MecVax, an Epitope- and Structure-Based Broadly Protective Subunit Vaccine Against Enterotoxigenic Escherichia coli...

No vaccines are licensed against enterotoxigenic Escherichia coli (ETEC), a leading diarrheal cause in children and travelers. ETEC adhesins and enterotoxins are the virulence determinants and become the primary targets in ETEC vaccine development. However, ETEC strains produce > 25 adhesins and two potent enterotoxins, particularly the poorly immunogenic heat-stable toxin (STa), greatly hindering ETEC vaccine development. To overcome these challenges, we developed a multiepitope-fusion-antigen (MEFA) platform. MEFA presented multiple adhesin epitopes on a backbone and generated a polyvalent adhesin immunogen, CFA/I/II/IV MEF. CFA/I/II/IV protected against the seven ETEC adhesins (CFA/I, CS1-CS6) associated with two-thirds of ETEC diarrheal cases. We further used toxoids as safe antigens and created a toxoid fusion, 3xSTa_N12S-mnLT_R192G/L211A. This antigen induced antibodies neutralizing the enterotoxicity of STa and heat-labile toxin (LT), which, alone or together, cause all ETEC diarrheal cases. By combining two polyvalent proteins, we developed a multivalent ETEC vaccine, MecVax, that protects against seven ETEC adhesins and two enterotoxins. MecVax is broadly immunogenic. MecVax prevents intestinal colonization by ETEC strains expressing any of the seven adhesins and protects against clinical diarrhea from ETEC strains producing LT or STa enterotoxin preclinically, becoming a broadly protective ETEC vaccine candidate against children's diarrhea and travelers' diarrhea.