Find in Library

<i>Clostridioides difficile</i> is an opportunistic gut pathogen which causes severe colitis, leading to significant morbidity and mortality due to its toxins, TcdA and TcdB. Two intra-muscular toxoid vaccines entered Phase III trials and strongly induced toxin-neutralising antibodies systemically but failed to provide local protection in the colon from primary <i>C. difficile</i> infection (CDI). Alternatively, by immunising orally, the ileum (main immune inductive site) can be directly targeted to confer protection in the large intestine. The gut commensal, non-toxigenic <i>C. difficile</i> (NTCD) was previously tested in animal models as an oral vaccine for natural delivery of an engineered toxin chimera to the small intestine and successfully induced toxin-neutralising antibodies. We investigated whether NTCD could be further exploited to induce antibodies that block the adherence of <i>C. difficile</i> to epithelial cells to target the first stage of pathogenesis. In NTCD strain T7, the colonisation factor, CD0873, and a domain of TcdB were overexpressed. Following oral immunisation of hamsters with spores of recombinant strain, T7-0873 or T7-TcdB, intestinal and systemic responses were investigated. Vaccination with T7-0873 successfully induced intestinal antibodies that significantly reduced adhesion of toxigenic <i>C. difficile</i> to Caco-2 cells, and these responses were mirrored in sera. Additional engineering of NTCD is now warranted to further develop this vaccine.