Attenuated Live Vibrio Cholerae-Vectored ETEC Vaccine

Vibrio cholerae vaccines which elicit antibodies against cholera toxin (CT) have been demonstrated to confer cross protection to human vaccines against strains of heat-labile toxin (LT) producing enterotoxigenic E. coli (ETEC). Vaccines were still vulnerable, however, to heat-stable toxin (ST) producing strains of ETEC. We are developing an attenuated strain of Vibrio cholerae, Peru-3, as a vaccine vector harboring ETEC-derived foreign genes encoding the major subunit of colonization factor antigen CFA/IV fimbriae, and a genetic toxoid of ST. Such a vector is expected to elicit i) anti-fimbrial antibodies, precluding binding of pathogenic ETEC strains to the human gut epithelium, and ii) anti-ST antibodies, negating the diarrheal effects of ST. Each vectored human ETEC vaccine construct will be evaluated for safety and immunogenicity in rabbits. Because there is no ETEC vaccine animal model concurrent with the human ETEC constructs, we will produce a vector possessing a gene encoding AF/R1; AF/R1 is derived from a pathogenic E. coli, (RDEC-1) infectious to rabbits. This vaccine will be orally administered to rabbits, evaluated for safety and immunogenicity, and animals will be challenged with virulent RDEC strains to assess the level of protection conferred. The ultimate goal of these studies is to construct a single-dose, orally administered, of live attenuated V. cholerae vectored ETEC vaccine in human volunteers.