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.
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Shigellosis remains a significant global health challenge, particularly in Asia and Africa, where it is a major cause of morbidity and mortality among children. Despite the urgent need, the development of a licensed vaccine has been hindered, partly due to the lack of suitable animal models for preclinical evaluation. In this study, we used an intragastric adult rhesus macaque challenge model to evaluate the safety, immunogenicity, and efficacy of five live-attenuated 1 vaccine candidates, all derived from the 1617 parent strain.
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Live, attenuated Shigella vaccine candidates, such as Shigella sonnei strain WRSS1, Shigella flexneri 2a strain SC602, and Shigella dysenteriae 1 strain WRSd1, are attenuated principally by the loss of the VirG(IcsA) protein. These candidates have proven to be safe and immunogenic in volunteer trials and in one study, efficacious against shigellosis. One drawback of these candidate vaccines has been the reactogenic symptoms of fever and diarrhea experienced by the volunteers, that increased in a dose-dependent manner.
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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.
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