title: Characterization of WRSs2 and WRSs3, new second-generation virG(icsA)-based Shigella sonnei vaccine candidates with the potential for reduced reactogenicity.
abstract: 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. New, second-generation virG(icsA)-based S. sonnei vaccine candidates, WRSs2 and WRSs3, are expected to be less reactogenic while retaining the ability to generate protective levels of immunogenicity seen with WRSS1. Besides the loss of VirG(IcsA), WRSs2 and WRSs3 also lack plasmid-encoded enterotoxin ShET2-1 and its paralog ShET2-2. WRSs3 further lacks MsbB2 that reduces the endotoxicity of the lipid A portion of the bacterial LPS. Studies in cell cultures and in gnotobiotic piglets demonstrate that WRSs2 and WRSs3 have the potential to cause less diarrhea due to loss of ShET2-1 and ShET2-2 as well as alleviate febrile symptoms by loss of MsbB2. In guinea pigs, WRSs2 and WRSs3 were as safe, immunogenic and efficacious as WRSS1.
authors.affiliation: Division of Bacterial & Rickettsial Diseases, Walter Reed Army Institute of Research 503, Robert Grant Avenue, Silver Spring, MD 208914, United States.
authors.forename: S
authors.initials: S
authors.lastname: Barnoy
authors.forename: K I
authors.initials: KI
authors.lastname: Jeong
authors.forename: R F
authors.initials: RF
authors.lastname: Helm
authors.forename: A E
authors.initials: AE
authors.lastname: Suvarnapunya
authors.forename: R T
authors.initials: RT
authors.lastname: Ranallo
authors.forename: S
authors.initials: S
authors.lastname: Tzipori
authors.forename: M M
authors.initials: MM
authors.lastname: Venkatesan
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D002460:Cell Line; D006224:Cricetinae; D004768:Enterotoxins / Q000172:deficiency; D017353:Gene Deletion; D006168:Guinea Pigs; D006801:Humans; D008050:Lipid A / Q000633:toxicity; D008297:Male; D022281:Shigella Vaccines / Q000009:adverse effects* / Q000276:immunology*; D012764:Shigella sonnei / Q000235:genetics / Q000276:immunology*; D013552:Swine; D014157:Transcription Factors / Q000172:deficiency*; D014613:Vaccines, Attenuated / Q000009:adverse effects / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D004768:Enterotoxins; D008050:Lipid A; D022281:Shigella Vaccines; D014157:Transcription Factors; D014613:Vaccines, Attenuated