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

• Published in: Vaccine Vol. 30; no. 28; pp. 4249 - 4258
• Main Authors: Tian, Jing-Hui, Fuhrmann, Steven R., Kluepfel-Stahl, Stefanie, Carman, Robert J., Ellingsworth, Larry, Flyer, David C.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 13.06.2012
• Subjects: Allergy and Immunology; animal disease models; Animal models; Animals; antibodies; 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; blood serum; Clostridium difficile; Clostridium difficile - genetics; Clostridium difficile - immunology; Clostridium difficile - pathogenicity; Clostridium difficile associated disease; Clostridium Infections - immunology; Clostridium Infections - mortality; Clostridium Infections - pathology; Clostridium Infections - prevention & control; Cricetinae; disease severity; Enterotoxins - genetics; Enterotoxins - immunology; Escherichia coli; Escherichia coli - genetics; Female; Fusion protein; Gene Expression; hamsters; human diseases; humans; immunity; immunization; lethal dose; Mesocricetus; Mice; Mice, Inbred C57BL; neutralization; receptors; recombinant fusion proteins; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; spores; Survival Analysis; Toxin; toxins; Vaccine; vaccines; Vaccines, Synthetic - administration & dosage; Vaccines, Synthetic - genetics; Vaccines, Synthetic - immunology; C-TAB.G5; PRAS; Toxin; RBD; Clostridium difficile; Clostridium difficile associated disease; ED50; Vaccine; CDAD; Fusion protein; C-TAB; MLD100; minimum 100% lethal dose; pre-reduced anaerobically sterilized; MLD 100; carboxy-terminal toxin A and B; ED 50; 50% effective dose; C-TAB generation 5; receptor binding domains
• ISSN: 0264-410X; 1873-2518; 1873-2518
• DOI: 10.1016/j.vaccine.2012.04.045

► C. difficile ToxinA:toxin B fusion protein. ► Induction of toxin neutralizing antibody. ► Immunoprotection against an in vivo C. difficile spore challenge. 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.