mVACS--mRNA Vaccines for C. difficile Suppression

SUMMARY - mVACS PROGRAM Clostridioides difficile is the most reported nosocomial pathogen in the United States and a major public health threat worldwide. Challenges in treating infections with conventional antibiotics and increasing rates of recurrent infection underscore the need for new interventions. To date, no vaccine has proven to be effective at clearing C. difficile from infected individuals. The mVACS program-"mRNA Vaccines for C. difficile Suppression"-is tightly focused on the goal of designing and implementing improved vaccines to mitigate or eliminate C. difficile infection (CDI). For this we will employ modified mRNA vaccine technology, which has been pioneered so successfully by team member Dr. Drew Weissman and his collaborators at BioNTech to immunize against SARS- CoV-2. Already Drs. Weissman, Alameh, and Zackular have established a collaboration with BioNTech to develop an mRNA targeting C. difficile toxins and other antigens and shown their lead formulation to be highly protective in mice challenged with a lethal dose of C. difficile. However, C. difficile is not fully cleared from the mice, and there is mild transient pathogenesis, so there is more to be done. The team is moving forward with this anti-toxin vaccine, but improvements in design are necessary for optimal efficacy. The mVACS team is a highly skilled and synergistic group dedicated to developing modified mRNAs to oppose C. difficile infection and pathogenesis. The program consists of three projects and three cores. Project 1 (Vaccine Development) (Project Leads: Alameh and Weissman) will test new mRNAs against multiple C. difficile targets, as well as mixtures of mRNAs and novel nanoparticle/lipid formulations. Project 2 (Antigen Discovery) (Project Lead: Zackular) will take advantage of advanced analysis of C. difficile microbiology and ecology of infection to produce a series of novel vaccine targets. Project 3 (Immunology) (Project Lead: Abt) will quantify mucosal adaptive immune responses against C. difficile in humans and mouse systems, identifying gaps and correlates of efficacy. Projects 2 (Antigen Discovery) and Project 3 (Immunology) will flow new data to Project 1 (Vaccine Development) to optimize vaccine design. The Projects will be complemented by three Cores: Core A (Administrative Core) (Core Leads: Bushman and Weissman), Core B (Genomics Core) (Core Leads: Bittinger, Bushman, and Moustafa) and Core C (Clinical Core) (Core Leads: Kelly and Conrad). Together with our industry partner BioNTech, we are highly optimistic that we can advance effective new vaccine designs to suppress C. difficile.