title: Safety and immunogenicity of WRSd1, a live attenuated Shigella dysenteriae type 1 vaccine candidate.
abstract: Among Shigella serotypes Shigella dysenteriae type 1 produces the most severe disease, including cases of hemolytic-uremic syndrome and pandemic outbreaks. WRSd1 is a live S. dysenteriae 1 strain attenuated by deletion of the virG(icsA) gene, which encodes a protein that mediates intercellular spread, and stxA and stxB, which encode the Shiga toxin. In this Phase I trial five groups of eight subjects ingested escalating doses of WRSd1 ranging from 10(3) to 10(7)CFU. No subject experienced fever or shigellosis, but 20% had diarrhea. Approximately two-thirds of subjects developed an IgA-ASC response to LPS. Days of fecal shedding of the vaccine strain, but not dose ingested, correlated with stronger immune responses. These results suggest that to be effective an attenuated Shigella vaccine must colonize well.
authors.affiliation: Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. rmckenz@jhmi.edu
authors.forename: Robin
authors.initials: R
authors.lastname: McKenzie
authors.forename: Malabi M
authors.initials: MM
authors.lastname: Venkatesan
authors.forename: Marcia K
authors.initials: MK
authors.lastname: Wolf
authors.forename: Dilara
authors.initials: D
authors.lastname: Islam
authors.forename: Shannon
authors.initials: S
authors.lastname: Grahek
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Jones
authors.forename: Arlene
authors.initials: A
authors.lastname: Bloom
authors.forename: David N
authors.initials: DN
authors.lastname: Taylor
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Hale
authors.forename: A Louis
authors.initials: AL
authors.lastname: Bourgeois
mesh_terms: D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000032:analysis; D001426:Bacterial Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003967:Diarrhea / Q000382:microbiology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007070:Immunoglobulin A / Q000032:analysis; D008297:Male; D008875:Middle Aged; D022621:Shiga Toxin / Q000235:genetics; D022281:Shigella Vaccines / Q000009:adverse effects* / Q000276:immunology*; D012762:Shigella dysenteriae / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics; D014613:Vaccines, Attenuated / Q000009:adverse effects / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D007070:Immunoglobulin A; D022281:Shigella Vaccines; D014157:Transcription Factors; D014613:Vaccines, Attenuated; C058483:virG protein, Shigella flexneri; D022621:Shiga Toxin