Saponins derived from the South-American Tree Quillaja saponaria have a lengthy adjuvant history going back to 1925 and several saponin fractions are currently being utilized in commercial vaccines in humans. These are all injected vaccines and no mucosal saponin adjuvant currently exists. LT(R192G/L211A), or dmLT, is the product of more than 35 years of research on the use of bacterial ADP-ribosylating enterotoxins as adjuvants. dmLT has recently had success in Phase 1 and 2 clinical trials for ETEC and polio virus, though success for oral delivery seems to be dependent upon the immunogenicity of the antigen. Both adjuvants are pursued independently for various vaccines and delivery routes but have not been pursued together. In preliminary studies, we have observed synergistic adjuvant activity when dmLT and saponins are co-administered by oral and sublingual vaccination. In the current project, we propose to evaluate the novel combination saponin dmLT adjuvant (SDA) for oral or sublingual delivery utilizing expertise by both Tulane, Q-Vant Biosciences and PATH. We will optimize SDA in globally relevant vaccines including the U.S. Navy’s adjuvanted subunit ETEC and Campylobacter vaccine (ASEC) targeting bacterial enteric infections and inactivated polio vaccine. We will also explore novel formation preparations specific to gastrointestinal delivery and conduct IND-enabling studies such as GLP and cGMP manufacturing, toxicology, and stability testing. The ultimate goal of these studies is to define the SDA adjuvant platform and formulation that provides potent systemic immunity and/or sustained mucosal immunity.