Vaccines against Botulism

Abstract

Botulinum neurotoxins (BoNT) cause the flaccid paralysis of botulism by inhibiting the release of acetylcholine from motor neurons. There are seven serotypes of BoNT (A-G), with limited therapies, and no FDA approved vaccine for botulism. An investigational formalin-inactivated penta-serotype-BoNT/A-E toxoid vaccine was used to vaccinate people who are at high risk of contracting botulism. However, this formalin-inactivated penta-serotype-BoNT/A-E toxoid vaccine was losing potency and was discontinued. This article reviews the different vaccines being developed to replace the discontinued toxoid vaccine. These vaccines include DNA-based, viral vector-based, and recombinant protein-based vaccines. DNA-based vaccines include plasmids or viral vectors containing the gene encoding one of the BoNT heavy chain receptor binding domains (HC). Viral vectors reviewed are adenovirus, influenza virus, rabies virus, Semliki Forest virus, and Venezuelan Equine Encephalitis virus. Among the potential recombinant protein vaccines reviewed are HC, light chain-heavy chain translocation domain, and chemically or genetically inactivated holotoxin.

Keywords: botulinum neurotoxins; botulism; genetically inactivated toxoids; plasmid vectors; toxoids; vaccines; viral vectors.

Figure 1

BoNT Structure-Function. (Upper) BoNTs are 150-kDa single chain proteins cleaved by bacterial or host proteases to a 50-kDa light chain (L, red) and a 100-kDa heavy chain (H), which are linked by a disulfide bond. H is organized into an N-terminal Translocation domain (HN, green) and a C-terminal Receptor Binding domain (HC, blue). L is a zinc metalloprotease with a conserved HEXXH motif (^▄) that coordinates the metal and is often subjected to mutagenesis to reduce catalytic activity (cytotoxicity) for multidomain vaccine candidates and structure-function studies. (Middle) Crystal structure of BoNT/A (PDB:3BTA). Note the independent nature of the three functional domains. (Lower) Organization of the various BoNT-derivatives which have been used in recombinant DNA-based and protein-based vaccines listed top to bottom; BoNT, LHN, HC, and HCc.