4
Safety: Introduction

Vaccines are important tools for the prevention of serious infectious diseases. Through vaccination programs, naturally occurring smallpox has been eradicated globally and the incidence of other diseases including diphtheria, measles, mumps, pertussis, polio, and rubella has declined substantially in the United States and many other countries. As with any pharmaceutical product or medical procedure, however, the use of vaccines carries a risk of adverse health effects that must be weighed against the expected health benefit. Expectations for the safety of vaccines are especially high because, in contrast to therapeutic agents, which are given when a disease is known to be present (or at least suspected), vaccines are usually given to healthy people to protect them against a disease that they may not be exposed to in the future.

Until 1990, Anthrax Vaccine Adsorbed (AVA) had been administered primarily to a small population of workers—veterinarians, processors of animal hair and hides, and laboratory personnel—with a high risk of exposure to anthrax. Administration of AVA to U.S. military personnel during the Gulf War and more recently under the Anthrax Vaccine Immunization Program (AVIP) substantially increased the numbers of persons vaccinated and produced concerns among some that the vaccine might be responsible for serious adverse health effects.

As with efficacy, it is important to note that safety is relative, not absolute. In general, the term safety reflects expectations of relative freedom from, but not necessarily the complete absence of, harmful effects when a product is used prudently, considering the condition of the recipient



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The Anthrax Vaccine: Is it Safe? Does it Work? 4 Safety: Introduction Vaccines are important tools for the prevention of serious infectious diseases. Through vaccination programs, naturally occurring smallpox has been eradicated globally and the incidence of other diseases including diphtheria, measles, mumps, pertussis, polio, and rubella has declined substantially in the United States and many other countries. As with any pharmaceutical product or medical procedure, however, the use of vaccines carries a risk of adverse health effects that must be weighed against the expected health benefit. Expectations for the safety of vaccines are especially high because, in contrast to therapeutic agents, which are given when a disease is known to be present (or at least suspected), vaccines are usually given to healthy people to protect them against a disease that they may not be exposed to in the future. Until 1990, Anthrax Vaccine Adsorbed (AVA) had been administered primarily to a small population of workers—veterinarians, processors of animal hair and hides, and laboratory personnel—with a high risk of exposure to anthrax. Administration of AVA to U.S. military personnel during the Gulf War and more recently under the Anthrax Vaccine Immunization Program (AVIP) substantially increased the numbers of persons vaccinated and produced concerns among some that the vaccine might be responsible for serious adverse health effects. As with efficacy, it is important to note that safety is relative, not absolute. In general, the term safety reflects expectations of relative freedom from, but not necessarily the complete absence of, harmful effects when a product is used prudently, considering the condition of the recipient

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The Anthrax Vaccine: Is it Safe? Does it Work? and the health risk the product is directed against.1 No single set of criteria defines acceptable limits on the frequency and severity of harmful effects. For this report the committee was charged with assessing the safety of AVA in terms of the frequency, types, and severities of adverse reactions, including differences in those reactions by sex, and long-term health implications of AVA vaccination. This chapter reviews the concerns about the safety of AVA that have been raised and discusses issues related to the identification of vaccine-related adverse events. The types of information examined by the committee regarding the safety of AVA are summarized as well. The details of the available data and the committee’s findings and recommendations regarding the safety of AVA and further safety monitoring are presented in the subsequent two chapters, with Chapter 5 reviewing the findings that have emerged from case reports of adverse reactions to AVA and Chapter 6 reviewing the results of formal epidemiologic studies. SAFETY CONCERNS ABOUT THE ANTHRAX VACCINE AVA was originally licensed in 1970. A Food and Drug Administration (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, has resulted in new concerns about its possible association with serious acute and chronic health problems. Some have proposed that vaccination with AVA could have contributed to the chronic multisystem health complaints of some Gulf War veterans (GAO, 1999b,c; 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 the Vaccine Adverse Event Reporting System (VAERS), operated by the Centers for Disease Control and Prevention and FDA (GAO, 1999d; Rovet, 1   The definition of safety used by FDA is “the relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time” (21 C.F.R. § 600.3 [1999]).

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The Anthrax Vaccine: Is it Safe? Does it Work? 1999). More than 400 members of the military who refused to accept vaccination with AVA have left military service voluntarily or involuntarily (Weiss, 2001), and mandatory vaccination against anthrax is 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). As described in Chapter 2, the symptoms associated with vaccination against anthrax reported by witnesses at congressional hearings and directly to this Institute of Medicine (IOM) committee included fever, headache, malaise, swelling, joint pain, and tinnitus. Several witnesses also reported conditions that they ascribed to receipt of the anthrax vaccine, including hypogonadism; Stevens-Johnson syndrome, which affected their vision as well as their skin; and fatal aplastic anemia. Recent reports from an IOM committee examining the potential health effects of agents to which Gulf War veterans may have been exposed concluded that receipt of AVA was associated with transient acute local and systemic effects (e.g., redness, swelling, and fever) but that the available evidence was “inadequate/insufficient” to determine whether any association with long-term adverse health effects exists (IOM, 2000a,b). That committee restricted its review, however, to the limited number of published studies. Since those IOM reports were completed, results of new Department of Defense (DoD) studies of health effects following vaccination with AVA have become available. The present report examines these new findings and reviews the older data. IDENTIFYING VACCINE-RELATED ADVERSE EVENTS An adverse event is an undesirable health outcome that follows a given exposure, as to a vaccine, but for which a causal relationship with the exposure may or may not have been established. If a causal relationship can be determined, adverse events can also be referred to as adverse effects or adverse reactions. Determining whether receipt of a vaccine has caused a subsequent adverse event can be difficult (Chen, 2000; Ellenberg and Chen, 1997; IOM, 1997). Several IOM committees have had the task of evaluating evidence regarding suspected links between various vaccines and particular adverse events (IOM, 1991, 1994a,b, 2000b, 2001). The available data indicate that some vaccines are associated with rare but serious adverse effects (IOM, 1991, 1994a). In other cases, however, the available evidence does not support the hypothesized associations between adverse events and vaccination (IOM, 1994a, 2001). Several factors involved in assessment of whether a vaccine is associated with adverse events are reviewed here.

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The Anthrax Vaccine: Is it Safe? Does it Work? Characterizing Adverse Events Adverse events can be characterized in terms of their extent, severity, duration, and timing of onset. The extent of adverse events can be either local or systemic. Local events, such as redness or soreness, affect a single area of the body, typically in the area of the injection. Systemic events, such as fever or malaise, have a more generalized effect on the body. The severity of adverse events is usually categorized as mild, moderate, or severe, and definitions of these categories vary.2 The duration of events can be characterized as acute or chronic, with acute events having a relatively short course and chronic events having a lingering, perhaps permanent, effect on health status. Immediate-onset events are ones that have an observed onset within minutes, hours, or days following vaccination, whereas later-onset events are ones that arise months or years after vaccination. The characterization of events as “short term” and “long term” has been avoided in this report because these terms can be confusing; sometimes they refer to the duration of the event (standing for “acute” and “chronic,” respectively), and other times they refer to the timing of onset (standing for “immediate” and “later,” respectively). Active Versus Passive Surveillance Surveillance to detect adverse events can be either active or passive. Active surveillance requires direct, systematic follow-up of all vaccinated individuals to determine the presence or absence of adverse events. Information is usually collected at specified time intervals. Active surveillance is used as part of the extensive clinical testing that must be conducted to establish the safety and efficacy of a vaccine before it is licensed for use. The resource demands of active surveillance generally make it practical only for formal research studies. In contrast to the routine checks made by active surveillance to ensure complete and uniform reporting, with passive surveillance one waits for medical personnel or vaccinees to provide reports (Noah, 1997). Such reports are inherently incomplete, and this is well recognized as a major limitation of passive surveillance. The information reviewed by the committee regarding the safety of vaccination with AVA is derived from both active and passive surveillance. 2   The committee notes that the term serious has a regulatory definition. A serious event is one that results in death, a life-threatening adverse experience, or an intervention to prevent inevitable development of a life-threatening experience, hospitalization or prolongation of hospitalization, or a congenital anomaly or birth defect (Postmarketing Reporting of Adverse Drug Experiences. 21 C.F.R. § 314.80 [2000]). Thus, adverse events described as severe nonetheless may not be considered serious from a regulatory perspective.

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The Anthrax Vaccine: Is it Safe? Does it Work? A passive spontaneous surveillance system, VAERS, is the principal tool used in the United States for the routine monitoring of adverse events that may occur following any vaccination. VAERS and the VAERS data related to AVA are discussed in Chapter 5. DoD has also used data from formal epidemiologic studies, both ad hoc studies and analyses of the data in the Defense Medical Surveillance System (DMSS), to look for evidence of an association between vaccination with AVA and adverse events. These methods and results are discussed in Chapter 6. Difficulties in Assessing Vaccine Safety Several factors are known to make it difficult to assess the safety of vaccines (IOM, 1997, 2000b). Small Study Populations The number of people who are included in clinical trials conducted before vaccine licensure is relatively small compared with the number of people who will receive a vaccine once it is in general use. These studies can detect frequent reactions that disqualify a product as unsafe or that are considered acceptable given the expected benefit and intended use of the product. Premarketing studies are too small to reliably detect rare events that may be observed only when a vaccine is used by a much larger population. Instead, postmarketing surveillance efforts, such as those that are conducted by vaccine manufacturers and through VAERS (see Chapter 5) and that include formal epidemiologic studies of the type described in Chapter 6, are used to help identify less common adverse events after a vaccine is marketed and used by larger numbers of individuals. Lack of Long-Term Follow-up Prospective vaccine studies are usually designed to monitor subjects for only a few weeks or months and so typically provide no evidence regarding adverse events that might occur in the future. Multiple Exposures In vaccine trials it is possible to establish some control over other clinical and environmental exposures that a study population may experience. Those controls help increase the likelihood that observed events can be attributed to the vaccine. For vaccines in routine use, however, vaccinees are often exposed to many other factors that might affect their health, including other vaccines (administered simultaneously in the same injec-

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The Anthrax Vaccine: Is it Safe? Does it Work? tion, at the same site, or at a distant location), making it difficult to isolate any effect of the vaccine in question. Lack of Unique Symptoms No unique set of symptoms or clinical test results establishes a diagnosis of a vaccine-related adverse event. Many symptoms that follow vaccination (e.g., fever and itching) can arise from various sources, and the fact that the symptom follows vaccination may be a coincidental rather than a causal relationship. Means of Data Collection As noted above, routine monitoring for adverse events following vaccination depends primarily on spontaneous reports of cases of adverse events. Such reports can signal possible vaccine-related problems but cannot be used to determine incidence rates of adverse events. Because such reporting is mostly voluntary, the data collected are typically incomplete and unrepresentative of the overall experience of the population of vaccine recipients. Reporting can be affected by factors such as the seriousness of the event, the time that has elapsed since vaccination, and levels of awareness or suspicion of an association between a particular adverse event and vaccination. Active surveillance also has limitations for assessment of vaccine safety. When conducted by a hands-on approach like ad hoc data collection, active surveillance can suffer from multiple potential sources of error in data collection, ranging from imbalanced respondent recall to respondent non-cooperation. Even when active surveillance is conducted with powerful tools like automated linked data systems, described in detail in this report because of the unique usefulness of the military’s DMSS, the data from such systems have important limitations (described in Chapter 6). Furthermore, the organization, analysis, and interpretation of the data in such massive data sets also pose many challenges, including lack of a current methodology to address the many thousands of possible simultaneous comparisons, problems with data quality and validation, and limitations in the nature of the medical care and other experiences being captured in the data sets. GAINING PERSPECTIVE ON ADVERSE EVENTS FOLLOWING VACCINATION Studies of the adverse events observed following vaccination with the other vaccines routinely administered to adults can provide some perspective on reports of adverse events following vaccination with AVA. The committee commissioned a review of published peer-reviewed reports from

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The Anthrax Vaccine: Is it Safe? Does it Work? prospective vaccine studies that included active surveillance of adverse events (Treanor, 2001). That review included an examination of data on sex differences in reports of adverse events. To identify studies for review, Treanor searched the Medline database for English-language reports on pertussis, Lyme disease, pneumococcal polysaccharide, meningococcal polysaccharide A and C, typhoid fever, influenza, hepatitis A, hepatitis B, and rabies vaccines and on diphtheria and tetanus (Td) toxoids, published from 1966 through 2000. Treanor also examined unpublished reports from a few directly relevant studies. All of the reports reviewed were limited to the acute events observed during limited follow-up periods. The rates of local and systemic reactions are summarized in Table 4-1. As with AVA, local effects observed included injection site pain or arm soreness, erythema, swelling, induration, and pruritis. For some vaccines, such local effects were common. For example, erythema or swelling was reported by 22 to 35 percent of recipients of Td toxoids (Halperin et al., 2000a; Macko and Powell, 1985; Middaugh, 1979; Van der Wielen et al., 2000) and by 11 to 21 percent of recipients of influenza vaccine (al-Mazrou et al., 1991; Banzhoff et al., 2000; Halperin et al., 1998; Scheifele et al., 1990). Local pain of any degree was reported by 50 percent or more of recipients of acellular pertussis vaccine (Englund et al., 1992; Halperin et al., 2000a,b; Keitel et al., 1999; Van der Wielen et al., 2000), Td toxoids (Halperin et al., 2000b; Macko and Powell, 1985; Van der Wielen et al., 2000), influenza vaccine (al-Mazrou, 1991; Aoki et al., 1993; Jackson et al., 1999; Nichol et al., 1996; Scheifele et al., 1990), Lyme disease vaccine (Keller et al., 1994), and meningococcal polysaccharide vaccine (Diez-Domingo et al., 1998). In other studies, however, pain was reported by less than 20 percent of recipients of recombinant hepatitis B vaccine (Rustgi et al., 1995; Schiff et al., 1995; Tron et al., 1989) and rabies vaccine (Anderson et al., 1980). Rates of moderate to severe pain were low. Reported systemic reactions included fever, malaise, fatigue, and joint pain. Such reactions affected less than 35 percent of vaccine recipients, with the highest rates observed in studies of influenza vaccine (al-Mazrou et al., 1991; Nichol et al., 1996). Rates of moderate to severe systemic reactions were generally less than 5 percent. Reports of fever ranged from none in studies of acellular pertussis vaccine recipients (Halperin et al., 2000b) and hepatitis A vaccine recipients (Czeschinski et al., 2000; Westblom et al., 1994) to 18 percent in studies of rabies vaccine recipients (Chutivongse et al., 1995); in most studies, fever was observed in less than 10 percent of vaccine recipients. Sex differences in reactions to AVA vaccination are a source of concern, but data from studies of other vaccines are limited because most have not reported separate results for men and women. When such data are available, they generally show higher rates of local pain for women. For

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The Anthrax Vaccine: Is it Safe? Does it Work? TABLE 4-1 Local and Systemic Event Rates Reported in Selected Prospective Vaccine Trials Vaccine Reference Number of Subjects Fever Acellular pertussis Van der Wielen et al., 2000 96 4   Halperin et al., 2000a 126 0 Halperin et al., 2000b 149 7 Hepatitis A Scheifele and Bjornson, 1993 64 3   Westblom et al., 1994 186 0 Hoke et al., 1995 91 3 Czeschinski et al., 2000 75 0 Hepatitis B Halliday et al., 1990 594 1   Schiff et al., 1995 382 0.3 Czeschinski et al., 2000 75 4 Influenza Schiefele et al., 1990 266 13   al-Mazrou et al., 1991 330 9 Aoki et al., 1993 76 2 Nichol et al., 1996 418 6 Banzhoff et al., 2000 61 2 Banzhoff et al., 2000 61 1 Halperin et al., 1998   1 Rabies Anderson et al., 1980 234 3   Chutivongse et al., 1995 202 18 Jaiiaroensup et al., 1998 599 2 Fritzell et al., 1992 46 — Tetanus-diphtheria Middaugh, 1979 697 —   Macko and Powell, 1985 100 7 Van der Wielen et al., 2000 98 9 Halperin et al., 2000a 126 0.8 aSystemic side effects include malaise, fatigue, and decreased energy, but headache was not included. bIn studies in which the category “any” was not reported, the rate of the most frequent systemic side effect is used.

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The Anthrax Vaccine: Is it Safe? Does it Work? Percent of Subjects Reporting the Following Side Effects Following Vaccination Systemica Erythema or Swelling Pain   Anyb Moderate or Severe Any Moderate or Severe Any Moderate or Severe Any Disability 27 1c 12 1c 72 0c —d 17 8 15 3 51 7 — 29 10 13 10e 77 11 — 16 — 8 — 52 — — 22 — 5 — 47 — — 4 — 4 — 40 — — 14 0 40 2 41 1 — — — 9 — 16 — — — — 0.5 — 11 — — 10 7 99 3 43 6 — — — 20 — 86 — — 33 — 18 — 24 — 1 17 — — — 61 — — 34 — — — 64 21 6 18 4 21 0 28 2 — 18 4 21 0 28 2 — 11 1c 11 8c 35 3c — 3 — 18 — 14 — — — — — — 4 — — — — 1 — 20 — — — — 13 — 52 — — — — 35 — 43 — — — — 30 — 75 27 — 17 1c 35 6c 83 0c — 26 8 22 11e 85 15 — cIn these studies, the descriptor “clinically significant” was used in place of “moderate or severe” or “greater than moderate.” dNot reported. eIn these studies, local reactions were dichotomized as >10 mm or <10 mm in diameter. SOURCE: Treanor (2001).

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The Anthrax Vaccine: Is it Safe? Does it Work? influenza vaccine, for example, rates of arm soreness were 34 percent for men and 49 percent for women, but rates of systemic effects were similar (Nichol et al., 1996). An analysis of 14 unpublished studies of influenza vaccine given to young adults also found that women had significantly higher rates of six of seven local effects and of two of five systemic effects (Beyer et al., 1996). The pooled odds ratio for any local symptom for men compared with that for women was 0.32 (95 percent confidence interval [CI] = 0.26 to 0.40), and the pooled odds ratio for any systemic symptom was 0.51 (95 percent CI = 0.39 to 0.67). An unpublished comparison based on acellular pertussis and hepatitis A vaccines found that for either vaccine women had higher rates of local reactions (redness, lumps, and swelling) than men and that women and men had similar (and low) rates of systemic reactions, including fever, chills, muscle aches, and decreased activity (Ward, 2001). An unpublished study of higher and lower doses of influenza vaccine also found a significantly higher rate of local pain among women who received the lower vaccine dose (Treanor, 2001). AVA differs from many vaccines in that it is licensed for subcutaneous rather than intramuscular administration, but few studies of any vaccine have compared the effects following administration of the vaccine by these two routes. For the hepatitis B (Yamamoto et al., 1986) and rabies (Selimov et al., 1988) vaccines, similar rates of local and systemic effects have been observed when the vaccine is administered by either route. For the meningococcal polysaccharide vaccine, local erythema was more common when it was administered by the subcutaneous route (Ruben et al., 2001). Also, a study of rabies vaccine found that intradermal administration was associated with lower rates of local pain (3 percent) compared with the rates after intramuscular administration (19 percent) but higher rates of local pruritis (29 versus 3 percent; Jaiiaroensup et al., 1998). Unpublished data from a pilot study of an adjuvanted pneumococcal vaccine show higher rates of local erythema and induration with subcutaneous administration but higher rates of pain on injection with intramuscular administration (Treanor, 2001). While a number of commonly used and well-tolerated vaccines are administered subcutaneously (e.g., inactivated poliovirus, measles-mumps-rubella, varicella, and meningococcal vaccines), they differ from AVA in that they are not inactivated bacterial vaccines. The findings from the studies that were reviewed are subject to limitations, many of which also apply to studies of AVA. In particular, the observed effects are linked to a vaccine because they are observed following administration of the vaccine but are not necessarily linked through other evidence of causality. In a few studies, comparisons with placebo controls help strengthen or weaken the observed association with those effects. For example, recipients of influenza vaccine reported substantially higher rates of arm soreness (64 percent) compared with recipients of a placebo (24

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The Anthrax Vaccine: Is it Safe? Does it Work? percent), but rates of fever were the same in vaccine and placebo recipients (6 percent; Nichol et al., 1996). In addition, because of the small sample sizes of most of these studies, the studies could not reliably detect rare events. Finally, most vaccine studies are conducted to assess efficacy rather than adverse effects. The lack of a standard set of adverse effects to be reported and the lack of standard definitions of such effects or of their severity can make it difficult to interpret or compare the results and data from different reports. SOURCES OF INFORMATION REGARDING THE SAFETY OF AVA To assess the safety of the anthrax vaccine, the committee examined information from individual case reports and from published and unpublished epidemiologic studies conducted with human populations. Individual case reports and case series provide information about illnesses that individuals or clinicians suspect may be linked with a specific exposure. Such reports can help to generate hypotheses about possible associations but are rarely helpful in confirming such associations. The case reports relating to AVA come from VAERS (see Chapter 5). The committee also heard personal testimony regarding adverse events following vaccination with AVA. These statements, some of which concerned cases reported to VAERS, added valuable insight into the conditions that some military personnel are experiencing. Epidemiologic studies, which examine relationships between exposures (e.g., vaccination) and health outcomes in defined populations, provide a stronger basis for assessing causality than case reports. Most of the information reviewed by the committee came from such sources. Data are available from two randomized controlled clinical trials (Brachman et al., 1962; Pittman et al., 2002) and from several observational studies. Some of the observational studies include control groups, which make it possible to compare rates of adverse events in those with and without vaccination. The studies are mixed in their use of active and passive surveillance for adverse events. The key features and findings of each study are presented in Chapter 6. The committee did not include various studies that have sought to identify risk factors for the health problems reported by some Gulf War veterans. Although some of these studies have suggested an association between veterans’ health problems and vaccinations (e.g., Cherry et al., 2001; Hotopf et al., 2000), they were not designed to study the effects of vaccine exposure. In addition, the analyses and the interpretation of their results are hindered by the veterans’ exposure to multiple vaccines, incomplete vaccination records, and the need to rely on self-reports of vaccine exposure. Results from animal and in vitro studies were also considered. However, most animal studies of vaccination with AVA do not present informa-

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The Anthrax Vaccine: Is it Safe? Does it Work? tion regarding the presence or absence of reactions. The few studies that do comment on reactions (Darlow et al., 1956; IOM, 2000a; Ivins et al., 1998; Wright et al., 1954) report no vaccine-related adverse effects. Two laboratory assessments of possible vaccine contaminants are discussed at the end of this chapter. However, although animal and laboratory studies can, in some instances, elucidate the biological plausibility of a possible association between vaccination and an adverse event, they cannot provide direct evidence of causality in humans. AVA contains aluminum hydroxide as an adjuvant. Aluminum has been used in vaccines for nearly 70 years in the form of the salts aluminum hydroxide, aluminum phosphate, and alum (Malakoff, 2000). Some have expressed concerns about the safety of aluminum adjuvants (e.g., Gherardi et al., 1998). For its assessment of the safety of AVA, the committee focused on data from studies of the complete vaccine product. This approach captures the contribution that aluminum might make to any vaccine-related adverse health effects associated with AVA, although it does not make it possible to attribute any effects to aluminum per se. Reviews such as this one are often restricted to reports published in the peer-reviewed literature because the peer-review process provides some assurance that a study meets essential standards of quality. The committee decided, however, to consider unpublished epidemiologic analyses conducted by DoD and other researchers, because such studies offered the best available and most direct analyses of the possible association between AVA and various health outcomes. Many of the manuscripts describing these studies were under review or were being prepared for submission to a journal at the time they were presented to the committee. Committee members heard presentations from the researchers who conducted these studies and had an opportunity to question them about their study methodologies and analyses as well as to review draft manuscripts.3 In some cases, the researchers conducted additional analyses in response to requests from the committee. Thus, sufficient information was available in these instances to judge the quality of the research and determine the degree to which results should contribute to conclusions about vaccine safety. The committee reviewed all safety-related information that was brought to its attention and weighed the scientific merits of each element in arriving at conclusions regarding the safety of AVA. As indicated above, individual case reports and case series are useful for raising concerns or stimulating further research but are rarely conclusive in establishing causal associa- 3   Documents and overheads provided to the committee are available to the public through the Public Access Records Office, National Academy of Sciences.

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The Anthrax Vaccine: Is it Safe? Does it Work? tions. Controlled epidemiologic studies provide the best evidence for the examination of associations of vaccination and subsequent adverse events. In evaluations of the studies presented to the committee, additional weight was given to those that (1) used active surveillance rather than self-reports of postimmunization events; (2) included sufficiently large numbers of subjects; (3) had clearly specified, objective criteria for the definition of adverse events; and (4) had sufficiently long postimmunization follow-up intervals to allow identification of later-onset events. Those studies that included a suitable unimmunized comparison group or in which evaluators were blinded to the subjects’ vaccination status were especially useful to the committee. TESTING FOR VACCINE CONTAMINATION Among the concerns that have been raised about the anthrax vaccine is that contaminants in the vaccine product are producing adverse health outcomes. Laboratory analyses have been conducted to test for the presence of two suggested contaminants, mycoplasma and squalene. Mycoplasma Mycoplasma contamination of the anthrax vaccine has been suggested as a possible cause of illness among Gulf War veterans (Nicolson et al., 2000). Mycoplasmas are a distinctive type of bacteria that lack cell walls (Baseman and Tully, 1997). Many mycoplasma species appear to be harmless constituents of the normal human microbial flora, but others are associated with various diseases, including atypical pneumonia, genitourinary infections, joint diseases, and opportunistic infections in persons with compromised immune systems. Mycoplasma contamination is considered possible in vaccines produced in cell cultures, and FDA requires testing to demonstrate the absence of such contamination (Hart et al., 2002). For vaccines like AVA that are not derived from cell cultures, contamination is considered unlikely. However, to respond to the concerns about AVA, DoD commissioned two nonmilitary laboratories to conduct studies with samples from five AVA lots. The samples were obtained from eight different DoD vaccination clinics. Hart and colleagues (2002) have reported on the results of those tests. Tests for the presence of live organisms were conducted at the National Cancer Institute’s Mycoplasma Laboratory, which is located in Frederick, Maryland, and operated by Science Applications International Corporation. No mycoplasma colonies could be cultivated from the vaccine samples tested. In addition, tests of a vaccine sample deliberately inoculated with mycoplasma showed no presence of viable organisms after 24 hours. Sepa-

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The Anthrax Vaccine: Is it Safe? Does it Work? rate tests by polymerase chain reaction assay, conducted at Charles River Tektagen, a commercial facility, showed no presence of mycoplasma DNA in any of the samples. Squalene Some Gulf War veterans and others have expressed concerns about whether squalene might be present in the anthrax vaccine and whether it has the potential to cause health effects. Squalene is a hydrocarbon compound found in many natural sources, including olive oil and the human body. In humans it is a precursor in the synthesis of cholesterol and is also found in oils of the skin (Kelly, 1999; Final Report, 1982). In the 1970s the average dietary intake of squalene was calculated to be 24 milligrams (mg) per day in a 2,000-calorie diet (Liu et al., 1976). Among people whose diets include more olive oil, squalene consumption can range from 200 to 400 mg/day (Smith, 2000). Roughly 60 percent of the squalene consumed in the diet is absorbed through the gastrointestinal tract; much of what is absorbed is converted into cholesterol (Strandberg et al., 1990). The IOM Committee on Health Effects Associated with Exposures During the Gulf War (IOM, 2000b) examined in detail evidence regarding the potential health effects of squalene, including those that might be related to its use as a vaccine adjuvant. In the United States, it has been tested in animal studies of anthrax vaccine and in human studies of other vaccines (GAO, 1999a; Ivins et al., 1995; Ott et al., 1995), but it is not used in any human vaccine currently in use in the United States. An influenza vaccine with squalene as an adjuvant has been approved and distributed in Europe and has not been associated with adverse health events. The prior IOM (2000b) review resulted in the conclusion that, in certain animals and under selected conditions, squalene has been found to produce arthritis and neuropathology, but it also resulted in the conclusion that the relevance of toxicity findings for animals to humans is uncertain, in part because humans absorb squalene differently from animals. The human studies testing a squalene-containing adjuvant in other vaccines found only transient acute effects. DoD sponsored a study by SRI International, a private company, to assay AVA and other pharmaceuticals for squalene at the level of parts per billion. The study report, dated August 14, 2001, found that 1 lot of over 30 lots tested contained measurable levels of squalene. Three samples from that lot contained squalene at 7, 9, and approximately 1 parts per billion, respectively. Use of vaccine from that lot has not been associated with elevated rates of adverse events (see the discussion of the Special Immunizations Program in Chapter 6).

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The Anthrax Vaccine: Is it Safe? Does it Work? Conclusion Because the available data demonstrate the absence of mycoplasma contamination and demonstrate that the presence of trace amounts of squalene is not associated with an increase in the rates of adverse events following vaccination with AVA, the committee concludes that further investigation of possible AVA contamination is not warranted at this time. REFERENCES al-Mazrou A, Scheifele DW, Soong T, Bjornson G. 1991. Comparison of adverse reactions to whole-virion and split-virion influenza vaccines in hospital personnel. Canadian Medical Association Journal 145(3):213–218. Anderson LJ, Winkler WG, Hafkin B, Keenlyside RA, D’Angelo LJ, Deitch MW. 1980. Clinical experience with a human diploid cell rabies vaccine. JAMA 244(8):781–784. Aoki FY, Yassi A, Cheang M, Murdzak C, Hammond GW, Sekla LH, Wright B. 1993. Effects of acetaminophen on adverse effects of influenza vaccination in health care workers. Canadian Medical Association Journal 149(10):1425–1430. Banzhoff A, Schwenke C, Febbraro S. 2000. Preservative-free influenza vaccine. Immunology Letters 71(2):91–96. Baseman JB, Tully JG. 1997. Mycoplasmas: sophisticated, reemerging, and burdened by their notoriety. Emerging Infectious Diseases 3(1):21–32. Beyer WE, Palache AM, Kerstens R, Masurel N. 1996. Gender differences in local and systemic reactions to inactivated influenza vaccine, established by a meta-analysis of fourteen independent studies. European Journal of Clinical Microbiology and Infectious Diseases 15(1):65–70. 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. Chen RT. 2000. Special methodological issues in pharmacoepidemiology studies of vaccine safety. In: Strom BL, ed. Pharmacoepidemiology. 3rd ed. West Sussex, England: John Wiley & Sons, Ltd . Pp. 707–732. Cherry N, Creed F, Silman A, Dunn G, Baxter D, Smedley J, Taylor S, Macfarlane GJ. 2001. Health and exposures of United Kingdom Gulf War veterans. Part II. The relation of health to exposure. Occupational and Environmental Medicine 58(5):299–306. Chutivongse S, Wilde H, Benjavongkulchai M, Chomchey P, Punthawong S. 1995. Postexposure rabies vaccination during pregnancy: effect on 202 women and their infants. Clinical Infectious Diseases 20(4):818–820. Czeschinski PA, Binding N, Witting U. 2000. Hepatitis A and hepatitis B vaccinations: immunogenicity of combined vaccine and of simultaneously or separately applied single vaccines. Vaccine 18(11–12):1074–1080. Darlow HM, Belton FC, Henderson DW. 1956. The use of anthrax antigen to immunize man and monkey. Lancet ii(Sept 8):476–479. Diez-Domingo J, Albert A, Valdivieso C, Ballester A, Diez LV, Morant A. 1998. Adverse events after polysaccharide meningococcal A&C vaccine. Scandinavian Journal of Infectious Diseases 30(6):636–638. Ellenberg SS, Chen RT. 1997. The complicated task of monitoring vaccine safety. Public Health Reports 112(1):10–20. Englund JA, Glezen WP, Barreto L. 1992. Controlled study of a new five-component acellular pertussis vaccine in adults and young children. Journal of Infectious Diseases 166(6): 1436–1441.

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