title: Anthrax vaccine-induced antibodies provide cross-species prediction of survival to aerosol challenge.
abstract: Because clinical trials to assess the efficacy of vaccines against anthrax are not ethical or feasible, licensure for new anthrax vaccines will likely involve the Food and Drug Administration's "Animal Rule," a set of regulations that allow approval of products based on efficacy data only in animals combined with immunogenicity and safety data in animals and humans. U.S. government-sponsored animal studies have shown anthrax vaccine efficacy in a variety of settings. We examined data from 21 of those studies to determine whether an immunological bridge based on lethal toxin neutralization activity assay (TNA) can predict survival against an inhalation anthrax challenge within and across species and genera. The 21 studies were classified into 11 different settings, each of which had the same animal species, vaccine type and formulation, vaccination schedule, time of TNA measurement, and challenge time. Logistic regression models determined the contribution of vaccine dilution dose and TNA on prediction of survival. For most settings, logistic models using only TNA explained more than 75% of the survival effect of the models with dose additionally included. Cross-species survival predictions using TNA were compared to the actual survival and shown to have good agreement (Cohen's κ ranged from 0.55 to 0.78). In one study design, cynomolgus macaque data predicted 78.6% survival in rhesus macaques (actual survival, 83.0%) and 72.6% in rabbits (actual survival, 64.6%). These data add support for the use of TNA as an immunological bridge between species to extrapolate data in animals to predict anthrax vaccine effectiveness in humans.
authors.affiliation: Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, 6700B Rockledge Drive, Bethesda, MD 20892-7630, USA. mfay@niaid.nih.gov
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fay
authors.forename: Dean A
authors.initials: DA
authors.lastname: Follmann
authors.forename: Freyja
authors.initials: F
authors.lastname: Lynn
authors.forename: Jarad M
authors.initials: JM
authors.lastname: Schiffer
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Stark
authors.forename: Robert
authors.initials: R
authors.lastname: Kohberger
authors.forename: Conrad P
authors.initials: CP
authors.lastname: Quinn
authors.forename: Edwin O
authors.initials: EO
authors.lastname: Nuzum
mesh_terms: D000336:Aerosols; D000818:Animals; D000881:Anthrax / Q000276:immunology / Q000401:mortality* / Q000517:prevention & control*; D022122:Anthrax Vaccines / Q000276:immunology* / Q000627:therapeutic use*; D000907:Antibodies, Bacterial / Q000276:immunology*; D008253:Macaca mulatta; D011817:Rabbits
chemical_list: D000336:Aerosols; D022122:Anthrax Vaccines; D000907:Antibodies, Bacterial