| Summary: | Non-typhoidal salmonellosis, caused by <i>Salmonella enterica</i> serovar Typhimurium is a common fecal-oral disease characterized by mild gastrointestinal distress resulting in diarrhea, chills, fever, abdominal cramps, head and body aches, nausea, and vomiting. Increasing incidences of antibiotic resistant invasive non-typhoidal <i>Salmonella</i> infections makes this a global threat requiring novel treatment strategies including next-generation vaccines. The goal of the current study was to formulate a novel vaccine platform against <i>Salmonella</i> infection that could be delivered orally. To accomplish this, we created a <i>Salmonella</i>-specific vaccine adjuvanted with <i>Burkholderia pseudomallei</i> outer membrane vesicles (OMVs). We show that adding OMVs to a heat-killed oral <i>Salmonella</i> vaccine (HKST + OMVs) protects against a lethal, oral challenge with <i>Salmonella</i>. Further, we show that opsonizing anti-<i>Salmonella</i> antibodies are induced in response to immunization and that CD4 T cells and B cells can be induced when OMVs are used as the oral adjuvant. This study represents a novel oral vaccine approach to combatting the increasing problem of invasive <i>Salmonella</i> infections.
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