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The Anthrax Vaccine: Is it Safe? Does it Work? 8 Future Needs As described in detail in preceding chapters, the committee found that the available evidence shows that the currently licensed anthrax vaccine, Anthrax Vaccine Adsorbed (AVA), is reasonably safe and effective, with the caveat that the studies reviewed were carried out in populations of healthy adults only. The committee’s research also suggested that the manufacturing process could be validated. As discussed in Chapter 3, the efficacy of the licensed anthrax vaccine—indeed, of any anthrax vaccine—for the stimulation of protective immunity against inhalational anthrax in humans cannot be demonstrated in clinical trials or field trials, as clinical trials that challenged humans with the anthrax bacillus would be impossible—and intolerable—and humans naturally encounter aerosolized Bacillus anthracis spores in few situations. The committee did, however, review evidence from a field trial that showed that a vaccine similar to AVA is effective against B. anthracis infection, that AVA itself is effective in stimulating immunity against inhalational challenge in animals, and that AVA and experimental vaccines that contain protective antigen are effective in protecting immunized animals against challenge with B. anthracis. The standard of reasonable safety does not mean that no adverse events are associated with AVA; indeed, local adverse events including tenderness, erythema, nodules, and some swelling are fairly common and seem to be more frequent in women than in men (Pittman et al., 2002). In addition, some vaccinees experienced systemic effects such as fever, but these effects were less common than local reactions and were transient. Some members
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The Anthrax Vaccine: Is it Safe? Does it Work? of the armed services have been concerned that AVA may cause later-onset systemic or multisystem adverse effects. To date there is limited information pertaining to any possible association between vaccination with AVA and later-onset health conditions, as with most vaccines. The available data, however, provide no evidence of a causal connection between receipt of AVA and later-onset or long-term adverse outcomes. The history of the facility that manufactures AVA has been fraught with difficulties. Over the course of the study, the committee reviewed extensive and detailed exchanges between the manufacturer, BioPort, and the Food and Drug Administration (FDA) regarding the changes to the manufacturing process that were needed. That BioPort has successfully met FDA requirements is welcome news. Nevertheless, the committee is convinced that relying only on the current anthrax vaccine and the current specifications for its use is far from satisfactory. Not only are many avenues for important research toward the development of a different and better vaccine available, but particular improvements in how the current vaccine is used are also urgently needed. Many of these improvements are feasible, which makes their implementation even more compelling. This chapter suggests some directions for further research and action. FUTURE USE OF AVA Finding: 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. Less than a month before this report went to press, BioPort received approval for the first release of lots of AVA produced since 1998. Because the supply of AVA has been limited, the Department of Defense’s (DoD’s) Anthrax Vaccine Immunization Program (AVIP) was proceeding at a reduced rate. Renewed availability of AVA will make possible the resumption of the AVIP schedule. Current events, including the deployment of U.S. troops to Afghanistan and surrounding areas and sabotage of the U.S. mail with items contaminated with B. anthracis spores, strongly suggest not only the resumption but also possibly the expansion of vaccination against anthrax. As stated in the new product label (see Appendix D), the licensed product is indicated for “individuals between 18 and 65 years of age who come in contact with animal products such as hides, hair, or bones that come from anthrax endemic areas, and that may be contaminated with B. anthracis spores. AVA, now carrying the brand name BioThrax,1 is also 1 Biothrax is the name under which AVA will be manufactured as of January 31, 2002.
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The Anthrax Vaccine: Is it Safe? Does it Work? indicated for individuals at high risk of exposure to B. anthracis spores such as veterinarians, laboratory workers, and others whose occupation may involve handling potentially infected animals or other contaminated materials.” This labeled indication has not changed from the original, which was developed in view of the plausible exposures at the time of licensure of the vaccine and was supported by field and observational studies of animal product processors. The subsequent weaponization of B. anthracis, however, changed for DoD the definition of the groups identified as “high-risk persons” to include not only veterinarians but also members of the armed services who were or who might be deployed to areas near countries where B. anthracis had been weaponized. As a result of the recent bioterrorist release of anthrax spores through the U.S. mail system, the definition of “high-risk persons” may be expanded further to include other occupational groups. The population receiving AVA has thus become considerably wider than that anticipated at the time of original licensure. Meanwhile, the supply of the currently licensed vaccine had been limited by manufacturing difficulties, which have now been overcome. As mentioned above and as discussed in more detail in Chapter 7, the AVA manufacturing facility and the AVA production process have both been the subject of numerous FDA citations and responses. Indeed, the manufacturer undertook a thorough renovation of its manufacturing facility starting in 1998 and modernized several aspects of the production process. These modifications, although certainly intended to improve the overall process of vaccine production, are still changes. Changes in facilities or processes, however, can result in changes in the product, and FDA is responsible for monitoring those changes (see Chapter 7). Noting the possibility that these changes may affect the final AVA product does not mean that the changes are necessarily bad; in this case they are surely improvements. On the basis of the information provided in presentations and in papers from both BioPort and FDA, the committee notes that modifications were undertaken to incorporate more modern technology into the manufacturing process and to increase assurance of the consistency of the final product (e.g., in the concentration of protective antigen), which still remains a relatively crude vaccine by current standards. Although greater assurance of product consistency will result from the modifications of the manufacturing facility and the production process that have been undertaken by BioPort and certified by FDA, the levels of immunogenicity, safety, and stability of the postrenovation AVA product must be characterized empirically, as the committee recommends below. The committee emphasizes that the surveillance methods recommended below are the same as those that would be expected for any widely used vaccine and are not unique to AVA.
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The Anthrax Vaccine: Is it Safe? Does it Work? Finding: 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. Recommendation: 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. SURVEILLANCE FOR ADVERSE EVENTS In addition to issuing statements about appropriate filing of reports to the Vaccine Adverse Event Reporting System (VAERS), DoD has supported the review of each VAERS report associated with AVA by an independent civilian advisory panel called the Anthrax Vaccine Expert Committee (AVEC), described in Chapter 5. The Future and AVEC A subgroup of the Institute of Medicine (IOM) committee participated in discussions with members of AVEC to explore their approach to the review of reports and their operating procedures. Although the committee found AVEC’s expert scrutiny of the reported cases and vigilance for signals that might require further action to be an important component of surveillance for concerns about the safety of AVA, the important aspects of the review may not be specific to AVA. The IOM committee is also skeptical of the general approach of attribution of causality from reports in surveillance systems. The way in which events are interpreted and used in analyses should take into account the inherent uncertainties of determining “cause” in such a system. There remains considerable potential for misclassification of reported events when considering them as possibly related or unrelated to vaccination. It is important to recognize that reviews of case reports only generate hypotheses. More emphasis should therefore be placed on the use of AVEC-derived hypotheses to trigger formal analyses, such as those that can be performed with data from the Defense Medical Surveillance System (DMSS). Toward that end, AVEC and the Army Medical Surveillance Activity (the office responsible for DMSS) should maintain regular and frequent communication, with signals from the former leading
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The Anthrax Vaccine: Is it Safe? Does it Work? to analyses by the latter. “Signals” are the earliest indication of a possible causal relationship between an exposure and a health event. Such signals can come from the anecdotal experiences of patients with an adverse event after the exposure or from preliminary analyses of data. A signal does not mean that a causal relationship exists, as there may be other explanations for the apparent association. Instead, a signal is merely an indication that further investigation is needed. Furthermore, AVA appears to be associated with certain adverse events that, although by no means desirable, are self-limited or that, in worst cases, seem to respond to palliative treatment with analgesics or antipyretics. The committee observes that no data to indicate the need for the continuation of special monitoring programs for AVA have emerged, but it recognizes the real concerns of service members ordered to take the vaccine. Vaccine safety in general, and the safety of less commonly used vaccines that members of the U.S. military in particular are required to receive, remains a concern. In the course of reviewing information from monitoring systems, the committee observed several areas in which surveillance for the safety of vaccines in general, including AVA, might be improved. Finding: 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 IOM committee’s observation about AVEC reflects no fault with the members of AVEC or its performance as that committee is constituted; rather, the IOM committee observes that AVEC was designed to pay extra attention to concerns regarding the safety of AVA and that the data do not warrant the continuation of such exceptional attention. The resources supporting AVEC activities related to AVA alone could be more wisely invested in improved monitoring of the safety of vaccines in general. Recommendation: 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 and Risk Management Advisory Committee might be an appropriate model.
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The Anthrax Vaccine: Is it Safe? Does it Work? Because AVEC was designed to review VAERS reports for signals of unexpected adverse events caused by AVA, AVEC had to attempt to discriminate correlation and causality on the basis of the VAERS reports. The VAERS reports, however, are not able to capture data sufficient to support conclusions related to causality. The committee therefore believes that DoD should recommend a shift in focus from making attributions of causality in individual cases to seeking evidence of any patterns or rate thresholds that have been crossed in terms of the serious adverse events reported to VAERS. AVEC’s replacement could then develop criteria for signals from VAERS data for any vaccine that warrant additional follow-up and could in general further systematize its processes by developing standard operating procedures and a regular schedule for examination of aggregate VAERS data. Background rates of illnesses as well as the biological plausibility of hypothesized effects must be taken into consideration as part of the method used to identify signals of possible safety concerns regarding AVA. Different roles for the panels that might replace AVEC are described in Table 8-1. TABLE 8-1 Functions of AVEC and Post-AVEC Panels Function AVEC Redeployed AVEC Panel Replacing AVEC Mission Individual review of VAERS reports to assess causal relationship of AVA and adverse events Provide ad hoc advice as needed on interpretation of potential signals in VAERS or other sources relevant to vaccine safety Provide oversight and advice on safety evaluations and advice in specific cases Scope All AVA-related VAERS reports All vaccines administered to service personnel Entire process of vaccine safety evaluations, plus provision of advice as needed on interpretation of potential signals from VAERS or other sources relevant to the safety of any vaccine Model Advisory Committee on Causality Assessment (Canada) Advisory committee (responding to ad hoc agency requests for advice on specific products) FDA Drug Safety and Risk Management Advisory Committee (broad mandate and oversight, as well as ad hoc advice)
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The Anthrax Vaccine: Is it Safe? Does it Work? Recommendation: 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. Although there are serious obstacles and some impassable informational gulfs between VAERS reports and conclusions related to causality for any vaccine, there are some additional difficulties for AVA because, at least to date, the population receiving the vaccine is small. More than 2 million doses of AVA have been distributed since 1990, and about 500,000 members of the armed forces have received the vaccine. By contrast, multiple doses of many other vaccines, such as the diphtheria and tetanus toxoid and acellular pertussis vaccine, the Haemophilus influenzae type b vaccine, or inactivated polio vaccine, are administered to some 3 million to 4 million children each year. Finding: 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. Additional Sources of Data on Adverse Events Although the IOM committee does not recommend continuation of AVEC as a program that monitors AVA-specific reports in VAERS, the committee does believe that it is essential for DoD to continue to work with CDC and FDA to ensure that VAERS reports are regularly and carefully monitored for any signals that vaccines administered to military service personnel might be associated with adverse health effects. Ensuring the best use and interpretation of VAERS reports, however, requires complementary information from other sources that can be used to help analyze the signals that may be suggested by VAERS reports. One such resource, as discussed earlier, is DMSS. DMSS can be used both to generate and test hypotheses. If VAERS raises a hypothesis, it can be further evaluated in DMSS. DMSS data can also be used to generate hypotheses (as in its quarterly screening reports); these then need to be evaluated in more detail within DMSS, including more detailed data analyses and efforts that might involve review of medical records, for example. Formal testing of these hypotheses would require additional studies, however, in separate datasets.
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The Anthrax Vaccine: Is it Safe? Does it Work? Finding: 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. A formal mechanism for the direct examination of signals from VAERS using DMSS data should be established. The committee was impressed with information presented on the types of data maintained in DMSS datasets on medical encounters for any reason in the military health care system. Finding: 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. Because DMSS is designed to capture records for all medical encounters without depending on the decision of a patient or a physician to report a particular encounter, DMSS data may be cross-checked with the more open-ended but much less complete case reports collected through VAERS. DoD personnel have already conducted some analyses of this sort, and such analyses should continue on a regular basis. But conducting these analyses on a timely basis will require additional analytic resources. The committee believes that DoD must enhance its internal analytic capacity. A proposed collaboration between CDC and the Army Medical Surveillance Activity (Schwartz, 2002) holds promise for increasing the human resources available to apply to hypothesis testing, while AMSA personnel retain their focus on surveillance. In addition, DoD should explore ways to take advantage of the analytic resources of the civilian research community as other federal agencies do. The Centers for Medicare and Medicaid Systems, for example, have developed mechanisms to give researchers access to large databases with information on individual program participants and their medical claims while maintaining appropriate protections for privacy and confidentiality. Similarly, research partnerships with the Canadian province of Saskatchewan may offer another useful model. Recommendation: 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. Finding: 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.
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The Anthrax Vaccine: Is it Safe? Does it Work? Recommendation: 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. Recommendation: 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. The main limitations of the DMSS databases with respect to the study of adverse events associated with vaccination are actually related to its main strength. That is, although DMSS collects records of all medical encounters, it cannot capture the adverse events that a vaccine recipient experiences but for which the recipient does not seek medical attention within the military medical system. Because most vaccine-related adverse events are relatively mild and self-limiting, they will not appear in the DMSS database. Finding: DMSS cannot be used to study mild adverse events, even if they are common. This limitation can be mitigated with prospective studies and active surveillance of limited populations of vaccinees. Recommendation: 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. Another aspect of the DMSS database that must be taken into consideration for overall monitoring of vaccine safety is that DMSS contains data on medical encounters only for active-duty personnel. Most service members do not become career military personnel, so DoD surveillance systems can monitor their health for only a few years. Later-onset effects of vaccines, if any, would thus not be captured for most service members. Finding: 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.
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The Anthrax Vaccine: Is it Safe? Does it Work? As discussed in Chapter 6, data on the later-onset adverse effects of vaccines are available for few, if any, vaccines. Although the committee found no data indicating that vaccination with AVA is associated with later-onset adverse events or with any serious or lasting adverse events, some service members have had serious concerns about possible links between AVA and such adverse events. To make it possible to conduct studies of later-onset health concerns, DoD could take steps to improve access to data on the chronic or later-onset effects, if any, of vaccines in general. Recommendation: 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 Study2 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. NEW ANTHRAX VACCINE DEVELOPMENT Although AVA appears to be sufficiently safe and effective for use and its use is certainly preferable to a substantial threat of contracting anthrax, 2 The Millennium Cohort Study is a survey recommended by the U.S. Congress and sponsored by the DoD. The study will monitor a total of 140,000 U.S. military personnel during and after their military service for up to 21 years to evaluate the health risks of military deployment, military occupations, and general military service (see http://www.millenniumcohort.org/about.html).
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The Anthrax Vaccine: Is it Safe? Does it Work? AVA is far from optimal whether it is considered from the point of view of the potential recipient, the manufacturer, or any involved party. Finding: 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. The committee urges that improvements in the route of administration and the number of injections of the existing licensed anthrax vaccine, AVA, be made as quickly as possible. As mentioned earlier in this report, the committee believes that the lot-to-lot consistency of AVA will be better assured when the vaccine is produced in the fully renovated facility using the newly certified manufacturing processes and that such an improvement is desirable. The committee also believes that it is likely that the rate of adverse events and the general acceptability of AVA will improve with a change in the route of administration and a reduction in the total number of injections required and that such improvements would be desirable. Research to assess the effects of those changes in the route of administration was under way as this report was being prepared. Any improvements to the way the current vaccine is used that can limit the occurrence of common local and systemic effects will be welcome by all parties involved. But the committee concludes that a new vaccine, developed according to more modern principles of vaccinology, is urgently needed. The committee proposes characteristics, based on experience with other vaccines, that might reasonably be sought in a new vaccine (see Box 8-1). It was beyond the committee’s charge to comment on any particular program to develop a new vaccine against anthrax or to review research related to the development of a new vaccine. The committee does understand that research on new vaccines against anthrax is well under way in several areas in DoD, the National Institutes of Health, and various university laboratories and strongly encourages continued and further support of work on promising new vaccines. The knowledge that has been and that is still being gained from research with AVA on topics such as correlates of immunity in animals, the components necessary to stimulate protective immunity, and the best way to administer the vaccine should be helpful in the development of new and improved vaccine products for protection against anthrax. Research to date shows anthrax to be a complex disease, with complicated protective immune responses. Additional research should speed the urgently needed development of improved means of protection against this disease.
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The Anthrax Vaccine: Is it Safe? Does it Work? BOX 8-1 Goals of Anthrax Vaccine Development Product characteristics Antigen: The vaccine antigen, which must be demonstrated to stimulate protective immunity, should consist of a purified protein, a mixture of defined and purified proteins, or a conjugate of a purified protein and the capsule. Dose requirements: The vaccine should require only two or three injections to elicit high titers of antibodies against the antigen. Immunogenicity: The vaccine should be sufficiently immunogenic to elicit protective antibodies within 30 days so that antibiotics given to exposed individuals could be safely discontinued at 30 days. Stability: The potency of the vaccine should remain stable for a long period of time, allowing it to be stockpiled. Product performance Efficacy: The vaccine should be demonstrated to protect monkeys challenged by the aerosol route, with immunity retained for at least a year after the completion of immunization. Local reactions: The vaccine should not cause severe local reactions. This is important not only for better tolerability but also because severe local reactions may create a perception that a vaccine is dangerous, even when the local effects are transient and self-limited. Systemic reactions: The vaccine should not cause severe systemic adverse reactions, as is expected of all vaccines. Manufacturing Production process: The production process for the vaccine should be easily scaled up and should ensure maintenance of product consistency. Recommendation: 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;
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The Anthrax Vaccine: Is it Safe? Does it Work? 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 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. Schwartz B. 2002. Hypothesis testing using the DMSS: outline for a CDC-AMSA collaboration. Presentation to the Institute of Medicine Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program, Meeting V, Washington, D.C.
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