Towards Development of a Non-Toxigenic Clostridioides difficile Oral Spore Vaccine against Toxigenic C. difficile

Hughes, Jaime; Aston, Carl; Kelly, Michelle L.; Griffin, Ruth

Abstract

Clostridioides difficile 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 C. difficile 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 C. difficile (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 C. difficile 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 C. difficile to Caco-2 cells, and these responses were mirrored in sera. Additional engineering of NTCD is now warranted to further develop this vaccine.

Citation

Hughes, J., Aston, C., Kelly, M. L., & Griffin, R. (2022). Towards Development of a Non-Toxigenic Clostridioides difficile Oral Spore Vaccine against Toxigenic C. difficile. Pharmaceutics, 14(5), Article 1086. https://doi.org/10.3390/pharmaceutics14051086

• Journal Article Type: Article
• Acceptance Date: May 16, 2022
• Online Publication Date: May 19, 2022
• Publication Date: 2022-05
• Deposit Date: Jul 19, 2022
• Publicly Available Date: Jul 20, 2022
• Journal: Pharmaceutics
• Electronic ISSN: 1999-4923
• Publisher: MDPI AG
• Peer Reviewed: Peer Reviewed
• Volume: 14
• Issue: 5
• Article Number: 1086
• DOI: https://doi.org/10.3390/pharmaceutics14051086
• Keywords: Pharmaceutical Science
• Public URL: https://nottingham-repository.worktribe.com/output/8138785
• Publisher URL: https://www.mdpi.com/1999-4923/14/5/1086