the definition of vaccine components, and identification of gaps in existing research. (See Appendix A for the Statement of Task.) The charge did not include evaluation of the DoD policy to vaccinate all service members, so the committee did not include an evaluation of the threat from biological warfare agents in its purview. Similarly, the committee was not asked to address the challenges in bio-weapons vaccine development and procurement generally, which have recently been discussed in a statement from the Council of the Institute of Medicine (http://www.iom.edu/IOM/IOMHome.nsf/Pages/Vaccine+Development) and in reports by the Gilmore Commission (http://www.rand.org/nsrd/terrpanel/) and DoD (http://www.defenselink.mil/pubs/ReportonBiologicalWarfareDefenseVaccineRDPrgras-July2001.pdf ). Since the terrorist attacks of September 11, 2001, and subsequent mail distribution of anthrax spores, interest in AVA has greatly increased. Consideration of the full range of topics concerning civilian use of the anthrax vaccine was beyond the purview of this report. However, some of the issues that the committee did address should also be of interest for civilians. The committee held eight deliberative meetings plus four public work-shops. At those workshops, the committee heard from representatives of DoD, FDA, and other federal agencies; from the manufacturer of AVA, BioPort; from researchers studying the efficacy and safety of the vaccine; and from service members and others with concerns about the safety or efficacy of the vaccine. The committee also commissioned a review of the available literature on adverse events associated with other vaccines routinely administered to adults. The committee examined both published and unpublished data from studies of the safety and efficacy of AVA. The investigators involved in many of those studies presented their data and discussed their findings at committee workshops. In addition, several analyses of existing data were carried out at the committee’s request.

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The Anthrax Vaccine: Is it Safe? Does it Work? ANTHRAX AND ANTHRAX VACCINE Anthrax is caused by infection with Bacillus anthracis, a gram-positive, nonmotile, spore-forming organism (Brachman and Friedlander, 1999; Dixon et al., 1999). It is primarily a disease of wild and domestic animals. Historically, humans have contracted the disease through contact with infected animals or animal products, such as hair or hides, contaminated with anthrax spores. Depending on the site of infection, anthrax can occur in a cutaneous, gastrointestinal, or inhalational form. The disease had become extremely uncommon in any form in the United States until the bioterrorist incidents of the autumn of 2001 caused an outbreak of both cutaneous and inhalational cases of the disease. As of November 28, 2001, there had been 11 cases of inhalational anthrax, 5 of which were fatal, and 7 confirmed and 5 suspected cutaneous anthrax infections (CDC, 2001b). More than 30,000 people may have been exposed to anthrax spores (CDC, 2001a,b). The virulence of B. anthracis derives from the production of a capsule and three toxin proteins: protective antigen (PA), edema factor (EF), and lethal factor (LF). To produce active toxins, PA must bind to cellular receptors and then to either EF or LF. AVA, the vaccine currently licensed for human use in the United States, is a cell-free filtrate containing PA as the principal immunogen. It is administered in six subcutaneous injections of 0.5 milliliters each. The first three doses are given 2 weeks apart, and the following doses are given 6, 12, and 18 months after administration of the first dose. Annual booster doses are required. ANTHRAX VACCINE EFFICACY The committee’s observations and findings addressed the efficacy of immunization with the licensed vaccine, AVA, against inhalational anthrax and all known anthrax strains (see Chapter 3). Of particular concern is exposure to anthrax spores processed for use in biological weapons. The committee also examined what is known and what must still be established regarding the correlation of protection in animal models with immunity in humans. It is important to note that efficacy is relative, not absolute. The degree of protection provided by a vaccine is determined by a variety of factors, which can include the size of the inoculum of exposure, the strain of the pathogen, and the host response. Even a vaccine considered highly effective may fail to protect some individuals under some circumstances. Evaluating Efficacy of AVA The efficacy of a PA-containing anthrax vaccine similar to AVA against anthrax infection was established by a randomized controlled field study of

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The Anthrax Vaccine: Is it Safe? Does it Work? textile mill workers (Brachman et al., 1962). Subsequent data from the Centers for Disease Control and Prevention (CDC) support the results of that study (FDA, 1985). The small number of inhalational cases in those studies provides insufficient information to establish the vaccine’s efficacy against inhalational infection, but the data suggest that the vaccine has a protective effect. Animal studies are essential for further investigation of the efficacy of AVA and other anthrax vaccines against inhalational disease because studies with humans are neither feasible nor ethical. Cases of inhalational anthrax are very rare, even where anthrax occurs naturally in the environment or as an occupational hazard. Moreover, human research subjects cannot be deliberately exposed to potentially lethal agents, such as anthrax spores, for no therapeutic reason and without the availability of a proven treatment. Finding: Because additional clinical trials to test the efficacy of AVA in humans are not feasible and challenge trials with volunteers are unethical, by necessity animal models represent the only sources of the supplementary data needed to evaluate AVA’s efficacy. Animal models with pathological and immunological characteristics similar to those of humans could be considered the most appropriate ones for the evaluation of vaccine efficacy. The pathophysiology of anthrax in nonhuman primates, such as the macaque, most closely resembles the patho-physiology of anthrax in humans. Among the smaller and more available laboratory animals, rabbits most closely resemble nonhuman primates in terms of the pathology of anthrax and their response to the anthrax vaccine. Finding: The macaque and the rabbit are adequate animal models for evaluation of the efficacy of AVA for the prevention of inhalational anthrax. Efficacy of AVA Against All Known B. anthracis Strains Several different B. anthracis strains are found in nature worldwide (Fellows et al., 2001; Keim et al., 2000), and analysis of tissue samples from victims of the release of anthrax spores from the Soviet biological weapons facility at Sverdlovsk in 1979 indicated the presence of several B. anthracis strains (Grinberg et al., 2001; Jackson et al., 1998). It is important to establish whether AVA can afford protection against the full range of naturally occurring or engineered B. anthracis strains. Studies have shown that the protection that AVA affords guinea pigs differs by bacterial strain (Auerbach and Wright, 1955; Fellows et al., 2001; Ivins et al., 1994; Little and Knudson, 1986; Turnbull et al., 1986),

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The Anthrax Vaccine: Is it Safe? Does it Work? but AVA and a predecessor vaccine protected rabbits and monkeys against the numerous strains tested (Auerbach and Wright, 1955), including those that defeated the vaccine in guinea pigs (Fellows et al., 2001). No AVA-resistant strains have been demonstrated in nonhuman primates. Observational data from studies with humans also support the efficacy of AVA against a variety of strains, though exposure strains were not evaluated in the studies (Brachman et al., 1962; CDC, 1967–1971). PA is the principal immunogen in AVA, and the efficacy of AVA against a broad spectrum of B. anthracis strains is consistent with the critical role of PA in the pathogenesis of anthrax (Bhatnagar and Batra, 2001; Cataldi et al., 1990; Smith and Keppie, 1954). As shown in Figure ES-1, PA must be competent to carry out multiple complicated tasks: it must bind to its receptor, form a heptamer, and bring EF and LF into the cell. There is concern that natural mutations or bioengineered alterations of the PA component of anthrax could result in vaccine-resistant strains. Studies (Sellman et al., 2001; see also Mogridge et al., 2001) have shown, however, that a PA heptamer is deactivated by the presence of even a few mutant subunits. A deactivated heptamer is unlikely to be able to deliver EF and LF to the cytosol. The committee considers it improbable that a mutant PA that retains its function yet escapes the vaccine-elicited protective antibodies directed to the wild-type PA could be constructed at this time. The likely difficulty of successfully altering PA is supported by evidence that the B. anthracis genome is highly conserved among strains isolated across a wide geographical area (Jackson, 2001; Keim et al., 1997) and that PA is also highly conserved (Jackson, 2001; Price et al., 1999). Because PA is critical to virulence and because its structure is so highly conserved, it appears likely that changing its structure would alter and thus eliminate its toxic action. Finding: It is unlikely that either naturally occurring or anthrax strains with bioengineered protective antigen could both evade AVA and cause the toxicity associated with anthrax. Establishing Animal Model Correlates of Anthrax Vaccine Efficacy Several recent studies have used passive protection to demonstrate a relationship between levels of circulating anti-PA antibody and protection from challenge with anthrax spores (Barnard and Friedlander, 1999; Beedham et al., 2001; Little et al., 1997; McBride et al., 1998; Pitt et al., 2001; Reuveny et al., 2001). Finding: The available data indicate that immunity to anthrax is associated with the presence of antibody to protective antigen.

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The Anthrax Vaccine: Is it Safe? Does it Work? FIGURE ES-1 Model of anthrax toxin action. (1) PA binds to cellular receptor. (2–3) The protein is cleaved and activated to form a heptameric prepore. (4) LF, EF, or both bind to the heptamer, and the resulting complex is taken into an acidic compartment in the cell through endocytosis. (5–6) The acidic pH initiates the heptamer to pierce the membrane of the cell and translocate LF, EF, or both into the cytosol, where the toxins lead to damage. [Reprinted, with permission, from Biochemistry 38:10432–10441 (1999). Copyright 1999 by American Chemical Society.] The information reviewed by the committee demonstrates that both humans and certain laboratory animals manifest the same disease after infection with the same anthrax organism and that both are protected by immunization with AVA, which elicits the production of antibodies to PA. This information establishes a qualitative correlation between protection in animal models and protection in humans. To move forward with research on the current anthrax vaccine or any new vaccines, however, a quantitative correlation of the protective levels of antibodies in animals with the antibody titers obtained after full immunization in humans is needed. Those correlates in animal models can then be used to test new vaccines for efficacy with confidence that the data from studies with animals will be predictive of the clinical results for immunized humans. The data from animal studies already developed suggest that serological correlates of human immunity can be developed in appropriate animal models. The committee commends this work and encourages its further development. Recommendation: Additional passive protection studies with rabbits

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The Anthrax Vaccine: Is it Safe? Does it Work? and monkeys including the transfer of animal and human sera are urgently needed to quantify the protective levels of antibody in vivo against different challenge doses of anthrax spores. Recommendation: Additional active protection studies should be conducted or supported to develop data that describe the relationship between immunity and both specific and functional quantitative antibody levels, including studies of the relationship between the vaccine dose and the resulting level of antibody in the blood of test animals that protects the animals from challenge; the relationship between the level of antibody that protects animals from challenge and the level of antibody present in humans vaccinated by the regimen currently recommended for the licensed product; and the vaccine dose that results in a level of antibody in the blood of human volunteers similar to that in the blood of protected animals. Postexposure Use of Anthrax Vaccine As a result of the inhalational exposure to anthrax spores from letters mailed in the autumn of 2001, questions about the postexposure efficacy of AVA have arisen. No data from studies with humans are available, but two papers provide information from studies with rhesus monkeys. These limited data suggest that use of the vaccine in combination with an appropriate antibiotic for 30 days could provide excellent postexposure protection against inhalational anthrax. Although the additional benefit from receiving the vaccine after a prolonged period of antibiotic use is not proven, reliance on the vaccine alone after exposure is clearly insufficient, as some protection is needed during the time required for an immune response to develop. Additional studies on the postexposure use of AVA with antibiotics are needed. Recommendation: DoD should pursue or support additional research with laboratory animals on the efficacy of AVA in combination with antibiotics administered following inhalational exposure to anthrax spores. Studies should focus on establishment of an appropriate duration for antibiotic prophylaxis after vaccine administration. Conclusions Regarding Efficacy A vaccine similar to AVA was shown to be effective against cutaneous anthrax in humans in the field trial supporting the original application for

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The Anthrax Vaccine: Is it Safe? Does it Work? licensure of AVA (Brachman et al., 1962). Although that study had too few cases to evaluate the vaccine’s efficacy for the prevention of inhalational disease, the five inhalational cases observed during the trial occurred only among nonvaccinated or placebo recipients. Data from CDC on cases reported between 1962 and 1974 also indicated that the vaccine offered protection against the cutaneous form of the disease (FDA, 1985). Further-more, laboratory experiments indicate that AVA provides effective protection against inhalational challenge in rabbits and macaques, the animal models in which the disease is most reflective of the disease in humans (Fellows et al., 2001; Ivins et al., 1996, 1998; Pitt et al., 2001). Because PA is critical to the virulence of B. anthracis and because PA’s structure is so highly conserved, it appears likely that changing its structure would alter and thus eliminate its toxic action. Data from studies with animals suggest that AVA will offer protection against strains with PA-based toxicity. Finally, the available data indicate that immunity to anthrax is associated with the presence of antibodies to PA, such as those stimulated by the anthrax vaccine. Finding: The committee finds that the available evidence from studies with humans and animals, coupled with reasonable assumptions of analogy, shows that AVA as licensed is an effective vaccine for the protection of humans against anthrax, including inhalational anthrax, caused by any known or plausible engineered strains of B. anthracis. ANTHRAX VACCINE SAFETY As with any pharmaceutical product or medical procedure, the use of vaccines carries a risk of adverse health effects that must be weighed against the expected health benefit. Expectations for the safety3 of vaccines are especially high because, in contrast to therapeutic agents, which are given when a disease is known to be present (or at least suspected), vaccines are usually given to people who are healthy to protect them against a disease that they may not be exposed to in the future. The committee evaluated case reports and epidemiologic studies providing information about the safety of the anthrax vaccine. Case reports can help to generate hypotheses about possible associations but are rarely sufficient by themselves to confirm such associations. Formal epidemiologic studies are usually needed to determine whether those adverse events iden- 3   For this report, safety reflects expectations of relative freedom from harmful effects when a product is used prudently, considering the condition of the recipient and the health risk the product is directed against.

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The Anthrax Vaccine: Is it Safe? Does it Work? tified in case reports occur in exposed populations at a rate that exceeds the background rate in unexposed populations. The case reports relating to AVA come primarily from the Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system that collects reports on adverse events following the use of any vaccine licensed in the United States (see Chapter 5). A subset of the committee reviewed each of 120 VAERS reports on serious adverse events associated with AVA. The committee also heard testimony regarding adverse events following vaccination with AVA. These statements, some of which concerned cases reported to VAERS, added valuable insight into the conditions that some military personnel are experiencing. In evaluating the epidemiologic studies of adverse events following receipt of AVA (see Chapter 6), the committee gave additional weight to those that (1) used active surveillance rather than self-reports of post-immunization events; (2) included sufficiently large numbers of subjects; (3) had clearly specified, objective criteria for the definition of adverse events; and (4) had sufficiently long postimmunization follow-up intervals to allow identification of later-onset events. Those studies that included a suitable unimmunized comparison group or in which evaluators were blinded to vaccination status were especially useful to the committee. Conclusions Regarding AVA Vaccination and Adverse Events Substantial data are now available from VAERS, epidemiologic studies with data from the Defense Medical Surveillance System (DMSS), and other epidemiologic studies for assessments of the health outcomes following vaccination with AVA. Immediate-onset health events are observable within hours or days following vaccination; later-onset events would be observable only months or years following vaccination. Epidemiologic studies that have used either active surveillance (Brachman et al., 1962; Pittman, 2001b,c; Pittman et al., 1997, 2002, in press) or passive surveillance (Hoffman et al., submitted for publication; Pittman, 2001a; Pittman et al., 2001a,b; Wasserman, 2001) have consistently found local injection-site reactions, including redness, induration, edema, itching, or tenderness (see Table 6-1 for details). Systemic events, such as fever, malaise, and myalgia, are also associated with vaccination with AVA but are generally less common than injection-site reactions. The types of local and systemic reactions associated with AVA and the rates at which they were observed are comparable to those observed with other vaccines regularly administered to adults, such as diphtheria and tetanus toxoids and influenza vaccines (Treanor, 2001). Although these immediate-onset health effects can result in brief limitation of activities or the loss of time from work (Hoffman et al., submitted for publication; Wasserman,

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The Anthrax Vaccine: Is it Safe? Does it Work? BOX ES-1 Chapter 3 Findings and Recommendations Findings The randomized field study carried out by Brachman and colleagues (1962) provides solid evidence indicating the efficacy of a vaccine similar to AVA against B. anthracis infection. The subsequent CDC data are supportive. However, the small number of inhalational cases in those studies provides insufficient information to allow a conclusion about the vaccine’s efficacy against inhalational infection to be made. Because additional clinical trials to test the efficacy of AVA in humans are not feasible and challenge trials with volunteers are unethical, by necessity animal models represent the only sources of the supplementary data needed to evaluate AVA’s efficacy. The macaque and the rabbit are adequate animal models for evaluation of the efficacy of AVA for the prevention of inhalational anthrax. It is unlikely that either naturally occurring or anthrax strains with bioengineered protective antigen could both evade AVA and cause the toxicity associated with anthrax. The available data indicate that immunity to anthrax is associated with the presence of antibody to protective antigen. The committee finds that the available evidence from studies with humans and animals, coupled with reasonable assumptions of analogy, shows that AVA as licensed is an effective vaccine for the protection of humans against anthrax, including inhalational anthrax, caused by any known or plausible engineered strains of B. anthracis. Recommendations Additional passive protection studies with rabbits and monkeys, including the transfer of animal and human sera, are urgently needed to quantify the protective levels of antibody in vivo against different challenge doses of anthrax spores. Additional active protection studies should be conducted or supported to develop data that describe the relationship between immunity and both specific and functional quantitative antibody levels, including studies of the relationship between the vaccine dose and the resulting level of antibody in the blood of test animals that protects the animals from challenge; the relationship between the level of antibody that protects animals from challenge and the level of antibody present in humans vaccinated by the regimen currently recommended for the licensed product; and the vaccine dose that results in a level of antibody in the blood of human volunteers similar to that in the blood of protected animals. The Department of Defense should support efforts to standardize an assay for quantitation of antibody levels that can be used across laboratories carrying out research on anthrax vaccines. The Department of Defense should pursue or support additional research with laboratory animals on the efficacy of AVA in combination with antibiotics administered following inhalational exposure to anthrax spores. Studies should focus on establishment of an appropriate duration for antibiotic prophylaxis after vaccine administration.

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The Anthrax Vaccine: Is it Safe? Does it Work? BOX ES-2 Chapter 5 Findings and Recommendations Findings The presence or absence of VAERS reports (or other case reports) cannot be considered in and of itself to provide adequate evidence of causal associations or its absence. Reports may suggest hypotheses for further investigation, but it must be borne in mind that many different factors beyond the presence of health symptoms can influence whether a report is filed. Concerns of service members that reporting to VAERS is sometimes discouraged within the military setting have been responded to appropriately with reminders to physicians that DoD policy requires submission of a VAERS report for postvaccination health events that result in hospitalization or the loss of time from duty of more than 24 hours. Additional steps, however, are possible to facilitate reporting to VAERS, including improvements in the coding of health care visits that are potentially vaccine related. The committee has reviewed the case materials and the methods applied by VAERS and AVEC to evaluate those materials and concurs with their conclusions that those materials present no signals of previously undescribed serious adverse reactions associated with exposure to AVA. Recommendations DoD should develop and implement a system to automate the generation of VAERS reports within the military health care system, using codes to identify from automated records those health care visits that are potentially vaccine related. Use of these codes should generate an automatic filing of a VAERS report that includes the specific diagnoses for the clinical event(s) that prompted the health care visit. However, the submission of reports to VAERS should not be restricted to visits assigned codes that identify them as potentially vaccine related.

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The Anthrax Vaccine: Is it Safe? Does it Work? BOX ES-3 Chapter 6 Findings and Recommendations Findings DMSS data are screened quarterly to identify statistically significant elevations in hospitalization and outpatient visit rate ratios associated with receipt of AVA. In this way, DMSS promises to be very useful as a tool for hypothesis generation. The elevated rates of specific diagnoses in the various analyses of DMSS data are not unexpected per se; that is, they appear to be explicable by chance alone. The bias of selection of healthy individuals for receipt of AVA is also a likely explanation for some observed associations. Thus these elevated rate ratios should not be automatically viewed as an indication of a causal association with the receipt of AVA. However, additional follow-up is needed. Examination of data from the DMSS database to investigate potential signals suggested by VAERS reports related to vaccination with AVA has not detected elevated risks for any of these signals for the vaccinated population, although continued monitoring is warranted. The data available from VAERS, DMSS, and epidemiologic studies indicate the following regarding immediate-onset health events following receipt of AVA: Local events, especially redness, swelling, or nodules at the injection site, are associated with receipt of AVA, are similar to the events observed following receipt of other vaccines currently in use by adults, and are fairly common. Systemic events, such as fever, malaise, and myalgia, are associated with receipt of AVA, are similar to the events observed following receipt of other vaccines currently in use by adults, but are much less common than local events. Immediate-onset health effects can be severe enough in some individuals to result in brief functional impairment, but these effects are self-limited and result in no permanent health impairments. There is no evidence that life-threatening or permanently disabling immediate-onset adverse events occur at higher rates in individuals who have received AVA than in the general population. The available data from both active and passive surveillance indicate that there are sex differences in local reactions following vaccination with AVA, as there are following the administration of other vaccines. For female service members, reactions following vaccination with AVA can have a transient adverse impact on their ability to perform their duties. The factors that account for these sex differences are not known. The currently licensed subcutaneous route of administration of AVA and the six-dose vaccination schedule appear to be associated with a higher incidence of immediate-onset, local effects than is intramuscular administration or a vaccination schedule with fewer doses of AVA. The frequencies of immediate-onset, systemic events were low and were not affected by the route of administration. The available data are limited but show no convincing evidence at this time that personnel who have received AVA have elevated risks of later-onset health events.

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The Anthrax Vaccine: Is it Safe? Does it Work? Recommendations AMSA staff should follow up the currently unexplained elevations in hospitalization rate ratios for certain diagnostic categories among the cohorts of AVA recipients. Studies might include additional analyses with the database or examination of medical records to validate and better understand the exposures and outcomes in question. A protocol should be developed to ensure that such follow-up regularly and reliably occurs after a potential signal is generated. Future monitoring and study of health events following vaccination(s) with AVA (and other vaccines) should continue to include separate analyses of data for men and women. DoD should continue to support the efforts of CDC to study the reactogenicity and immunogenicity of an alternative route of AVA administration and of a reduced number of vaccine doses. DoD should develop systems to enhance the capacity to monitor the occurrence of later-onset health conditions that might be associated with the receipt of any vaccine; the data reviewed by the committee do not suggest the need for special efforts of this sort for AVA. BOX ES-4 Chapter 7 Findings FDA’s process of plant inspection and FDA’s validation of the vaccine manufacturing process have changed and have become more stringent with time. With high-priority efforts by the manufacturer and FDA, the manufacturing process for AVA has been validated so that vaccine manufactured postrenovation has been approved for release and distribution. AVA will now be produced by a newly validated manufacturing process under strict controls, according to current FDA requirements. As a result the postrenovation product has greater assurance of consistency than that produced at the time of original licensure.

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The Anthrax Vaccine: Is it Safe? Does it Work? BOX ES-5 Chapter 8 Findings Current events in both the military and the civilian arenas highlight and confirm the importance of ensuring both the availability and the quality of the nation’s anthrax vaccine. The AVA product produced in a renovated facility by a newly validated manufacturing process could differ from the prerenovation product in terms of its reactogenicity, immunogenicity, and stability. The information available to the committee suggests that AVA lots manufactured postrenovation may show less variation in reactogenicity because of greater consistency in the production process, and there is no a priori basis to believe that the postrenovation product will be more reactogenic or less immunogenic than the older vaccine. Given the concerns raised by some service members about the safety of the anthrax vaccine, the creation of AVEC was an appropriate complement to other resources in FDA, the Centers for Disease Control and Prevention (CDC), and DoD for the monitoring of vaccine safety concerns. The results of the extra monitoring did not indicate the existence of any sentinel events that were not detected in the existing FDA and CDC reviews. The committee finds no scientific reason for the continued operation of AVEC in its present form. The possibility of detecting a signal in VAERS will be even more limited for AVA than for many other vaccines, given the relatively small population (primarily military personnel) exposed to the vaccine and the low rates at which the hypothesized health effects of greatest concern might be expected to occur in that population. VAERS is a critically important source of signals, that is, hypotheses about potential associations between a vaccine and a health event, but these hypotheses must be tested through other means. DMSS gives DoD a unique resource with which to conduct such testing. DMSS is a unique and promising population-based resource for monitoring the emergence of both immediate-onset and later-onset (perhaps up to 5 years) health concerns among military personnel and for testing hypothesized associations between such health concerns and exposures resulting from military service, including vaccines. DoD personnel have used DMSS to conduct valuable analyses in response to concerns about health effects that might be associated with vaccination with AVA. Yet DoD personnel working with DMSS data are necessarily limited in time and focus. DMSS data could therefore yield valuable insights in the hands of civilian researchers. DMSS cannot be used to study mild adverse events, even if they are common. Because DMSS captures health care data only for military personnel on active duty, it cannot be used to study the later-onset effects of vaccines over periods of time beyond the normal length of active military service. The current anthrax vaccine is difficult to standardize, is incompletely characterized, and is relatively reactogenic (probably even more so because it is administered subcutaneously), and the dose schedule is long and challenging. An anthrax vaccine free of these drawbacks is needed, and such improvements are feasible.

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The Anthrax Vaccine: Is it Safe? Does it Work? BOX ES-6 Chapter 8 Recommendations As with all vaccines, AVA lots produced postrenovation should continue to be monitored for immunogenicity and stability, and individuals receiving these lots should be monitored for possible acute or chronic events of immediate or later onset. DoD should disband AVEC in its current form and instead assist FDA and CDC in establishing an independent advisory committee charged with overseeing the entire process of evaluating vaccine safety. The proposed advisory committee can also assist on an ad hoc basis in the interpretation of potential signals detected in VAERS or other sources regarding the safety of any vaccine. The newly established FDA drug safety committee might be an appropriate model. If DoD chooses to continue AVEC, DoD should consider redefining the panel’s role so that it serves as an independent advisory committee that responds on an ad hoc basis to specific requests to assist in the interpretation of potential signals detected by others (e.g., CDC and FDA) and reported to VAERS or other sources regarding the safety of all vaccines administered to service personnel rather than continuing the panel’s current role of rereviewing each VAERS report related to AVA. DoD should develop a capability for the effective use of DMSS to regularly test hypotheses that emerge from VAERS and other sources regarding vaccine-related adverse events. DoD should actively support and advance the development of DMSS data resources and the staffing of units that will allow the continuing rapid and careful analysis of these data, including but not limited to the proposed collaboration between CDC and the Army Medical Surveillance Activity. DoD should investigate mechanisms that can be used to make DMSS data available to civilian researchers, as is done by civilian agencies, with appropriate controls and protections for privacy. DoD should develop ad hoc prospective cohort studies in one or more military settings to test hypotheses that emerge from VAERS, DMSS, or other sources. However, the committee does not recommend that such studies targeted at AVA be conducted at present since no convincing evidence of new adverse events in AVA recipients sufficient to merit a prospective investigation has been presented. Rather, further studies of the effects of AVA should be performed in the context of studies of the effects of all vaccines administered to members of the military. DoD should carefully evaluate options for longer-term follow-up of the possible health effects of vaccination against anthrax (and other service-related exposures). The committee recommends consideration of the following specific steps: Encourage participation in the Millennium Cohort Study as part of a program to ensure adequate monitoring for any possible later-onset health effects that might be associated with vaccination with AVA or other service-related exposures. Collaborate with the Department of Veterans Affairs (VA) to monitor service members who receive medical care through VA facilities after separation from military service. Linking of data from DMSS to data from VA is a possible tool. Even though those who receive their medical care through VA may be an unrepresentative minority of all former military personnel, valid comparisons may be pos-

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The Anthrax Vaccine: Is it Safe? Does it Work? sible between those within that population who received a vaccine or other exposure and those who did not. Collaborate with VA to obtain fact-of-death information from the Beneficiary Identification and Records Locator System and with the Social Security Administration to obtain death files. Data on the cause of death should be obtained from the National Death Index as needed. Ensure the long-term maintenance of DMSS and other relevant paper and electronic records so that retrospective studies will be feasible if health concerns are identified in the future. DoD should continue and further expedite its research efforts pertaining to anthrax disease, the B. anthracis organism, and vaccines against anthrax. Research related to anthrax should include, in particular, efforts such as the following: DoD should pursue and encourage research to develop an anthrax vaccine product that can be produced more consistently and that is less reactogenic than AVA; DoD should pursue and encourage research regarding the B. anthracis capsule; DoD should pursue and encourage research on the mechanisms of action of the anthrax toxins; such research could lead to the development of small-molecule inhibitors; DoD should pursue and encourage research to map the epitopes of the protective antigen that correlate with specific functional activities; DoD should pursue and encourage research to test the therapeutic potential of antitoxin proteins or antibodies; and DoD should pursue and encourage research into additional potential virulence factors in B. anthracis and into other possible vaccine candidates. REFERENCES AMSA (Army Medical Surveillance Activity). 2001a. Quarterly Report—January 2001. Surveillance of Adverse Effects of Anthrax Vaccine Adsorbed. Washington, D.C.: Army Medical Surveillance Activity, U.S. Army Center for Health Promotion and Preventive Medicine. AMSA. 2001b. Quarterly Report—April 2001. Surveillance of Adverse Effects of Anthrax Vaccine Adsorbed. Washington, D.C.: Army Medical Surveillance Activity, U.S. Army Center for Health Promotion and Preventive Medicine. AMSA. 2001c. Surveillance of Adverse Effects of Anthrax Vaccine Adsorbed: Results of Analyses Requested by the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine. Washington, D.C.: Army Medical Surveillance Activity, U.S. Army Center for Health Promotion and Preventive Medicine. Auerbach BA, Wright GG. 1955. Studies on immunity in anthrax. VI. Immunizing activity of protective antigen against various strains of Bacillus anthracis. Journal of Immunology 75:129–133.

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