Preclinical safety assessment of recombinant botulinum vaccine A/B (rBV A/B)

A recombinant botulinum vaccine (rBV A/B) is being developed to protect adults 18–55 years of age from fatal botulism caused by inhalational intoxication with botulinum neurotoxin complex (BoNT) serotype A, subtype A1 (BoNT/A1) and BoNT serotype B, subtype B1 (BoNT/B1). Fundamental to the advanced development process is an initial demonstration of product safety in animals. A comprehensive series of studies was conducted to evaluate the general toxicity, neurobehavioral toxicity and local reactogenicity of the rBV A/B vaccine prior to first use in humans. Toxicity was evaluated in CD-1 mice vaccinated with control material and three dosages of rBV A/B with or without Alhydrogel® by intramuscular (IM) injection on Study Days 0, 28, 56 and 70 in a volume of 100 μL. Total immunizing protein given in each dose was either 0, 2, 4 or 8 μg/animal. Local reactogenicity was evaluated in mice at the dosages given and in New Zealand white (NZW) rabbits using the same injection volume (0.5 mL) and formulations (10, 20 and 40 g/mL total antigen with 0.2% (w/v) Alhydrogel®) intended for human use. The rBV A/B vaccine produced no apparent systemic or neurobehavioral toxicity and only transient mild inflammation at the injection site. Together these results indicated a favorable safety profile for rBV A/B and supported its use in a Phase 1 clinical trial.

► Repeat-dose toxicity (mice) – no vaccine related adverse findings. ► Neurobehavioral toxicity (mice) – no vaccine related adverse findings. ► Local reactogenicity (rabbits) – no vaccine related adverse findings. ► All study designs reviewed by FDA prior to implementation. ► Enabled execution of Phase 1 clinical study.