2
Background

Anthrax is primarily a disease of animals, and historically, humans have generally contracted the disease through contact with infected animals or contaminated animal products. Depending on the site of anthrax infection, disease can occur in three forms: cutaneous, gastrointestinal, or inhalational anthrax. The disease had become extremely uncommon in any form in the United States until the intentional distribution of anthrax spores through the postal system in the fall of 2001. These bioterrorist events led to 11 cases of inhalational anthrax, 5 of which were fatal, and to 8 confirmed and 4 suspected cutaneous anthrax infections (CDC, 2001b, 2002). More than 30,000 people may have been exposed to anthrax spores (CDC, 2001a,b).

Anthrax vaccines for use in animals were first developed in 1881 (Turnbull, 1991). Work on vaccines suitable for human use gained urgency in the 1940s because of fears that anthrax would be used as a biological warfare agent. A human vaccine was developed in the 1950s by the Army Chemical Corps and produced by a pharmaceutical company under contract with the Army. The current vaccine, Anthrax Vaccine Adsorbed (AVA), which differed minimally from the original preparation, was licensed in 1970 and was recommended for use by workers with occupational risk of exposure to anthrax, such as textile mill workers, veterinarians, and laboratory scientists.

In 1990, concerns that Iraq had biological weapons containing anthrax spores motivated the U.S. military to administer AVA to 150,000 or more service members deployed for the Gulf War. The existence of an Iraqi biological weapons program was confirmed in the mid-1990s (Henderson, 1999; Zilinskas, 1997), and in 1997, the Department of Defense (DoD) announced a plan to vaccinate all U.S. service members with the licensed anthrax vaccine. DoD’s Anthrax Vaccine Immunization Program (AVIP) began in March 1998 with personnel scheduled for deployment to higher-risk areas (e.g., South Korea and Southwest Asia). By 2001, however, a limited supply of AVA had significantly slowed plans to vaccinate all military personnel.

The limited supply of AVA was the result of an interruption in vaccine production. In 1998, Michigan Biological Products Institute (MBPI), the manufacturer of the anthrax vaccine, stopped production to renovate the vaccine manufacturing facility after receiving notification from the Food and Drug Administration (FDA) that corrective actions were needed to avoid revocation of the facility’s license (Zoon, 1997). In late 1998 the facility was transferred to its current owner, BioPort. Several FDA inspections were necessary before the facility reached compliance with FDA’s manufacturing regulations. FDA approved the license supplement for the renovations of the BioPort facilities and for an offsite contract filling operation and released new vaccine lots in late December 2001 and January 2002 (Maseillo, 2001, 2002).



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2 Background Anthrax is primarily a disease of animals, and historically, humans have generally contracted the disease through contact with infected animals or contaminated animal products. Depending on the site of anthrax infection, disease can occur in three forms: cutaneous, gastrointestinal, or inhalational anthrax. The disease had become extremely uncommon in any form in the United States until the intentional distribution of anthrax spores through the postal system in the fall of 2001. These bioterrorist events led to 11 cases of inhalational anthrax, 5 of which were fatal, and to 8 confirmed and 4 suspected cutaneous anthrax infections (CDC, 2001b, 2002). More than 30,000 people may have been exposed to anthrax spores (CDC, 2001a,b). Anthrax vaccines for use in animals were first developed in 1881 (Turnbull, 1991). Work on vaccines suitable for human use gained urgency in the 1940s because of fears that anthrax would be used as a biological warfare agent. A human vaccine was developed in the 1950s by the Army Chemical Corps and produced by a pharmaceutical company under contract with the Army. The current vaccine, Anthrax Vaccine Adsorbed (AVA), which differed minimally from the original preparation, was licensed in 1970 and was recommended for use by workers with occupational risk of exposure to anthrax, such as textile mill workers, veterinarians, and laboratory scientists. In 1990, concerns that Iraq had biological weapons containing anthrax spores motivated the U.S. military to administer AVA to 150,000 or more service members deployed for the Gulf War. The existence of an Iraqi biological weapons program was confirmed in the mid-1990s (Henderson, 1999; Zilinskas, 1997), and in 1997, the Department of Defense (DoD) announced a plan to vaccinate all U.S. service members with the licensed anthrax vaccine. DoD’s Anthrax Vaccine Immunization Program (AVIP) began in March 1998 with personnel scheduled for deployment to higher-risk areas (e.g., South Korea and Southwest Asia). By 2001, however, a limited supply of AVA had significantly slowed plans to vaccinate all military personnel. The limited supply of AVA was the result of an interruption in vaccine production. In 1998, Michigan Biological Products Institute (MBPI), the manufacturer of the anthrax vaccine, stopped production to renovate the vaccine manufacturing facility after receiving notification from the Food and Drug Administration (FDA) that corrective actions were needed to avoid revocation of the facility’s license (Zoon, 1997). In late 1998 the facility was transferred to its current owner, BioPort. Several FDA inspections were necessary before the facility reached compliance with FDA’s manufacturing regulations. FDA approved the license supplement for the renovations of the BioPort facilities and for an offsite contract filling operation and released new vaccine lots in late December 2001 and January 2002 (Maseillo, 2001, 2002).

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After the deliberate distribution of anthrax spores in bioterrorist incidents in the fall of 2001, AVA was offered in combination with antibiotics as prophylactic treatment for as many as 10,000 of the civilians who may have been exposed. Fewer than 200 chose to take the vaccine, which was offered under the provisions of an Investigational New Drug application because the vaccine is not licensed for postexposure use and the vaccine lot used had not yet been released by FDA. In late June 2002, DoD announced a partial resumption of the AVIP (Wolfowitz, 2002; see Appendix E). Military personnel to be vaccinated under the resumed program are those “assigned to or deployed for more than 15 days in higher threat areas whose performance is essential for certain mission critical capabilities,” with vaccination to begin 45 days before deployment, if possible. This chapter briefly summarizes the basic pathophysiology of anthrax and the history of anthrax vaccine development. It describes some unanswered questions concerning the efficacy and immunogenicity of AVA and reviews the newly approved rule that permits FDA to use data from animal tests as the basis for evaluating the efficacy of vaccines and other products against certain lethal agents. The chapter then outlines the concerns that have been expressed by some people about adverse health outcomes that might be associated with use of AVA. Also described are two important tools for surveillance for adverse events following vaccination with AVA: the Vaccine Adverse Event Reporting System (VAERS) and the Defense Medical Surveillance System (DMSS). ANTHRAX DISEASE Anthrax is caused by infection with the bacterium Bacillus anthracis, a gram-positive, nonmotile, spore-forming organism (Brachman and Friedlander, 1999; Dixon et al., 1999). It is primarily a disease of wild and domestic animals exposed to spores in the soil. The spore form of B. anthracis is very hardy— anthrax spores can lie dormant in soil for many years and are resistant to physical and chemical challenges such as heat, dryness, and disinfectants. As noted, depending on the site of anthrax infection, disease can occur in three forms: cutaneous, gastrointestinal, or inhalational anthrax. Cutaneous anthrax is generally associated with handling infected animals or their products and is manifested as a lesion that forms a vesicle and finally an ulcer marked by a characteristic black eschar. Eating meat from infected animals can lead to an oropharyngeal lesion (cutaneous-like anthrax inside the mouth or larynx) or to gastrointestinal anthrax, which can cause severe abdominal pain, bloody diarrhea, and ascites. Inhalation of aerosolized spores of sufficiently small particle size can cause inhalational anthrax, characterized by severe respiratory distress, with dyspnea, cyanosis, diaphoresis, and strident cough (Brachman and Friedlander, 1999). Radiographic examination of the chest usually shows a characteristic widening of the mediastinum and pleural effusions. Shock may develop, and hemorrhagic meningitis may occur in about 50 percent of cases (Brachman and Friedlander, 1999). Even with aggressive treatment, this form of anthrax has been associated with a high fatality rate within a matter of days after the onset of symptoms, which can initially resemble a common upper respiratory infection. Inhalational anthrax is generally seen only in industrial settings where conditions permit aerosolization of a sufficiently large number of spores in an enclosed area (Brachman and Friedlander, 1999). After spores enter the body through any route, they are ingested by macrophages in a process called phagocytosis. Once in the macrophages, the spores germinate into vegetative bacteria that can multiply and secrete toxins that produce local edema and necrosis. If bacteria are carried to regional lymph nodes, they multiply further and produce additional edema and necrosis and enter the bloodstream to produce a systemic infection (Brachman and Friedlander, 1999; Dixon et al. 1999) The virulence of B. anthracis derives from a bacterial capsule and three toxin proteins. The production of the capsule and toxin proteins is encoded on two separate plasmids, and both plasmids are required for full virulence. Plasmid pXO2 contains the gene that encodes the synthesis of a polyglutamyl capsule that inhibits phagocytosis of the vegetative bacteria. Plasmid pXO1 encodes the synthesis of the three toxin proteins: protective antigen (PA), edema factor (EF), and lethal factor (LF). To produce active tox-

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ins, PA must bind to cellular receptors and then bind to either EF, to form edema toxin, or LF, to form lethal toxin. In both cases, PA appears to mediate binding of the toxin to the target cell and its translation to the cell’s interior. EF is an adenylate cyclase dependent on the eukaryotic protein calmodulin (Brossier and Mock, 2001). EF is responsible for the ability of edema toxin to increase levels of cyclic adenosine monophosphate inside the eukaryotic cell, which interferes with the cell’s water balance and results in edema. Edema toxin may also impair neutrophil function (Alexeyev et al., 1994; Dixon et al., 1999; O’Brien et al., 1985). LF is a zinc metalloprotease that cleaves two mitogen-activated protein kinase kinases. The mechanism by which lethal toxin, through the action of LF, leads to death of the host remains unknown but may involve suppression of the inflammatory response (Erwin et al., 2001; Pellizzari et al., 1999.) ANTHRAX VACCINE Attenuated spore vaccines against anthrax have been developed with bacterial strains missing one or both plasmids. The livestock vaccine currently in use in the United States and other countries, known as the Sterne vaccine, is derived from a noncapsulated B. anthracis variant that lacks the pXO2 plasmid. To develop an anthrax vaccine for humans, however, U.S. researchers used B. anthracis cultures in a synthetic medium without proteins or other macromolecules (Turnbull, 2000). A production system for an anthrax vaccine for human use, first described in 1954 (Wright et al., 1954b), incorporated a chemically defined growth medium and a method of concentrating, stabilizing, and partially purifying PA by precipitation. A controlled trial to evaluate the safety and efficacy of this vaccine was conducted between 1955 and 1959 at goat hair-processing mills in the eastern United States (Brachman et al., 1962). The study indicated that the vaccine was effective in this population. The initial production method was soon modified for scale-up, with changes in the culture conditions, in the product purification method (a change from precipitation with alum to adsorption onto aluminum hydroxide gel), in the preservative (from thimerosal to benzethonium chloride, with formaldehyde as a stabilizer), and in the strain of the organism used, resulting in development of the currently licensed vaccine, AVA (Auerbach and Wright, 1955; Puziss and Wright, 1963; Wright and Puziss, 1957; Wright et al., 1962; see IOM, 2002 for a review of the changes). AVA is a cell-free filtrate containing PA as the principal immunogen. The anthrax vaccine is adsorbed to aluminum hydroxide (Alhydrogel), which acts as an adjuvant.1 AVA was licensed in 1970 for manufacture by the Michigan Department of Public Health. Michigan transferred its production plant to MBPI in 1995. In 1998, both the plant and the product line of MBPI were sold to BioPort, a private company that at the time of this report was the sole U.S. manufacturer of an anthrax vaccine for human use. The product license for AVA calls for subcutaneous administration of a basic series of six doses of 0.5 milliliters (ml) each. After administration of the initial dose, subsequent doses are administered at 2 weeks, 4 weeks, 6 months, 12 months, and 18 months. Annual booster doses are required. The evidence to justify this dosing schedule is limited. Wright and colleagues (1954a) administered an alum-precipitated predecessor of AVA to 55 volunteers in two 0.5 ml injections given subcutaneously 2 weeks apart. A group of 660 people were then given 3 subcutaneous injections of the same vaccine at 2-week intervals, followed by a booster dose of 0.25 ml after 6 months. Brachman and colleagues (1962) used the same vaccine with a schedule of three 0.5 ml subcutaneous injections given at 2-week intervals, followed by three 0.5 ml booster doses given at 6-month intervals. Thereafter booster doses were given at yearly intervals. This schedule was then used for the studies leading to licensure of AVA. A pilot study has been conducted to evaluate changes in both the route of administration and the dosing schedule (Pittman et al., 2002). As described in detail elsewhere in this report, the Centers for Disease Control and Pre- 1   An adjuvant is a component that augments the immune response. Many vaccines require adjuvants for efficient elicitation of an immune response.

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vention (CDC) research plan includes a clinical trial to further evaluate the effect of these modifications on the safety and efficacy of the vaccine. IMMUNOGENICITY AND EFFICACY ISSUES Despite a body of evidence demonstrating the efficacy of AVA for prevention of anthrax disease in laboratory animals (reviewed in another report from the Institute of Medicine [IOM, 2002]), some important questions remain relating to the efficacy and immunogenicity of this vaccine. One need is to establish correlates of immunity to anthrax disease so that it will be possible to predict with a good degree of certainty whether an individual is sufficiently protected. While immunity to anthrax is associated with the presence of antibodies against PA, a quantitative relationship between protection and any correlate of immunity has not been firmly established (see IOM, 2002). Establishing an immune correlate of protection in animals will help to enhance understanding of the degree to which AVA or newly developed anthrax vaccines will be protective in humans. Both active protection studies and passive protection studies have crucial roles. The IOM study noted that passive protection studies involving 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” (IOM, 2002, p. 75). Such studies can identify or confirm the amount of antibody to PA that must be present to provide protection against challenge by B. anthracis spores. A related question that has arisen in light of the bioterrorist use of anthrax concerns the efficacy of AVA in contributing to protection from anthrax disease when the vaccine is administered in conjunction with antibiotics following exposure to anthrax spores (IOM, 2002). How long does it take to develop protective immunity, and therefore for how long must antibiotics be administered for postexposure protection? Clearly, antibiotics must be taken until the immune response reaches a protective level, and passive protection studies are needed to establish what that protective level is. The IOM report also noted the need to standardize an assay for quantitation of antibody levels that can be used across laboratories carrying out research on anthrax vaccines (IOM, 2002). Such efforts are being undertaken as part of the CDC research program. REGULATORY CONSIDERATIONS The pilot study carried out by Pittman and colleagues (2002) evaluated the immunogenicity and adverse event profile associated with a change from SQ to IM administration of AVA and with the use of fewer doses of AVA. The study indicated that the IM route of administration was associated with fewer injection-site reactions and was as immunogenic as SQ administration, as indicated by anti-PA IgG antibodies and toxin neutralization antibody (TNA) assay. The data were also supportive of a reduction in the number of doses. Additional data confirming these findings are necessary to gain FDA approval to change the product license and labeling. A human clinical trial to evaluate changes in the number of doses and the route of administration of AVA has been planned as part of the CDC research program. (The study is discussed in detail in Chapters 4 and 5.) CDC consulted with FDA to determine the criteria for establishing “non-inferiority” for immunogenicity, as well as the necessary measures for evaluating adverse events. If the data support a reduction in the number of doses required and/or a change in route of administration from SQ to IM, the vaccine will be easier to administer and more useful for the populations at high risk, at whom it would be targeted. Although an improvement in the mode of administration of the currently licensed vaccine is needed, it is also crucial to move rapidly to a newer vaccine. However, a challenge faced with any vaccine developed to counter a potentially lethal agent such as anthrax or other biowarfare agents is the impossibility of directly evaluating its efficacy in humans. It would be neither feasible nor ethical to use humans to test the efficacy of anthrax vaccines against inhalational challenge, because there are no naturally occurring situations where humans are predictably at risk from airborne anthrax and the disease untreated is usually lethal.

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In May 2002, FDA published a rule to address such situations (see Appendix D). The new rule amends the regulations governing new drugs and biological products to allow for the use in certain cases of appropriate studies in animals to provide evidence of the efficacy of products to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances, when traditional efficacy studies in humans are not feasible and cannot be ethically conducted. Key provisions of the rule are stated as follows: …FDA can rely on the evidence from animal studies to provide substantial evidence of the effectiveness of these products when: 1) There is a reasonably well understood pathophysiological mechanism for the toxicity of the chemical, biological, radiological, or nuclear substance and its amelioration or prevention by the product; 2) the effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model (meaning the model has been adequately evaluated for its responsiveness) for predicting the response in humans; 3) the animal study endpoint is clearly related to the desired benefit in humans, which is generally the enhancement of survival or prevention of major morbidity; and 4) the data or information on the pharmacokinetics and pharmacodynamics of the product or other relevant data or information in animals and humans is sufficiently well understood to allow selection of an effective dose in humans, and it is therefore reasonable to expect the effectiveness of the product in animals to be a reliable indicator of its efficacy in humans. (FDA, 2002, p. 37989) The rule, which became effective July 1, 2002, provides an outline to permit efforts to license new prophylactic measures for lethal agents, including new anthrax vaccines. CDC’s planned nonhuman primate and correlates of protection studies, in conjunction with the human clinical trial, should indicate the levels of anti-PA antibodies or other immune response factors that correlate with protection from inhalational challenge. This information should be useful in the evaluation of a licensure application for a new anthrax vaccine that has been shown to be protective in animals and to stimulate an immune response that is expected to be protective in humans. SAFETY CONCERNS ABOUT THE ANTHRAX VACCINE An FDA review completed in 1975 classified AVA as safe and effective and found that use of AVA is indicated “only for certain occupational groups with a risk of uncontrollable or unavoidable exposure to the organism. It is recommended for individuals in industrial settings who come in contact with imported animal hides, furs, wool hair (especially goat hair, bristles, and bone meal), as well as in laboratory workers involved in ongoing studies on the organism” (FDA, 1985, p. 51058). More widespread use of the vaccine during the Gulf War and as part of AVIP, however, resulted in new concerns about its possible association with serious acute and chronic health problems. Some proposed that vaccination with AVA could have contributed to the chronic multisystem health complaints of some Gulf War veterans (GAO, 1999a,b; Nicolson et al., 2000). With the expansion of mandatory vaccination under AVIP, there have also been concerns that the health impact of vaccination with AVA was being missed because adverse events were underreported to military health care providers and to VAERS (GAO, 1999c; Rovet, 1999). Reportedly, more than 400 members of the military who refused to accept vaccination with AVA have left military service voluntarily or involuntarily (Weiss, 2001). Mandatory vaccination against anthrax is also reported to have been an important factor to some Air National Guard and Air Force Reserve personnel when making their decision to leave military service or move to inactive status (GAO, 2000). The symptoms associated with vaccination against anthrax that were reported by witnesses at congressional hearings and directly to this IOM committee included fever, headache and malaise, swelling, joint pain, and tinnitus (Bates, 2001; Moore, 2001; Starkweather, 2001; Vick, 2001). Several witnesses also reported conditions that they ascribed to receipt of AVA, including hypogonadism; Stevens-Johnson syndrome, which affected their vision as well as their skin; and a case of fatal aplastic anemia (Eberhart, 2001; Nietupski, 2001; Rugo, 2001).

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As noted in Chapter 1, the IOM’s Committee to Assess the Safety and Efficacy of the Anthrax Vaccine reviewed case reports and epidemiologic studies, both unpublished and published, and concluded from these data that AVA is reasonably safe, even though injection-site reactions such as redness, itching, swelling, and tenderness are fairly common (IOM, 2002). The committee did not find evidence that vaccinees face an increased risk of life-threatening or permanently disabling adverse events compared with non-vaccinees. The limited evidence did not indicate elevated risk for developing adverse events over the long term. The IOM report identified some questions and needs still outstanding with respect to safety (IOM, 2002). Review of these needs and opportunities provides a context for evaluating CDC’s plans for anthrax vaccine research. For example, the report recommended that individuals receiving vaccine from postrenovation lots of AVA should be monitored for possible health events. The capacity for effective use of DoD’s DMSS to regularly test hypotheses that emerge from VAERS and other sources is needed. The report also stated that options for longer-term follow-up of the possible health effects of vaccination against anthrax should be evaluated, including collaboration between DoD and the Department of Veterans Affairs, and use of data from the Millennium Cohort Study.2 A complete listing of the findings and recommendations of the IOM report is found in Appendix G. VACCINE ADVERSE EVENT REPORTING SYSTEM VAERS is a passive surveillance system begun in 1990 as part of the response to the National Childhood Vaccine Injury Act of 1986.3 It is the nation’s principal system for the collection of reports on adverse events following the use of any vaccine licensed in the United States. The system is co-administered by CDC and FDA. Reporting to VAERS VAERS receives spontaneous reports of adverse events following vaccination. Anyone can submit a report to VAERS, including vaccine recipients or their family members, and more than one report can be submitted about the same adverse event. Reporting is encouraged for any clinically significant event following vaccination and required for certain specified events (VAERS, 2001). Most reports are submitted by health care providers directly (30 percent) or through the vaccine manufacturer (42 percent) (Iskander, 2001b). Each year, reporting forms along with instructions and a cover letter encouraging reporting are mailed to about 200,000 health care providers (Iskander, 2001a). The forms are also available on the Internet (http://www.vaers.org/, http://www.fda.gov/cber/vaers/vaers.htm, http://www.cdc.gov/nip/). A VAERS report form includes spaces for the reporter to provide demographic information about the vaccine recipient and an open-ended description of the adverse event(s), treatment, outcome, relevant laboratory or diagnostic information, timing of the vaccination and the adverse event, vaccine type and lot number, and preexisting conditions. Reports can be submitted by mail or fax, or the information can be provided over the telephone. Limitations of VAERS As the only system for the collection of information on adverse events reported in association with the use of all U.S. licensed vaccines after they are marketed, VAERS is an essential resource for the monitoring of vaccine safety. An unexpected increase in the numbers of reports about a product or a series of reports of an unexpected or unusual adverse event can catalyze additional information gathering 2   The Millennium Cohort Study is a survey recommended by the U.S. Congress and sponsored by 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). 3   National Childhood Vaccine Injury Act of 1986. P. L. No. 99-660 (1986).

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and investigation. However, VAERS also has certain critical limitations (Chen, 2000; Ellenberg and Chen, 1997; IOM, 1994a,b). Adverse events that occur soon after a vaccination may be reported to VAERS whether or not they are causally related to the vaccination.4 Duplicate reports of the same case may be submitted. The medical information provided on the form may be incorrect or incomplete. The complexity of the information that comes into the system (e.g., multiple exposures and multiple outcomes) also makes analysis difficult. In addition, VAERS provides no information on the incidence of similar events among persons who have not been vaccinated. Because VAERS is a passive system that relies on spontaneous reporting, adverse events are likely to be underreported to an unknown extent, and underreporting may also vary over time and among various kinds of adverse events. One analysis found that the “reporting efficiency” of VAERS ranged from 68 percent for vaccine-associated poliomyelitis following administration of oral polio vaccine to less than 1 percent for rash following administration of the measles-mumps-rubella vaccine (Rosenthal and Chen, 1995). Moreover, for most vaccines there are no data about the number of doses actually administered, although there may be data from other sources on the number of doses distributed. As a result of these limitations, it is nearly impossible to calculate accurate rates of adverse events from VAERS data. A numerator based on the number of reports can be assumed to differ from the true number of events, and there are no data on the total number of doses administered for the denominator (Mootrey, 2000; Singleton et al., 1999; Tilson, 1992). In the case of AVA, however, DoD has maintained records on vaccine doses administered since the start of the AVIP in 1998. This information provides a denominator that is useful in the interpretation of changes in the frequencies of conditions reported to VAERS. In addition, the availability of data from DMSS on diagnoses for hospitalizations and outpatient visits (see below) gives DoD a unique opportunity to evaluate the completeness of reporting to VAERS. Adverse events for which medical attention was received can be systematically identified within DMSS, and efforts can be made to determine whether those events are included in VAERS. A spontaneous reporting system like VAERS should be used to generate signals of possible problems that can then be followed up by more specific investigations. The prior IOM report on AVA emphasized that increased reporting to VAERS is not a goal in and of itself (IOM, 2002). There is little expectation of complete reporting with spontaneous reporting systems like VAERS, and this inherent characteristic must be recognized to properly interpret the data that they produce. Instead, the IOM report encouraged more detailed and insightful reporting to VAERS (and other spontaneous reporting systems), including more clinical data on each case and the selective reporting of cases that are novel or serious, or both (IOM, 2002). The report also stated that more effort was needed in formal studies to follow up on the hypotheses emerging from VAERS. DEFENSE MEDICAL SURVEILLANCE SYSTEM Surveillance and analysis of adverse events following vaccination of military personnel are aided by the availability of databases that permit linkage of personnel and demographic information with information on military experience, location, immunizations, and medical events for active-duty personnel. The individual branches of the armed services maintain such databases, but even more useful are various DoD-wide databases, particularly the system of databases of health-related information (reported by each of the armed services) that make up DMSS (see http://amsa.army.mil/AMSA/AMSA_DMSS.htm). DMSS is coordinated by the Army Medical Surveillance Activity (AMSA). 4   In response to a request from the Army Surgeon General, the Department of Health and Human Services convened a committee of civilian physicians and experts—the Anthrax Vaccine Expert Committee—who provide independent expert medical review of VAERS reports related to anthrax vaccination and attempt to assess the probability of a causal relationship between the reported adverse event and the anthrax vaccine. Further discussion of this committee and efforts to evaluate the likelihood of causal relationships between events reported to VAERS and any given vaccine can be found in IOM, 2002.

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Medical data in DMSS are derived from Standard Inpatient Data Records and the Standard Ambulatory Data Records for all inpatient and outpatient encounters at military facilities. For each hospitalization, up to eight discharge diagnoses are coded using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Records on inpatient care in military medical facilities date from 1990 and those for ambulatory care begin in 1996. At present, the DMSS records on immunizations with AVA are more complete than those for immunizations with other vaccines. Records on reportable health events cover a set of diseases and health conditions named in the list of Tri-Service Reportable Events (AMSA, 1998; Mazzuchi, 1998). This list includes any adverse event following vaccination that results in admission to a health care facility or the loss from duty of more than 1 day. Because DMSS and other DoD-wide databases can produce data on the entire population of active-duty military personnel and on the subpopulation vaccinated under AVIP, they have denominator data that are unavailable from VAERS, making it possible to assess vaccine-associated adverse event rates (number of adverse events/number of vaccine administrations) for some types of health events following vaccination. Adverse event rates can be compared between populations that did and that did not receive the vaccine. The DMSS databases also make it possible to monitor postvaccination medical histories over the length of active service. Even though this period is limited (typical Army enlistment is 2 to 6 years [Grabenstein, 2001]), it is a longer period of observation than that available for most vaccine safety studies. Although DMSS is a substantially richer analytic resource than VAERS, it still has certain limitations. Whereas VAERS has the potential to receive reports on any type of adverse event following vaccination, including mild events, DMSS will capture only events that require inpatient or ambulatory medical care in a military facility or that result in the loss of time from duty. DMSS data may also be affected by problems common to large databases, such as administrative and operational differences in the ways data are collected and delays in the transmission of data from the systems in which they are originally collected. Ultimately, properly conducted studies performed using DMSS will often require access to primary medical records in order to validate medical diagnoses and obtain data that are not already in DMSS. REFERENCES Alexeyev OA, Morozov VG, Suzdaltseva TV, Mishukov AS, Steinberg LA. 1994. Impaired neutrophil function in the cutaneous form of anthrax. Infection 22(4):281–282. AMSA (Army Medical Surveillance Activity). 1998. Tri-Service Reportable Events: Guidelines and Case Definitions. Washington, D.C.: Army Medical Surveillance Activity, U.S. Army Center for Health Promotion and Preventive Medicine. Auerbach BA, Wright GG. 1955. Studies on immunity in anthrax. VI. Immunizing activity of protective antigen against various strains of Bacillus anthracis. Journal of Immunology 75:129–133. Bates SG. 2001. Written statement. Institute of Medicine Joint Meeting of the Committee to Assess the Safety and Efficacy of the Anthrax Vaccine and the Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program, Meeting III, Washington, D.C. Brachman PS, Friedlander AM. 1999. Anthrax. In: Plotkin SA, Orenstein WA, eds. Vaccines, 3rd ed. Philadelphia: W. B. Saunders Co. Pp. 629–637. Brachman PS, Gold H, Plotkin S, Fekety FR, Werrin M, Ingraham NR. 1962. Field evaluation of a human anthrax vaccine. American Journal of Public Health 52:632–645. Brossier F, Mock M. 2001. Toxins of Bacillus anthracis.Toxicon 39(11):1747–1755. CDC (Centers for Disease Control and Prevention). 2001a. Update: investigation of bioterrorism-related anthrax and adverse events from antimicrobial prophylaxis. MMWR (Morbidity and Mortality Weekly Report) 50(44):973– 976. CDC. 2001b. Update: investigation of bioterrorism-related inhalational anthrax—Connecticut, 2001. MMWR (Morbidity and Mortality Weekly Report) 50(48):1077–1079. CDC. 2002. Update: cutaneous anthrax in a laboratory worker—Texas, 2002. MMWR (Morbidity and Mortality Weekly Report) 51(22):482.

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