Project 1: Neutralizing and decolonizing Clostridioides difficile using mRNA vaccines

总结-项目1（疫苗开发） 艰难梭菌是一种革兰氏阴性孢子形成病原体， 老年人、免疫受损个体和暴露于全身性抗生素的人的疾病和死亡。 抗生素治疗后复发率增加和治疗困难突出了需要 开发新的治疗和预防策略。迄今为止，针对C.显示艰难 有希望的结果，但未能满足减轻/减少原发性感染的主要结局标准。因此，我们认为， 需要新的和创新的战略/办法。我们的目标是开发一种临床相关的 高效多价mRNA-LNP疫苗预防定植和治疗C.艰难感染 我们的策略依赖于我们在核苷修饰的mRNA和mRNA-LNP平台方面的丰富经验， 大型可电离脂质库，以及疫苗开发和新靶点的多管齐下的方法 发现，以及独特的多学科专业知识和资源提供给我们。我们假设 致病毒素和细菌蛋白质的多价靶向（例如，表面蛋白）将1） 减轻健康个体的原发感染，以及2）预防疾病并促进非殖民化， 感染的人。肌内施用mRNA-LNP后改善粘膜免疫 通过配体和电荷介导的向性，口服递送封装在水凝胶中的mRNA-LNP疫苗 和/或加入免疫调节剂将提高多价疫苗去定居C. 肠腔中的艰难梭菌。从提出的多组学方法中获得的目标发现见解（项目2和核心 B），更好地了解人类对艰难梭菌的免疫反应（项目3和核心C）将支持 翻译工作流程，利用基础科学和基于知识的方法， 合理设计治疗和预防C.很难

SUMMARY- PROJECT 1 (VACCINE DEVELOPMENT) Clostridioides difficile is a gram negative spore forming pathogen that causes mild to severe gastrointestinal disorders and death in the elderly, immune compromised individuals and those exposed to systemic antibiotics. Increased recurrence and difficulties treating the disease following antibiotic administration highlight the need to develop novel therapeutic and prophylactic strategies. To date, vaccines against C. difficile demonstrated promising results but failed to meet primary outcome criteria to mitigate/reduce primary infections. Therefore, novel and innovative strategies/approaches are required. Our objective is to develop a clinically relevant highly effective multivalent mRNA-LNP vaccine to prevent colonization and treat C. difficile infection. Our strategy relies on our extensive experience with the nucleoside-modified mRNA and mRNA-LNP platforms, large libraries of ionizable lipids, and a multipronged approach to vaccine development and novel target discovery, as well as the unique multidisciplinary expertise and resources available to us. We hypothesize that multivalent targeting of disease causing toxins and bacterial proteins (e.g., surface proteins) will 1) mitigate primary infection in healthy individuals, and 2) prevent disease and promote decolonization in infected individuals. Improving mucosal immunity following intramuscular administration of mRNA-LNP through ligand and charge mediated tropism, oral delivery of mRNA-LNP vaccines capsulated in hydrogels and/or the addition of immune modulators will improve the efficacy of the multivalent vaccine to decolonize C. difficile in the gut lumen. Insight from the proposed multi-omic approach for target discovery (Project 2 and Core B), and a better understanding of human immune responses to C difficile (Project 3 and Core C) will support a translational workflow that leverages fundamental science and knowledge based approach for the discovery and rational design of novel vaccine targets to treat and prevent C. difficile.