Recent clinical trials involving live attenuated Shigella vaccine strains SC602 and WRSS1 have revealed that deletion of the virG(icsA) gene dramatically reduces virulence in human volunteers. These strains can be given at low oral doses and induce a strong, and in some cases, protective immune responses. However, residual vaccine associated reactogenicity suggests that further attenuation is required. A recent clinical trial indicated that the set and sen enterotoxin genes contribute to the symptoms of fever and diarrhea observed with live Shigella vaccine strains. Based on these findings, a Shigella flexneri 2a vaccine candidate, WRSf2G11, with deletions in the virG(icsA), set and sen genes has been constructed using the lambda red recombinase system. The immunogenicity and protective efficacy of WRSf2G11 compares favorably with SC602 following either intranasal (IN) or ocular (OC) immunization of guinea pigs. Taken together, these data indicate that second generation virG-based Shigella vaccine strains which lack enterotoxin genes, such as WRSf2G11, will likely show lower levels of reactogenicity without hampering the robust immune responses achieved with previous live vaccines.
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