title: Characterization of Salmonella enterica derivatives harboring defined aroC and Salmonella pathogenicity island 2 type III secretion system (ssaV) mutations by immunization of healthy volunteers.
abstract: The attenuation and immunogenicity of two novel Salmonella vaccine strains, Salmonella enterica serovar Typhi (Ty2 Delta aroC Delta ssaV, designated ZH9) and S. enterica serovar Typhimurium (TML Delta aroC Delta ssaV, designated WT05), were evaluated after their oral administration to volunteers as single escalating doses of 10(7), 10(8), or 10(9) CFU. ZH9 was well tolerated, not detected in blood, nor persistently excreted in stool. Six of nine volunteers elicited anti-serovar Typhi lipopolysaccharide (LPS) immunoglobulin A (IgA) antibody-secreting cell (ASC) responses, with three of three vaccinees receiving 10(8) and two of three receiving 10(9) CFU which elicited high-titer LPS-specific serum IgG. WT05 was also well tolerated with no diarrhea, although the administration of 10(8) and 10(9) CFU resulted in shedding in stools for up to 23 days. Only volunteers immunized with 10(9) CFU of WT05 mounted detectable serovar Typhimurium LPS-specific ASC responses and serum antibody responses were variable. These data indicate that mutations in type III secretion systems may provide a route to the development of live vaccines in humans and highlight significant differences in the potential use of serovars Typhimurium and Typhi.
authors.affiliation: Microscience, Wokingham Berkshire RG41 5TU, United Kingdom.
authors.forename: Zoë
authors.initials: Z
authors.lastname: Hindle
authors.forename: Steven N
authors.initials: SN
authors.lastname: Chatfield
authors.forename: Jo
authors.initials: J
authors.lastname: Phillimore
authors.forename: Matthew
authors.initials: M
authors.lastname: Bentley
authors.forename: Julie
authors.initials: J
authors.lastname: Johnson
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Cosgrove
authors.forename: Marjan
authors.initials: M
authors.lastname: Ghaem-Maghami
authors.forename: Amy
authors.initials: A
authors.lastname: Sexton
authors.forename: Mohammad
authors.initials: M
authors.lastname: Khan
authors.forename: Frank R
authors.initials: FR
authors.lastname: Brennan
authors.forename: Paul
authors.initials: P
authors.lastname: Everest
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.forename: Derek
authors.initials: D
authors.lastname: Pickard
authors.forename: David W
authors.initials: DW
authors.lastname: Holden
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.forename: George E
authors.initials: GE
authors.lastname: Griffin
authors.forename: Deborah
authors.initials: D
authors.lastname: House
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Santangelo
authors.forename: Shahid A
authors.initials: SA
authors.lastname: Khan
authors.forename: Jaqueline E
authors.initials: JE
authors.lastname: Shea
authors.forename: Robert G
authors.initials: RG
authors.lastname: Feldman
authors.forename: David J M
authors.initials: DJ
authors.lastname: Lewis
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D006304:Health Status; D064368:Healthy Volunteers; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D016296:Mutagenesis; D019761:Phosphorus-Oxygen Lyases / Q000235:genetics / Q000276:immunology*; D012480:Salmonella Infections / Q000517:prevention & control*; D012485:Salmonella typhi / Q000235:genetics / Q000276:immunology*; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology*; D014435:Typhoid Fever / Q000276:immunology / Q000517:prevention & control; D014611:Vaccination
chemical_list: D001426:Bacterial Proteins; D008565:Membrane Proteins; C440638:SPI-2 protein, Salmonella; C019895:chorismate synthase; D019761:Phosphorus-Oxygen Lyases