Advancing a second generation C. difficile vaccine

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PROJECT SUMMARY (Overall) Our goal in the Oklahoma C. difficile U19 program is to transform a strong research base on enteric bacterial pathogens into a nationally-recognized center of excellence for research on C. difficile. Our research goals, commensurate with RFA-AI-022-001 are to provide basic knowledge that explains why vaccine-induced immunity provides suboptimal protection against C. difficile, to understand the human memory B cell response to the pathogen, and to advance the development and testing of second generation vaccine candidates. To achieve these goals, three independent but complementary Research Projects have been devised which are supported by an Administrative Core that includes bio-statistics support, and a Research Core to allow for integrated and consistent C. difficile challenge experiments within and between the Research Projects. The following Specific Aims will therefore be accomplished: Specific Aim 1: Establish a center of excellence for research on C. difficile. Specific Aim 2: Test a second-generation vaccine candidate that shifts the balance between the pathogen and host resulting in a more efficacious vaccine response and determine how C. difficile toxin B subverts those responses (Project 1). Specific Aim 3: Determine the functional diversity of human TcdB- specific memory B cell-derived antibody (Project 2). Specific Aim 4: Determine the impact of TcdA and TcdB on the enteric nervous system-coordinated humoral response to vaccination and infection (Project 3). These efforts will also be supported by NIH-funded programs at OUHSC that provide vital additional resources. By the end of the first five year funding period we will advance the goal of understanding why vaccine responses to C. difficile are sub-optimal, advance a second generation vaccine, and establish the means for a sustained research program on C. difficile.