Bridging non-human primate correlates of protection to reassess the Anthrax Vaccine Adsorbed booster schedule in humans

Abstract

Anthrax Vaccine Adsorbed (AVA, BioThrax) is approved for use in humans as a priming series of 3 intramuscular (i.m.) injections (0, 1, 6 months; 3-IM) with boosters at 12 and 18 months, and annually thereafter for those at continued risk of infection. A reduction in AVA booster frequency would lessen the burden of vaccination, reduce the cumulative frequency of vaccine associated adverse events and potentially expand vaccine coverage by requiring fewer doses per schedule. Because human inhalation anthrax studies are neither feasible nor ethical, AVA efficacy estimates are determined using cross-species bridging of immune correlates of protection (COP) identified in animal models. We have previously reported that the AVA 3-IM priming series provided high levels of protection in non-human primates (NHP) against inhalation anthrax for up to 4 years after the first vaccination. Penalized logistic regressions of those NHP immunological data identified that anti-protective antigen (anti-PA) IgG concentration measured just prior to infectious challenge was the most accurate single COP. In the present analysis, cross-species logistic regression models of this COP were used to predict probability of survival during a 43 month study in humans receiving the current 3-dose priming and 4 boosters (12, 18, 30 and 42 months; 7-IM) and reduced schedules with boosters at months 18 and 42 only (5-IM), or at month 42 only (4-IM). All models predicted high survival probabilities for the reduced schedules from 7 to 43 months. The predicted survival probabilities for the reduced schedules were 86.8% (4-IM) and 95.8% (5-IM) at month 42 when antibody levels were lowest. The data indicated that 4-IM and 5-IM are both viable alternatives to the current AVA pre-exposure prophylaxis schedule.

Keywords: AVA; Animal model; Anthrax; Anthrax Vaccine Adsorbed; Bacillus anthracis; Biothrax; Clinical trial; Correlates of protection; Non-clinical trial.

Fig. 1.

Predicted probability of human survival at month 42 in the Minimum Schedule 4-IM Study Group using a single-correlate model with last anti-PA IgG. NHP survivors (●) (1.0 on the Y-axis) and non-survivors (◯) (0 on the Y-axis) are plotted with slight vertical Y-axis displacements so that overlapping points may be seen. NHP immune response data were binned by anti-PA IgG concentration range; bin 1 > LLOD (0.4 μg/mL); bin 2 LLOD to LLOQ (2.3 μg/mL); remaining bins contain NHP with anti-PA IgG in 2-fold increases above the LLOQ (e.g. ≥2.3 to <4.6, ≥4.6 to <9.2, etc.). Key: (–) logistic regression curve of predicted survival based on the NHP last anti-PA IgG measurements; (∎) mean survival of NHP binned by anti-PA IgG concentration; (Δ) individual human anti-PA IgG responses from the 4IM study group measured at month 42 immediately prior to receiving the booster vaccination, also shown with slight vertical Y-axis displacement so that overlapping points maybe seen; (–) mapping of predicted survival for individual human subjects; (→) mean predicted probability of survival for the human 4-IM cohort at month 42.

Fig. 2.

Dual-correlate model surface plot mapping of predicted probability of survival at month 42 in the Human 4-IM Study Group. The surface grid illustrates the relationship among peak ED50, last anti-PA IgG response and survival probability calculated from the NHP survival data. Key: (|) mapping of peak ED50 and last anti-PA IgG response of individual humans from the 4-IM study group measured at month 42; (–) mapping of immune response to predicted survival probability from the surface grid; (→) mean predicted survival probability for the human 4-IM cohort at month 42.