Studying the differential efficacy of post-symptom antitoxin treatment in type A versus type B botulism using a rabbit spirometry model

Abstract

Botulinum neurotoxin (BoNT) serotypes A, B and E are responsible for most cases of human botulism. The only approved therapy for botulism is antitoxin treatment administered to patients after symptom onset. However, a recent meta-analysis of antitoxin efficacy in human botulism cases over the last century concluded that a statistically significant reduction in mortality is associated with the use of type-E and type-A but not type-B antitoxin. Animal models could be highly valuable in studying post-symptom antitoxin efficacy (PSAE). However, the only few attempts to evaluate PSAE in animals relied on subjective observations and showed approximately 50% protection. Recently, we developed a novel spirometry model for quantitative evaluation of PSAE in rabbits and used it to demonstrate full protection against BoNT/E. In the current study, comparative evaluation of PSAE in botulism types A and B was conducted using this quantitative respiratory model. A lethal dose of each toxin induced a comparable course of disease both in terms of time to symptoms (TTS, 41.9±1.3 and 40.6±1.1 h, respectively) and of time to death (TTD, 71.3±3.1 and 66.3±1.7 h, respectively). However, in accordance with the differential serotypic PSAE in human, post-symptom antitoxin treatment was fully effective only in BoNT/A-intoxicated rabbits. This serotypic divergence was reflected by a positive and statistically significant correlation between TTS and TTD in BoNT/A- (r=0.91, P=0.0006) but not in BoNT/B- (r=0.06, P=0.88) intoxicated rabbits. The rabbit spirometry system may be useful in the evaluation toolkit of botulism therapeutics, including those under development and intended to act when antitoxin is no longer effective.