Evaluation of early immune response-survival relationship in cynomolgus macaques after Anthrax Vaccine Adsorbed vaccination and Bacillus anthracis spore challenge

Abstract

Anthrax vaccine adsorbed (AVA, BioThrax) is approved by the US Food and Drug Administration for post-exposure prophylaxis (PEP) of anthrax in adults. The PEP schedule is 3 subcutaneous (SC) doses (0, 14 and 28 days), in conjunction with a 60 day course of antimicrobials. The objectives of this study were to understand the onset of protection from AVA PEP vaccination and to assess the potential for shortening the duration of antimicrobial treatment (http://www.phe.gov/Preparedness/mcm/phemce/Documents/2014-phemce-sip.pdf). We determined the efficacy against inhalation anthrax in nonhuman primates (NHP) of the first two doses of the PEP schedule by infectious challenge at the time scheduled for receipt of the third PEP dose (Day 28). Forty-eight cynomolgus macaques were randomized to five groups and vaccinated with serial dilutions of AVA on Days 0 and 14. NHP were exposed to Bacillus anthracis Ames spores on Day 28 (target dose 200 LD50 equivalents). Anti-protective antigen (PA) IgG and toxin neutralizing antibody (TNA) responses to vaccination and in post-challenge survivors were determined. Post-challenge blood and selected tissue samples were assessed for B. anthracis at necropsy or end of study (Day 56). Pre-challenge humoral immune responses correlated with survival, which ranged from 24–100% survival depending on vaccination group. Surviving, vaccinated animals had elevated anti-PA IgG and TNA levels for the duration of the study, were abacteremic, exhibited no apparent signs of infection, and had no gross or microscopic lesions. However, survivors had residual spores in lung tissues. We conclude that the first two doses of the PEP schedule provide high levels of protection by the scheduled timing of the third dose. These data may also support consideration of a shorter duration PEP antimicrobial regimen.

Cross-species prediction of human survival probabilities for accelerated anthrax vaccine absorbed (AVA) regimens and the potential for vaccine and antibiotic dose sparing

“…Figs. S1 and S2 [16] present the estimated logistic regression models with 95 percent confidence intervals for anti-PA IgG ELISA and TNA NF 50 , respectively, for Day 28. The observed data are shown as the proportion of animals that survived in binned ranges of the immune response.…”

“…The animal study is described in detail by Sivko [16]. In brief, 48 cynomolgus macaques (24 males and 24 females) were assigned to one of 5 AVA dose groups, which ranged from 1:3 to 1:243 dilutions of the human dose or to receive saline only.…”

“…Here we report on a cross-species analysis between the accelerated two-dose NHP study data [16] and the human immunogenicity trial [8]. The primary objective of the analysis was to investigate the predicted probabilities of survival in humans at Day 28 receiving a full-dose or half-dose of AVA at only the 0 and 2 week time points of the accelerated PEP regimen (0, 2, and 4 weeks) when extrapolated from NHP data on a matching schedule.…”

Single dose of DPX-rPA, an enhanced-delivery anthrax vaccine formulation, protects against a lethal Bacillus anthracis spore inhalation challenge

“…The animals were challenged via inhalation with B. anthracis Ames spores on Day 70 as previously described. 4,27 Briefly, the animals were anesthetized with Telazol (3 mg/kg, i.m.) and placed into a plethysmography chamber and a Class III Biosafety Cabinet (BSCIII) system and were aerosol challenged by head-only inhalation of B. anthracis Ames spores aerosolized by a Collison nebulizer with a targeted ±200 LD 50 (1.24 × 10 7 CFU) dose.…”

“…The anti-rPA IgG ELISA analysis in NHPs was conducted according to validated procedures at Batelle Biomedical Research Center as previously described. 27 Briefly, the assay is designed to quantify IgG antibodies against anthrax PA using purified rPA as the solid-phase immobilized antigen and an enzyme-conjugated anti-γ chain secondary antibody as the reporter system. The assay is reported as the Log 10 serum mean concentration of anti-PA-specific IgG (μg/mL).…”