The Anthrax Vaccine Is It Safe? Does It Work? (2002) / Chapter Skim
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3 Anthrax Vaccine Efficacy
3 Anthrax Vaccine Efficacy
Pages 56-82
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From page 56... ...
the correlation of the effectiveness of the vaccine in animal models to its ability to protect humans. This chapter presents the committee's observations and findings regarding the efficacy of AVA against inhalational anthrax and all known strains.
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From page 57... ...
EVALUATING EFFICACY OF AVA FOR INHALATIONAL ANTHRAX The data used to evaluate the efficacy of AVA come from three sources. Studies with textile mill workers tested the efficacy of AVA and a related vaccine against occupational exposures to anthrax spores.
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From page 58... ...
. Twenty-one of the 26 cases were cutaneous anthrax and 5 were cases of inhalational anthrax, all of which occurred during the outbreak at Mill A
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Two retrospective serological studies evaluating the effect of the dosing interval on the human antibody response (Pittman et al., 2000) served as preliminary studies for the larger prospective study described later (Pittman et al., 2002~.
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These findings indicate that AVA administered by its licensed dosing schedule as well as by schedules that omit the dose administered at 2 weeks generates substantial antibody responses (at least 25 ,ug/mI) in 96 to 100 percent of recipients.
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Field studies that rely on natural exposure to disease are not feasible as a means of evaluating the efficacy of the anthrax vaccine because inhalational anthrax is very rare, even in areas where anthrax occurs naturally or where it is an occupational hazard. Moreover, the particular concern regarding inhalational anthrax is exposure to anthrax spores processed for use as biological weapons.
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From page 62... ...
Pathology of Inhalational Anthrax in Humans As discussed in Chapter 2, inhaled anthrax spores are phagocytosed (taken up) by macrophages and transported from the lungs to the nearby peribronchial and mediastinal effect is independently substantiated in multiple animal species, including species expected to react with a response predictive for humans; the animal study endpoint is clearly related to the desired benefit in humans, generally the enhancement of survival or prevention of major morbidity; and the data or information on the kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans, allows selection of an effective dose in humans."
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From page 63... ...
Necropsies were performed and tissue samples and microscopic slides were preserved for 42 cases, providing a wealth of additional information demonstrating the pathological changes in human tissue that occur as a result of inhalational exposure to anthrax spores. The most striking pathological features in the anthrax cases from Sverdiovsk were prominent and consistent lesions of hemorrhagic thoracic lymphadenitis and hemorrhagic mediastinitis (Abramova et al., 1993; Walker, 2001~.
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From page 64... ...
As seen in other animal models, the cellular inflammatory response observed after inhalational exposure is limited, consistent with a fulminating septicemia rather than a primary pulmonary infection (Albrink and Goodiow, 1959; Ross, 1957~. Rabbits In rabbits the effects observed from inhalational infection with B
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From page 65... ...
Several studies have reported on the gross pathological changes observed in rhesus monkeys exposed to inhaled aerosolized anthrax spores (BerUjis et al., 1962; Fritz et al., 1995; Gleiser et al., 1963~. BerUjis and colleagues (1962)
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From page 66... ...
anthracis strains and in the protection from challenge afforded by AVA and other anthrax vaccines (Welkos and Friediander, 1988~. In fact, the bacterial capsule rather than the toxin appears to be the primary virulence factor for mice, so that vaccines such as AVA based on the PA aspect of anthrax toxins (LF or EF)
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From page 67... ...
Several studies in which guinea pigs were administered anthrax spores intramuscularly have indicated that the anti-PA antibodies stimulated by AVA are not sufficient to protect guinea pigs from intramuscular challenge with all strains of B anthracis (Fellows et al., 2001; Ivins et al., 1994; Little and Knudson, 1986; Turnbull et al., 1986~.
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From page 68... ...
In another study, AVA was found to completely protect rabbits from four of six anthrax isolates3 Of diverse geographical origin found to be highly virulent in guinea pigs and protected 90 percent of the animals from the other two isolates (Fellows et al., 2001~. Nonhuman Primates (MacaquesJ Several studies have evaluated the efficacy of AVA against aerosol challenge with anthrax spores in rhesus monkeys.
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From page 69... ...
For certain strains, protection in guinea pigs is enhanced by particular adjuvants known to stimulate cell-mediated immunity, although such adjuvants do not appear to be necessary for the protection of primates. Finding: The macaque and the rabbit are adequate animal models for evaluation of the efficacy of AVA for the prevention of inhalational anthrax.
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From page 70... ...
anthracis isolates shown to be lethal in AVA-immunized guinea pigs. Since macaques and rabbits appear to be the best available animal models of inhalational anthrax in humans, as discussed earlier in this chapter, the efficacy of AVA in protecting these species from aerosol challenge with a variety of virulent isolates is noteworthy.
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From page 71... ...
Because PA is critical to virulence and because its structure is so highly conserved, it appears likely that changing its structure would alter and thus eliminate its toxic action. Finding: It is unlikely that either naturally occurring or anthrax strains with bioengineered protective antigen could both evade AVA and cause the toxicity associated with anthrax.
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DOES IT STORK? CORRELATION OF PROTECTION: ANIMAL MODELS AND HUMAN IMMUNITY Establishing Animal Model Correlates of Anthrax Vaccine Efficacy Reuveny and colleagues (2001)
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From page 73... ...
To move forward with research on the current anthrax vaccine or any new vaccines, however, a quantitative correlation of the protective levels of antibodies in animals with the antibody titers obtained after full immunization in humans is needed. Those correlates in animal models can then be used to test new vaccines for efficacy with confidence that the data from animal studies will be predictive of the clinical results obtained with immunized humans.
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From page 74... ...
After the intraspecies passive transfer assay in animal models, the next step extends to the human vaccinee. Here, appropriate laboratory animals would receive different concentrations of antibody-containing serum from humans vaccinated with anthrax vaccine.
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Recommendation: The Department of Defense should support efforts to standardize an assay for quantitation of antibody levels that can be used across laboratories carrying out research on anthrax vaccines. POSTEXPOSURE USE OF ANTHRAX VACCINE Evidence that postal workers and congressional staff were exposed to aerosolized anthrax spores from anthrax-laden letters sent through the U.S.
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Additional studies on the postexposure use of AVA with antibiotics are needed. Recommendation: The Department of Defense should pursue or support additional research with laboratory animals on the efficacy of AVA in combination with antibiotics administered following inhalational exposure to anthrax spores.
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This can be considered very effective protection. However, simulation studies conducted by Canadian researchers suggest that a person opening a letter filled with anthrax spores and standing over it for 10 minutes could inhale up to 3,000 times, and perhaps as much as 9,000 times, the amount of spores expected to kill half of a group of exposed people (Brown, 2001, 2002~.
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2001. Efficacy of a human anthrax vaccine in guinea pigs, rabbits, and rhesus macaques against challenge by Bacillus anthracis isolates of diverse geographical origin.
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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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2001. Animal models for anthrax vaccine efficacy.
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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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2001. The pathology of experimental inhalational anthrax in rabbits and rhesus monkeys.
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