1
Introduction

In the autumn of 2001, following the terrorist attacks of September 11, anthrax and the anthrax vaccine became prominent national concerns. The deliberate distribution of anthrax spores through the U.S. mail resulted in 5 deaths from inhalational anthrax, 6 additional cases of inhalational anthrax that were successfully treated, 12 cutaneous anthrax infections (confirmed and suspected; CDC, 2001), and the treatment of thousands of others with known or suspected exposure to anthrax spores. Previously, concerns about anthrax had focused on its possible use as a biological weapon in a military context.

During the 1991 Gulf War, concerns that Iraq had prepared anthrax spores for use as a biological weapon motivated the U.S. military to administer the licensed anthrax vaccine to an estimated 150,000 service members. After the war, admission by Iraq that it had indeed produced weapons containing anthrax spores confirmed fears of the potential use of anthrax as a biological weapon (Henderson, 1999; Zilinskas, 1997). As a response to this threat, in December 1997 Secretary of Defense William Cohen announced a plan to vaccinate all U.S. service members for anthrax using the licensed anthrax vaccine. The universal vaccination plan was to be phased in gradually, starting with service members judged most likely to encounter the threat. Service members scheduled for deployment to areas considered to be “high risk” began to receive vaccinations through the Department of Defense’s (DoD’s) Anthrax Vaccine Immunization Program starting in March 1998. As more service members received the mandatory vaccines,



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The Anthrax Vaccine: Is it Safe? Does it Work? 1 Introduction In the autumn of 2001, following the terrorist attacks of September 11, anthrax and the anthrax vaccine became prominent national concerns. The deliberate distribution of anthrax spores through the U.S. mail resulted in 5 deaths from inhalational anthrax, 6 additional cases of inhalational anthrax that were successfully treated, 12 cutaneous anthrax infections (confirmed and suspected; CDC, 2001), and the treatment of thousands of others with known or suspected exposure to anthrax spores. Previously, concerns about anthrax had focused on its possible use as a biological weapon in a military context. During the 1991 Gulf War, concerns that Iraq had prepared anthrax spores for use as a biological weapon motivated the U.S. military to administer the licensed anthrax vaccine to an estimated 150,000 service members. After the war, admission by Iraq that it had indeed produced weapons containing anthrax spores confirmed fears of the potential use of anthrax as a biological weapon (Henderson, 1999; Zilinskas, 1997). As a response to this threat, in December 1997 Secretary of Defense William Cohen announced a plan to vaccinate all U.S. service members for anthrax using the licensed anthrax vaccine. The universal vaccination plan was to be phased in gradually, starting with service members judged most likely to encounter the threat. Service members scheduled for deployment to areas considered to be “high risk” began to receive vaccinations through the Department of Defense’s (DoD’s) Anthrax Vaccine Immunization Program starting in March 1998. As more service members received the mandatory vaccines,

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The Anthrax Vaccine: Is it Safe? Does it Work? however, some raised concerns about the safety and the efficacy of the vaccine being administered. Responding to those concerns, the U.S. Congress included language in the conference report accompanying the 2000 DoD appropriations legislation directing DoD to enter into a contract with the National Research Council to study the effectiveness and safety of the anthrax vaccine.1 Congress called for the study to examine the safety and efficacy of the licensed vaccine, including consideration of the types and severities of adverse reactions, differences in reactions by sex, long-term health implications, its efficacy against inhalational exposure to all known anthrax strains, and 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 the validation of the manufacturing process, with consideration of discrepancies identified by the Food and Drug Administration in February 1998, definition of vaccine components, and identification of gaps in existing research. (See Appendix A for the Statement of Task.) In June 2000 a contract between DoD and the Institute of Medicine (IOM) was finalized to carry out the study requested by Congress. IOM convened the Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, and this report reflects the work of that committee. STUDY PROCESS AND INFORMATION SOURCES Reflecting the components of the statement of task, the members of the Committee to Assess the Safety and Efficacy of the Anthrax Vaccine brought expertise in microbiology; vaccine research, development, manufacture, and evaluation; postmarketing surveillance of adverse events; regulatory and licensing procedures; epidemiology; biostatistics; immunology; and health surveillance (see Appendix B for biographical sketches of the committee members). The committee’s 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 ). 1   Making Appropriations for the Department of Defense for the Fiscal Year Ending September 30, 2000, and for Other Purposes, P. L. No. 106-79 (1999).

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The Anthrax Vaccine: Is it Safe? Does it Work? 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 gathered information for the study through several means. The committee held a total of four public workshops to collect relevant information; the dates and locations of these meetings are provided in Appendix C. At these meetings, researchers presented the committee with data gathered in studies of the safety of the vaccine. In addition, the committee heard from service members and others with concerns about the safety and efficacy of the vaccine, as well as additional information about the manufacture of the vaccine and the disease itself. The committee also commissioned a paper to review the available literature regarding the rates of adverse events associated with several vaccines routinely administered to adults. Information on the anthrax vaccine was obtained from DoD, the Food and Drug Administration, and BioPort, the current manufacturer. In addition to its four public workshops, the committee met in two additional meetings and two conference calls. The committee sought access to all possible data, not just published data. Only a few studies on the safety of the anthrax vaccine had been published by the time the committee preparing this report began its work in October 2000. However, several studies had been conducted by DoD investigators, who were urged by IOM and DoD to publish their work. Over the course of this study, investigators made available to the committee several manuscripts submitted or planned for submission for publication. The investigators involved in many of the studies, published or unpublished, also attended open committee meetings to present their data and discuss their findings with the committee. In addition, several analyses of existing data were carried out at the committee’s request, and these provided some of the most compelling information supporting the committee’s findings on safety. RELATED REPORTS IOM Letter Report on Anthrax Vaccine The conference report mandating the current study required that a preliminary report be submitted to Congress by April 1, 2000. At the time of the legislation, the IOM Committee on Health Effects Associated with Exposures During the Gulf War was active in its work to evaluate the published scientific literature concerning the agents to which Gulf War veterans may have been exposed. Since the anthrax vaccine was among these exposures, the committee had already reviewed the available database

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The Anthrax Vaccine: Is it Safe? Does it Work? regarding the safety, but not the efficacy, of the vaccine. To be responsive to Congress and DoD, that committee issued a letter report on March 30, 2000 (see Appendix H). The letter report summarized the IOM committee’s review of the literature on the safety of the anthrax vaccine. After a review of only primary peer-reviewed literature, the committee concluded that there was inadequate or insufficient evidence to determine whether an association does or does not exist between vaccination against anthrax and long-term adverse health outcomes. The committee noted the large body of results that had not yet been published and strongly urged investigators conducting relevant studies to submit their results to peer-reviewed scientific journals for publication. The same committee released the first volume of its full report in September 2000 (IOM, 2000). In its chapter on vaccines, the Committee on Health Effects Associated with Exposures During the Gulf War provided a review of the published studies available. In addition to the conclusion about long-term health outcomes noted above, the committee concluded that “there is sufficient evidence of an association between anthrax vaccination and transient acute local and systemic effects (e.g., redness, swelling, fever) typically associated with vaccination” (IOM, 2000, p. 16). Again, that committee urged publication of additional studies in peer-reviewed scientific journals. IOM Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program In the 2000 Department of Health and Human Services appropriations legislation, Congress provided funding to the Centers for Disease Control and Prevention (CDC) for an effort to study the safety and efficacy of vaccines used against biological agents. The mandate was to (1) address risk factors for adverse events, (2) determine immunological correlates of protection and document vaccine efficacy, and (3) determine the optimal vaccination schedule and routes of administration.2 CDC contracted with IOM to establish an expert panel to review the completeness and appropriateness of the CDC plan for responding to the congressional mandate. The IOM Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program began its work in October 2000. The committee’s interim report, which provided preliminary findings and recommendations about the CDC research plans, was released to the public on July 2, 2001 2   An Act Making Consolidated Appropriations for the Fiscal Year Ending September 30, 2000, and for Other Purposes, P. L. No. 106-113 (1999).

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The Anthrax Vaccine: Is it Safe? Does it Work? (IOM, 2001). Four members of the committee also serve on the IOM Committee to Evaluate the Safety and Efficacy of the Anthrax Vaccine, which carried out the study described in this report. ACIP Recommendations In December 2000 a report regarding recommendations for use of the anthrax vaccine was released by the Advisory Committee on Immunization Practices (ACIP) (CDC, 2000). This committee consists of 15 experts selected to provide advice to the Secretary of Health and Human Services and CDC regarding the routine use of vaccines (http://www.cdc.gov/nip/ACIP/). In Use of Anthrax Vaccine in the United States, ACIP reviewed safety and efficacy data and recommended routine vaccination with Anthrax Vaccine Adsorbed (AVA) for those working with large quantities or concentrations of Bacillus anthracis and those conducting activities with a high potential for B. anthracis aerosol production (CDC, 2000). ACIP did not recommend preexposure vaccination for emergency first responders, federal responders, medical practitioners, or private citizens for bioterrorism preparedness because “the target population for bioterrorist release of B. anthracis cannot be predetermined, and the risk of exposure cannot be calculated. . . . For the military and other select populations or for groups for which a calculable risk can be assessed, pre-exposure vaccination may be indicated” (CDC, 2000, p. 12). Since the release of that report, the intentional mailing of anthrax spores in letters in October 2001 and the subsequent illnesses and deaths from anthrax have heightened interest in the use of AVA for a wider population. At the time of this writing, however, ACIP had not altered its recommendations regarding the populations for whom vaccination would be indicated. GENERAL PRINCIPLES REGARDING USE OF VACCINES Like all medical interventions, vaccines should be used only when the potential benefits from the intervention warrant the risks of adverse effects. Vaccines, however, differ from drugs used for treatment, and in the case of a vaccine against anthrax, some additional special considerations affect the trade-off. First, vaccines share with other preventive interventions the burden of being used prophylactically for otherwise healthy individuals. Their use is intended for prevention rather than treatment. As such, they are given to healthy individuals, so it is less tolerable if they cause adverse effects in the course of promoting overall health. The burden of proof for the safety of vaccines is therefore even higher than the burden of proof for the safety of

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The Anthrax Vaccine: Is it Safe? Does it Work? other medical interventions. This makes it even more important that their risk-benefit balance be as favorable as possible. Second, one must consider very carefully the appropriate target group that should receive the vaccine. For some vaccines, the target group is the entire population. Often, that is because of the phenomenon of “herd immunity”; that is, for diseases that can be transmitted from person to person (e.g., poliomyelitis), it benefits the entire population to have others protected from the disease, as it reduces the risk to the population as well as to the individual. For other vaccines (e.g., tetanus toxoid), the illness cannot be passed from person to person, but the vaccine is nevertheless recommended for use by everyone since everyone is at sufficiently high risk of the disease. For still other vaccines, there are clearly identifiable target groups at higher risk; for example, typhoid vaccine is recommended for use by travelers to developing countries. In the case of a vaccine against anthrax, the situation is even more complex. The illness cannot be transmitted from person to person. There-fore, there is no possibility of herd immunity, nor is there a reason to vaccinate the entire population. Thus, the vaccine should be targeted to those at higher risk of disease. In light of recent events, however, that target population has become very fluid, whereas formerly it was definable. Historically, the licensed vaccine was recommended only for those at risk for occupational exposure to anthrax bacteria or spores. However, in recent years the risk of biological warfare led to a judgment that military personnel were at occupational risk of exposure and should receive the anthrax vaccine. Recent bioterrorist use of anthrax spores in the U.S. mail system has indicated that some civilian populations might even be considered at sufficient risk to warrant their use of an anthrax vaccine, if one were available, sufficiently safe, and sufficiently effective. As noted earlier, this report does not address the military policy to vaccinate all service members, nor does it consider which other populations should be considered for vaccination. These questions were not part of the charge to the committee, nor is biological warfare or bioterrorist risk assessment part of its expertise. Rather, the report focuses on the efficacy and safety of the current licensed vaccine and provides information for those who must establish vaccination policy. ORGANIZATION OF THE REPORT The varied components of the committee’s statement of task (see Appendix A) fall into broad categories of efficacy, safety, manufacturing, and future needs. This report is organized into these categories as well. Chapter 2 provides background material about the disease known as anthrax, the licensed anthrax vaccine, and the data available for evaluation of its safety

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The Anthrax Vaccine: Is it Safe? Does it Work? and efficacy. Information relevant to assessing the efficacy of the vaccine is presented in Chapter 3. The establishment of efficacy is crucial before one can consider the use of any such intervention, and no safety risk is tolerable in the absence of efficacy. Chapter 4 introduces the types of information available concerning the assessment of vaccine safety, whereas Chapters 5 and 6 review the safety data available on this vaccine from case reports and from epidemiologic studies, respectively. Issues related to manufacturing are reviewed in Chapter 7, and in Chapter 8 the committee discusses needs for future efforts, including gaps in research. REFERENCES CDC (Centers for Disease Control and Prevention). 2000. Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR (Morbidity and Mortality Weekly Report) 49(RR-15):1–20. CDC. 2001. Update: investigation of bioterrorism-related inhalational anthrax—Connecticut, 2001. MMWR (Morbidity and Mortality Weekly Report) 50(47):1049–1051. Henderson DA. 1999. The looming threat of bioterrorism. Science 283(5406):1279–1282. IOM (Institute of Medicine). 2000. Gulf War and Health. Washington, D.C.: National Academy Press. IOM. 2001. CDC Anthrax Vaccine Safety & Efficacy Research Program. Interim Report. Washington, D.C.: National Academy Press. Zilinskas RA. 1997. Iraq’s biological weapons: the past as future? JAMA 278(5):418–424.