Abstract
ABSTRACTClostridium difficile infection (CDI) is a leading cause of nosocomial and antibiotic-associated diarrhea. A vaccine, based on formalin-inactivated toxins A and B purified from anaerobic cultures of C. difficile strain VPI 10463 (toxinotype 0), has been in development for the prevention of symptomatic CDI. We evaluated the breadth of protection conferred by this C. difficile toxoid vaccine in cross-neutralization assessments using sera from vaccinated hamsters against a collection of 165 clinical isolates. Hamster antisera raised against the C. difficile toxoid vaccine neutralized the cytotoxic activity of culture supernatants from several toxinotype 0 strains and heterologous strains from 10 different toxinotypes. Further assessments performed with purified toxins confirmed that vaccine-elicited antibodies can neutralize both A and B toxins from a variety of toxinotypes. In the hamster challenge model, the vaccine conferred significant cross-protection against disease symptoms and death caused by heterologous C. difficile strains from the most common phylogenetic clades, including the most prevalent toxinotypes.
Highlights
C lostridium difficile, a Gram-positive, spore-forming anaerobic bacterial pathogen, is a leading cause of nosocomial and antibiotic-associated diarrheal disease worldwide [1]
Despite the existence of at least 12 different toxinotypes, extensive genetic analysis of C. difficile indicates that there is a high degree of sequence conservation between exotoxins A and B, the major bacterial virulence factors, which suggests that a vaccine composed of these toxoids could provide broad protection against circulating virulent strains
Preclinical studies performed with the C. difficile toxoid vaccine in the hamster model have shown that the vaccine elicits systemic toxin A- and B-neutralizing antibodies and provides protection against C. difficile lethal challenge with a number of toxinotype strains [23]
Summary
C lostridium difficile, a Gram-positive, spore-forming anaerobic bacterial pathogen, is a leading cause of nosocomial and antibiotic-associated diarrheal disease worldwide [1]. CDI pathogenicity is mainly mediated by two exotoxins termed TcdA and TcdB (toxins A and B, respectively). (5–7), which makes them suitable targets for vaccine development; both toxins are monoglycosyl transferases, capable of causing cytoskeleton disorganization, via inactivation of Rho family GTPases. These toxins are responsible for the loss of epithelial barrier function, leading to increased intestinal permeability and fluid accumulation followed by the onset of diarrhea, a key characteristic feature of CDI [5,6,7]. Clostridium difficile infection (CDI) is a leading cause of nosocomial and antibiotic-associated diarrhea.
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