title: Protective efficacy induced by recombinant Clostridium difficile toxin fragments.
abstract: Clostridium difficile is a spore-forming bacterium that can reside in animals and humans. C. difficile infection causes a variety of clinical symptoms, ranging from diarrhea to fulminant colitis. Disease is mediated by TcdA and TcdB, two large enterotoxins released by C. difficile during colonization of the gut. In this study, we evaluated the ability of recombinant toxin fragments to induce neutralizing antibodies in mice. The protective efficacies of the most promising candidates were then evaluated in a hamster model of disease. While limited protection was observed with some combinations, coadministration of a cell binding domain fragment of TcdA (TcdA-B1) and the glucosyltransferase moiety of TcdB (TcdB-GT) induced systemic IgGs which neutralized both toxins and protected vaccinated animals from death following challenge with two strains of C. difficile. Further characterization revealed that despite high concentrations of toxin in the gut lumens of vaccinated animals during the acute phase of the disease, pathological damage was minimized. Assessment of gut contents revealed the presence of TcdA and TcdB antibodies, suggesting that systemic vaccination with this pair of recombinant polypeptides can limit the disease caused by toxin production during C. difficile infection.
authors.affiliation: Novartis Vaccines and Diagnostics SRL, Siena, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Leuzzi
authors.forename: Janice
authors.initials: J
authors.lastname: Spencer
authors.forename: Anthony
authors.initials: A
authors.lastname: Buckley
authors.forename: Cecilia
authors.initials: C
authors.lastname: Brettoni
authors.forename: Manuele
authors.initials: M
authors.lastname: Martinelli
authors.forename: Lorenza
authors.initials: L
authors.lastname: Tulli
authors.forename: Sara
authors.initials: S
authors.lastname: Marchi
authors.forename: Enrico
authors.initials: E
authors.lastname: Luzzi
authors.forename: June
authors.initials: J
authors.lastname: Irvine
authors.forename: Denise
authors.initials: D
authors.lastname: Candlish
authors.forename: Daniele
authors.initials: D
authors.lastname: Veggi
authors.forename: Werner
authors.initials: W
authors.lastname: Pansegrau
authors.forename: Luigi
authors.initials: L
authors.lastname: Fiaschi
authors.forename: Silvana
authors.initials: S
authors.lastname: Savino
authors.forename: Erwin
authors.initials: E
authors.lastname: Swennen
authors.forename: Osman
authors.initials: O
authors.lastname: Cakici
authors.forename: Ernesto
authors.initials: E
authors.lastname: Oviedo-Orta
authors.forename: Monica
authors.initials: M
authors.lastname: Giraldi
authors.forename: Barbara
authors.initials: B
authors.lastname: Baudner
authors.forename: Nunzia
authors.initials: N
authors.lastname: D'Urzo
authors.forename: Domenico
authors.initials: D
authors.lastname: Maione
authors.forename: Marco
authors.initials: M
authors.lastname: Soriani
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Pizza
authors.forename: Gillian R
authors.initials: GR
authors.lastname: Douce
authors.forename: Maria
authors.initials: M
authors.lastname: Scarselli
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology; D000942:Antigens, Bacterial / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology*; D001427:Bacterial Toxins / Q000276:immunology*; D001428:Bacterial Vaccines / Q000276:immunology*; D016360:Clostridioides difficile / Q000276:immunology; D003015:Clostridium Infections / Q000276:immunology* / Q000517:prevention & control; D006224:Cricetinae; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D004768:Enterotoxins / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D011994:Recombinant Proteins / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D057134:Antibodies, Neutralizing; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D001428:Bacterial Vaccines; D004768:Enterotoxins; D011994:Recombinant Proteins; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile