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.
These findings and recommendations appear in The Anthrax Vaccine: Is It Safe? Does It Work? (Institute of Medicine, 2002; LM Joellenbeck, LL Zwanziger, JS Durch, BL Strom, eds.; Washington, D.C.: National Academy Press). The complete report is available on the Internet at http://www.nap.edu/catalog/10310.html.
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Appendix G Institute of Medicine: The Anthrax Vaccine: Is It Safe? Does It Work? Findings and Recommendations1 CHAPTER 3 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. 1 These findings and recommendations appear in The Anthrax Vaccine: Is It Safe? Does It Work? (Institute of Medicine, 2002; LM Joellenbeck, LL Zwanziger, JS Durch, BL Strom, eds.; Washington, D.C.: National Academy Press). The complete report is available on the Internet at http://www.nap.edu/catalog/10310.html.
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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 the 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. CHAPTER 5 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. Recommendation 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
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care visit. However, the submission of reports to VAERS should not be restricted to visits assigned codes that identify them as potentially vaccine-related. CHAPTER 6 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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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. 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. 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.
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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 of the emergence of both immediate-onset and later-onset (perhaps up to 5 years) health concerns among military personnel and for testing of 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. 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.
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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 possible 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.