Suchergebnisse

There is considerable variability in the published lethality values for inhalation exposures of Bacillus anthracis. The lack of consensus on an acceptable dose‐response relationship poses a significant challenge in the development of risk‐based management approaches for use following a terrorist release of B. anthracis spores. This article reviewed available B. anthracis dose‐response modeling and literature for the nonhuman primate, evaluated the use of the U.S. Environmental Protection Agency's Benchmark Dose Software (BMDS) to fit mathematical dose‐response models to these data, and reported results of the benchmark dose analysis of suitable data sets. The BMDS was found to be a useful tool to evaluate dose‐response relationships in microbial data, including that from B. anthracis exposure. An evaluation of the sources of variability identified in the published lethality data and the corresponding BMDS‐derived lethality values found that varying levels of physical characterization of the spore product, differing receptor‐specific exposure assumptions, choice of dose metrics, and the selected statistical methods all contributed to differences in lethality estimates. Recognition of these contributors to variability could ultimately facilitate agreement on a B. anthracis dose‐response relationship through provision of a common description of necessary study considerations for acceptable dose‐response data sets.

Anthrax toxin consists of protective antigen (PA) and two toxic components, lethal factor (LF) and edema factor (EF). PA binds to mammalian cellular receptors and delivers the toxic components to the cytoplasm. PA is the primary antigenic component of the current anthrax vaccine. Immunity is due to the generation of antibodies that prevent the PA-mediated internalization of LF and EF. In this study, we characterized sera obtained from vaccinated military personnel. Anthrax vaccine is administered in a series of six injections at 0, 2, and 4 weeks and 6, 12, and 18 months, followed by annual boosters. The vaccination histories of the subjects were highly varied; many subjects had not completed the entire series, and several had not received annual boosters. We developed a simple colorimetric assay using alamarBlue dye to assess the antibody-mediated neutralization of LF-mediated toxicity to the J774A.1 murine macrophage cell line. Recently vaccinated individuals had high antibody levels and neutralizing activity. One individual who had not been boosted for 5 years had low immunoglobulin G antibody levels but a detectable neutralization activity, suggesting that this individual produced low levels of very active antibodies.

Survival models are developed to predict response and time‐to‐response for mortality in rabbits following exposures to single or multiple aerosol doses of Bacillus anthracis spores. Hazard function models were developed for a multiple‐dose data set to predict the probability of death through specifying functions of dose response and the time between exposure and the time‐to‐death (TTD). Among the models developed, the best‐fitting survival model (baseline model) is an exponential dose–response model with a Weibull TTD distribution. Alternative models assessed use different underlying dose–response functions and use the assumption that, in a multiple‐dose scenario, earlier doses affect the hazard functions of each subsequent dose. In addition, published mechanistic models are analyzed and compared with models developed in this article. None of the alternative models that were assessed provided a statistically significant improvement in fit over the baseline model. The general approach utilizes simple empirical data analysis to develop parsimonious models with limited reliance on mechanistic assumptions. The baseline model predicts TTDs consistent with reported results from three independent high‐dose rabbit data sets. More accurate survival models depend upon future development of dose–response data sets specifically designed to assess potential multiple‐dose effects on response and time‐to‐response. The process used in this article to develop the best‐fitting survival model for exposure of rabbits to multiple aerosol doses of B. anthracis spores should have broad applicability to other host–pathogen systems and dosing schedules because the empirical modeling approach is based upon pathogen‐specific empirically‐derived parameters.