title: Cross-species prediction of human survival probabilities for accelerated anthrax vaccine absorbed (AVA) regimens and the potential for vaccine and antibiotic dose sparing.
abstract: Anthrax vaccine adsorbed (AVA, BioThrax) was recently approved by the Food and Drug Administration (FDA) for a post-exposure prophylaxis (PEP) indication in adults 18-65years of age. The schedule is three doses administered subcutaneous (SC) at 2-week intervals (0, 2, and 4weeks), in conjunction with a 60-day course of antimicrobials. The Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) developed an animal model to support assessment of a shortened antimicrobial PEP duration following Bacillus anthracis exposure. A nonhuman primate (NHP) study was completed to evaluate the efficacy of a two dose anthrax vaccine absorbed (AVA) schedule (0, 2weeks) aerosol challenged with high levels of B. anthracis spores at week4- the time point at which humans would receive the third vaccination of the approved PEP schedule. Here we use logistic regression models to combine the survival data from the NHP study along with serum anthrax lethal toxin neutralizing activity (TNA) and anti-PA IgG measured by enzyme linked immunosorbent assay (ELISA) data to perform a cross-species analysis to estimate survival probabilities in vaccinated human populations at this time interval (week4 of the PEP schedule). The bridging analysis demonstrated that high levels of NHP protection also yield high predicted probability of human survival just 2weeks after the second dose of vaccine with the full or half antigen dose regimen. The absolute difference in probability of human survival between the full and half antigen dose was estimated to be at most approximately 20%, indicating that more investigation of the half-antigen dose for vaccine dose sparing strategies may be warranted.
authors: Battelle Memorial Institute, Columbus, OH 43201, USA. Electronic address: starkg@battelle.org.
authors: G V
authors: GV
authors: Stark
authors: Battelle Memorial Institute, Columbus, OH 43201, USA.
authors: G S
authors: GS
authors: Sivko
authors: Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-9825, USA.
authors: M
authors: M
authors: VanRaden
authors: Centers for Disease Control and Prevention, Atlanta, GA 30329-4027, USA.
authors: J
authors: J
authors: Schiffer
authors: Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-9825, USA.
authors: K L
authors: KL
authors: Taylor
authors: Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-9825, USA.
authors: J A
authors: JA
authors: Hewitt
authors: Centers for Disease Control and Prevention, Atlanta, GA 30329-4027, USA.
authors: C P
authors: CP
authors: Quinn
authors: Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-9825, USA.
authors: E O
authors: EO
authors: Nuzum
mesh_terms: D000818:Animals; D000881:Anthrax / Q000401:mortality* / Q000517:prevention & control*; D022122:Anthrax Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D006801:Humans; D015233:Models, Statistical; D056990:Post-Exposure Prophylaxis / Q000379:methods*; D011323:Primates; D016019:Survival Analysis
chemical_list: D022122:Anthrax Vaccines; D000900:Anti-Bacterial Agents
keywords: Anthrax; Bacillus anthracis; Bootstrap; Correlate of protection; Cross-species prediction; Logistic regression