Licensed Anthrax Vaccine Research Articles

In vitro correlate of immunity in an animal model of inhalational anthrax

The incidence of anthrax in humans is extremely low. Human vaccine efficacy studies for inhalational anthrax cannot be conducted. The identification of a correlate of protection that predicts vaccine efficacy is crucial for determining the immune status of immunized humans. This surrogate marker of immunity can only be established by using an appropriate animal model. Numerous studies showed that protective antigen (PA) is the principle protective antigen in naturally- or vaccine-induced immunity. However, attempts to correlate the quantity of anti-PA antibodies with protective immunity in the guinea pig model for anthrax and various vaccine formulations have failed. In these studies, we used the licensed anthrax vaccine adsorbed (AVA) in rabbits. Groups of New Zealand white rabbits, 10 or 20 per group, were immunized intramuscularly (two doses, 4 weeks apart) with varying doses of AVA, ranging from a human dose to 1:256 dilution in sterile phosphate-buffered saline (PBS). Control rabbits received PBS/Alhydrogel according to the same schedule. Each rabbit was bled 2 weeks after the second dose, and antibody levels to PA measured by both the quantitative anti-PA IgG ELISA and the toxin-neutralizing antibody (TNA) assay. Rabbits were aerosol-challenged 10 weeks from day 0 with a lethal dose of Ames spores. All the rabbits that received the undiluted and 1:4 dilution of vaccine survived, whereas those receiving the higher dilutions of vaccine (1:16, 1:64 and 1:256) had deaths in their groups. All the controls died. Rabbit survival was compared with the antibody response. Statistical models were used to test for significance of the peak antibody responses to predict survival. Results showed that both the amount of anti-PA IgG and TNA titres present in the sera at the time of the peak antibody response were significant (P < 0.0001) predictors of survival. These results demonstrate that the humoral immune response to AVA can predict protection in the rabbit model of inhalational anthrax.

Focal herpes simplex virus type 1 (HSV-1) encephalitis (HSE) of the olfactory system: A primary infection rabbit model of human disease : RJ Wanklin, JM Holden, H Neyndorff, SL Sacks. The University of British Columbia Department of Medicine, Vancouver, BC, Canada

We report the results of a phase I dose escalation, safety and immunogenicity trial of a new recombinant protective antigen (rPA102) anthrax vaccine.Hundred healthy volunteers were randomized in a 4:1 ratio to receive intramuscular doses of rPA102 in the following formulations: 5, 25, 50, or 75 μg of rPA102 in 82.5 μg aluminum hydroxide adjuvant at 0, 4, and 8 weeks; or the US licensed Anthrax Vaccine Adsorbed (AVA) at weeks 0 and 4.Local reactogenicity (mostly pain) was more common with AVA than with rPA102 following the first (94.7% versus 44.4%; p < 0.001) and the second (84.2% versus 35.4%; p < 0.001) vaccinations. Systemic reactogenicity (mostly headache) was more common among rPA102 vaccinees, but only following the first vaccination (49.4% versus 15.8%; p = 0.025). A dose-response relationship for anti-PA antibodies was present after the 2nd and 3rd vaccinations. Two weeks following the 2nd vaccination, the geometric mean titers (GMT) for lethal toxin neutralization activity (TNA), for the 5, 25, 50 and 75 μg rPA102 and AVA groups were 38.6, 75.4, 373.9, 515.3, and 855.2, respectively. The geometric mean concentrations (GMC) measured by anti-PA IgG ELISA were 3.7, 11.5, 25.9, 44.1, and 171.6, respectively. Two weeks following the 3rd vaccination, TNA GMTs for the four rPA102 groups, were: 134.7, 719.7, 2116.6, 2422.4; and ELISA GMCs were: 22.9, 104.7, 196.4, and 262.6, respectively.No clinically serious or dose-related toxicity or reactogenicity was observed. The TNA response after two injections of the 75 μg dose of rPA102 was similar to the response after two injections of AVA. The third rPA102 vaccination substantially increased the antibody response.