No licensed vaccines are available for the largely antibiotic-resistant or enterotoxigenic (ETEC), the two most common bacteria causing children's diarrhea and travelers' diarrhea. Virulence heterogeneity is a key obstacle to developing vaccines against 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 or ETEC strains. In this study, we combined a polyvalent 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: 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 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 or 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 and ETEC, suggesting ShecVax can be a /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.IMPORTANCEThere are no effective countermeasures against and enterotoxigenic (ETEC), two antibiotic-resistant groups of bacteria and the leading causes of diarrhea in children in developing countries (children's diarrhea) and international travelers (travelers' diarrhea). Vaccines are a more practical approach to protect against infectious diseases, including diarrhea caused by or ETEC. A combined vaccine cross-protective against and ETEC can save hundreds of thousands of lives and prevent hundreds of millions of diarrhea cases yearly; it can also reduce antibiotic prescription and decrease antibiotic resistance, thus significantly improving global health. In addition, we may apply the MEFA platform to develop combined vaccines against heterogeneous pathogens or different diseases to accommodate an increasingly crowded expanded program on immunization (EPI).