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.

Grant Number: 5R21AI190682-02
NIH Institute/Center: NIH
Principal Investigator: Jacob Bitoun