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. US government sponsored animal studies have shown anthrax vaccine efficacy in a variety of settings. We examined data from 21 of those studies to determine if 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.

Humoral and Cell-Mediated Immune Responses to Alternate Booster Schedules of Anthrax Vaccine Adsorbed in Humans

“…The primary immunogen in AVA is anthrax toxin protective antigen (PA). Serum anti-PA antibody levels are accurate immune correlates of protection in nonhuman primate (NHP) models of inhalation anthrax and for predicted probability of survival in humans (1)(2)(3). There is a significant lack of data in humans regarding the onset, duration, quantitative analysis, and functional activity of humoral antibody and cell-mediated immunity (CMI) responses following priming and boosting with AVA.…”

Intramuscular Delivery of Adenovirus Serotype 5 Vector Expressing Humanized Protective Antigen Induces Rapid Protection against Anthrax That May Bypass Intranasally Originated Preexisting Adenovirus Immunity

“…Previous studies have suggested that the PA-neutralizing humoral response is well-correlated with protective immunity (20). Here, a single inoculation of Ad5-PAopt resulted in robust and sustained anti-PA serum antibody and neutralizing antibody responses.…”

Protective-antigen (PA) based anthrax vaccines confer protection against inhalation anthrax by precluding the establishment of a systemic infection

“…survival to an aerosol challenge. 8 Although, both AVA and rPA also induce TNA antibodies in vaccinated mice whether these TNA antibody levels in mice correlate with protection has not been firmly established. The data shown in Table 2 suggests the possible existence of such a correlate.…”

“…The underlying premise being that the toxins released from vegetatively growing B. anthracis as a result of the germination of inhaled spores requires neutralization for the survival of vaccinated subjects. [6][7][8] Recently we reported that a cohort of rabbits immunized with a vaccinia-based PA vaccine created by the integration of the pag gene and an immune enhancing cytokine IL-15 into the genome of licensed smallpox vaccine (Wyeth/IL-15/PA), conferred sterile protection against an inhalation challenge exceeding 200 LD 50 of fully virulent Ames strain (A0462; pXO1 + pXO2 + ) spores. 9 The absence of bacteremia was also observed in the positive comparator group vaccinated with AVA suggesting perhaps PA based vaccines protect vaccinated subjects from inhalation anthrax by aborting the early events of the establishment of B. anthracis infection in the respiratory tract.…”