Botulinum neurotoxin vaccines: past, present, and future.

In the early 1930s, a formalin-inactivated toxoid against botulinum neurotoxin was first tested in humans. In 1965, a pentavalent botulinum toxoid (PBT) received Investigational New Drug (IND) status under the Centers for Disease Control's IND 161 (for at-risk workers), and in 1991 under the United States Army's Office of the Surgeon General IND 3723 (for military deployment). This PBT vaccine has been shown to be safe, with over 20,000 injections given to date, and continues to be used in at-risk individuals. During the past decade, recombinant DNA technology has been employed to develop second-generation vaccines to prevent botulism. Recombinant subunit vaccines utilizing the receptor-binding domains of botulinum neurotoxin (BoNT) have been shown to be safe and efficacious in protecting animal models against BoNT serotypes A, B, C1, D, E, and F. In 2004, the first recombinant subunit vaccine [rBV A/B (Pichia pastoris) vaccine] was tested in humans during a phase I clinical trial. Results from that study demonstrated that the recombinant bivalent vaccine was safe and well tolerated at all dosage levels tested and stimulated serotype-specific neutralizing antibodies among the majority of vaccine recipients.