title: Evaluation of a phoP/phoQ-deleted, aroA-deleted live oral Salmonella typhi vaccine strain in human volunteers.
abstract: 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.
authors.affiliation: Infectious Disease Unit, Massachusetts General Hospital, Boston 02114, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Hohmann
authors.forename: C A
authors.initials: CA
authors.lastname: Oletta
authors.forename: S I
authors.initials: SI
authors.lastname: Miller
mesh_terms: D051229:3-Phosphoshikimate 1-Carboxyvinyltransferase; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019883:Alkyl and Aryl Transferases; D000907:Antibodies, Bacterial / Q000096:biosynthesis; D001426:Bacterial Proteins / Q000235:genetics; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics*; D004353:Drug Evaluation, Preclinical; D005260:Female; D017353:Gene Deletion; D005798:Genes, Bacterial / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012485:Salmonella typhi / Q000235:genetics* / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology; D014166:Transferases / Q000235:genetics* / Q000276:immunology*; D014435:Typhoid Fever / Q000517:prevention & control; D014613:Vaccines, Attenuated / Q000009:adverse effects / Q000235:genetics* / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D001428:Bacterial Vaccines; C079792:PhoQ protein, Bacteria; D014157:Transcription Factors; D014613:Vaccines, Attenuated; C061064:PhoP protein, Bacteria; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051229:3-Phosphoshikimate 1-Carboxyvinyltransferase