title: 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.
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.
authors.affiliation: Intercell, USA, 22 Firstfield Road, Gaithersburg, MD 20878, USA.
authors.forename: Jing-Hui
authors.initials: JH
authors.lastname: Tian
authors.forename: Steven R
authors.initials: SR
authors.lastname: Fuhrmann
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kluepfel-Stahl
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Carman
authors.forename: Larry
authors.initials: L
authors.lastname: Ellingsworth
authors.forename: David C
authors.initials: DC
authors.lastname: Flyer
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000992:Antitoxins / Q000097:blood; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology*; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D016360:Clostridioides difficile / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D003015:Clostridium Infections / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D006224:Cricetinae; D004768:Enterotoxins / Q000235:genetics / Q000276:immunology*; D004926:Escherichia coli / Q000235:genetics; D005260:Female; D015870:Gene Expression; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D000992:Antitoxins; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D001428:Bacterial Vaccines; D004768:Enterotoxins; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile