Efficacy of different AV7909 dose regimens in a nonclinical model of pulmonary anthrax

Abstract

Pulmonary anthrax caused by exposure to inhaled Bacillus anthracis, the most lethal form of anthrax disease, is a continued military and public health concern for the United States. The vaccine AV7909, consisting of the licensed anthrax drug substance AVA adjuvanted with CpG7909, induces high levels of toxin neutralizing antibodies in healthy adults using fewer doses than AVA. This study compares the ability of one- or two-dose regimens of AV7909 to induce a protective immune response in guinea pigs challenged with a lethal dose of aerosolized B. anthracis spores 6 weeks after the last vaccine dose. The results indicated that AV7909 was less effective when delivered as a single dose compared to the two-dose regimen that resulted in dose-dependent protection against death. The toxin neutralizing assay (TNA) titer and anti-PA IgG responses were proportional to the protective efficacy, with a 50% TNA neutralizing factor (NF₅₀) greater than 0.1 associated with survival in animals receiving two doses of vaccine. The strong protection at relatively low TNA NF₅₀ titers in this guinea pig model supports the exploration of lower doses in clinical trials to determine if these protective levels of neutralizing antibodies can be achieved in humans; however, protection with a single dose may not be feasible.

Keywords: Anthrax; BARDA; Bacillus anthracis; post-exposure prophylaxis; vaccine.

Figure 1.

Dose-dependent survival after challenge. a. Kaplan–Meier curves representing time to death and survival data for each group vaccinated with AV7909. b. fitted logistic model for survival in the groups of vaccinated animals as a function of dilution factor and vaccine (parallel slope) overlaid on the observed data.

Figure 2.

Immune correlates of protection a. geometric means and 95% confidence intervals for anti-PA IgG ELISA concentration (µg/ml). b. logistic regression model fitted to survival as a function of log-transformed anti-PA IgG ELISA concentration for vaccinated groups with a fixed effect for vaccine dose group on study day 69. c. group geometric means and 95% confidence intervals TNA NF₅₀. d. fitted logistic regression model for survival in the vaccinated groups as a function of log10 TNA NF₅₀ on study day 69.