After the deliberate distribution of anthrax spores in bioterrorist incidents in the fall of 2001, AVA was offered in combination with antibiotics as prophylactic treatment for as many as 10,000 of the civilians who may have been exposed. Fewer than 200 chose to take the vaccine, which was offered under the provisions of an Investigational New Drug application because the vaccine is not licensed for postexposure use and the vaccine lot used had not yet been released by FDA.

In late June 2002, DoD announced a partial resumption of the AVIP (Wolfowitz, 2002; see Appendix E). Military personnel to be vaccinated under the resumed program are those “assigned to or deployed for more than 15 days in higher threat areas whose performance is essential for certain mission critical capabilities,” with vaccination to begin 45 days before deployment, if possible.

This chapter briefly summarizes the basic pathophysiology of anthrax and the history of anthrax vaccine development. It describes some unanswered questions concerning the efficacy and immunogenicity of AVA and reviews the newly approved rule that permits FDA to use data from animal tests as the basis for evaluating the efficacy of vaccines and other products against certain lethal agents. The chapter then outlines the concerns that have been expressed by some people about adverse health outcomes that might be associated with use of AVA. Also described are two important tools for surveillance for adverse events following vaccination with AVA: the Vaccine Adverse Event Reporting System (VAERS) and the Defense Medical Surveillance System (DMSS).

ANTHRAX DISEASE

Anthrax is caused by infection with the bacterium Bacillus anthracis, a gram-positive, nonmotile, spore-forming organism (Brachman and Friedlander, 1999; Dixon et al., 1999). It is primarily a disease of wild and domestic animals exposed to spores in the soil. The spore form of B. anthracis is very hardy— anthrax spores can lie dormant in soil for many years and are resistant to physical and chemical challenges such as heat, dryness, and disinfectants.

As noted, depending on the site of anthrax infection, disease can occur in three forms: cutaneous, gastrointestinal, or inhalational anthrax. Cutaneous anthrax is generally associated with handling infected animals or their products and is manifested as a lesion that forms a vesicle and finally an ulcer marked by a characteristic black eschar. Eating meat from infected animals can lead to an oropharyngeal lesion (cutaneous-like anthrax inside the mouth or larynx) or to gastrointestinal anthrax, which can cause severe abdominal pain, bloody diarrhea, and ascites. Inhalation of aerosolized spores of sufficiently small particle size can cause inhalational anthrax, characterized by severe respiratory distress, with dyspnea, cyanosis, diaphoresis, and strident cough (Brachman and Friedlander, 1999). Radiographic examination of the chest usually shows a characteristic widening of the mediastinum and pleural effusions. Shock may develop, and hemorrhagic meningitis may occur in about 50 percent of cases (Brachman and Friedlander, 1999). Even with aggressive treatment, this form of anthrax has been associated with a high fatality rate within a matter of days after the onset of symptoms, which can initially resemble a common upper respiratory infection. Inhalational anthrax is generally seen only in industrial settings where conditions permit aerosolization of a sufficiently large number of spores in an enclosed area (Brachman and Friedlander, 1999).

After spores enter the body through any route, they are ingested by macrophages in a process called phagocytosis. Once in the macrophages, the spores germinate into vegetative bacteria that can multiply and secrete toxins that produce local edema and necrosis. If bacteria are carried to regional lymph nodes, they multiply further and produce additional edema and necrosis and enter the bloodstream to produce a systemic infection (Brachman and Friedlander, 1999; Dixon et al. 1999)

The virulence of B. anthracis derives from a bacterial capsule and three toxin proteins. The production of the capsule and toxin proteins is encoded on two separate plasmids, and both plasmids are required for full virulence. Plasmid pXO2 contains the gene that encodes the synthesis of a polyglutamyl capsule that inhibits phagocytosis of the vegetative bacteria. Plasmid pXO1 encodes the synthesis of the three toxin proteins: protective antigen (PA), edema factor (EF), and lethal factor (LF). To produce active tox-



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