Project 1: Neutralizing and decolonizing Clostridioides difficile using mRNA vaccines

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.