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An optimized, synthetic DNA vaccine encoding the toxin A and toxin B receptor binding domains of Clostridium difficile induces protective antibody responses in vivo
Journal article   Open access   Peer reviewed

An optimized, synthetic DNA vaccine encoding the toxin A and toxin B receptor binding domains of Clostridium difficile induces protective antibody responses in vivo

Scott M Baliban, Amanda Michael, Berje Shammassian, Shikata Mudakha, Amir S Khan, Simon Cocklin, Isaac Zentner, Brian P Latimer, Laurent Bouillaut, Meredith Hunter, …
Infection and immunity, v 82(10), pp 4080-4091
Oct 2014
DOI: https://doi.org/10.1128/IAI.01950-14
PMID: 25024365
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1128/IAI.01950-14View
Published, Version of Record (VoR) Open

Abstract

Vaccines, DNA - genetics Antitoxins - blood Bacterial Vaccines - genetics Vaccines, DNA - immunology Cross Protection Neutralization Tests Macaca mulatta Vaccines, Synthetic - immunology Vaccines, DNA - administration & dosage Enterotoxins - immunology Bacterial Toxins - genetics Electrophoresis Female Bacterial Proteins - immunology Antibodies, Bacterial - blood Bacterial Toxins - immunology Mice, Inbred C57BL Vaccines, Synthetic - genetics Bacterial Proteins - genetics Recombinant Proteins - genetics Injections, Intramuscular Enterotoxins - genetics Animals Bacterial Vaccines - administration & dosage Bacterial Vaccines - immunology Recombinant Proteins - immunology Survival Analysis Mice Vaccines, Synthetic - administration & dosage Antibodies, Neutralizing - blood
Clostridium difficile-associated disease (CDAD) constitutes a large majority of nosocomial diarrhea cases in industrialized nations and is mediated by the effects of two secreted toxins, toxin A (TcdA) and toxin B (TcdB). Patients who develop strong antitoxin antibody responses can clear C. difficile infection and remain disease free. Key toxin-neutralizing epitopes have been found within the carboxy-terminal receptor binding domains (RBDs) of TcdA and TcdB, which has generated interest in developing the RBD as a viable vaccine target. While numerous platforms have been studied, very little data describes the potential of DNA vaccination against CDAD. Therefore, we created highly optimized plasmids encoding the RBDs from TcdA and TcdB in which any putative N-linked glycosylation sites were altered. Mice and nonhuman primates were immunized intramuscularly, followed by in vivo electroporation, and in these animal models, vaccination induced significant levels of both anti-RBD antibodies (blood and stool) and RBD-specific antibody-secreting cells. Further characterization revealed that sera from immunized mice and nonhuman primates could detect RBD protein from transfected cells, as well as neutralize purified toxins in an in vitro cytotoxicity assay. Mice that were immunized with plasmids or given nonhuman-primate sera were protected from a lethal challenge with purified TcdA and/or TcdB. Moreover, immunized mice were significantly protected when challenged with C. difficile spores from homologous (VPI 10463) and heterologous, epidemic (UK1) strains. These data demonstrate the robust immunogenicity and efficacy of a TcdA/B RBD-based DNA vaccine in preclinical models of acute toxin-associated and intragastric, spore-induced colonic disease.

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UN Sustainable Development Goals (SDGs)

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#3 Good Health and Well-Being

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Collaboration types
Industry collaboration
Domestic collaboration
Web of Science research areas
Immunology
Infectious Diseases
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