Recombinant protective antigen-based vaccines. No adverse effects were reported after vaccination of mice or guinea pigs with either Bacillus subtilis expressing recombinant PA (Welkos, 1987; Welkos and Friedlander, 1988; Miller et al., 1998) or DNA encoding for PA (Gu et al., 1999). Using recombinant techniques, Singh and colleagues (1998) generated a noncleavable PA mutant that bound to the receptor with an affinity equal to that of native PA but failed to bind LF or EF. The authors did not comment on adverse effects when they used the mutant PA to vaccinate guinea pigs (Singh et al., 1998).
Protective antigen-based vaccines with miscellaneous adjuvants. In an attempt to increase the effectiveness of PA vaccines, investigators have employed different adjuvant preparations in combination with PA. Ivins and coworkers (1992) immunized mice with PA and a bacterial cell wall adjuvant preparation. This combination occasionally resulted in a small, nonnecrotic granuloma. A later study by Ivins and colleagues (1995) used many combinations of adjuvants with PA. The authors reported adverse effects only when they used purified PA combined with all of the following: squalene, Tween, Pluronic block copolymer L121, and threonyl muramyl dipeptide. Five of the twenty animals immunized with this combination died within 1 to 5 days. The cause of death was unknown, but significant vascular congestion in multiple organs suggested that the animals suffered from shock and cardiovascular collapse. Other adjuvants (including other combinations that included squalene) provided adequate protection and did not elicit adverse reactions.
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. Additionally, animal studies using the PA vaccine typically have reported only on short-term local reactions to injection of the vaccine. Further, most of the studies do not indicate whether the authors monitored for adverse consequences of vaccination.
The committee used only the peer-reviewed literature to form its conclusions on the weight of the evidence for associations of the anthrax vaccine with adverse health effects. Only a few published peer-reviewed studies have examined potential adverse effects of the anthrax vaccine when administered to humans. In considering the need for future research, the committee evaluated other studies in addition to peer-reviewed publications.