title: Development and evaluation of an ovine antibody-based platform for treatment of Clostridium difficile infection.
abstract: Treatment of Clostridium difficile is a major problem as a hospital-associated infection which can cause severe, recurrent diarrhea. The currently available antibiotics are not effective in all cases and alternative treatments are required. In the present study, an ovine antibody-based platform for passive immunotherapy of C. difficile infection is described. Antibodies with high toxin-neutralizing titers were generated against C. difficile toxins A and B and were shown to neutralize three sequence variants of these toxins (toxinotypes) which are prevalent in human C. difficile infection. Passive immunization of hamsters with a mixture of toxin A and B antibodies protected them from a challenge with C. difficile spores in a dose-dependent manner. Antibodies to both toxins A and B were required for protection. The administration of toxin A and B antibodies up to 24 h postchallenge was found to reduce significantly the onset of C. difficile infection compared to nonimmunized controls. Protection from infection was also demonstrated with key disease isolates (ribotypes 027 and 078), which are members of the hypervirulent C. difficile clade. The ribotype 027 and 078 strains also have the capacity to produce an active binary toxin and these data suggest that neutralization of this toxin is unnecessary for the management of infection induced by these strains. In summary, the data suggest that ovine toxin A and B antibodies may be effective in the treatment of C. difficile infection; their potential use for the management of severe, fulminant cases is discussed.
authors.affiliation: Health Protection Agency, Porton Down, Salisbury, Wilts, United Kingdom.
authors.forename: April
authors.initials: A
authors.lastname: Roberts
authors.forename: Joanna
authors.initials: J
authors.lastname: McGlashan
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Al-Abdulla
authors.forename: Roger
authors.initials: R
authors.lastname: Ling
authors.forename: Harriet
authors.initials: H
authors.lastname: Denton
authors.forename: Steve
authors.initials: S
authors.lastname: Green
authors.forename: Ruth
authors.initials: R
authors.lastname: Coxon
authors.forename: John
authors.initials: J
authors.lastname: Landon
authors.forename: Clifford
authors.initials: C
authors.lastname: Shone
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology* / Q000627:therapeutic use*; D001427:Bacterial Toxins / Q000276:immunology; D016360:Clostridioides difficile / Q000145:classification / Q000276:immunology*; D006224:Cricetinae; D004761:Enterocolitis, Pseudomembranous / Q000276:immunology*; D004768:Enterotoxins / Q000276:immunology; D007116:Immunization, Passive; D012756:Sheep
chemical_list: D000907:Antibodies, Bacterial; D001427:Bacterial Toxins; C488583:Clostridium difficile lethal toxin B; D004768:Enterotoxins; C041348:tcdA protein, Clostridium difficile