Evaluation of a phoP/phoQ-deleted, aroA-deleted live oral Salmonella typhi vaccine strain in human volunteers.

Improved live oral typhoid fever vaccines may be engineered by deletion of Salmonella-specific virulence genes in Salmonella typhi. Ty445, an aroA-deleted S. typhi Ty2 strain also deleted for the phoP/phoQ Salmonella typhimurium virulence regulatory locus, was tested in human volunteers. Volunteers received escalating single doses of the vaccine; subsequently 14 individuals received two doses of 10(10) c.f.u. without significant side-effects. Control vaccinees received four doses of the live oral typhoid vaccine Ty21a. Of controls, 5/8 seroconverted as measured by increases in serum IgG directed against S. typhi O antigen or whole bacterial antigens in ELISAs. Only 2/14 volunteers receiving the experimental vaccine Ty445 seroconverted. Although a delta aroA delta phoP/phoQ S. typhi strain is overattenuated for use as a typhoid fever vaccine, our data demonstrate that the deletion of the phoP/phoQ locus in S. typhi significantly attenuates this human pathogen.