Safety of Live OralSalmonella typhiVaccine Strains with Deletions inhtrAandaroC aroDand Immune Response in Humans

A single-dose, oral Salmonella typhi vaccine strain has been sought as a carrier or vector of cloned genes encoding protective antigens of other pathogens. Such a hybrid vaccine, administered orally, would stimulate immuneresponsesbothatthemucosalsurfaceandinthesystemiccompartmentandwouldpotentiallyprovide protection against multiple pathogens. S. typhi CVD 908 and CVD 906, which harbor deletions in aroC and aroD, were further engineered by deletion in htrAto produce strains CVD 908-htrAand CVD 906-htrA, which are unable to sustain growth and are severely impaired in their ability to survive in host tissues. These strains were fed to humans at doses of 5 310 7 to 5 310 9 CFU with buffer, and safety and immune responses were assessed.CVD908-htrAandCVD906-htrAwerewelltoleratedinvolunteers;milddiarrheain3of36volunteers and mild fever in 1 volunteer were the only notable adverse responses. The vaccine strains were not detected inbloodculturesandonlytransientlydetectedinstool.Serumimmuneresponsesto S. typhilipopolysaccharide and H antigens were observed in 75 to 100% of volunteers who received 5 3 10 8 to 5 3 10 9 CFU, and cells secreting S. typhi-specific antibodies were found in all volunteers after ingestion of either strain. Sixty-three percent to 83% of volunteers developed lymphoproliferative responses to S. typhi flagellar and particulate antigens after the higher doses. These studies demonstrate the potential of CVD 908-htrAas a live vector for the delivery of heterologous genes, and a clinical trial of such a construct is planned.