Gulf War and Health Volume 1: Depleted Uranium, Sarin, Pyridostigmine Bromide, and Vaccines (2000) / Chapter Skim
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Vaccines
Vaccines
Pages 267-324
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Concerns prior to the Gulf War regarding Iraq's offensive biological warfare capabilities, led to decisions that available vaccines should be utilized as preventive measures against biological warfare agents. It is estimated that 310,680 doses of the anthrax vaccine licensed by the Food and Drug Administration (FDA)
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This chapter discusses several vaccine-related issues that have been of particular concern to Gulf War veterans. The chapter discusses animal and human studies that have been conducted on the safety of the anthrax vaccine and the botulinum toxoid vaccine.
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. Studies on the botulinum toxoid and anthrax vaccines have relied primarily on passive surveillance approaches and have involved only relatively short periods of follow-up.
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· Multiple vaccinations. Individuals often receive several vaccines at a time or over a short period, which makes it difficult to identify the culprit vaccine in the event of an adverse effect.
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Thus, even careful and extensive earlier studies may not be generalizable to current experience. Difficulties in Detecting Adverse Events Due to Vaccinations in Animals Focus on Vaccine Efficacy Most animal studies focus on the efficacy of the vaccine and do not examine adverse effects.
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Animal studies have limitations in detecting adverse effects due to Types II through IV hypersensitivity because the time course of such responses may involve months or years to become clinically apparent in an animal, which is beyond the time frame monitored in most animal studies. Genetic inheritance strongly influences the immune response, both to immunization and to actual infection (Box 7.1)
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as a stabilizer (BioPort, 1999; Friedlander et al., 1999~. 4During the Gulf War, British troops received the U.K.
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Toxicology Anthrax disease results from exposure to the bacterium Bacillus anthracis through three primary routes: cutaneous, inhalation, and gastrointestinal. Regardless of the route of exposure, the presence of the organism provokes an immune response.
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Live spore vaccines induce a humoral immune response. However, the live spore vaccine also elicits a cell-mediated immune response (Shlyakhov and Rubinstein, 1994b)
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Animal Studies As noted earlier in this chapter, adverse health outcomes in animals after injection may result from the toxic effects of the injected substances or from stimulation of the immune system. Injection of the live spore vaccine can cause infection.
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Guinea pigs vaccinated with the live spore vaccine have delayed-type hypersensitivity reactions 1 year after vaccination (Shlyakhov, 1970; Shlyakhov and Rubinstein, 1994b) , indicating stimulation of the cellular immune response.
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Most studies in laboratory animals with the protective antigen vaccine have not mentioned adverse effects associated with vaccination. Many studies conducted in guinea pigs employed different vaccination regimens using culture filtrates of PA with and without alum adjuvant.
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Conclusions on Animal Studies Few meaningful conclusions for humans can be drawn from animal studies of the anthrax vaccine. Many of the animal studies have used the anthrax live spore vaccine and therefore, have limited applicability for evaluating the toxicity of protective antigen vaccines.
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. There was an increase in the number of persons experiencing pain after the second dose, and local reactions 5The one live spore vaccine study that met the Cochrane criteria was a field trial conducted by Burgasov and colleagues.
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Although the vaccine used in this study was similar to the current vaccine (used to immunize Gulf War troops and currently available in the United States) in that it was a PA vaccine, the manufacturing process has since changed and a different strain of anthrax bacillus is now used (GAO, l 999c)
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, mild local reactions (<3 cm) occurred in 3-20 percent of all doses, moderate local reactions (>3 to <12 cm)
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As described earlier in this chapter, the Vaccine Adverse Event Reporting System is a passive surveillance system consisting of reports filed by health care providers, individuals receiving vaccinations, family members, or others. As noted earlier, VAERS data are useful as a sentinel for adverse events but are limited in their usefulness for assessing the rate of adverse events since underreporting is likely and the information may be incomplete or duplicative, or may not always have been confirmed by medical personnel (IOM, 1994~.
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of either the anthrax or the botulinum toxoid vaccine, or both, depending on what they had received in 1990-1991. The report states that there was daily monitoring for systemic and local reactions but does not state the total duration of follow-up.
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The committee located only one randomized peer-reviewed study of the type of anthrax vaccine used in the United States (Brachman et al., 1962~. However, the formulation of the vaccine used in that study differs somewhat from the vaccine given to Gulf War veterans (and currently in use)
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The committee concludes that there is sufficient evidence of an association between anthrax vaccination and transient acute local and systemic effects (e.g., redness, swelling, fever) typically associated with vaccination.
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Additionally, it is estimated that 8,000 U.S. troops received the toxoid during the Gulf War.
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After exposure to formaldehyde they are tested for toxicity in mice and guinea pigs to ensure that the neurotoxin was inactivated. Animal Studies As noted earlier in this chapter, adverse health outcomes can result either from toxic effects of the injected toxoid preparation or from stimulation of the immune system.
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In none of these studies did the authors mention adverse effects, which may indicate that no adverse effects occurred, that adverse events were not monitored, or that the adverse events were not sufficiently severe to warrant termination of the experiment. Studies in guinea pigs suggest that skin-sensitizing anaphylactic antibodies may be produced in response to the administration of a combination of type B botulinum toxoid with the complex typhoid antigen (Yefremova, 1980~.
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Subsequent experiments used purified neurotoxin fragments, and no toxicity occurred after repeated vaccination of these recombinant preparations. Conclusions on Animal Studies Animal studies using botulinum toxoid vaccines have reported minimal transient local reactions and swelling at the injection site.
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, and the authors stated that the incidence of mild local reaction was somewhat greater for the pentavalent toxoids than the control group toxoids (Flock et al., 1962~. Other Studies and Reports The committee received reports on several other studies, discussed below, with information on the botulinum toxoid vaccine.
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Summary tables in the CDC report record the number of reactions for the 16,676 injections of the botulinum toxoid administered between 1970 and 1997 (CDC, 1998~. Ofthis total, local reactions were characterized as 15,207 (91.2 percent)
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MULTIPLE VACCINATIONS Military personnel often receive several vaccinations as they prepare for service in an environment with many endemic diseases. People have been expressed concerns that multiple vaccinations prior to and during Gulf War service may have caused adverse health effects.
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These guidelines are similar to civilian guidelines developed by the CDC and the Advisory Committee on Immunization Practices (IOM, 1996~. Combining several vaccines into a single injection or administering multiple vaccinations at the same clinical visit decreases the number of injections re
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reports that described a set of specific adverse effects remained constant compared to the frequency reported for separate administrations, with one exception: local reactions were more frequent with simultaneous vaccinations (Chen et al., 19951. The MSAEFI system was a passive surveillance system based on reports by people who had been vaccinated, family members, and other individuals.
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found that simultaneous injections of live vaccines for anthrax, plague, tularemia, and brucellosis in guinea pigs reduced the development of protective immunity to anthrax without adversely affecting the response to the other live vaccines. The only adverse effect of the vaccination itself was erythema and an infiltrate at the site of injection of the live spore anthrax vaccine, a response that resolved within 3 to 5 days.
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Good protection was afforded to all antigens, and the authors did not mention any adverse effects. In guinea pigs, a comparative study was done to assess the efficacy of a protective antigen anthrax vaccine, either alone or in combination with a pertussis vaccine (Turnbull, 1990~.
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The second group of studies followed laboratory workers at Fort Detrick who received an intensive vaccination program for occupational reasons. Further, the committee examined several studies of Gulf War veterans.
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Study results suggest that transient RF and IC reactions may be related to the immune response to intensive vaccination. However, the number of subjects with positive results was small, and no control group was used to test for spontaneous fluctuations in RF response.
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who had not undergone multiple vaccinations served as the control group for the electrophoretic studies (controls were not done for the other tests)
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The vaccination program was discontinued 10 months before this study. As in the previous studies, each subject underwent a complete medical history, physical examination, electrocardiogram, and extensive laboratory tests.
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Gulf War Veterans Several studies of Gulf War veterans have looked for associations between health outcomes and exposure to a variety of agents, including vaccinations. The methodology and general results of these studies are described in Chapter 2.
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The total number of vaccinations received bore a weak but significant relationship to the occurrence of the multisymptom outcome among all Gulf War veterans, even when the cohort was subdivided into groups according to whether the subject possessed his vaccination records or not. The association still existed after controlling for the receipt of biological warfare vaccines and for experiencing side effects after vaccination (although the addition of this independent variable weakened the association)
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, Fukuda and colleagues (1998) performed clinical evaluations on a group of Gulf War veterans (n = 158)
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The U.K. Gulf War studies provide some limited evidence of an association between multiple vaccinations and long-term multisymptom outcomes, particularly for vaccinations given during deployment (Unwin et al., 1999; Hotopf et al., 2000~.
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report found that at the time of the Gulf War, DoD had concerns about having a sufficient quantity of the anthrax vaccine and suff~cient time to fully immunize the troops (GAO, 1999a)
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Animal Studies There are few published studies of squalene toxicity in animals or humans (Kelly, 1999~. Kamimura and colleagues (1989)
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Although the mechanisms are not fully understood, the inflammation is blocked by agents that suppress T cells (Yoshino, 1996; Sverdrup et al., 1998~. Animal studies do not report whether injection of squalene produces antisqualene antibodies.
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MTP-PE was associated with moderate to severe local reactions as well as with self-limited severe systemic reactions that resolved within 2-3 days. The same vaccines in the MF59 emulsion alone were well tolerated (Keefer et al., 1996~.
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Sample sizes were small, and the study may suffer from misclassification errors since the group of Gulf War veterans categorized as healthy (n = 12) was not devoid of individuals with serious symptoms (1 had fibromyalgia, 1 had thyroid disease, 3 had memory loss, and 4 had chronic fatigue)
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The committee located only one randomized peer-reviewed study of the type of anthrax vaccine used in the United States (Brachman et al., 19624. However, the formulation of the vaccine used in that study differs somewhat from the vaccine given to Gulf War veterans (and currently in use)
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Botulinum Toxoid Studies have noted transient local and systemic effects of the botulinum toxoid vaccine. However, studies of the botulinum toxoid vaccine have not used active surveillance to systematically evaluate long-term health outcomes.
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The U.K. Gulf War studies provide some limited evidence of an association between multiple vaccinations and long-term multisymptom outcomes, particularly for vaccinations given during deployment (Unwin et al., 1999; Hotopf et al., 2000~.
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2000. Antibodies to squalene in Gulf War syndrome.
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1998. Report of the Special Investigation Unit on Gulf War Illnesses.
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1998. Chronic multisymptom illness affecting Air Force veterans of the Gulf War.
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1999a. Gulf War mnesses: Questions About the Presence of Squalene Antibodies in Veterans Can Be Resolved.
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1995. Experimental anthrax vaccines: Efficacy of adjuvants combined with protective antigen against an aerosol Bacillus anthracis spore challenge in guinea pigs.
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II. Levels of immunity against Bacillus anthracis obtained with protective antigen and live vaccine.
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1986. Comparative efficacy of Bacillus anthracis live spore vaccine and protective antigen vaccine against anthrax in the guinea pig.
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1997. Gulf War syndrome: Is it due to a systemic shift in cytokine balance towards a Th2 profile?
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1986. Development of antibodies to protective antigen and lethal factor components of anthrax toxin in humans and guinea pigs and their relevance to protective immunity.
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1999. Health of UK servicemen who served in Persian Gulf War.
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