Evaluation of the botulinum neurotoxin neutralizing efficiency in immunoglobulin purified from clinical volunteers vaccinated with recombinant botulinum vaccine (46.5)

Abstract

Abstract Efficacy of the Recombinant Botulinum Vaccine A/B (rBV A/B) against lethal intoxication with botulinum neurotoxin complex (BoNT) cannot be evaluated directly in humans; therefore, efficacy will be based on meeting the requirements of the FDA Animal Rule. Serum BoNT neutralizing antibody concentration (NAC) is being proposed as a correlate of protection to evaluate efficacy in nonclinical models. Under this approach, NAC levels in animals vaccinated either with rBV A/B or passively immunized with BoNT neutralizing antibody will be used to estimate the potential level of protection in humans with similar NAC levels. Estimating the level of protection based on NAC requires establishing NAC neutralizing efficiency (the amount of BoNT neutralized per NAC unit). The neutralizing efficiency of human BoNT neutralizing antibody was evaluated using immunoglobulin purified from pooled sera of clinical volunteers vaccinated with rBV A/B. Solutions of immunoglobulin were prepared at three different NAC levels, mixed with serial dilutions of BoNT serotype A or serotype B and injected into mice. At each NAC level, 50% and 99% neutralization of BoNT was determined by probit analysis of mortality dose-response curves. A simple linearly proportional relationship does not exist between NAC level and the amount of BoNT neutralized. Extrapolations of level of protection must consider variability in BoNT neutralizing efficiency at different NAC levels.