title: Development of a Novel Vaccine Containing Binary Toxin for the Prevention of Clostridium difficile Disease with Enhanced Efficacy against NAP1 Strains.
abstract: Clostridium difficile infections (CDI) are a leading cause of nosocomial diarrhea in the developed world. The main virulence factors of the bacterium are the large clostridial toxins (LCTs), TcdA and TcdB, which are largely responsible for the symptoms of the disease. Recent outbreaks of CDI have been associated with the emergence of hypervirulent strains, such as NAP1/BI/027, many strains of which also produce a third toxin, binary toxin (CDTa and CDTb). These hypervirulent strains have been associated with increased morbidity and higher mortality. Here we present pre-clinical data describing a novel tetravalent vaccine composed of attenuated forms of TcdA, TcdB and binary toxin components CDTa and CDTb. We demonstrate, using the Syrian golden hamster model of CDI, that the inclusion of binary toxin components CDTa and CDTb significantly improves the efficacy of the vaccine against challenge with NAP1 strains in comparison to vaccines containing only TcdA and TcdB antigens, while providing comparable efficacy against challenge with the prototypic, non-epidemic strain VPI10463. This combination vaccine elicits high neutralizing antibody titers against TcdA, TcdB and binary toxin in both hamsters and rhesus macaques. Finally we present data that binary toxin alone can act as a virulence factor in animal models. Taken together, these data strongly support the inclusion of binary toxin in a vaccine against CDI to provide enhanced protection from epidemic strains of C. difficile.
authors.affiliation: Vaccine Basic Research, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Susan
authors.identifier: http://orcid.org/0000-0002-0879-3442
authors.initials: S
authors.lastname: Secore
authors.affiliation: Vaccine Basic Research, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Su
authors.initials: S
authors.lastname: Wang
authors.affiliation: Vaccine Basic Research, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Doughtry
authors.affiliation: Vaccine Basic Research, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Jinfu
authors.initials: J
authors.lastname: Xie
authors.affiliation: Eurofins Laboratories, Lancaster, Pennsylvania, United States of America.
authors.forename: Matt
authors.initials: M
authors.lastname: Miezeiewski
authors.affiliation: Vaccine Analytical Development, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Rustandi
authors.affiliation: Vaccine Basic Research, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Melanie
authors.initials: M
authors.lastname: Horton
authors.affiliation: Vaccine Basic Research, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Rachel
authors.initials: R
authors.lastname: Xoconostle
authors.affiliation: Vaccine Drug Product Development, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.affiliation: Vaccine Analytical Development, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lancaster
authors.affiliation: Vaccine Process Development, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Adam
authors.initials: A
authors.lastname: Kristopeit
authors.affiliation: Vaccine Process Development, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Sheng-Ching
authors.initials: SC
authors.lastname: Wang
authors.affiliation: Vaccine Process Development, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Sianny
authors.initials: S
authors.lastname: Christanti
authors.affiliation: Vaccine Analytical Development, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vitelli
authors.affiliation: Vaccine Process Development, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Gentile
authors.affiliation: Vaccine Process Development, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Aaron
authors.initials: A
authors.lastname: Goerke
authors.affiliation: Vaccine Basic Research, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Skinner
authors.affiliation: Vaccine Drug Product Development, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Erica
authors.initials: E
authors.lastname: Strable
authors.affiliation: Vaccine Drug Product Development, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: David S
authors.initials: DS
authors.lastname: Thiriot
authors.affiliation: Vaccine Basic Research, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Bodmer
authors.affiliation: Vaccine Basic Research, Merck Research Laboratories, Merck and Company, Incorporated, West Point, Pennsylvania, United States of America.
authors.forename: Jon H
authors.initials: JH
authors.lastname: Heinrichs
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics* / Q000633:toxicity; D001428:Bacterial Vaccines / Q000008:administration & dosage* / Q000235:genetics; D016360:Clostridioides difficile / Q000187:drug effects / Q000472:pathogenicity; D003015:Clostridium Infections / Q000235:genetics / Q000382:microbiology / Q000517:prevention & control*; D006224:Cricetinae; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000235:genetics* / Q000633:toxicity; D006801:Humans; D008253:Macaca mulatta / Q000382:microbiology; D008647:Mesocricetus / Q000382:microbiology
chemical_list: D001427:Bacterial Toxins; D001428:Bacterial Vaccines; D004768:Enterotoxins; C041348:tcdA protein, Clostridium difficile