Safety and immunogenicity of WRSd1, a live attenuated Shigella dysenteriae type 1 vaccine candidate.
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.
McKenzie
Robin
R
Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. rmckenz@jhmi.edu
Venkatesan
Malabi M
MM
Wolf
Marcia K
MK
Islam
Dilara
D
Grahek
Shannon
S
Jones
Andrea M
AM
Bloom
Arlene
A
Taylor
David N
DN
Hale
Thomas L
TL
Bourgeois
A Louis
AL
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
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