Abstract Clostridioides difficile infection, the cause of antibiotic-associated pseudomembraneous colitis, is a growing national health problem. The incidence of primary C. difficile-infection in the hospitalized U.S. population is >300,000 cases annually. There is a high incidence of relapse. For these reasons there is an urgent need for new non-antibiotic based therapeutic approaches to treat this potentially life threatening disease. The novel therapeutic approach proposed in this application is an orally administered immunotherapy consisting of polyclonal human monomeric and secretory IgA (sIgA) formed by the innovative technical process of combining plasma derived dimeric IgA with recombinant human secretory component. This innovative immunotherapy will provide a significant clinical advantage over passive immunization with parenterally administered recombinant monoclonal and polyclonal IgG antibodies. Proof of Principle is established. We have demonstrated that plasma derived sIgA provides a survival advantage to hamsters infected with C. difficile and treated with a subtherapeutic dose of vancomycin. Others have found that plasma derived sIgA was effective in preventing relapse of C. difficile disease in a mouse model. The long-term goal of this project is to commercialize orally administered semisynthetic human secretory immunoglobulin A for the treatment of C. difficile infection. The Specific Aims are: 1) Determine the minimal dose of orally administered IgA and sIgA that is an effective prophylactic treatment in the hamster model of C. difficile disease. 2) Determine whether orally administered human IgA- sIgA mixture results in any toxicity in a 2 week mouse toxicity model. 3) Assess the intestinal microbiome of mice before and after treatment with sIgA. 4) Determine whether orally administered IgA and sIgA is effective when treatment begins after the C. difficile spore challenge. 5. Evaluate the stability of plasma derived IgA and sIgA during storage. 6: Determine whether there is systemic absorption of orally administered human IgA. 7. Establish GLP level Standard Operating Procedures (SOP) for purity and identity of product batches. and 8) Transfer production methods to Emergent BioSolutions, a contract development and manufacturing organization (CDMO) for scale-up.