Advancing a second generation C. difficile vaccine

项目概要（总体） 我们在俄克拉荷马州的目标。艰难梭菌U19计划是将一个强大的研究基础， 病原体进入一个国家认可的卓越中心的研究C。很难我们的研究目标， 与RFA-AI-022-001相当的是提供解释为什么疫苗诱导 免疫提供了针对C的次优保护。很难理解人类记忆B细胞的反应 并推动第二代候选疫苗的开发和测试。到 为了实现这些目标，我们设计了三个独立但互补的研究项目， 由一个包括生物统计支持的行政核心和一个研究核心支持， 综合性和一致性C.研究项目内部和之间的艰难挑战实验。的 因此，将实现以下具体目标：具体目标1： 对C.很难具体目标2：测试改变平衡的第二代候选疫苗 在病原体和宿主之间产生更有效的疫苗应答，并确定C.艰难 毒素B破坏了这些反应（项目1）。具体目标3：确定人TcdB的功能多样性- 特异性记忆B细胞衍生抗体（项目2）。具体目标4：确定TcdA和TcdB对 肠神经系统对疫苗接种和感染的协调体液反应（项目3）。这些努力 还将得到OUHSC NIH资助的项目的支持，这些项目提供了至关重要的额外资源。年底前 在第一个五年的资助期内，我们将推进理解为什么疫苗对C.艰难 是次优的，推进第二代疫苗，并建立持续研究的手段， 程序在C.很难

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.