The Anthrax Vaccine Is It Safe? Does It Work? (2002) / Chapter Skim
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6 Safety: Epidemiologic Studies
6 Safety: Epidemiologic Studies
Pages 118-179
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From page 118... ...
. 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.
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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.
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DOES IT WORK? TABLE 6-1 Ad Hoc Studies of Immediate-Onset Adverse Events Following Anthrax Vaccination: Local Events Rates of Study Study Population and Observation Period Local Ev' Data Number of Collection Subjects Method(s)
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SAFETY: EPIDEMIOLOGIC STUDIES 12 Rates of Local Eventsa Knot, Lump, Edema Overall Mild Moderate Severe Redness Induration Nodule Swelling Other ~'°/ + + + 2.8% Itching, pain, ~~ ,0 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% 63.4%d 38%d 63.4%d 9 g%d Tenderness, 63%; itching, 6% Tenderness, 63%d; .
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From page 122... ...
f 1966-1971 Special Ft. Detrick Passive 1,583 persons 3.6% 1.6% 1 Immunizations laboratory self-report; 10,722 doses Program workers, reported adverse (Pittman et al., 1973-1999 events assessed 2001a,b)
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, . 1tcnlng, 2.4%d; lymph node enlargement, 0.4 % d; arm motion ..
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Forces Korea Personnel covered Retrospective 2,824 (CDC, 2000; by Camp Casey self-report Hoffman et al., Troop Medical through submitted for Clinic, Aug. publications 1998-July 1999 Menh 2,214 31.5- 7.2 39.7%i 7.7% Womenh 610 59.9- 11.7 67.9%d~i 13.5%d Tripler Army Military health Self-report 601 care workers, through 1998-2000 Medical Center (Wasserman, 2001)
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From page 125... ...
SAFETY: EPIDEMIOLOGIC STUDIES 125 Rates of Local Eventsa Knot, Lump, Edema or or Overall Mild Moderate Severe Redness Induration Nodule Swelling Other 27.9% 4.7% 0 16.0% 9.3% 0.7% 31 5- 7.2- 3.9- 0.4- 21.4- 2.5- Pain, 9.6 397%i 7.7% 4.8% 1.1% 28.9% 3.4% 10.2%; itching, 5.5-7.5% 59 9- 11.7- 10.7- 2.0- 49.8- 3.9- Pain, 15 67 9%d~i l3 s%d 13.3%d 4 1%d 62.4%d 9 4%d 18 8%d; itching, 20.4_37%d 1523% 1 56-65 % 7-10 % Itching, 24-31%; pain limiting motion, 5-10%; muscle soreness, 50-66% Continued
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surveyed Jan. questionnaire events only 2000 NOTES: AVA, Anthrax Vaccine Adsorbed; PBT, pentavalent botulinum toxoid; +, reaction reported as present.
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Severe reactions are defined as any reaction measuring >12 cm in diameter or accompanied by marked limitation of arm motion or axiliary node tenderness. "Mild reactions are areas of erythema (redness)
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DOES IT WORK? TABLE 6-2 Ad Hoc Studies of Immediate-Onset Adverse Events Following Anthrax Vaccination: Systemic Events Rates of Systemic Study Overall Muscle Aches Fever Headache Randomized Controlled Trials Field study (Brachman et al., 1962)
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SAFETY: EPIDEMIOLOGIC STUDIES 129 ates of Systemic Eventsa Functional Impact or ver Headache Malaise Other Health Care Use 2 persons Work loss: 6 days lo 11% 5% Anorexia, 5%; nausea, 4%; itching, 0 TO 10% 9% Anorexia, 1%; nausea, 2%; itching, 2% 0% 9.1% 9.8% Anorexia, 2.3%; nausea, 2.3%; itching, 2.3% 4% 11.3% 8.5% Anorexia, 0; nausea, 2.8%; itching, 2.8% %, 0 % 0, 1 1 % Tiredness, 0, 22 % Decreased performance reported: 17% after second dose Sought medical care: 1 cadet after first dose No hospitalizations or missed training NO, 7% 0, 5% Tiredness, 0, 7% Decreased performance reported: 7% after second dose Sought medical care: none No hospitalizations or missed training Continued
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Special Immunizations Program 1% 0.3% 0.1% 0.4% (Pittman, 2001a; Pittman et al., 2001a,b) Men 0.2% <0.1% 0.3% Women 0.4% o.2%e o.7%e Ft.
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8-4.4 % 8.4-15.4%e Chills, 3-5.5%e; other, 2.7-5.2%e Among those reporting any local or systemic event:C Less active: 2.8-5.7% Work limitation: 0.0-0.4 % Work loss: 0.4-0.7% Sought health care: 0.4-1.7% Used medications: 0-0.2% Among those reporting any local or systemic effect:C Less active: 3.1-6.7% Work limitation: 0.4-1.9%e Work loss: 0.0-1. 1% Sought health care: 0.8-2.2% Used medications: 0-0.
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f NOTES: AVA, Anthrax Vaccine Adsorbed; PBT, pentavalent botulinum toxoid; +, reaction reported as present. aThe rates are per dose unless noted otherwise.
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Sought health care: 4-14% (doses 1 to 3) Sought treatment: 29.5 % Missed >1 day of duty: 17.3% Not returned to full duty: 7.2% dData are for doses 1 and 2, respectively.
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DOES IT WORK? TABLE 6-3 Ad Hoc Studies of Later-Onset Adverse Events Following Anthrax Vaccination Study Study Population and Observation Period Data Collection Method(s)
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; 11 Inconsistent laboratory abnormalities; no evidence of review deceased cohort illness attributable to immunization members; 26 age and gender-matched unvaccinated controls ds, 4,092 women Vaccinated versus unvaccinated women odds ratio dentify ( 95 % CI) : n Pregnancy: 0.9 (0.7-1.1)
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DOES IT WORK? TABLE 6-4 Record-Linkage Studies of Adverse Events Following Anthrax Vaccination Study Study Population and Observation Period Data Collection Method(s)
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Risk for hospitalization within 42 days of vaccination for any of 14 summary ICD-9-CM diagnostic categories is significantly lower for vaccinated men and women Range for adjusted relative risk (vaccinated versus unvaccinated; 95% CI)
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Number Army Medical Surveillance Activity DMSS analyses (AMSA, 2001a,b,c) DMSS records on inpatient and outpatient visits and .
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from these analyses Vaccinated: 757,540 person-years Unvaccinated: 3.4 million person-years Vaccinated: 515,389 person-years Unvaccinated: 2.8 million person-years Postvaccination: 738,382 person-years Prevaccination: 478,093 person-years Postvaccination: 0-45 days: 165,682 person-years >45 days: 572,700 person-years Prevaccination: 478,093 person-years No significant elevation of risk among vaccinated personnel for inpatient, outpatient, or incident visits for any of 14 summary ICD-9-CM diagnostic categories No significant elevation of risk among vaccinated personnel for any of 12 inpatient and 14 outpatient diagnoses Of 843 diagnoses, adjusted RR significantly lowered for 12 diagnoses and significantly elevated for 15 (see Appendix G Table G-1)
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DOES IT WORK? Study Population and Study Observation Period Data Collection Method(s)
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Of 12 specific diagnoses, none with significantly elevated adjusted RR (see Appendix G Table G-5)
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Third, recipients were directly monitored for the occurrence of adverse events following vaccination, reducing the possibility of reporting biases. Fourth, the criteria for determination of the presence and magnitudes of the reactions were explicitly defined.
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A control group was administered AVA by the licensed six-dose schedule and subcutaneous administration. Study participants were evaluated clinically for local and systemic reactions at 30 minutes, 1, 2, and 3 days, 1 week, and 1 month after each vaccination.
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Other Controlled Studies ROTC Cadets Inadvertent administration of higher than recommended doses of anthrax vaccine to Reserve Officer Training Corps (ROTC) cadets provided an opportunity to compare their reports of acute effects with reports from cadets who received the recommended doses (Gunzenhauser et al., 2001~.
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came only from the standard-dose group. This opportunistic study provides information on adverse events following the receipt of a double vaccine dose and standard vaccine doses.
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Adverse events following vaccination were reported by the investigators administering the vaccines, who were required to record any reaction observed 48 hours after administration of the vaccine and to notify the National Communicable Disease Center (NCDC) of any severe reactions.
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When participants came into the clinic to report adverse events, study staff evaluated and recorded the adverse events, classifying them as local or systemic. Local reactions of some type were reported for 3.6 percent of the 10,722 doses of vaccine administered.
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However, the majority of systemic reactions occurred after the administration of a dose to individuals who had already received vaccine doses with no systemic reaction. No sustained adverse events were noted, but long-term follow-up was not conducted.
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Local reactions commonly occurred within 4 days of receipt of the booster dose. Systemic reactions were also frequent following receipt of the vaccine booster dose, but the investigators noted that the study participants were also engaged daily in strenuous physical exercise, which could produce systemic reactions as well.
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From page 150... ...
However, the results confirm those of other studies that women report more adverse events following vaccination with AVA but that they also report less pain than men. Tripler Army Medical Center Survey The nature and frequency of adverse events following vaccination with AVA were assessed in a group of 601 military health care workers at Tripler Army Medical Center in Hawaii who began receiving vaccinations in September 1998 (AVIP, 2001; CDC, 2000; GAO, 1999; Wasserman, 2001~.
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9th Airlift Squadron Survey A survey of the members of the 9th Airlift Squadron at Dover Air Force Base in Delaware collected information on the systemic symptoms that they experienced following vaccination with AVA (Tanner, 2001~. Vaccination of this squadron with AVA began in the autumn of 1998.
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The members of this study population received multiple doses of many different vaccines, including an anthrax vaccine, because of the potential for occupational exposure to virulent microorganisms. The 99 white male workers in the initial cohort (Peeler et al., 1958)
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From page 153... ...
In addition, during the time frame covered by these studies, workers received both earlier anthrax vaccine products and the currently licensed AVA product. Although the number of anthrax vaccine recipients increased over the study period from 28 to at least 76, without apparent coincident changes in the health status of the group, the small size of the cohort provides little statistical power to detect increased risk of illness.
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Severe local reactions and systemic reactions are much less common. These studies are relatively small, however, and none of them provides adequate information concerning the occurrence of later-onset events.
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This list includes any adverse event following vaccination that results in admission to a health care facility or the loss of time from duty for 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 the Anthrax Vaccine Immunization Program, they
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, making it possible to assess vaccineassociated adverse event rates (number of adverse events/number of vaccine administrations) for some types of health events following vaccination.
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No difference in the rate of postUeployment use of Air Force ambulatory health care services within the 6 months following vaccination with AVA was found between the vaccinated and the unvaccinated personnel. Women were more likely than men to have had a postUeployment ambulatory health care visit (relative risk 1.38, 95 percent CI = 1.30 to 1.46)
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used data from DoD databases on hospitalizations of active-duty military personnel to determine whether those who had received AVA had an excess of hospitalizations within 42 days of AVA vaccination compared with those who had not received AVA. The study included all U.S.
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were very low, with the relative risks for most personnel falling between 0.2 and 0.6. Relative risks less than 1.0 would be expected if service personnel who received AVA were also more likely to be deployed and deployment is associated with a healthy soldier effect.
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The analyses found that, for all major diagnostic categories, crude and adjusted rates of hospitalization and of outpatient visits and incident visits (incident visits include inpatient and outpatient visits combined) were lower in the group that received AVA than in the cohort that did not.
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For each of the diagnostic categories examined, both the unadjusted and the adjusted rate ratios for hospitalization or outpatient visit rates for the group that received AVA compared with those for the group that did not receive AVA did not differ significantly from 1.0 (the ratio observed when the rates are equal)
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These data indicate that there was no excess risk of selected adverse health events that required either hospitalization or an outpatient visit among active-duty military personnel receiving AVA over a 2.5-year period. In fact, the group that received AVA tended to have fewer hospitalizations or outpatient visits than the group that did not receive AVA.
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of the diagnoses and were lower than those in the period before vaccination for the others. Of the conditions with rate ratios significantly different from 1.0, hospitalization rates in the period after vaccination were statistically significantly elevated for 15 conditions (see Appendix G
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Diagnoses for which adjusted rate ratios were statistically significantly greater than 1.0 included diabetes mellitus (adjusted rate ratio = 3.49, 95 percent CI = 1.39 to 8.79) and other disorders of the intestine (ICD-9-CM code 569; adjusted rate ratio = 4.16, 95 percent CI = 1.51 to 11.49~.
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From page 165... ...
Significantly elevated adjusted rate ratios in the cohort that received four or more doses included malignant neoplasms of the thyroid gland (rate ratio = 2.35, 95 percent CI = 1.01 to 5.48) , diabetes mellitus (rate ratio = 3.05, 95 percent CI = 1.31 to 7.09)
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From page 166... ...
were less than 1.0, as would be expected if those who would receive AVA were healthier than those who never received AVA. These rate ratios ranged from 0.29 to 0.91, indicating for many conditions a substantial healthy soldier effect.
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From page 167... ...
When analyses were restricted to incident cases so that multiple hospitalizations of the same woman would not be counted, the adjusted rate ratio for multiple sclerosis in the postimmunization interval versus that in the preimmunization interval was no longer significantly elevated (rate ratio = 1.26; 95 percent CI = 0.50 to 3.14~. The major limitation of this sex-specific analysis is that postimmunization rates (which are, by definition, based only on those for persons who received AVA)
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From page 168... ...
One possibility for observing a significant increase in rates of hospitalization for diabetes would simply be chance. In fact, 27 different conditions were found to be statistically significantly associated with AVA (15 conditions with rate ratios greater than 1.0 and 12 conditions with rate ratios less than 1.0)
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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~.
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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.
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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)
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From page 172... ...
CONCLUSIONS REGARDING AVA VACCINATION AND ADVERSE EVENTS The committee has reviewed information from a variety of sources, including VALKS and DMSS, on the association between vaccination with AVA and adverse events. For AVA, as with any vaccine, it is essential in 1 1 ~ ~ r ~ ~~ ~ 1 ~ ~ ¢~ 1 · · 1 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.
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From page 173... ...
, 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~.
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From page 174... ...
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.
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From page 175... ...
· 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.
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From page 176... ...
Surveillance of Adverse Effects of Anthrax Vaccine Adsorbed. Washington, D.C.: Army Medical Surveillance Activity, U.S.
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From page 177... ...
2001a. Screening for adverse events following anthrax immunization using the Defense Medical Surveillance System.
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2002. Assessment of birth defects among infants of women who received anthrax vaccine: information for the Institute of Medicine, Washington, D.C.
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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.
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