A novel fusion protein containing the receptor binding domains of C. difficile toxin A and toxin B elicits protective immunity against lethal toxin and spore challenge in preclinical efficacy models

Jing-Hui Tian; Steven R Fuhrmann; Stefanie Kluepfel-Stahl; Robert J Carman; Larry Ellingsworth; David C Flyer

doi:10.1016/j.vaccine.2012.04.045

A novel fusion protein containing the receptor binding domains of C. difficile toxin A and toxin B elicits protective immunity against lethal toxin and spore challenge in preclinical efficacy models

Vaccine. 2012 Jun 13;30(28):4249-58. doi: 10.1016/j.vaccine.2012.04.045. Epub 2012 Apr 23.

Authors

Jing-Hui Tian¹, Steven R Fuhrmann, Stefanie Kluepfel-Stahl, Robert J Carman, Larry Ellingsworth, David C Flyer

Affiliation

¹ Intercell, USA, 22 Firstfield Road, Gaithersburg, MD 20878, USA.

PMID: 22537987
DOI: 10.1016/j.vaccine.2012.04.045

Abstract

Antibodies targeting the Clostridium difficile toxin A and toxin B confer protective immunity to C. difficile associated disease in animal models and provided protection against recurrent C. difficile disease in human subjects. These antibodies are directed against the receptor binding domains (RBD) located in the carboxy-terminal portion of both toxins and inhibit binding of the toxins to their receptors. We have constructed a recombinant fusion protein containing portions of the RBD from both toxin A and toxin B and expressed it in Escherichia coli. The fusion protein induced high levels of serum antibodies to both toxins A and B capable of neutralizing toxin activity both in vitro and in vivo. In a hamster C. difficile infection model, immunization with the fusion protein reduced disease severity and conferred significant protection against a lethal dose of C. difficile spores. Our studies demonstrate the potential of the fusion protein as a vaccine that could provide protection from C. difficile disease in humans.

MeSH terms

Animals
Antibodies, Bacterial / blood
Antitoxins / blood
Bacterial Proteins / genetics
Bacterial Proteins / immunology*
Bacterial Toxins / genetics
Bacterial Toxins / immunology*
Bacterial Vaccines / administration & dosage
Bacterial Vaccines / genetics
Bacterial Vaccines / immunology*
Clostridioides difficile / genetics
Clostridioides difficile / immunology*
Clostridioides difficile / pathogenicity
Clostridium Infections / immunology
Clostridium Infections / mortality
Clostridium Infections / pathology
Clostridium Infections / prevention & control*
Cricetinae
Enterotoxins / genetics
Enterotoxins / immunology*
Escherichia coli / genetics
Female
Gene Expression
Mesocricetus
Mice
Mice, Inbred C57BL
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / immunology
Survival Analysis
Vaccines, Synthetic / administration & dosage
Vaccines, Synthetic / genetics
Vaccines, Synthetic / immunology

Substances

Antibodies, Bacterial
Antitoxins
Bacterial Proteins
Bacterial Toxins
Bacterial Vaccines
Enterotoxins
Recombinant Fusion Proteins
Vaccines, Synthetic
tcdA protein, Clostridium difficile
toxB protein, Clostridium difficile