title: Subunit vaccine efficacy against Botulinum neurotoxin subtypes.
abstract: Botulinum neurotoxins (BoNT) are classified into 7 serotypes (A-G) based upon neutralization by serotype-specific anti-sera. Several recombinant serotype-specific subunit BoNT vaccines have been developed, including a subunit vaccine comprising the receptor binding domain (HCR) of the BoNTs. Sequencing of the genes encoding BoNTs has identified variants (subtypes) that possess up to 32% primary amino acid variation among different BoNT serotypes. Studies were conducted to characterize the ability of the HCR of BoNT/A to protect against challenge by heterologous BoNT/A subtypes (A1-A3). High dose vaccination with HCR/A subtypes A1-A4 protected mice from challenge by heterologous BoNT/A subtype A1-A3, while low dose HCR vaccination yielded partial protection to heterologous BoNT/A subtype challenge. Absolute IgG titers to HCRs correlated to the dose of HCR used for vaccination, where HCR/A1 elicited an A1 subtype-specific IgG response, which was not observed with HCR/A2 vaccination. Survival of mice challenged to heterologous BoNT/A2 following low dose HCR/A1 vaccination correlated with elevated IgG titers directed to the denatured C-terminal sub-domain of HCR/A2, while survival of mice to heterologous BoNT/A1 following low dose HCR/A2 vaccination correlated to elevated IgG titers directed to native HCRc/A1. This implies that low dose vaccinations with HCR/A subtypes elicit unique IgG responses, and provides a basis to define how the host develops a neutralizing immune response to BoNT intoxication. These results may provide a reference for the development of pan-BoNT vaccines.
authors.affiliation: Medical College of Wisconsin, Microbiology and Molecular Genetics, Milwaukee, WI, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Henkel
authors.forename: William H
authors.initials: WH
authors.lastname: Tepp
authors.forename: Amanda
authors.initials: A
authors.lastname: Przedpelski
authors.forename: Robert B
authors.initials: RB
authors.lastname: Fritz
authors.forename: Eric A
authors.initials: EA
authors.lastname: Johnson
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Barbieri
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D057134:Antibodies, Neutralizing / Q000097:blood; D000992:Antitoxins / Q000097:blood; D001428:Bacterial Vaccines / Q000276:immunology*; D019274:Botulinum Toxins, Type A / Q000276:immunology*; D001906:Botulism / Q000276:immunology / Q000517:prevention & control*; D056738:Cross Protection; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D008813:Mice, Inbred ICR; D021122:Protein Subunits / Q000276:immunology; D016019:Survival Analysis; D022223:Vaccines, Subunit / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D057134:Antibodies, Neutralizing; D000992:Antitoxins; D001428:Bacterial Vaccines; D007074:Immunoglobulin G; D021122:Protein Subunits; D022223:Vaccines, Subunit; D019274:Botulinum Toxins, Type A