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1 Introduction and Background l Anthrax is a disease caused by a common ant! wiclespreact organism, Bacillus anthracis, whose characteristics make it a feasible choice for biological warfare; examples of weapons development programs using B. anthracis are well known. Because of the potential that biological weapons using B. anthracis might be directed against the United States military, on May 18, 1998, the Department of Defense (DoD) ordered all service personnel to be fully vaccinated for protection against anthrax (the Anthrax Vaccine immunization Program, AV1P). Limited availability of the anthrax vaccine forced at least a temporary siow-clown in attaining this goal. But in acIdition to supply problems, the anthrax vaccine and AVTP have also been the subject of an unusual degree of concern from service personnel, regarding possible adverse events associated with the vaccine. Because of the importance of protecting service personnel against biological warfare using B. anthracis, and because of concern among troops and their families about adverse events possibly associated with the anthrax vaccine, the Congress has also been interested in the policy and its justification and ramifications. The DoD and the Centers for Disease Control and Prevention (CDC) were directed to undertake additional research on the vaccine, both individually and collaboratively. The CDC contracted with the Institute of Medicine (IOM) to establish an expert pane] to review the completeness and appropriateness of the CDC plan for responding to the congressional mandate that CDC conduct research on the safety and efficacy of anthrax vaccine. The committee's Statement of Task (Box 1-~) reflects the congressional appropriations language (which became the Department of Health and Human Services Appropriations Act of 2000, now Public I,aw 106-1 13) almost exactly, as comparison with Box I-2 shows. Congress (Erected the CDC and the NIH and DoD to collaborate and cooperate fully in this effort. Meanwhile, the DoD received congressional direction in the DoD Appropriations Act of 2000, now Public Law 106- 79, whose conference report language called for study of technical matters regarding the safety and efficacy of the licensed anthrax vaccine. DoD therefore also contracted! with the lOM for a separate study (see Box I-3 for that committee's Statement of Task). The DoD-sponsored study is aimed at currently existing data on the safety and efficacy of the currently administerecl vaccine. The CDC-sponsorect study was intenclec3 as a review of the CDC's plans for further research into the safety, effectiveness, and acceptability of the anthrax vaccine. The CDC- 11

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12 CDC ANTHRAX VA CCINE SAFETY & EFFICA CY RESEARCH PROGRAM sponsored study contract also called for this interim report. The full study is planner! for a total duration of 24 months. This interim report sets out the committee's findings, eight months into the project. Both the committee's review anti the CDC's research program are ongoing, and further clevelopments are expected. BOX 1-1 Statement of Task: Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program This committee will advise the Centers for Disease Control and Prevention (CDC) on the completeness and appropriateness of the CDC plan to respond to the Congressional man- date to study the safety and efficacy of anthrax vaccine, addressing (1) risk factors for ad- verse reactions, including gender differences; (2) determining immunologic correlates of protection and documenting vaccine efficacy; (3) optimizing the vaccination schedule and routes of administration to assure efficacy while minimizing the number of doses required and the occurrence of adverse events. The CDC, the National Institutes of Health (NIH), and the Department of Defense (DoD) are directed by Congress to collaborate and coop- erate fully in this effort. BOX 1-2 Congressional Language Regarding Anthrax Vaccine Research, FY 2000-1 Public Law 106-1 13 provided fiscal year 2000 funding "to the Centers for Disease Control and Prevention (CD CJ for a collaborative effort to study the safety and efficacy of vaccines used against biological agents. The study shall address: (1J the risk factors for adverse events, including differences in rates of adverse events be- tween men and women; (2J determining immunological correlates of protection and docu- menting vaccine efficacy; and (3J optimizing the vaccination schedule and administration to assure efficacy while minimizing the number of doses recluired and the occurrence of ad- verse events. It is intended that NIH, CD C, and the Department of Defense will fully coop- erate in this effort." This excerpt of PL 106-113 is the language that formed the basis of the contract for this project. In the succeeding year, however, Congress made additional comment as follows in the House-Senate conference report that was generated during fiscal year 2001 appropria- tions legislation, with fiscal year 2001 funding finally provided by Public Law 106-554. "Regarding the anthrax study, the conferees understand that clinical studies will be greatly facilitated by the establishment of the Vaccine Healthcare Center Network, with the first site at Walter Reed Army Medical Center. The Network will facilitate data collection, standardi- zation of the anthrax immunization, training and general data collection for this project."

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INTRODUCTION & BACKGROUND 13 BOX ~ -3 Statement of Task: DoD-Sponsorec' Committee to Assess the Safety ant! Efficacy of the Anthrax Vaccine The committee will analyze available information, hold workshops, and make specific rec- ommendations on technical aspects regarding the safety and efficacy of the licensed an- thrax vaccine. The issues include the types and severity of adverse reactions, including gender differences; long-term health implications; inhalational efficacy of the vaccine against all known anthrax strains; correlation of animal models to safety and effectiveness in humans; validation of the manufacturing process focusing on, but not limited to discrep- ancies identified by the Food and Drug Administration in February 1998; definition of vac- cine components in terms of the protective antigen and other bacterial products and con- stituents; and identification of gaps in existing research. ANTHRAX DISEASE AND PREVENTION Anthrax Disease Anthrax disease is caused by an infection with Bacillus anthracis (Brachman ant! Friediander, 1999; Dixon, 19991. The endospores of B. anthracis remain dormant in soil and are very resistant to physical and chemical conditions like heat, dryness, and disinfectants to which many organisms are susceptible. This hardiness is one characteristic that makes the organism practical as a weapons component (Tnglesby, 1999; Zilinskas, 1997~. B. anthracis can cause cutaneous, gastrointestinal, or inhalational anthrax disease, ciepencling on the route of entry into the body (Brachman and FriedIander, 19991. Grazing animals can become infected and, in turn, can infect humans, but transmission of inhalational anthrax between human beings has not been documented. Cutaneous anthrax is generally associates! with handling infected animals or their products, and is manifested as lesions that form vesicles and finally ulcers marked by a characteristic black eschar. Patients can be treated with antibiotics, and the survival rate is then over 95%. Gastrointestinal anthrax can be causer! by eating infected meat. The fatality rate is variable, estimated at 25 to 75%. Inhalational anthrax is usually, if not always, fatal, even with aggressive treatment, within a matter of (lays after onset of symptoms (Brachman and FriedIander, ~ 9991. Inhalational anthrax is the primary focus of the current United States military immunization program because this clisease manifestation is of interest as a possible outcome of biological warfare. Tnhalational anthrax depends on aerosolization of the endospores, which does not normally occur in nature but can happen under industrial conditions (as in goat hair, wool and hicle processing plants) or by means of weapons. B. anthracis infection and pathogenesis begin with the introduction of endospores through abrasions in the skin, or by ingestion or inhalation. The endospores then are phagocytosecl by macrophages, wherein they germinate and are released as vegetative bacilli, which multiply in lymph nodes and then may enter the blood stream in great numbers, causing massive septicemia. The latter condition is more likely in inhalational anthrax than in the other forms. The virulence of the anthrax bacilli depends on expression of both bacterial capsule and toxins, the genes for which are carried on two plasmids. The loss of either the plasmid bearing the genes for the toxins, or the capsule gene plasmitl, attenuates the bacterium such that it becomes unable to cause disease. It is the effects of those toxins that actually cause human disease, but the capsule inhibits the phagocytosis of vegetative bacteria. The plasmid carrying the toxin genes actually codes for three distinct proteins: protective antigen (PA), edema factor (EF), and lethal factor (LF). These factors then combine to form two toxins, each with an active domain and a binding

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14 CDC ANTHRAX VACCINE SAFETY & EFFICACY RESEARCH PROGRAM domain. The toxins are eclema toxin, comprising PA and EF, and lethal toxin, composed of PA and EF. In both cases, PA seems to mediate binding of the toxin to the target cell and its translation to the cell's interior. The eclema toxin includes an actenylate cycIase, which causes increased levels of cAMP and interferes with the cell's water balance, resulting in edema. The lethal toxin includes a protease that stimulates the release from macrophages of tumor necrosis factor or and interIeukin-1 0, which along with other cytokines may be the specific effect of lethal toxin in mortality (Brachman and FriedIander, 1999; Dixon, 1999; Little and Ivins, 19991. Anthrax Vaccine Anthrax is among the first diseases for which the protective efficacy of vaccination was evaluated (Turnbull, 19914. The human efficacy data for the currently licensed vaccine comes from a field study of a similar vaccine in mill workers (Brachman et al., 1962, and see FriedIander, et al., 1999 for review). The stucly (which was randomized and placebo-controlled) was conducted among the workers in four northeastern United States mills that were engaged in the processing of raw goat hair. Cutaneous anthrax was a problem in the mills, and the results of the study showed 92.5% protection against cutaneous anthrax among vaccinees (gastrointestinal anthrax was not a problem in the mills, and the number of cases of inhalational anthrax was too small to serve as evidence for or against vaccine efficacy). That vaccine has been shown to be effective in protecting animals from aerosolized B. anthracis anthrax spores. The licensed anthrax vaccine is a sterile filtrate, the major active ingredient being PA, from cultures of an avirulent, non-encapsulated strain of B. anthracis. The V770-NPl-R strain of anthrax bacilli is grown in a chemically cleaned culture medium. The whole bacteria in the culture are removed by filtration from the culture medium. The antigen is then adsorbed onto aluminum hydroxide, and the product is caller! Anthrax Vaccine Adsorbed, or AVA. The current vaccine differs slightly from the initial field trial tested vaccine in that it starts with a different avirulent strain cultured under different conclitions, and uses a different aluminum preparation (Myers, presentation, 2001~. There have been no randomizes! placebo-controlled clinical trials of the efficacy of this vaccine, but its protective efficacy has been demonstrated in several animal species. AVA is not at this time being procluced, but is licensed to be manufactured by Bioport Corporation of Michigan. (Bioport, ~ 9991. The composition of the filtrate includes PA, possibly with traces of lethal toxin (and perhaps previously edema toxin, as mentioned in Brachman and FriedIander, ~ 999, though not according to recent company information) and other materials. The amount of protective antigen and other proteins per 0.5 m! dose is variable, approximately 50 micrograms of protein, of which 10 to 20 micrograms are PA, per dose (Bioport, presentation, 2001~. The vaccine contains no more than 0.83 mg of aluminum per (lose, 0.0025% benzethonium chloride as a preservative, and formaldehyde in final concentration not to exceed 0.02%. The potency and safety of the product comply with Focal and Drug Administration (FDA) regulations. The content (purity) of PA averaged 50% with a standard deviation of 7%. Some data suggest that immunity is largely, if not entirely, a response to PA (On relevance of PA, see, for example, Gladstone, 1946; Dixon et al., 1999; Little and Ivins, 1999; and on aluminum hydroxide as an adjuvant, see for example, Wright et al., 1954, 1962; Ivins et al., 19951. Modification of the current dosage and route of administration for the licensed product might improve its acceptability. AVA is given subcutaneously, a route that is typically associated with greater reactogenicity relative to intramuscular administration (ACIP, 19941. AVA is an unusual vaccine product because it is the only licensed vaccine to include aluminum hydroxide and to be labeled for subcutaneous administration. The immunization schedule of multiple doses and

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INTRODUCTION & BACKGROUND 15 boosters that is currently specified in the package insert was based on the number of immunizations found to afford protection against cutaneous anthrax in the field study by Brachman et al. (1962), and this inoculation schedule was not evaluated against other possible scheclules. The dosage schedule is currently a 0.5 m! injection at 0, 2, and 4 weeks, again at 6, 12 and 18 months, and annually thereafter. The number of inoculations alone can be objectionable to some vaccinees. VACCINE RELATED ADVERSE EVENTS Adverse events following immunization with the licensed vaccine include local and systemic reactions. The most common local reactions are erythema (raciness), subcutaneous nodules at the site of injection, ant! less commonly, forearm swelling due to eclema. Frequent systemic reactions include malaise and lassitude, and less commonly fever anct chills. Such local and short term systemic reactions are common to a number of different bacterial vaccines in current routine use. The standard regulatory terms for any undesirable effect of a vaccine (or other biologic or drug) are adverse event or adverse reaction. Adverse events can range from mile! to serious or life threatening. The stanciard term uses! by regulatory agencies to describe the characteristic profile of a product and its associated adverse events is the safety of the pro cluct. We have used the term "aclverse events" wherever possible, as "safety" may seem to over-emphasize serious or life threatening events. The primary means of learning of adverse events associated with any licensee! vaccine is the Vaccine Adverse Event Reporting System (VAERS), aciministered by the CDC and the Food and Drug Administration (FDA). VAERS collects and analyzes information from reports of possible adverse events following immunization (http://www.vaers.org, accessed 8/29/001. The VAERS program encourages reporting of any clinically significant adverse event following any immunization, anct anyone can file a report to VAERS. VAERS is a passive surveillance system- it accepts reports but does not actively seek out vaccinees or health care providers to make inquiries and as with any such system, it is safe to presume that the rate of reporting is low relative to the rate of events (though it is ctifficult to estimate how low), and varies due to the rate of events but also due to other factors such as awareness of alleged problems with a particular vaccine (Singleton et al., ~ 9991. Between January ~ 990 and August 2000, ~ 544 reports of adverse events following administration of the anthrax vaccine were filed with VAERS. During that time period, 1,859,500 closes were given to 463,000 people (Mootrey, presentation, 10/31/001. VAERS is not designed to track the absolute rate of adverse events experienced per a given number of doses administered. Rather it is a signal-capturing or hypothesis-generating system: for example, if VAERS should receive a significant increase in reports of adverse events associated with some particular product, then that serves as a signal to investigate possible causes such as perhaps a particular lot or batch of the product that might be unusually reactogenic (see also Tilson, 19921. In the special case of the anthrax vaccine, the VAERS reports receive indiviclual review by an inclependent civilian committee of medical experts, the Anthrax Vaccine Expert Committee (AVEC), which considers causality and forwards conclusions to the DoD. The AVEC had reviewed some 1 530 reports as of March 15, 2001, but their first report has not yet been published (Caserta, presentation, 2000; personal communication; and http://www.anthrax.osd.mil, accessed 4/6/011.

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16 CDC ANTHRAX VACCINE SAFETY & EFFICACY RESEARCH PROGRAM POLICY CONTEXT OF REPORT Beginning in 1970 anct continuing through today, the licensed anthrax vaccine has been routinely administered to United States workers with occupational exposure to anthrax bacteria or spores. Although human anthrax due to contact with infected animals or their products remains a health problem in some areas, currently in the United States the licensed anthrax vaccine is in use primarily by the military to protect troops from weaponized anthrax (Brachman and Friec3lander, 1999; Mazzuchi et al., 20001. In 1979, an outbreak of human anthrax occurred in SverdIovsk, U.S.S.R. (Abramova et al., 1993' Meselson et al., 1994; Jackson et al., 19984. Although initially it was officially blamed on consumption of contaminated meat, subsequent investigations of a series of cases shower} pathologic lesions diagnostic of inhalational anthrax (Abramova et al., 1993), which is now admitted by the Russian government. The admission that Iraq haci produced weapons containing anthrax spores during the 1991 Gulf War confirmed fears of the potential use of anthrax as a biological weapon (Zilinskas, 19971. Approximately 268,000 doses of the vaccine were distributed to troops in ~ 990 (IOM, 2000b). Anthrax Vaccination Policy Secretary of Defense William Cohen decided in late ~ 997 to proceed with a plan to vaccinate all United States service members against anthrax, ant! immunizations began in 1998. By March 15, 2001, 2.l million closes of anthrax vaccine had been administered to approximately 505,000 military personnel (http://www.anthrax.osct.mil, accessed 4/6/014. The DoD's AV1P has had, and continues to have, many formidable difficulties to manage. The licensee! anthrax vaccine was only produced by one company, which is not in itself unusual, but the facility changed hands in 1998 and the company, now called BioPort, has had difficulty meeting regulatory requirements for good manufacturing practices. In fact, the product has not been manufactured since the winter of 1997. The DoD has been able to continue immunizations in spite of the limited supply of vaccine, but not at the rate first planned. In July 2000, then more officially in November 2000, the DoD slowed dramatically its immunization program, focusing only on troops thought to be at greatest potential risk (http://www.anthrax.osd.mil, accessed 9/5/00; Marshall, 20001. In addition to supply problems, some vaccinees have objected to the immunization policy. There have been, for example, complaints among Gulf War veterans of chronic multisystem clinical conditions that still lack definable relationship to anthrax vaccine and to other events in the Gulf War experience (for farther information on Gulf War experience and concerns, see, for example, Presidential Advisory Committee, 1996; Iowa Persian Gulf Study Group, 1997; Fukuda et al., 1998; Hotopf et al., 2000; lOM, 1996, 2000a, 2000b). Even though there is no definable relationship of anthrax vaccine to illnesses of long-term late appearance or duration, there has been a perception in a small minority of military personnel that the anthrax vaccine is dangerous. The AV]P, and the anthrax vaccine itself, have become a focal point of great concern on the part of at least a segment of the military and interested public. The Congress has responded to that concern, and several hearings have been held by relevant committees. The Congress also appropriated funds to the DoD and to the CDC for the further study of the anthrax vaccine (see Figure I).

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INTRODUCTION & BACKGROUND DoD-sponsorec! study to evaluate the safety and efficacy of anthrax vaccine 17 CDC-sponsorec! study to evaluate CDC research plan on safety and ef- ficacy of anthrax vaccine Congressional actions regarding IOM study of anthrax vaccine research T T DoD Appropriations Act 2000 PL 106-79 DoD is directed to enter into a contract with the IOM to independently study the effectiveness and safety of the anthrax vaccine IOM letter report an anthrax | ~t vaccine afety3/3012000 DoD contracted With IOM to study the safety and efficacy of the an- thrax vaccine 1 IOM Committee to Assess the Safety and Efficacy of the Anthrax Vaccine Meetings to date: October 3, 2000 January 29-30, 2001 April 17-18, 2001 ! Final Report due June 2002 l DHHS Appropriations Act, 2000 PL 106-113 CDC is provided $20 million for a collaborative effort to study the safety and efficacy of anthrax vaccine L CDC requested that IOM review the CDC research plan IOM Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program Meetings to date: October 31, 2000 February 8-9, 2001 April 18-19, 2001 Interim Report due June 2001 | Final Report due August 2002 | FIGURE ~ Origins of TOM Activities Related to the Anthrax Vaccine

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18 CDC ANTHRAX VA CCINE SAFETY & EFFICA CY RESEARCH PROGRAM CDC'S REPONSE TO CONGRESS The CDC intends to comply with the congressional mandate to stucly adverse events and the efficacy of the anthrax vaccine by conducting various activities inclucling studies by two of its subsidiary units, the National Center for Infectious Disease (NCID) and the National Immunization Program (NIP). The CDC's research program addresses various and interwoven aspects of the licensee! anthrax vaccine (anthrax vaccine adsorbecI, or AVA) on a variety of levels. On the level of the immunological properties of the vaccine, for example, the CDC plans include studies to determine the amount of specific types of antibodies produced in response to immunization. On the level of the medical symptoms that some vaccinees may experience, and that may influence acceptability of the vaccine, the CDC plans include studies of the effects of different routes of administration on the frequency and extent of such adverse reactions. On the level of perceptual factors that affect the acceptability of a vaccine, the CDC plans include a survey to assess service members' knowledge, attitudes, and beliefs about the anthrax vaccine. NCID's projects to identify risk factors and improve use of the vaccine itself are also very relevant to the vaccine's adverse event profile. The NCID's effort is the investigation of vaccine immunogenicity and effectiveness, while the NIP concentrates on vaccine adverse events and acceptability. The NCID, in collaboration with the DoD-USAMRIlD, issued a three-part request for proposals for studies acIdressing the dosage, route of administration, and immunologic correlates of protection of the AVA. The acceptability of the vaccine wouict improve, and acute local reactions would likely decrease, if it could be administered intramuscularly and if fewer closes were required. Recent data suggest that these changes may be possible (Pittman et al., submitted for publication), and the NCID studies are clesignect to further evaluate these changes. If the studies support the reduction in doses or change in route of administration, then the results couIc! support a supplementary application to change the labeling of the AVA product. Although the FDA does not regulate medical practice, and specifically does not oversee whether health care providers prescribe regulated products according to the directions in the product labeling, the administration of medical products by the Uniter! States military is a special situation. The Gulf War was the occasion of issuance of special rules that allowed! the administration of investigational products, such as pyridostigmine bromicle, for specific wartime indications, as cleemect necessary to protect troops from chemical or biological weapons (note, however, that while the anthrax vaccine was administered} during the Gulf War, it was a licensed, not investigational, vaccine). The intervening decade has seen a great clear of policy and regulations development related to the use of new medical products in the military (see Raub, 1999, and FDA, 19991. In general, the military is not in a position to adopt a policy endorsing uses of drugs or vaccines in ways other than directecl in the FDA-approved product labeling. Any such usage is called "off-label" use. Concern in the FDA (and the DoD) about officially sanctioned off-label use of medical products was underscored in a letter in response to unspecified! reports of off-label anthrax vaccine administration, from Dr. Katherine Zoon, Director of FDA's Center for Biologics Evaluation and Research to Dr. Sue Bailey, Assistant Secretary of Defense for Health Affairs (Zoon, ~ 9991. In sum, in orcler for the DoD to administer the anthrax vaccine by a different route or with a reduction in total closes, it is first necessary that the product labeling be formally changed. The NIP is, as noted, concerned with tracking vaccine adverse events and improving vaccine acceptability. In order to assess the vaccine adverse event profile' the NIP hopes to improve the detection of true adverse events, and in orcler to improve vaccine acceptability, the NIP hopes to

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INTRODUCTION & BACKGROUND 19 improve eclucation ant! communication about the vaccine, anc} confidence among vaccinees that adverse events will be registered and prevented or treated. The plans of the NIP to improve the adverse event profile ant! the acceptability of the vaccine include research and programmatic components, with only the former (research) to be actUressed in this interim report. As part of the research effort, the NIP will be conducting focus groups and knowledge, attitudes, and beliefs (KAB) surveys among military personnel who have or will receive the anthrax vaccine, with a view to improving education and communications. The NIP is also proposing to stu(ly KAB among health care providers about VAERS reporting. The NIP is working to develop strategies and techniques for more complete analysis of the (lata ("clata- mining") in VAERS as well. In ad(lition, the NIP is working on several other projects in support of the NCID-directed human clinical trials.

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