Perhaps the most effective approach towards mitigation of the bioterrorist threat is the development of an effective, scaleable, technologically advanced vaccine platform that can not only respond to likely threat agents, but also has the flexibility to respond to novel and re-emergent pathogens. Vaccines will need to be designed for imminent threats and post-exposure settings; products targeted against the likeliest threats will need to be stockpiled for rapid, practical deployment. A brief review of the current state of vaccines for select Category A agents follows; smallpox vaccine is discussed on p. 342. More comprehensive reviews of biodefense vaccines can be found elsewhere (Cieslak et al., 2000; Ales and Katial, 2004).

Anthrax vaccine adsorbed (AVA) is currently the only licensed anthrax vaccine in the US, and consists of a cell-free filtrate derived from a non-encapsulated, attenuated strain of B. anthracis developed in the 1950s (Friedlander et al., 1999). It is licensed and beneficial for adults in both the pre- and post-exposure settings. It has a complicated dosing schedule and requires frequent boosting

(Nass, 1999). While generally safe, the vaccine is difficult to produce and is associated with significant local reactions. Recent work has focused on the development of a recombinant subunit vaccine targeted against the anthrax protective antigen (PA); antibodies to PA inhibit binding to its cellular receptor and correlate with protection against anthrax (Friedlander, 2001). Purified PA and DNA plasmids that express PA in vivo are in clinical trials as next-generation anthrax vaccines.

Although antibodies to PA address the initiation of anthrax infection, antibodies against additional virulence factors such as the capsule or somatic antigens in the spore may be needed to induce sterilizing immunity (Brey, 2005). DNA vaccines provide an attractive new platform, as they are thought to be relatively safe and easy to produce. A plasmid DNA vaccine encoding genetically detoxified PA and lethal factor, the latter a major component of anthrax lethal toxin, has been effective in protecting animals from aerosolized spore challenge, and is currently undergoing human clinical trials (Hermanson et al., 2004).

Francisella tularensis represents an example of an intracellular pathogen that requires the induction of a wide range of immune responses, in particular CD8+ T-cell activation, to achieve protective immunity. The existing vaccine, consisting of live attenuated strains of F tularensis, has been used extensively in the former Soviet Union (Alibek, 1999). One strain, LVS, was produced by multiple passages of a fully virulent strain of F tularensis subspecies holarctica, and was shown to protect against aerosol challenge in animal and human models of the disease (Saslaw et al., 1961; Isherwood et al., 2005). However, LVS vaccine licensure was recently revoked due to several problems: it affords incomplete protection against laboratory-acquired tularemia (Eigelsbach and Down, 1961; Saslaw, et al., 1961; Burke, 1977); the genetic and immunological basis for its attenuation and immunogenicity remains unknown (Oyston et al., 2004); and it provides suboptimal protection against aerosol challenge in animal and human studies (Eigelsbach et al., 1961; Hornick and Eigelsbach, 1966). To date, an incomplete understanding of correlates of protection in tularemia has hindered development of an effective subunit vaccine. Completion of the genetic sequence for the infective strain F tularensis SCHU S4 and the vaccine strain LVS may further the discovery of proteins which are likely to induce protective immunity (Larsson et al., 2005; Oyston and Quarry, 2005; Twine et al., 2005).

Whereas anthrax and tularemia efforts demonstrate models for bacterial vaccines, Clostridium botulinum is an example of a vaccine effort directed against an important toxin agent of bioterrorism. Antitoxin remains a scarce resource, and is only useful in certain clinical settings; vaccines are an important approach to mass prophylaxis against this toxin (Artenstein, 2003). Botulinum toxin is expressed by C. botulinum in seven structural forms designated toxins A-G (Arnon et al., 2001). There is currently a pseudo-licensed US vaccine against serotypes A-E, developed in the early 1970s (Byrne and Smith, 2000). It consists of formalin-deactivated purified toxins (toxoids) combined to form a pentavalent vaccine. An individual monovalent vaccine against serotype F has been developed in the United Kingdom (Hatheway, 1976). For purposes of mass production, DNA-based vaccines are under development. The carboxyl half of botulinum toxin appears to be the best vaccine candidate, and several vaccine expression systems in yeast and viral vectors are currently being tested in animal models (Lee et al, 2005; Middlebrook, 2005).

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