Immunogenicity and preclinical efficacy characterization of ShecVax, a combined vaccine against Shigella and enterotoxigenic Escherichia coli

No licensed vaccines are available for the largely antibiotic-resistant Shigella or enterotoxigenic Escherichia coli (ETEC), the two most common bacteria causing children’s diarrhea and travelers’ diarrhea. Virulence heterogeneity is a key obstacle to developing vaccines against Shigella or ETEC. By applying a multiepitope fusion antigen (MEFA) vaccinology platform, we recently constructed epitope- and structure-based polyvalent proteins to induce cross-protective antibodies against heterogeneous Shigella or ETEC strains. In this study, we combined a polyvalent Shigella protein with two polyvalent ETEC proteins, examined antigen compatibility and broad immunogenicity, and evaluated the potential of developing a combined vaccine against the two groups of bacteria. Data showed that mice intramuscularly immunized with the combined vaccine candidate (ShecVax) developed antibodies to all the following target virulence factors: Shigella IpaB, IpaD, VirG, GuaB, StxA, Stx2A, and StxB, and ETEC STa, LT, CFA/I, CS1, CS2, CS3, CS4, CS5, and CS6. ShecVax-induced antibodies significantly inhibited the invasion of all Shigella species and important serotypes, prevented the adherence of all important ETEC pathotypes, and neutralized the enterotoxicity of ETEC toxins STa and LT. Moreover, ShecVax prevented mice from lethal pulmonary infection with Shigella sonnei or S. flexneri 2a, significantly reduced ETEC bacterial colonization in rabbit small intestines, and passively protected newborn pigs against ETEC toxin-mediated clinical diarrhea. These results indicated that ShecVax is broadly immunogenic and cross-protective against Shigella and ETEC, suggesting ShecVax can be a Shigella/ETEC combined vaccine against children’s and travelers’ diarrhea, and the MEFA platform can be generally applied for vaccine development against heterogeneous pathogens or different diseases.