ExPEC Vaccine Development

PROJECT SUMMARY The evolution of bacterial resistance to antibiotics is precipitating a medical crisis that will cause millions of deaths and cost trillions in dollars. A major bacterial driver of resistance is so-called extraintestinal pathogenic E. coli (ExPEC), a member of the human microbiome that has reached

pandemic status because of its deadly combination of resistance and virulence. ExPEC is now the leading cause of resistance-related human mortality worldwide. There is no FDA-approved vaccine, and efforts to identify novel targets for vaccine development have been hampered by the pleiotropic nature of this bacterium’s pangenome. Using an exhaustive comparative genomics

approach of > 20,000 sequenced strains covering all sequence types, pathotypes, and phylogenies, we uncovered two high-priority virulence factor targets that met multiple vaccine- development criteria. Hypothesizing that immunological blockade of the function of these two factors will provide a one-two punch that prevents critical steps in systemic infection and invasive

disease, we propose here pre-clinical studies aimed at testing the prophylactic efficacy of such an approach. This includes a comprehensive evaluation of the vaccine’s performance to prevent three distinct types of ExPEC infection, a thorough optimization of basic vaccine parameters, innovation around novel adjuvants, and finally, the immunological mechanism of protection.

Successful completion of this project will yield knowledge as to whether targeting factors important for invasive infection is an effective strategy to reduce or eliminate global ExPEC-induced mortality and morbidity.