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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines 7 Vaccines The U.S. military implements a comprehensive immunization1 program that is designed to protect the armed forces against potential disease risks (Takafuji and Russell, 1990). A standard set of vaccinations is required for each military recruit; this set varies slightly by branch of service. Additionally, when troops are assigned to specific duty stations they are given the vaccinations that are targeted to protect them from the risks found in their assigned geographic locale or that are specifically related to their assignment (IOM, 1996). During the Gulf War, a number of different immunobiologics (e.g., cholera, meningitis, rabies, tetanus, and typhoid vaccines) were sent to protect against potential exposures to biological threats (Committee on Veterans’ Affairs, 1998). 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) were distributed to the Gulf War theatre and that 150,000 U.S. troops received at least one anthrax vaccination (Christopher et al., 1997; Committee on Veterans’ Affairs, 1998). 1 The committee used the definitions of the Advisory Committee on Immunization Practices (ACIP), which defines “vaccination” as the physical act of administering any vaccine or toxoid and “immunization” as a more inclusive term denoting the process of inducing or providing immunity artificially by administering an immunobiologic. The ACIP states that although the terms are often used interchangeably, they are not synonymous because the administration of an immunobiologic does not automatically equate with the development of adequate immunity (CDC, 1994a).
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Approximately 137,850 doses of botulinum toxoid were sent to the Gulf, and it is estimated that 8,000 individuals were vaccinated (Committee on Veterans’ Affairs, 1998). However, medical records from the Gulf War contain little or no information about who received vaccines, how frequently vaccines were administered, or the timing of vaccinations relative to the other putative exposures (OSAGWI, 1999). Further, existing record entries show no consistency in recording the type of vaccine (notations include “A-Vax,” “Vacc A,” “Vacc B,” and “B Vaccination”). A report by the Office of the Special Assistant for Gulf War Illnesses (OSAGWI) found that documents from the Gulf War indicate confusion about where, or whether, the vaccinations were to be recorded (OSAGWI, 1999). Investigations since the war by the United Nations Special Commission (UNSCOM) and the International Atomic Energy Agency have found that Iraq had biological weapons prior to the Gulf War, but no evidence was found of their release. Investigators found that Iraq had produced 200 biological bombs in 1990; 100 were filled with botulinum toxin, 50 with anthrax, and 7 with aflatoxin (Zilinskas, 1997). Additionally, 13 Al Hussein (SCUD) warheads were found to have contained botulinum toxin, 10 warheads contained anthrax, and 2 contained aflatoxin (USAMRIID, 1996). 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. Additionally, the issue of multiple vaccinations is addressed. Finally, the chapter provides an overview of the scientific literature regarding squalene, an issue the committee was asked to address. The committee issued a letter report on the safety of the anthrax vaccine in April 2000 (IOM, 2000). This letter report was issued in response to a congressional conference report (House Report 106-371). The Institute of Medicine (IOM) is currently conducting a separate two-year study on the safety and efficacy of the anthrax vaccine. That study will review some of the unpublished non-peer-reviewed information that was not available to this committee. ISSUES IN IDENTIFYING ADVERSE EFFECTS Vaccines are acknowledged to be one of the most effective tools in the prevention of infectious diseases. Dramatic reductions have been seen in the incidence of many diseases including pertussis, polio, rubella, measles, diphtheria, and mumps in the United States, and globally, smallpox has been eradicated (Keusch and Bart, 1998). In general, individuals experience either no adverse effects from a vaccination or mild local effects (e.g., tenderness, soreness) at the injection site. The administration of some vaccines has been determined to be associated with the potential for transient local or systemic adverse health outcomes (e.g., increased risk of fever, local pain, and/or swelling near the injection site) (Keusch and Bart, 1998). More serious reactions are rare (IOM, 1994). This section highlights some of the major issues that must be considered in deter-
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines mining whether an adverse health outcome is associated with receiving a vaccine. Several Institute of Medicine reports (IOM, 1991, 1994, 1997) have examined the complex issues involved in vaccine safety in greater depth. Surveillance Postmarketing surveillance of licensed vaccines in the United States relies on the voluntary reporting of adverse events. In 1990, the Vaccine Adverse Event Reporting System (VAERS) became operational and is overseen jointly by the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration. VAERS reports are open-ended forms that allow for description of the symptoms, time course, laboratory tests, vaccine(s) received, and treatment provided. While health care providers and manufacturers are obligated to report specific adverse effects to vaccines covered by the National Vaccine Injury Compensation Program, anyone can file a VAERS report. For the 65,720 VAERS reports received between January 1, 1991, and December 31, 1996, the sources of reports were health care providers (47.3 percent), manufacturers (39 percent), parents (2.4 percent), and others or unknown (11.3 percent) (CDC, 1999b). There is no long-term follow-up mechanism for VAERS reports. VAERS is a passive reporting system in that it relies on incoming reports. Adverse events are therefore likely to be underreported (IOM, 1997). Further, some reports have incomplete medical information, and the same case may be reported by different sources. VAERS data are useful in signaling potential new adverse events but are limited in their usefulness for assessing the rate or causality of adverse events (IOM, 1994). Although the number of doses distributed is usually available, the number of doses administered is not. Further, the extent of underreporting of adverse events is unknown. FDA and CDC are responsible for monitoring VAERS data to detect unusual trends and occurrences of adverse health effects. This monitoring assists FDA and CDC in responding appropriately to adverse events. Studies of vaccine safety use either active or passive methods of surveillance in assessing the extent of adverse events. Active surveillance methods involve direct follow-up by investigators of all individuals in the study. At a minimum, active surveillance seeks to systematically contact all vaccine recipients at prespecified intervals following vaccination. Often, in addition to posing open-ended questions about possible adverse effects, active surveillance asks explicitly about specific symptoms, and sometimes specific physical or laboratory examinations are conducted. Passive surveillance methods rely on the vaccine recipient to provide information (e.g., self-reports, surveys) or use other information that may indicate adverse outcomes (e.g., days missed from work, number of visits to the clinic following vaccination). 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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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Difficulties in Detecting Adverse Events Due to Vaccinations in Humans Detecting adverse events associated with vaccination and determining whether the health outcome is a result of the vaccination are complex tasks due to a number of factors (IOM, 1997) including the following: Lack of long-term follow-up. Many controlled studies are geared toward monitoring immediate reactions to the administration of the vaccine; subjects are often followed for 6 months at the most. Small sample sizes. Vaccine trials to determine immunogenicity often involve sample sizes of no more than several hundred individuals. Trials of this size are unlikely to detect rare effects since large sample sizes are needed to detect rare occurrences. 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. Controlled safety trials of vaccine combinations would have to include as many study groups as there are combinations of vaccines under study, plus at least one reference group, and thus would require large sample sizes. Multiple end points. The large number of symptoms potentially associated with vaccination complicates surveillance because the reporting mechanism must allow for numerous symptom categories in addition to as-yet-unreported symptom types. Lack of symptoms specific to vaccination. Since there is no unique clinical syndrome or laboratory diagnosis associated with vaccination, it is difficult to differentiate whether symptoms, such as fatigue or seizures, are due to receiving the vaccine or to some unrelated factor coincident with vaccination. Passive reporting systems. Passive surveillance systems are most useful as a sentinel for identifying rare or previously unrecognized side effects of newly marketed vaccines and for monitoring the safety of individual vaccine lots. However, these systems do not provide information about the rates of reactions to vaccines. As discussed above, VAERS is a passive system that relies on health care providers, those receiving vaccinations, and others to report health outcomes that may be linked to vaccine exposure in the recent or more distant past. Reporting is likely to depend on the gravity of the effect, the time lapsed since exposure, and the diligence in symptom reporting by the patient’s health care workers. Thus, underreporting is an inherent issue. Furthermore, supporting information (e.g., laboratory results) to infer causality may be inaccurate or missing. High vaccination rates. For widely administered vaccines, it is difficult to find a comparable control group that has not received the vaccine. Unvaccinated individuals constitute a small, highly selected group that may differ from those vaccinated in other aspects and, thus, are not generally suitable as a control group. Further, their small number is unlikely to allow for the study of background rates of rare medical events.
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Restricted population. The large majority of controlled vaccine trials are geared toward investigating childhood vaccines. Adverse effects in children may not be generalizable to adults. Progress in vaccine technology. Earlier vaccines against a particular infectious agent that have been subjected to considerable animal and human study may be substantially different from vaccines currently in use against the same infectious agent. 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. Further, adverse effects that produce symptoms, rather than objectively measurable pathology, are difficult or impossible to study in animals (some studies use animal behavior to infer animal symptoms such as fatigue). The lack of data on adverse events in animal studies can indicate that no adverse events occurred, that adverse events were not monitored, or that adverse events were not sufficiently severe to warrant termination of the experiment. Additionally, most animal studies are concerned with monitoring immediate toxicity to the administration of the vaccine. Animals are most often followed for short periods of time (i.e., weeks to months), and the long-term effects of vaccination are not considered. Possibility of Immune Stimulation Studies in animals have generally not considered the mechanism responsible for adverse health effects. In some cases, adverse effects of the vaccination could be due to the toxicity of the antigen in the vaccine, the preservatives or contaminants in the vaccine, or the vaccine adjuvant.2 Adverse effects may also result from the intended goal of immunization (i.e., stimulation of the immune system). Immune stimulation may result in a state of immune enhancement, hypersensitivity, or an immune-mediated pathological response. The pathological immune response may be directed toward the antigens administered in the vaccine or to self-antigens (i.e., autoimmunity). Immune-mediated tissue damage requires an initial exposure to the antigen to sensitize the animal. The symptoms of immune-mediated tissue damage may occur on subsequent exposures. A discussion of the immunological reactions that can cause disease has been included in a previous IOM (1994) report and is summarized only briefly here. Classically, such immune-mediated pathology is divided into Types I–IV hyper- 2 An adjuvant is a substance that is used to increase the immune response to specific vaccine components.
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines sensitivity as proposed by Coombs and Gell (1968). However, the response to any one antigen may involve a combination of types of hypersensitivity, depending on the antigen dose, site of exposure, and duration of antigen stimulation. Type I hypersensitivity is a response to the antigen that occurs within minutes; symptoms range from a mild rash or urticaria to airway obstruction or acute life-threatening anaphylactic shock. In Type II reactions, antibodies combine with a tissue antigen, resulting in complement system activation and damage to the tissue by the inflammatory process. Drug-induced hemolytic anemia is an example of a Type II hypersensitivity reaction. Type III hypersensitivity involves the interaction of circulating antibody and antigen to form immune complexes that deposit on the walls of blood vessels. The resultant fixation of complement and neutrophil recruitment leads to tissue destruction. The pathology of Type III hypersensitivity tends to be seen in the lung, kidney, joints, and brain in animal studies. A localized reaction in the skin can lead to pain, swelling, induration, and edema. Type IV hypersensitivity or delayed-type hypersensitivity is dependent on the stimulation of antigen-specific lymphocytes and recruitment of macrophages by cytokines. The resultant inflammation leads to tissue destruction. Contact dermatitis to poison ivy is an example of a Type IV hypersensitivity reaction. 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), in animals and humans, which explains why immunologically mediated adverse reactions to vaccination are so variable from one animal, or person, to the next. ANTHRAX VACCINE Work on a vaccine to provide protection against the zoonotic disease anthrax3 began with the work of Pasteur and Greenfield who developed heat-attenuated anthrax vaccines in the 1880s (Turnbull, 1991). In the 1930s, Sterne developed a live attenuated spore vaccine, and versions of this vaccine continue to be used effectively to immunize livestock. The primary use of the anthrax vaccine in humans was initially to protect persons working with animal hair or hides, including goat hair mill workers, tannery workers, and veterinarians. 3 Anthrax occurs most commonly in herbivores who ingest anthrax spores from the soil. Naturally occurring cases of human anthrax are the result of contact with anthrax-infected animals or contaminated animal products. There are three clinical forms of human anthrax infection: inhalation, cutaneous, and gastrointestinal. Inhalation anthrax naturally occurs only rarely, but the mortality rate approaches 100 percent (Fauci et al., 1998). Since 1950, the incidence of the disease in animals and man has dropped markedly due in large part to the availability of the vaccine, the use of antibiotics, and the implementation of strict quarantine laws in many countries (Whitford, 1987).
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Box 7.1 Genetics and the Immune Response Genetic factors can influence the host’s response, including the immune system’s response, to foreign antigens in many ways—for example, metabolism of the antigen, antigen processing, alteration of self-antigens, stimulation or suppression of the immune response, the nature of the humoral immune response (e.g., different immunoglobulin subclasses), the nature of the cellular immune response (e.g., Th1 versus Th2 response), or the development of an autoimmune response/disease. There are several examples of genetic factors that have been associated with the development and severity of infectious diseases. Polymorphisms (variant gene patterns) for the HLA gene alter the risk for severe pulmonary tuberculosis. Certain polymorphisms of the gene for cytokine tumor necrosis factor are associated with more severe malaria. The immune response is also modulated by hormonal factors. Sex hormones affect the immune response as do adrenal hormones; estrogen tends to enhance the immune response, and cortisone tends to diminish it. The immune response is also modulated by various cytokines (molecules released by immune system cells that direct actions by other immune system cells), some of which increase and others of which decrease the immune response. Normally the human body is “immunologically tolerant” to its own self-antigens, and the immune system does not attack the body’s own tissues. However, in some circumstances this tolerance appears to be broken, resulting in autoimmune disorders. Theoretically, there are several ways in which autoimmune diseases are thought to occur: Environmental agents (such as chemicals) may enter the body and alter certain native body substances (usually proteins) so that these native substances are perceived by the immune system as being foreign. Antigens from an infectious agent may have a structure that is similar to that of one or more normal host antigens. When the immune system reacts to the foreign antigen, it may also “inadvertently” attack the normal host antigens that are structurally similar. Genetic factors that affect the immune response may encourage an autoimmune attack. For example, autoimmune diseases are often strongly associated with certain histocompatibility antigen (HLA) genes. There is evidence that infection with Coxsackie virus is more likely to cause Type I diabetes mellitus in people with the HLA DR4 allele. Estrogens may also affect the clinical expression of certain autoimmune diseases. A number of autoimmune diseases are found more frequently in females including: Hashimoto thyroiditis, Graves disease, systemic lupus erythematosus, and scleroderma. HLA B27 associated spondyloarthropathies are found more frequently in males, although it is not clear that this is caused by male sex hormones. SOURCES: Ahmed et al., 1999; Albert and Inman, 1999; Cooper et al., 1999; Miller, 1999; Rao and Richardson, 1999.
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Currently three anthrax vaccines are commercially available for human use. A live attenuated spore vaccine for humans was developed in the 1940s from a Sterne strain derivative and has been tested and used on a large scale in humans in the countries of the former Soviet Union (Shlyakhov and Rubinstein, 1994a). The British and U.S. anthrax vaccines were developed in the 1950s using filtrates of anthrax strains. Protective antigen, one of the three toxin proteins (discussed below), produced by the anthrax bacillus is the immunogenic component of both the U.S. and the U.K. vaccines. The British vaccine is an alum-precipitated cell-free filtrate of an attenuated Sterne strain culture and was licensed in 1979 (Pile et al., 1998).4 The U.S. vaccine is an aluminum hydroxide-adsorbed cell-free culture filtrate of an unencapsulated strain (Pile et al., 1998). The anthrax vaccine was first produced on a large scale in the United States by Merck, Sharp, and Dohme in the 1950s for Fort Detrick (GAO, 1999c). Production was turned over to the Michigan Department of Public Health (MDPH) in the 1960s, and some changes were made in the manufacturing process; a different strain of anthrax was used in the MDPH vaccine, and the yield of protective antigen was increased (GAO, 1999c). In 1966, the Investigational New Drug (IND) application was submitted to the Division of Biologic Standards (DBS), formerly in the National Institutes of Health (NIH). Product licensure for Anthrax Vaccine Adsorbed was granted on November 10, 1970. The safety study of the anthrax vaccine submitted to the DBS contained information on the administration of approximately 16,000 doses. In 1985, an FDA advisory panel reviewing the status of bacterial vaccines and toxoids categorized the anthrax vaccine in Category 1 (safe, effective, and not misbranded) (FDA, 1985). In December 1997, the Secretary of Defense announced that all U.S. military forces would receive anthrax vaccinations for protection against the threat of biological warfare. The Anthrax Vaccine Immunization Program (AVIP) began vaccinations in March 1998; the first personnel vaccinated were members of units deployed or scheduled to deploy to high-threat areas (Claypool, 1999). It is estimated that 68,000 doses of the U.S. anthrax vaccine were distributed from 1974 to 1989; 268,000 doses in 1990; and 1.2 million doses from 1991 to July 1999 (Ellenberg, 1999). The exact number of people who received the vaccine is not known. The current dosing schedule is 0.5 ml administered subcutaneously at 0, 2, and 4 weeks and 6, 12, and 18 months, followed by yearly boosters. BioPort Corporation (previously Michigan Biologic Products Institute, formerly MDPH) manufactures the U.S. vaccine, approved for use in men and women age 18 to 65 years. The vaccine contains no more than 2.4 mg aluminum hydroxide per 0.5-ml dose as an adjuvant, formaldehyde as a stabilizer (final concentration ≤ 0.02 percent), and benzethonium chloride (0.0025 percent) as a stabilizer (BioPort, 1999; Friedlander et al., 1999). 4 During the Gulf War, British troops received the U.K. anthrax vaccine administered simultaneously with the pertussis vaccine in an adjacent site in the deltoid muscle (U.K. Ministry of Defence, 2000).
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines The length of the dosage schedule, along with questions about the extent of the efficacy of the current vaccine against newly engineered strains of anthrax, has led to ongoing research efforts to produce a second-generation recombinant vaccine (Ibrahim et al., 1999; Nass, 1999). Additionally, researchers hope that new processes will be designed to ensure a more precise amount and a more highly purified component of protective antigen in the vaccine (GAO, 1999b; Russell, 1999). 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. Both humoral and cell-mediated immunity play a role in defending against B. anthracis (Turnbull et al., 1986; Shlyakhov and Rubinstein, 1994b). An individual who has recovered from B. anthracis infection is protected against a subsequent infection with the same organism. Some studies have correlated protective immunity in animals with the antibody response to B. anthracis (Barnard and Friedlander, 1999), but other studies have not confirmed this finding (Little and Knudson, 1986; Turnbull et al., 1986). Knowledge of the pathogenic mechanisms of Bacillus anthracis can provide insight into the potential adverse effects associated with administration of the various anthrax vaccines (Friedlander, 1997; Ibrahim et al., 1999). B. anthracis is pathogenic by virtue of its capsule and protein exotoxins. The capsule of the bacillus is encoded by an extrachromosomal plasmid pX02 (Little and Knudson, 1986). Another plasmid (pX01) encodes for all three toxin proteins: edema factor (EF), lethal factor (LF), and protective antigen (PA). PA, the transport protein, is required for transport of the enzymatic proteins EF and LF into the target cells of the host; PA must be present for the toxins to confer virulence (Ibrahim et al., 1999). In vitro studies of the toxins have revealed that PA binds to cells and undergoes limited proteolysis, which exposes a potential binding site for LF and EF. The LF–PA and EF–PA complexes enter the target cell by receptor-mediated endocytosis, followed by translocation of LF or EF to the cytosol (Friedlander, 1986; Leppla et al., 1990). The edema toxin complex, composed of EF and PA, acts through calmodulin-dependent adenylate cyclase activity to cause the excessive fluid accumulation that is associated with anthrax infection (Leppla, 1982; Ibrahim et al., 1999). The lethal toxin complex, composed of LF and PA, is the primary cause of shock and death (Ibrahim et al., 1999). Lethal toxin is a zinc metallopeptidase that is rapidly cytolytic for macrophages in vitro and induces the release of the cytokine tumor necrosis factor (TNF) from macrophages (Hanna et al., 1993). Studies in mice indicate that TNF and interleukin-1, in particular, contribute to the death induced by injection of lethal toxin (Friedlander, 1986).
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines Mechanism of Action Live attenuated spore vaccines. Live spore vaccines used in veterinary practice, as well as the Soviet Sterne live spore vaccine used in humans, are (pX01+, pX02−) unencapsulated strains of B. anthracis. These vaccines are administered intramuscularly, subcutaneously, or by scarification. The host mounts an immune response to the organism and its toxin proteins. Live spore vaccines induce a humoral immune response. However, the live spore vaccine also elicits a cell-mediated immune response (Shlyakhov and Rubinstein, 1994b). The absence of the capsule reduces the virulence of the organism, yet the bacillus can still produce the toxin proteins PA, EF, and LF. Thus, the formation of active edema toxin and lethal toxin is possible. Protective antigen vaccines. The U.K. and U.S. vaccines for humans are alum-precipitated cell-free filtrates of Bacillus anthracis. In the case of the U.S. vaccine, this precipitate is adsorbed onto aluminum hydroxide. The aluminum hydroxide adjuvant is included in the vaccine preparation to boost the immune response to the PA. Aluminum hydroxide is used in many vaccines and is thought to stimulate humoral rather than cell-mediated immunity (Ivins et al., 1998). The culture filtrates are processed to maximize the content of PA. The cell-free filtrate is primarily PA but also contains EF, LF, and other contaminants from culture (Ivins et al., 1998; Miller et al., 1998). PA vaccine for humans also elicited antibody production to EF and LF in rats and guinea pigs (Ivins et al., 1986; Turnbull et al., 1986; Ivins, 1988), suggesting that the contamination is sufficient to elicit a biological response. The primary goal of anthrax vaccination is to produce neutralizing antibodies to PA. Subsequent exposure to anthrax infection would then eliminate the pathogenic potential of B. anthracis by eliciting the production of antibodies that neutralize PA. Without PA, EF and LF are incapable of acting as virulence factors. Barnard and Friedlander (1999) vaccinated guinea pigs with several different live recombinant Bacillus anthracis strains (pX01−, pX02−) that each produced a different amount of PA without producing the capsule, EF, or LF. The protective effect of these strains correlated with the production of PA and with the anti-PA antibody titer elicited in vivo. Studies by Turnbull and colleagues (1988) and Ivins (1988) in guinea pigs have provided evidence that PA is an essential component of the vaccine and that protection against anthrax in guinea pigs is possible in the absence of any detectable antibody to LF or EF. However, some studies have suggested that the protective effect of anthrax vaccine does not necessarily correlate with the antibody titer to PA in vivo. Studies by Little and Knudson (1986) indicated that a high titer to PA did not necessarily reflect the level of expected protection from infection. Studies by Turnbull and colleagues (1988) suggested that it is also important for the PA antigen to be presented to the immune system in such a way as to stimulate more than just a humoral immune response. Challenge tests with aerosol anthrax spores have shown that the Sterne live spore vaccine was more efficacious than PA-based
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines vaccines (Ivins, 1988), suggesting that cellular immunity as well as humoral immunity is important for protection against anthrax infection. 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. Injection of protective antigen vaccines can result in adverse effects associated with administration of the exotoxins. Live attenuated spore vaccines. Studies in veterinary use. Many of the studies using the live spore vaccine have involved large-scale vaccination of animals of economic importance. Avirulent, nonencapsulated strains of B. anthracis, including the Sterne live spore vaccine, have been used for vaccination. In general, these studies have relied on anecdotal reports from farmers and veterinarians to measure the incidence of reactions of livestock (primarily horses, cows, calves, sheep, lambs, and goats) to the vaccination. In some cases, data on the number of animals vaccinated and the number of deaths from anthrax have been collected by survey or from veterinarian reports. In most cases, the primary focus has been on evaluating the efficacy of the vaccine, rather than on monitoring adverse effects; therefore, many studies of veterinary use of the live spore vaccine have not commented on adverse effects associated with vaccination (Sterne et al., 1942; Kaufmann et al., 1973; Salmon and Ferrier, 1992). The primary health outcomes in animal studies are edema at the site of injection, a febrile response, or death. The extent of the edema ranged from no reaction, to mild irritation, to lameness in some animals. Edema is due to elaboration of the edema toxin or to an allergic response to a previously administered vaccine. An early study by Sterne (1939) used a retrospective questionnaire to solicit complaints regarding the effectiveness and adverse effects of vaccinating sheep and cattle with live spore vaccines. With a limited response to the questionnaire, the majority of reports for cattle indicated that no reactions occurred. However, some cattle experienced lameness and transient decreases in milk yield. Some animals showed severe swelling at the site of injection and one death occurred. Kolksov and Mikhailov (1959) described either insignificant or mild reactions in the majority of 650,000 animals that were vaccinated. Some horses and cattle had swelling at the injection site measuring 12–40 cm2 and lasting 3 to 4 days, along with a slight temperature rise. Of the 650,000 animals (including cattle, horses, oxen, sheep, and goats) 20 animals were reported as dying from unspecified causes. In another study of the Sterne live spore vaccine, it was noted that three of the 34,000 cattle, horses, mules, hogs, and sheep receiving the vaccine experienced instances of excessive swelling (Lindley, 1963). Increased temperature of the animals, lasting for days, has been observed in other studies (Kolksov and Mikhailov, 1959; Kolosov and Borisovich, 1968;
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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines The latter finding means that the evidence reviewed by the committee is of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association between the vaccine and a health outcome in humans. Multiple Vaccinations Certain multiple vaccination regimens can lead to suboptimal antibody responses, but there is little evidence, largely because of a lack of active monitoring, of other adverse clinical or laboratory consequences beyond the transient local and systemic effects seen frequently with any vaccination. No long-term identifiable clinical sequelae attributable to intense long-term immunization occurred in the Fort Detrick cohort. There was some evidence of a chronic inflammatory response, but these changes cannot necessarily be attributed to the vaccinations, since the workers studied were occupationally exposed to a number of virulent microbes. This series of longitudinal clinical studies also had several shortcomings. However, the studies are valuable because careful monitoring did not disclose any evidence of serious unexplained illness in a cohort that received a series of intense vaccination protocols over many years. 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). There are some limitations and confounding factors in these studies, and further research is needed. The committee concludes that there is inadequate/insufficient evidence to determine whether an association does or does not exist between multiple vaccinations and long-term adverse health effects. This finding means that the evidence reviewed by the committee is of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association between multiple vaccinations and health outcomes in humans. REFERENCES Ahmed SA, Hissong BD, Verthelyi D, Donner K, Becker K, Karpuzoglu-Sahin E. 1999. Gender and risk of autoimmune diseases: Possible role of estrogenic compounds. Environ Health Perspect 107(Suppl 5):681–686. Aho K, Wager O. 1961. Production of anti-antibodies in rabbits. Ann Med Exper Fenn 39:79–87. Aho K, Konttinen A, Wager O. 1962. Transient appearance of the rheumatoid factor in connection with prophylactic vaccinations. Acta Pathologica et Microbiologica Scandinavica 56(4):478–479.
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Representative terms from entire chapter: