6
Safety: Epidemiologic Studies

A small body of published reports as well as results from newer studies by Department of Defense (DoD) researchers provided data regarding adverse events following administration of Anthrax Vaccine Adsorbed (AVA). The studies examined a variety of outcomes, including local and systemic reactions occurring soon after vaccination, hospitalizations and outpatient visits, long-term health status, and reproductive outcomes. Since many of the studies are as yet unpublished, this report discusses them in detail. They are described in this chapter in three general categories: (1) ad hoc studies about immediate-onset adverse events, (2) ad hoc studies about later-onset adverse events, and (3) record-linkage studies. Studies within each of these three categories are described in the following order: (a) randomized controlled trials, (b) other controlled studies, and (c) uncontrolled studies. A few additional studies were known to the committee but were not reviewed. The committee could not obtain sufficient documentation for those studies, despite efforts to do so, to conduct an appropriate scientific review.

The synthesis of studies of local and systemic adverse events following receipt of AVA is hindered by several factors. First, the studies report on different types of adverse events and use different definitions of the events and of the severity of those events. For example, some studies include pruritis (itching), whereas others do not, and some studies count erythema (redness of the skin) only if it exceeds a certain size. Some studies use standardized quantitative definitions for an adverse event following inoculation with AVA, whereas others rely on the recipient’s self-reported perception of a reaction. Second, adverse events are monitored or reported for



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The Anthrax Vaccine: Is it Safe? Does it Work? 6 Safety: Epidemiologic Studies A small body of published reports as well as results from newer studies by Department of Defense (DoD) researchers provided data regarding adverse events following administration of Anthrax Vaccine Adsorbed (AVA). The studies examined a variety of outcomes, including local and systemic reactions occurring soon after vaccination, hospitalizations and outpatient visits, long-term health status, and reproductive outcomes. Since many of the studies are as yet unpublished, this report discusses them in detail. They are described in this chapter in three general categories: (1) ad hoc studies about immediate-onset adverse events, (2) ad hoc studies about later-onset adverse events, and (3) record-linkage studies. Studies within each of these three categories are described in the following order: (a) randomized controlled trials, (b) other controlled studies, and (c) uncontrolled studies. A few additional studies were known to the committee but were not reviewed. The committee could not obtain sufficient documentation for those studies, despite efforts to do so, to conduct an appropriate scientific review. The synthesis of studies of local and systemic adverse events following receipt of AVA is hindered by several factors. First, the studies report on different types of adverse events and use different definitions of the events and of the severity of those events. For example, some studies include pruritis (itching), whereas others do not, and some studies count erythema (redness of the skin) only if it exceeds a certain size. Some studies use standardized quantitative definitions for an adverse event following inoculation with AVA, whereas others rely on the recipient’s self-reported perception of a reaction. Second, adverse events are monitored or reported for

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The Anthrax Vaccine: Is it Safe? Does it Work? various periods following inoculation, with some study reports not indicating the lengths of such periods. Thus, some adverse event rates apply to the first 24 to 48 hours postimmunization, whereas others may apply to the period from days to weeks following vaccination. Third, studies differ in their methods of ascertaining the presence of adverse events. Some studies used active surveillance to identify local and systemic reactions, with all recipients monitored on a regular basis at specified intervals. Other studies relied on passive surveillance, with vaccine recipients deciding whether an adverse event had occurred and whether to report that event. Fourth, the anthrax vaccine formulation was not constant across studies, and in some studies the anthrax vaccine was administered in combination with other vaccines. In addition, studies differed in the number of anthrax vaccine doses given. Finally, the adverse event rates reported were sometimes based on the number of doses administered and were sometimes based on the number of persons vaccinated. It should be noted that the same considerations affect the evaluation of safety for other vaccines as well.1 The summary of findings presented below and in Tables 6-1 to 6-4 (referred to as the adverse events tables) should be read with the foregoing considerations in mind. AD HOC STUDIES Studies of Health Effects with Immediate Onset Randomized Controlled Trials Brachman Study Brachman and colleagues (1962) conducted the only randomized, placebo-controlled trial of the efficacy of a protective antigen anthrax vaccine. Information on events of immediate onset following immunization is presented here; information on the efficacy of the vaccine is reported in Chapter 3. The vaccine studied was not AVA but was an earlier formulation produced from the R1-NP strain of anthrax (see Chapter 7 for more details). The study was carried out from January 1955 through March 1959 in four mills in the eastern United States that processed raw imported goat hair, which was commonly contaminated with anthrax spores. The worker population eligible for the study included 1,249 men and women with no history of prior anthrax infection. The numbers of study 1   An international effort is under way to standardize case definitions of many of the adverse events that can follow vaccination. The Brighton Collaboration was launched in the autumn of 2000 and has now developed several definitions in draft form (http://brightoncollaboration.org/index.cfm).

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The Anthrax Vaccine: Is it Safe? Does it Work? TABLE 6-1 Ad Hoc Studies of Immediate-Onset Adverse Events Following Anthrax Vaccination: Local Events Study Study Population and Observation Period Data Collection Method(s) Number of Subjects or Doses Randomized Controlled Trials Field study (Brachman et al., 1962)b U.S. goat hair mill workers (4 mills), 1955–1959 Examination at 24 and 48 hours (2 mills) 1,249 persons (4 mills) Placebo   Route of administration pilot study (Pittman, 2001b; Pittman et al., 2002)c Military and civilian study volunteers, 1998 Active surveillance 173 persons; 117 with all doses Intramuscular   118 doses Subcutaneous   203 doses Subcutaneous Men   132 doses Subcutaneous Women   71 doses Other Controlled Studies Double dose (Gunzenhauser et al., 2001) ROTC cadets, Ft. Lewis, summer 2000 Self-report; postvaccination survey 73 cadets Doubled first dosee   25 Standard dosese   48

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The Anthrax Vaccine: Is it Safe? Does it Work? Rates of Local Eventsa Overall Mild Moderate Severe Redness Induration Knot, Lump, or Nodule Edema or Swelling Other 35%   + + + 2.8% Itching, pain, warmth, tenderness   3 persons   6% 2% 0   Tenderness, 56%; warmth, 5%         36% 15% 38%   Tenderness, 70%; warmth, 16%   22.0% 3.0% 24.2% 2.3% Tenderness, 63%; itching, 6%   63.4%d 38%d 63.4%d 9.9%d Tenderness, 63%d; itching, 30%d 92%, 72%   0, 39%   88%, 44% 84%, 50% Sore arm, 92%, 67% 92%, 67% 0, 19%   42%, 29% 42%, 19% Sore arm, 83%, 67%

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The Anthrax Vaccine: Is it Safe? Does it Work? Study Study Population and Observation Period Data Collection Method(s) Number of Subjects or Doses Uncontrolled Studies Investigational new drug reports (CDC, 1967–1971)f Textile, laboratory workers; 1966–1971   ~7,000 persons ~16,000 doses Special Immunizations Program (Pittman et al., 2001a,b)g Ft. Detrick laboratory workers, 1973–1999 Passive self-report; reported adverse events assessed and recorded by occupational health clinic medical personnel 1,583 persons 10,722 doses Meng   1,249 men 8,797 doses Womeng   334 women 1,925 doses

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The Anthrax Vaccine: Is it Safe? Does it Work? Rates of Local Eventsa Overall Mild Moderate Severe Redness Induration Knot, Lump, or Nodule Edema or Swelling Other   8.4% 0.9% 0.2%   3.6% 1.6% 1.4% 0.2% 2.5% 2.8% + 0.1% Tenderness, 1.7%; itching, 0.8%; lymph node enlargement, 0.1%   1.2% 0.9% 0.1% 1.7% 2.0% + <0.1% Tenderness, 1.3%; itching, 0.4%; lymph node enlargement, 0.1%; arm motion limitation, 0.1% 3.5%d 3.5%d 0.5%d 6.3%d 6.4%d + 0.3%d Tenderness, 3.6%d; itching, 2.4%d; lymph node enlargement, 0.4%d; arm motion limitation, 0.2%

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The Anthrax Vaccine: Is it Safe? Does it Work? Study Study Population and Observation Period Data Collection Method(s) Number of Subjects or Doses Ft. Bragg Booster Study (Pittman et al., 2002) Army personnel; Desert Shield/Desert Storm AVA vaccinees given booster doses of AVA alone or with PBT, 1992, 1994 Active surveillance 495 men Recipients of AVA onlyg   43 AVA arm for recipients of AVA and PBTg   452 U.S. Forces Korea (CDC, 2000; Hoffman et al., submitted for publication)c Personnel covered by Camp Casey Troop Medical Clinic, Aug. 1998–July 1999 Retrospective self-report through questionnaire 2,824 Menh   2,214 Womenh   610 Tripler Army Medical Center (Wasserman, 2001) Military health care workers, 1998–2000 Self-report through questionnaire; medical record review 601 Men   416

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The Anthrax Vaccine: Is it Safe? Does it Work? Rates of Local Eventsa Overall Mild Moderate Severe Redness Induration Knot, Lump, or Nodule Edema or Swelling Other   27.9% 4.7% 0     16.0% 9.3% 0.7%   31.5–39.7%i 7.2–7.7% 3.9–4.8% 0.4–1.1%   21.4–28.9% 2.5–3.4% Pain, 9.6–10.2%; itching, 5.5–7.5% 59.9–67.9%d,i 11.7–13.5%d 10.7–13.3%d 2.0–4.1%d   49.8–62.4%d 3.9–9.4%d Pain, 15–18.8%d; itching, 20.4–37%d   15–23%j   56–65% 7–10% Itching, 24–31%; pain limiting motion, 5–10%; muscle soreness, 50–66%

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The Anthrax Vaccine: Is it Safe? Does it Work? Study Study Population and Observation Period Data Collection Method(s) Number of Subjects or Doses Women   185 Adjusted odds ratios for women versus men (95% CI)   Dover Air Force Base (Tanner, 2001) 9th Airlift Squadron, surveyed Jan. 2000 Self-report through questionnaire 252 eligible; 139 responses NOTES: AVA, Anthrax Vaccine Adsorbed; PBT, pentavalent botulinum toxoid; +, reaction reported as present. aThe rates are per dose. bStudy subjects received only the Merck vaccine and not AVA. cData are for doses 1 to 3. dSignificant difference between men and women (p < .05). eData are for doses 1 and 2, respectively. fReaction rates are for doses of AVA and were calculated by the committee from data in the CDC reports. Mild reactions are defined as areas of erythema (redness) only

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The Anthrax Vaccine: Is it Safe? Does it Work? Rates of Local Eventsa Overall Mild Moderate Severe Redness Induration Knot, Lump, or Nodule Edema or Swelling Other   37–43%j   81–93% 8–15% Itching, 56–68%; pain limiting motion, 8–17%; muscle soreness, 56–80% 2.44 (2.04–2.93)   3.02 (2.52–3.62)k   4.48 (3.55–5.65) 1.41 (1.08–1.84) Itching, 4.45 (3.74–5.31); pain limiting motion, 1.62 (1.23–2.12); muscle soreness, 1.54 (1.29–1.84); muscle ache, 1.44 (1.20–1.72) Reports on systemic events only   or of measurable edema or induration of ≤3 cm in diameter. Moderate reactions are defined as areas of edema or induration of >3 cm to <12 cm in diameter. Severe reactions are defined as any reaction measuring >12 cm in diameter or accompanied by marked limitation of arm motion or axiliary node tenderness. gMild reactions are areas of erythema (redness) and/or induration (E/I) of < 5 cm in diameter, moderate reactions are areas of E/I of 5 to 12 cm, and severe reactions are areas of E/I of >12 cm. hData on mild, moderate, and severe events are for areas of redness of <5, 5 to 12, and >12 cm in diameter, respectively. iLocal or systemic effects. jData are for areas of redness of >5 cm in diameter. kThe outcome measure is the ratio of reports of areas of redness of >5 cm in diameter to reports of areas of <5 cm in diameter.

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The Anthrax Vaccine: Is it Safe? Does it Work? TABLE 6-2 Ad Hoc Studies of Immediate-Onset Adverse Events Following Anthrax Vaccination: Systemic Events   Rates of Systemic Eventsa   Study Overall Muscle Aches Fever Headache Malaise Other Functional Impact or Health Care Use Randomized Controlled Trials   Field study (Brachman et al., 1962)b 0.2%   2 persons   Work loss: 6 days Route of administration pilot study (Pittman 2001b; Pittman et al., 2002)c   Intramuscular   4% 1% 11% 5% Anorexia, 5%; nausea, 4%; itching, 0   Subcutaneous   4% 2% 10% 9% Anorexia, 1%; nausea, 2%; itching, 2%   Subcutaneous (Men)   3.0% 3.0% 9.1% 9.8% Anorexia, 2.3%; nausea, 2.3%; itching, 2.3%   Subcutaneous (Women)   7.0% 1.4% 11.3% 8.5% Anorexia, 0; nausea, 2.8%; itching, 2.8%   Other Controlled Studies   Doubled dose (Gunzenhauser et al., 2001)   Doubled first dosed   12%, 0% 0, 11%   Tiredness, 0, 22% Decreased performance reported: 17% after second dose Sought medical care: 1 cadet after first dose No hospitalizations or missed training Standard dosed   8%, 7% 0, 5%   Tiredness, 0, 7% Decreased performance reported: 7% after second dose Sought medical care: none No hospitalizations or missed training

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The Anthrax Vaccine: Is it Safe? Does it Work? would be a lower than normal rate of hospitalization for diabetes before vaccination among those who would ultimately receive AVA. Comparison of a normal rate of hospitalization for diabetes after vaccination with this lower rate before vaccination would produce the false appearance of a positive association, and this false signal would persist, regardless of whether one were examining the time period right after the vaccination (0 to 45 days) or the time period thereafter (>45 days). How can one be confident that the true explanation is this selection bias rather than a causal connection? A separate analysis compared the rates of hospitalization for any of 843 diagnoses in the prevaccination period with the rates for those who were never vaccinated. In general, the rates of hospitalization prevaccination were lower than the rates in the group that was never vaccinated, confirming the healthy soldier effect. The adjusted rate ratios varied, but most often they were about 0.7 or 0.8. However, for diabetes the comparable adjusted rate ratio was 0.12 (95 percent CI = 0.06 to 0.24). Thus, those who received AVA were dramatically less likely to be hospitalized for diabetes than those who were never vaccinated. The normal rate of spontaneous development of diabetes after vaccination would therefore falsely appear as an increased risk. The same was true when the prevaccination rates were compared with the rates in those who never received AVA for some of the other apparent signals, such as regional enteritis (rate ratio = 0.14, 95 percent CI = 0.06 to 0.35) and other disorders of the intestine (rate ratio = 0.28, 95 percent CI = 0.12 to 0.64). For multiple sclerosis a selection bias seems even more likely, with a hospitalization rate ratio of about 0.06 for the preimmunization cohort versus those never vaccinated with AVA (based on only one preimmunization case of multiple sclerosis). Overall, the analyses of data from DMSS were very reassuring. They indicate that exposure to AVA is not associated with a significantly increased risk for any condition of later onset that cannot be otherwise explained by biases inherent in this type of analysis. Several possible “signals” were observed, however. Signals are the earliest indication of a possible causal relationship between an exposure and a health event. These conditions include diabetes, regional enteritis, and multiple sclerosis. The committee’s judgment is that these signals are probably not causally linked to exposure to AVA but most likely are due to random error or biases. However, a causal link cannot be completely excluded. Thus, these signals deserve continued surveillance; in addition, ad hoc studies are required to further explore the possible links of these signals with exposure to AVA. Such studies could involve additional analyses with data from DMSS, as well as examination of medical records to validate the diagnosis and the timing of the onset of symptoms in relation to the vaccine exposure. The committee was impressed by the creativity and rigor of the military

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The Anthrax Vaccine: Is it Safe? Does it Work? professional staff working with the data in the DMSS databases and their productivity. However, the committee also counsels great caution in the use of approaches that use such data collected through automated systems for signal generation. As expected by chance alone, the rates of several diseases and conditions will predictably appear to be elevated in one group or another. Although random error and bias are likely explanations for these increases, other conclusions might also be drawn. In other words, these preliminary findings should lead to further examination of the data. The current DoD approach and organization focus on screening DMSS data for hypotheses. DoD should, however, devote more attention and resources to the evaluation of these hypotheses, as was begun in response to the committee’s inquiries. As has been articulated in a set of good epidemiology practices developed for use with similar administrative and clinical data sets in civilian practice (Andrews et al., 1996), analysis of such data requires the exercise of great caution and a commitment to devote the necessary resources to explore the possible associations that might surface from such exercises. Chapter 8 discusses recommended improvements for use of DMSS data. Thus, finding an increased rate of occurrence of one or more adverse events must be considered a signal until proper review provides an alternative explanation. Criteria for determination of which signals should be further evaluated need to be developed and routinely applied. At a minimum, a system for retrieval and review of primary medical records is required to be able to rule out coding and classification errors, to search for subtle but possibly explanatory variables that may confound an association, or to differentiate a true signal from a statistical chance event. Finding: DMSS data are screened quarterly to identify statistically significant elevations in hospitalization and outpatient visit rate ratios associated with receipt of AVA. In this way, DMSS promises to be very useful as a tool for hypothesis generation. Finding: The elevated rates of specific diagnoses in the various analyses of DMSS data are not unexpected per se; that is, they appear to be explicable by chance alone. The bias of selection of healthy individuals for receipt of AVA is also a likely explanation for some observed associations. Thus these elevated rates should not be automatically viewed as an indication of a causal association with the receipt of AVA. However, additional follow-up is needed. Recommendation: AMSA staff should follow up the currently unexplained elevations in hospitalization rate ratios for certain diagnostic categories among the cohorts of AVA recipients. Studies might include

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The Anthrax Vaccine: Is it Safe? Does it Work? additional analyses with the database or examination of medical records to validate and better understand the exposures and outcomes in question. A protocol should be developed to ensure that such follow-up regularly and reliably occurs after a potential signal is generated. Finding: Examination of data from the DMSS database to investigate potential signals suggested by VAERS reports related to vaccination with AVA has not detected elevated risks for any of these signals for the vaccinated population, although continued monitoring is warranted. PRELIMINARY INFORMATION ON ANALYSIS OF DATA ON BIRTH DEFECTS As it was completing its work, the committee received information about a record-linkage study at the DoD Center for Deployment Health Research by Ryan and colleagues (Ryan, 2002) of the risk of birth defects among children born to women in the military who were vaccinated with AVA. Although the analysis was not complete as of February 2002, preliminary results suggesting a possible increase in risk were noted in the January 2002 revision of the product insert for AVA and in informed-consent documents provided in December 2001 to individuals who were offered vaccination with AVA as supplemental prophylaxis following possible exposure to anthrax spores in the autumn 2001. The analysis compares the prevalence of birth defects among children born to women in the military who received AVA during the first trimester of pregnancy with the prevalence of birth defects among children of military women who received AVA at any other times, according to records in the DoD Birth Defects Registry and the DoD database that stores information on AVA immunizations given to military personnel. Established in 1998, the DoD Birth Defects Registry contains information on infants with birth defects (ICD-9-CM codes 740.0–760.71) diagnosed within the first year of life (Ryan et al., 2001). The registry data are captured from databases on DoD-financed hospitalizations and ambulatory care in military and civilian facilities. For the period 1998-1999, approximately 3,000 infants were born to military women with a record of having received at least one dose of AVA. Comparisons were adjusted for maternal age, race, marital status, service branch, rank, and occupational group. No quantitative results from this study were available to the committee, but they were reported to indicate a small but statistically significant association between anthrax vaccine exposure in the first trimester of pregnancy and the frequency of birth defects diagnoses.

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The Anthrax Vaccine: Is it Safe? Does it Work? The authors acknowledge several of the limitations of their preliminary analysis. The timing of exposure to AVA (i.e., whether or not it occurred in the first trimester) was not precisely known for each infant but rather was estimated based on traditional gestational age cut points for term, preterm, and very preterm infants. Thus, time of exposure was subject to mis-classification because of the manner in which exposure periods were estimated. Inexact vaccination dates could also contribute to misclassification of time of exposure. In addition, it appears that all “major” birth defects were combined, which may not be biologically appropriate. The accuracy of identification of birth defects is uncertain, and analyses were not adjusted for differences between groups in other factors that might influence risk of birth defects such as maternal alcohol use, exposure to medications, or use of folic acid supplements. The number of infants exposed during the first trimester is relatively small, making estimates of risk derived from such analyses highly uncertain. These limitations again emphasize the need to distinguish possible “signals” generated by exploration of large databases, which require further and more definitive studies, from findings of causal associations. These study results remain preliminary and therefore may change with further analysis. Because of the importance of this issue, the study investigators are working rapidly to validate both exposures and outcomes using primary data sources, which is highly appropriate. In the meantime, the standing DoD policy to avoid immunization of women during pregnancy has been reiterated, which is also appropriate. Further conclusions about the safety of AVA during pregnancy must await the results of this and other studies. CONCLUSIONS REGARDING AVA VACCINATION AND ADVERSE EVENTS The committee has reviewed information from a variety of sources, including VAERS and DMSS, on the association between vaccination with AVA and adverse events. For AVA, as with any vaccine, it is essential in assessing questions regarding the safety of the vaccine to distinguish between immediate-onset health events that are observable within hours or days following vaccination and later-onset events that would be observable only months or years following vaccination. On the question of immediate-onset health events, substantial amounts of data are now available from VAERS, DMSS, and epidemiologic studies. The committee concluded that vaccination with AVA is associated with certain acute local and systemic effects. Epidemiologic studies have consistently found, using either active surveillance (Brachman et al., 1962; Pittman, 2001b,c; Pittman et al., 1997, 2002, in press) or passive surveil-

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The Anthrax Vaccine: Is it Safe? Does it Work? lance (Hoffman et al., submitted for publication; Pittman, 2001a; Pittman et al., 2001a,b; Wasserman, 2001), that some AVA vaccinees experience local reactions at the injection site that include redness, induration, edema, itching, or tenderness. Systemic events, such as fever, malaise, and myalgia, are also associated with vaccination with AVA, but these reactions are generally less common than reactions at the injection site. The types of local and systemic reactions associated with AVA and the rates at which they were observed are comparable to those observed with other vaccines regularly administered to adults, such as diphtheria and tetanus toxoids and influenza vaccines (Treanor, 2001). The available data also indicate that although these immediate-onset health effects can be serious enough in some individuals to result in brief limitation of activities or the loss of time from work (Hoffman et al., submitted for publication; Wasserman, 2001), the effects are self-limited and result in no serious, permanent health impairments (AMSA, 2001a,b,c; Grabenstein, 2000; Lange et al., 2001a,b; Mason et al., 2001, submitted for publication; Rehme, 2001; Rehme et al., 2002; Sato, 2001a,b; Sato et al., 2001). Questions have been raised about differences between men and women in their reactions following vaccination with AVA. The committee concluded that the available data from studies that have used both active and passive surveillance indicate that there are sex differences in local reactions at the injection site following vaccination with AVA. Women are more likely than men to experience and report erythema, local tenderness, subcutaneous nodules, itching, and edema (Hoffman et al., submitted for publication; Pittman, 2001a,b; Pittman et al., 2001a,b, 2002; Wasserman, 2001). In addition, some systemic effects, including fever, headache, malaise, and chills, were sometimes reported more often by women than by men (Hoffman et al., submitted for publication; Pittman, 2001a; Pittman et al., 2001a,b), but, unlike local reactions, the rates of systemic reactions did not differ substantially between men and women when the outcomes were evaluated clinically (Pittman, 2001b; Pittman et al., 2002). For female service members, reactions following vaccination with AVA may be more likely to have an adverse effect on their ability to perform their duties (Hoffman et al., submitted for publication; Wasserman, 2001). Studies of other vaccines have generally found higher rates of local reactions among women but similar rates of systemic reactions between men and women (Treanor, 2001). The factors that account for these sex differences are not known, but they could be a function of differences in muscle mass, the dose per unit of body mass, physiologic factors, or care-seeking behavior. Because of the reported sex differences in reactions following vaccination with AVA, it will be important that future studies of vaccination with AVA continue to analyze data separately for men and women. Some of the data reviewed by the committee provided evidence of lot-

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The Anthrax Vaccine: Is it Safe? Does it Work? to-lot differences in the reactogenicity of AVA (Pittman, 2001a; Pittman et al., 2001a,b; CDC, 1967–1971). The information presented to the committee on the recertification of the AVA manufacturing process suggests that AVA lots released for use in the future may show less variation in reactogenicity because of greater consistency in production, but there is no a priori basis for prediction of the level of reactogenicity. This and other concerns related to the future use of AVA are discussed further in Chapter 7. AVA is unusual compared with other vaccines in that it is licensed for subcutaneous rather than intramuscular administration. The limited evidence available from a small study that tested changes in the dosing schedule and route of administration of the vaccine (Pittman, 2001b; Pittman et al., 2002) points to subcutaneous administration as a contributing factor in the local reactions associated with AVA. The route of administration did not appear to affect rates of systemic reactions. A few studies of other vaccines (Treanor, 2001) have also shown that subcutaneous administration is associated with higher rates of local erythema or induration, reactions commonly reported following administration of AVA. The committee concluded that further investigations should be conducted to confirm whether a change from subcutaneous to intramuscular administration of AVA could reduce the rates of local reactions without impairing the efficacy of the vaccine. Service members and others have also expressed concerns about potential later-onset and chronic health effects resulting from receipt of AVA. The committee examined the available information regarding later-onset health effects, but the data are limited, as they are for all vaccines. DMSS, which provides the best source of data for studying later-onset health effects, currently has data on service personnel who have documented histories of vaccination with AVA and other vaccines and who have been observed for up to a maximum of 3 years. Although AVA has been administered to military personnel for more than 3 years, unreliable documentation of vaccinations before 1998 limits the use of DMSS data for observation of potential vaccine-related health effects over longer periods. The evidence available to date from analyses of DMSS data (AMSA, 2001a,b,c; Grabenstein, 2000; Lange et al., 2001a,b; Mason et al., 2001, submitted for publication; Rehme, 2001; Rehme et al., submitted for publication; Sato, 2001a,b; Sato et al., 2001) provides no convincing evidence at this time of elevated risks of later-onset health events among personnel who have received AVA. Repeated examination of a small population of heavily vaccinated laboratory workers provides no indication that vaccination with AVA is associated with an obvious increase in the risk of illness with later onset (Peeler et al., 1958, 1965; White et al., 1974). The committee notes that the studies reviewed did not examine the use

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The Anthrax Vaccine: Is it Safe? Does it Work? of AVA in children, elderly individuals, or persons with chronic illnesses. In addition, information regarding outcomes of pregnancy following use of the vaccine is limited. These limitations would have to be taken into account if AVA were being considered for use in the general population. FINDINGS AND RECOMMENDATIONS Immediate-Onset Health Events Finding: The data available from VAERS, DMSS, and epidemiologic studies indicate the following regarding immediate-onset health events following receipt of AVA: Local events, especially redness, swelling, or nodules at the injection site, are associated with receipt of AVA, are similar to the events observed following receipt of other vaccines currently in use by adults, and are fairly common. Systemic events, such as fever, malaise, and myalgia, are associated with receipt of AVA, are similar to the events observed following receipt of other vaccines currently in use by adults, but are much less common than local events. Immediate-onset health effects can be severe enough in some individuals to result in brief functional impairment, but these effects are self-limited and result in no permanent health impairments. There is no evidence that life-threatening or permanently disabling immediate-onset adverse events occur at higher rates in individuals who have received AVA than in the general population. Finding: The available data from both active and passive surveillance indicate that there are sex differences in local reactions following vaccination with AVA, as there are following the administration of other vaccines. For female service members, reactions following vaccination with AVA can have a transient adverse impact on their ability to perform their duties. The factors that account for these sex differences are not known. Recommendation: Future monitoring and study of health events following vaccination(s) with AVA (and other vaccines) should continue to include separate analyses of data for men and women. Finding: The currently licensed subcutaneous route of administration of AVA and the six-dose vaccination schedule appear to be associated

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The Anthrax Vaccine: Is it Safe? Does it Work? with a higher incidence of immediate-onset, local effects than is intramuscular administration or a vaccination schedule with fewer doses of AVA. The frequencies of immediate-onset, systemic events were low and were not affected by the route of administration. Recommendation: DoD should continue to support the efforts of CDC to study the reactogenicity and immunogenicity of an alternative route of AVA administration and of a reduced number of vaccine doses. Later-Onset Health Events Finding: The available data are limited but show no convincing evidence at this time that personnel who have received AVA have elevated risks of later-onset health events. Recommendation: DoD should develop systems to enhance the capacity to monitor the occurrence of later-onset health conditions that might be associated with the receipt of any vaccine; the data reviewed by the committee do not suggest the need for special efforts of this sort for AVA. REFERENCES 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. AMSA. 2001a. Quarterly Report—January 2001. Surveillance of Adverse Effects of Anthrax Vaccine Adsorbed. Washington, D.C.: Army Medical Surveillance Activity, U.S. Army Center for Health Promotion and Preventive Medicine. AMSA. 2001b. Quarterly Report—April 2001. Surveillance of Adverse Effects of Anthrax Vaccine Adsorbed. Washington, D.C.: Army Medical Surveillance Activity, U.S. Army Center for Health Promotion and Preventive Medicine. AMSA. 2001c. Surveillance of Adverse Effects of Anthrax Vaccine Adsorbed: Results of Analyses Requested by the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine. Washington, D.C.: Army Medical Surveillance Activity, U.S. Army Center for Health Promotion and Preventive Medicine. Andrews EB, Avorn J, Bortnichak EA, Chen R, Dai WS, Dieck GS, Edlavitch S, Freiman J, Mitchell AA, Nelson RC, Neutel CI, Stergachis A, Strom B. L., Walker AM. 1996. Guidelines for good epidemiology practices for drug, device, and vaccine research in the United States. Pharmacoepidemiology and Drug Safety 5:333–338. AVIP (Anthrax Vaccine Immunization Program). 2001. Section H: TAMC-601 Survey. Detailed safety review of Anthrax Vaccine Adsorbed. [Online]. Available: http://www.anthrax.osd.mil/Site_Files/articles/INDEXclinical/safety_reviews.htm [accessed January 18, 2001]. 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.

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The Anthrax Vaccine: Is it Safe? Does it Work? CDC (Centers for Disease Control and Prevention). 1967–1971. Application and Report on Manufacture of Anthrax Protective Antigen, Aluminum Hydroxide Adsorbed (DBS-IND 180). Observational Study. Atlanta, Ga.: Centers for Disease Control and Prevention. CDC. 2000. Surveillance for adverse events associated with anthrax vaccination—U.S. Department of Defense, 1998–2000. MMWR (Morbidity and Mortality Weekly Report) 49(16):341–345. GAO (General Accounting Office). 1999. Medical Readiness: Issues Concerning the Anthrax Vaccine. GAO/T-NSIAD-99-226. Washington, D.C.: GAO. Grabenstein JD. 2000. The AVIP: status and future. Presentation to the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, Meeting I, Washington, D.C. Grabenstein JD. 2001. VAERS information; average length of active duty. E-mail to Joellenbeck L, Institute of Medicine, Washington, D.C., November 13. Gunzenhauser JD, Cook JE, Parker ME, Wright I. 2001. Acute side effects of anthrax vaccine in ROTC cadets participating in advanced camp, Fort Lewis, 2000. MSMR (Medical Surveillance Monthly Report) 7(5):9–14. Hoffman K, Costello C, Engler RJM, Grabenstein J. Submitted for publication. Using a patient-centered structured medical note for aggregate analysis: determining the side-effect profile of anthrax vaccine at a mass immunization site. IOM (Institute of Medicine). 2000. Fulco CE, Liverman, CT, Sox HC, eds. Gulf War and Health. Washington, D.C.: National Academy Press. Lange JL, Lesikar SE, Brundage JF, Rubertone MV. 2001a. Screening for adverse events following anthrax immunization using the Defense Medical Surveillance System. Presentation to the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, Meeting II, Washington, D.C. Lange JL, Lesikar SE, Brundage JF, Rubertone MV. 2001b. Update: surveillance of adverse events of Anthrax Vaccine Adsorbed. Presentation to the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, Meeting IV, Washington, D.C. Mason KT, Grabenstein JD, McCracken LR. 2001. Hearing loss after anthrax vaccination among US Army aircrew members. Unpublished manuscript. Mason KT, Grabenstein JD, McCracken LR. Submitted for publication. US Army Aviation Epidemiology Data Register: physical findings after anthrax vaccination among US Army aircrew members, a prospective matched-pair, case-control study. Mazzuchi JF. 1998. Tri-service reportable events document. Memorandum to Deputy Surgeon General of the Army, Deputy Surgeon General of the Navy, and Deputy Surgeon General of the Air Force. Department of Defense, Washington, D.C. Peeler RN, Cluff LE, Trever RW. 1958. Hyper-immunization of man. Bulletin of the Johns Hopkins Hospital 103:183–198. Peeler RN, Kadull PJ, Cluff LE. 1965. Intensive immunization of man: evaluation of possible adverse consequences. Annals of Internal Medicine 63(1):44–57. Pittman PR. 2001a. Anthrax vaccine: an analysis of short-term adverse events in an occupational setting—the Special Immunization Program experience over 30 years. Presentation to the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, Meeting II, Washington, D.C. Pittman PR. 2001b. Anthrax vaccine: dose reduction/route change pilot study. Presentation to the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, Meeting II, Washington, D.C. Pittman PR. 2001c. Anthrax vaccine: the Fort Bragg Booster Study. Presentation to the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, Meeting II, Washington, D.C.

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The Anthrax Vaccine: Is it Safe? Does it Work? Pittman PR, Sjogren MH, Hack D, Franz D, Makuch RS, Arthur JS. 1997. Serologic Response to Anthrax and Botulinum Vaccines. Protocol No. FY92-5, M109, Log No. A-5747. Final report to the Food and Drug Administration. Fort Detrick, Md.: U.S. Army Medical Research Institute of Infectious Diseases. Pittman PR, Gibbs PH, Cannon TL, Friedlander AM. 2001a. Anthrax vaccine: short-term safety experience in humans. Manuscript. Pittman PR, Gibbs PH, Cannon TL, Friedlander AM. 2001b. Anthrax vaccine: short-term safety experience in humans. Vaccine 20(5–6):972–978. Pittman PR, Kim-Ahn G, Pifat DY, Coon K, Gibbs P, Little S, Pace-Templeton J, Myers R, Parker GW, Friedlander AM. 2002. Anthrax vaccine: safety and immunogenicity of a dose-reduction, route comparison study in humans. Vaccine 20(9–10):1412–1420. Pittman PR, Hack D, Mangiafico J, Gibbs P, McKee KT Jr, Friedlander AM, Sjogren MH. In press. Antibody response to a delayed booster dose of anthrax vaccine and botulinum toxoid. Vaccine. Puziss M, Manning LC, Lynch JW, Barclay E, Abelow I, Wright GG. 1963. Large-scale production of protective antigen of Bacillus anthracis in anaerobic cultures. Applied Microbiology 11(4):330–334. Rehme P. 2001. Ambulatory medical visits among anthrax-vaccinated and unvaccinated personnel after return from Southwest Asia. Presentation to the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, Meeting IV, Washington, D.C. Rehme PA, Williams R, Grabenstein JD. 2002. Ambulatory medical visits among anthrax-vaccinated and unvaccinated personnel after return from Southwest Asia. Military Medicine 167:205–210. Robles DT, Eisenbarth GS. 2001. Type 1A diabetes induced by infection and immunization. Journal of Autoimmunity 16(3):355–362. Ryan M. 2002. Assessment of birth defects among infants of women who received anthrax vaccine: information for the Institute of Medicine, Washington, D.C. Microsoft Power Point slides. Ryan MA, Pershyn-Kisor MA, Honner WK, Smith TC, Reed RJ, Gray GC. 2001. The Department of Defense Birth Defects Registry: overview of a new surveillance system. Teratology 64(Suppl 1):S26-S29. Sato PA. 2001a. DoD-wide surveillance of hospitalizations for long-term adverse events potentially associated with anthrax immunization. Presentation to the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, Meeting IV, Washington, D.C. Sato PA. 2001b. Questions on updated data. E-mail to Joellenbeck L, Institute of Medicine, Washington, D.C., November 21. Sato PA, Reed RJ, Smith TC, Wang LZ. 2001. DoD-wide medical surveillance for potential long-term adverse events associated with anthrax immunization: hospitalizations. Provisional report for IOM of data from January 1998 to March 2000. Unpublished manuscript. Tanner J. 2001. Survey results of the 9th Airlift Squadron. Presentation to the Joint Meeting of the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine and the Institute of Medicine Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program, Meeting III, Washington, D.C. Treanor JJ. 2001. Adverse reactions following vaccination of adults. Commissioned paper. Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, Institute of Medicine, Washington, D.C.

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The Anthrax Vaccine: Is it Safe? Does it Work? Wasserman GM. 2001. Analysis of adverse events after anthrax vaccination in U.S. Army medical personnel. Presentation to the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, Meeting IV, Washington, D.C. White CS, Adler WH, McGann VG. 1974. Repeated immunization: possible adverse effects. Annals of Internal Medicine 81(5):594–600. Wiesen AR. 2001a. Lack of effect of anthrax vaccination on pregnancy. Presentation to the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, Meeting IV, Washington, D.C. Wiesen AR. 2001b. Clarifications of the research presented to the Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine held July 10–11, 2001. E-mail and attached letter to Joellenbeck L, Institute of Medicine, Washington, D.C., July 16. Wiesen AR, Littell CT. 2001. Lack of effect of anthrax vaccination on pregnancy, birth, and adverse birth outcome among women in active service with the U.S. Army. Unpublished abstract. Wright GG, Green TW, Kanode RG Jr. 1954. Studies on immunity in anthrax. V. Immunizing activity of alum-precipitated protective antigen. Journal of Immunology 73:387–391.