Evaluation of Immunogenicity and Efficacy of Anthrax Vaccine Adsorbed for Postexposure Prophylaxis

Abstract

b Antimicrobials administered postexposure can reduce the incidence or progression of anthrax disease, but they do not protect against the disease resulting from the germination of spores that may remain in the body after cessation of the antimicrobial regimen. Such additional protection may be achieved by postexposure vaccination; however, no anthrax vaccine is licensed for postexposure prophylaxis (PEP). In a rabbit PEP study, animals were subjected to lethal challenge with aerosolized Bacillus anthracis spores and then were treated with levofloxacin with or without concomitant intramuscular (i.m.) vaccination with anthrax vaccine adsorbed (AVA) (BioThrax; Emergent BioDefense Operations Lansing LLC, Lansing, MI), administered twice, 1 week apart. A significant increase in survival rates was observed among vaccinated animals compared to those treated with antibiotic alone. In preexposure prophylaxis studies in rabbits and nonhuman primates (NHPs), animals received two i.m. vaccinations 1 month apart and were challenged with aerosolized anthrax spores at day 70. Prechallenge toxin-neutralizing antibody (TNA) titers correlated with animal survival postchallenge and provided the means for deriving an antibody titer associated with a specific probability of survival in animals. In a clinical immunogenicity study, 82% of the subjects met or exceeded the prechallenge TNA value that was associated with a 70% probability of survival in rabbits and 88% probability of survival in NHPs, which was estimated based on the results of animal preexposure prophylaxis studies. The animal data provide initial information on protective antibody levels for anthrax, as well as support previous findings regarding the ability of AVA to provide added protection to B. anthracis-infected animals compared to antimicrobial treatment alone.

Efficacy and Immunogenicity of Single-Dose AdVAV Intranasal Anthrax Vaccine Compared to Anthrax Vaccine Absorbed in an Aerosolized Spore Rabbit Challenge Model

“…It is currently unknown whether the noninferiority of the single-dose AdVAV vaccine demonstrated in this study will translate to the clinical setting. Antibody levels at the time of challenge have recently been used to compare the immunogenicity of AVA vaccination in rabbits and nonhuman primates to that in humans (21), so it is interesting that, at the time of the challenge in this study, the immunogenicity induced by the lowest dose of AdVAV either approximated (TNA) or was greater than (anti-PA IgG) that of AVA diluted 1:16.…”

“…The rapid immune response afforded by AdVAV could also be an important feature of an effective postexposure prophylaxis (PEP) indication. In this scenario, individuals who were recently exposed to B. anthracis spores would begin a course of antibiotic therapy (21,(30)(31)(32). Antibiotics, however, only affect the vegetative state of B. anthracis, so vaccination against PA would be prudent to protect against the germination of any cryptic spores after the cessation of antibiotic therapy (32).…”

“…In this design, the AVA comparator arm received two intramuscular doses of AVA diluted 1:16. The AVA dose and schedule were based on the rabbit preexposure prophylaxis schedule developed by the National Institute of Allergy and Infectious Diseases in which vaccinations occur on days 0 and 28, with spore challenge on day 70 (20), and reports showing that a 1:16 dilution of AVA given on that schedule resulted in near complete survival following challenge (5,21) and good correlation between the immunogenicity observed in the rabbit model and that of vaccinated humans (21). An additional AVA group that received the intramuscular vaccine at a 1:64 dilution on study days 0 and 28 was not part of the noninferiority analysis but was included to gain additional information on AVA vaccine response.…”

Comprehensive Analysis and Selection of Anthrax Vaccine Adsorbed Immune Correlates of Protection in Rhesus Macaques

“…However, TNA is considered to be species neutral since it does not rely on a species-specific conjugate antibody, allowing a direct comparison in the same assay of serum antibody functional activity across animal species and genera. TNA features prominently in the literature as an immunological bridge to extrapolate data in animals in order to predict anthrax vaccine effectiveness in humans (4,27). Furthermore, anti-PA IgG and TNA levels in NHP were highly correlated (15), and corresponding data in humans are available (12,13,15).…”

“…More recently, serum TNA has been the focal point for correlates of protection in animal models and estimates of survival probability in humans (4,27,35). Despite this focus, there has been no systematic evaluation of the relationship between PA-stimulated humoral and cell-mediated immune responses, their relative contributions to protection, or their comparative importance when used singly or in combination to predict the probability of survival.…”