Grant: Operating Grant: Industry-partnered Collaborative Research

In the late 1990s, an attenuated Salmonella typhimurium strain (YS1646) had promise as a anti-cancer therapy agent but stumbled in clinical trials. However, several of the characteristics that limited this organism's usefulness in human cancer can be exploited by repurposing it as a novel vaccine vector for delivery to the gastrointestinal tissues (mucosa). Furthermore, a single mutation (zwf) has been found that is associated with enhanced capacity of YS1646 to replicate in humans. Vaccines that target mucosal surfaces (eg: gut, lung, vagina) are currently a critical unmet need for a wide range of conditions. We will assess the potential of this novel vaccine platform using mouse models of two important gastrointestinal infections: a parasite Schistosoma mansoni and a bacterium Clostridium difficile. The former has massive impact in >70 low-income countries where ~200 million people are infected. The latter is among the most important hospital infections, costing ~$5 billion/year in the USA alone. We will engineer both the YS1646 parent strain and the zwf mutant to produce well-known microbial targets (catB/Prx and A/B toxins respectively). Candidate vaccines will be tested in mouse challenge models to examine immune responses and protection. Our immediate goal is to establish proof-of-concept to validate the YS1646 platform. However, we hope to move one or both candidate vaccines forward through more advanced animal testing and clinical trials. The assembled team has all of the skills necessary to achieve both the long- and short-term goals. Success in this project could establish a powerful new platform for mucosal vaccine development.