Development of an ETEC multivalent subunit vaccine using outer membrane vesicles

Project Summary Vaccines are one of the most important medical interventions in history, yet no vaccines exist that protect against enterotoxigenic Escherichia coli (ETEC) - one of the major diarrheagenic pathogens in children in low-resource settings. ETEC pathogenesis begins with fecal-oral dissemination, attachment to the small intestinal epithelium via colonization factors (CFs), and elaboration of the heat-labile (LT) and heat-stable (ST) enterotoxins. The majority of ETEC vaccine efforts have focused primarily on generation of protective immune responses to CFs and LT, and vaccine antigens that provide coverage to ST are a critical gap in achieving full vaccine protection. Addressing this gap is imperative since large epidemiological studies have shown that ST is associated with the most severe cases of ETEC diarrheal disease. Here we will test the central hypothesis that immunization with outer membrane vesicle (OMV)-adjuvanted multivalent vaccines can establish anti-ETEC immunity in the gastrointestinal tract, where it is needed to neutralize enterotoxins and block bacterial colonization. Our hypothesis is supported by preliminary data demonstrating that OMV-adjuvanted ST and OMV-adjuvanted CFs induce ST- and CF-specific antibodies, respectively. Studies in Aim 1 will test the hypothesis that antibodies produced following immunization with OMV-adjuvanted ST and LT toxoids will protect against toxin-mediated secretory diarrhea. Studies in Aim 2 will test the hypothesis that antibodies produced following immunization with OMV-adjuvanted CFs will prevent ETEC colonization of the small intestinal epithelium. Development of an effective multivalent vaccine against ETEC would have a major impact on public health by reducing the global burden of bacterial diarrhea.