title: Toxicity assessment of Clostridium difficile toxins in rodent models and protection of vaccination.
abstract: Clostridium difficile is the leading cause of hospital-acquired diarrhea, also known as C. difficile associated diarrhea. The two major toxins, toxin A and toxin B are produced by most C. difficile bacteria, but some strains, such as BI/NAP1/027 isolates, produce a third toxin called binary toxin. The precise biological role of binary toxin is not clear but it has been shown to be a cytotoxin for Vero cells. We evaluated the toxicity of these toxins in mice and hamsters and found that binary toxin causes death in both animals similar to toxins A and B. Furthermore, immunization of mice with mutant toxoids of all three toxins provided protection upon challenge with native toxins. These results support the concept that binary toxin contributes to the pathogenicity of C. difficile and provide a method for monitoring the toxicity of binary toxin components in vaccines.
authors.affiliation: Vaccine Basic Research, Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Wang
authors.affiliation: Vaccine Analytical Development, Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA. Electronic address: richard_rustandi@merck.com.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Rustandi
authors.affiliation: Vaccine Analytical Development, Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lancaster
authors.affiliation: Vaccine Analytical Development, Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Hong
authors.affiliation: Vaccine Drug Product Development, Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Thiriot
authors.affiliation: Vaccine Basic Research, Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Jinfu
authors.initials: J
authors.lastname: Xie
authors.affiliation: Vaccine Basic Research, Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Secore
authors.affiliation: Vaccine Process Development, Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Kristopeit
authors.affiliation: Vaccine Process Development, Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Sheng-Ching
authors.initials: SC
authors.lastname: Wang
authors.affiliation: Vaccine Basic Research, Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Jon H
authors.initials: JH
authors.lastname: Heinrichs
mesh_terms: D036002:ADP Ribose Transferases / Q000633:toxicity; D000818:Animals; D001426:Bacterial Proteins / Q000633:toxicity; D001427:Bacterial Toxins / Q000633:toxicity*; D016360:Clostridioides difficile / Q000472:pathogenicity*; D006224:Cricetinae; D004768:Enterotoxins / Q000633:toxicity; D005260:Female; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014121:Toxoids / Q000633:toxicity*
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D014121:Toxoids; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile; D036002:ADP Ribose Transferases; C410164:actin-specific ADP-ribosyltransferase, Clostridium
keywords: Binary toxin; Clostridium difficile toxins; LD(50); Mice model; Protection; Vaccine