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Subunit vaccine efficacy against Botulinum neurotoxin subtypes

Henkel, James S., Tepp, William H., Przedpelski, Amanda, Fritz, Robert B., Johnson, Eric A., Barbieri, Joseph T.
Vaccine 2011 v.29 no.44 pp. 7688-7695
amino acids, botulinum toxin, genes, immune response, immunoglobulin G, mice, neutralization, poisoning, serotypes, vaccination, vaccines
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.