Enhancing C. difficile vaccination in the context of TcdB-mediated immunosuppression.

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PROJECT SUMMARY (Project 1) The most recent reports indicate Clostridioides difficile is the cause of over 400,000 cases of gastrointestinal illness and nearly 30,000 deaths annually. The goals of this project are to develop an effective next generation vaccine to prevent C. difficile disease and investigate the virulence-related activities of C. difficile that might reduce vaccine effectiveness. A leading candidate developed for vaccination in the Ballard lab is a mutant of TcdB lacking a key cell entry sequence. This mutant is unable to interact with cells but appears to retain aspects critical to promoting a neutralizing antibody response. This vaccine candidate will be further optimized and modified to ensure stability and a total absence of toxicity. Comparisons will be made between this mutant and a toxoid of TcdB. Next, the TcdB derivative will be used in combination with a polysaccharide antigen derived from C. difficile to generate a novel combination vaccine. All vaccine candidates will be tested for protection against C. difficile disease in a mouse model and the most promising of those will be further tested in a hamster model of infection. Using strains of C. difficile genetically engineered to express inactive TcdB, we will also determine if C. difficile inactivates key immune cells needed to provide effective memory responses in vaccinated animals. Together, these studies will both identify new C. difficile vaccines and determine the extent to which this pathogen can subvert their effectiveness.