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

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

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


Authors

Jaime Hughes

Carl Aston

Michelle L. Kelly

RUTH GRIFFIN Ruth.Griffin1@nottingham.ac.uk
Assistant Professor



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
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

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