Abstract
Clostridioides difficile is the main cause of health-care-associated infectious diarrhoea. Toxins, TcdA and TcdB, secreted by this bacterium damage colonic epithelial cells and in severe cases this culminates in pseudomembranous colitis, toxic megacolon and death. Vaccines in human trials have focused exclusively on the parenteral administration of toxin-based formulations. These vaccines promote toxin-neutralising serum antibodies but fail to confer protection from infection in the gut. An effective route to immunise against gut pathogens and stimulate a protective mucosal antibody response (secretory immunoglobulin A, IgA) at the infection site is the oral route. Additionally, oral immunisation generates systemic antibodies (IgG). Using this route, two different antigens were tested in the hamster model: The colonisation factor CD0873 and a TcdB fragment. Animals immunised with CD0873 generated a significantly higher titre of sIgA in intestinal fluid and IgG in serum compared to naive animals, which significantly inhibited the adherence of C. difficile to Caco-2 cells. Following challenge with a hypervirulent isolate, the CD0873-immunised group showed a mean increase of 80% in time to experimental endpoint compared to naïve animals. Survival and body condition correlated with bacterial clearance and reduced pathology in the cecum. Our findings advocate CD0873 as a promising oral vaccine candidate against C. difficile.
Highlights
IntroductionClostridioides difficile is a Gram-positive, spore-forming anaerobic bacillus found in the intestinal tract of humans and certain animals (dogs, cats, pigs and birds) and in the environment
Clostridioides difficile is a Gram-positive, spore-forming anaerobic bacillus found in the intestinal tract of humans and certain animals and in the environment
In order to obtain the cleaved version of CD0873, the form that would be expressed on vegetative cells, the IMPACT-TWIN system was used as it enables purification of recombinant proteins possessing an N-terminal cysteine
Summary
Clostridioides difficile is a Gram-positive, spore-forming anaerobic bacillus found in the intestinal tract of humans and certain animals (dogs, cats, pigs and birds) and in the environment. 5% of healthy adults and 15–70% of infants are colonised by C. difficile but its prevalence is much greater in hospitalised patients or nursing home residents [1]. The incidence and severity of C. difficile infection (CDI) has increased over the past 20 years [2] such that it is the leading cause of hospital-acquired infection worldwide [3]. Risk factors associated with CDI are mainly antibiotic therapy [6] and age (over 65 years) [1], immunosuppressive therapy, severe underlying illness, recent surgery and prolonged hospitalization or nursing home stay [7,8,9,10,11,12,13]. Recent studies show that the incidence of community-acquired
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