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首页> 外文OA文献 >Construction and Characterization of Bivalent Shigella flexneri 2a Vaccine Strains SC608(pCFAI) and SC608(pCFAI/LTB) That Express Antigens from Enterotoxigenic Escherichia coli
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Construction and Characterization of Bivalent Shigella flexneri 2a Vaccine Strains SC608(pCFAI) and SC608(pCFAI/LTB) That Express Antigens from Enterotoxigenic Escherichia coli

机译：表达肠毒素性大肠杆菌抗原的二价弗氏志贺氏菌2a疫苗株SC608（pCFAI）和SC608（pCFAI / LTB）的构建和表征

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An invasive strain of Shigella flexneri 2a (SC608) has been developed as a vector for the expression and delivery of heterologous antigens. SC608 is an aspartate semialdehyde dehydrogenase (asd) derivative of SC602 (icsA iuc), a well-characterized live attenuated vaccine strain which has undergone several clinical trials in human volunteers. When administered orally at a single 104 (CFU) dose, SC602 is both immunogenic and efficacious against shigellosis. Using asd-based plasmid vectors, we designed SC608 to express the enterotoxigenic Escherichia coli (ETEC) fimbrial subunit CfaB (CFA/I structural subunit) alone or in combination with the E. coli B subunit of heat-labile enterotoxin (LTB). The expression of each heterologous protein in SC608 was verified by immunoblot analysis. Each strain was comparable to the parent strain, SC602, in a HeLa cell invasion assay. After intranasal immunizations of guinea pigs, serum and mucosal immune responses were detected against both Shigella lipopolysaccharide and heterologous ETEC antigens by enzyme-linked immunosorbent assay and ELISPOT analysis. All immunized animals were subsequently protected against a challenge with wild-type S. flexneri 2a in a keratoconjunctivitis Sereny test. Serum antibodies generated against LTB and CfaB demonstrated antitoxin and agglutination activities, respectively. These results suggest that CfaB and LTB expressed in SC608 retain important conformational epitopes that are required for the generation of antibodies that have functional activities. These initial experiments demonstrate that a fully invasive Shigella vaccine strain can be engineered to deliver antigens from other diarrheal pathogens.
机译：已经开发了弗氏志贺氏菌2a（SC608）的侵袭性菌株作为表达和递送异源抗原的载体。 SC608是SC602（icsA iuc）的一种天冬氨酸半醛脱氢酶（asd）衍生物，是一种特性良好的减毒活疫苗株，已在人类志愿者中进行了多项临床试验。当以单次104（CFU）剂量口服给药时，SC602具有免疫原性并且对志贺氏菌病有效。使用基于asd的质粒载体，我们设计了SC608以单独表达肠毒素性大肠杆菌（ETEC）纤维亚基CfaB（CFA / I结构亚基），也可以与不耐热肠毒素（LTB）的E. coli B亚基组合表达。通过免疫印迹分析验证了SC608中每种异源蛋白的表达。在HeLa细胞侵袭测定中，每个菌株与亲本菌株SC602相当。豚鼠鼻内免疫后，通过酶联免疫吸附法和ELISPOT分析检测到针对志贺氏菌脂多糖和异源ETEC抗原的血清和粘膜免疫反应。随后在角膜结膜炎Sereny试验中保护所有免疫的动物免受野生型弗氏链球菌2a的攻击。针对LTB和CfaB产生的血清抗体分别显示出抗毒素和凝集活性。这些结果表明，在SC608中表达的CfaB和LTB保留了重要的构象表位，这些表位是产生具有功能活性的抗体所必需的。这些初始实验表明，可以对全侵袭性志贺氏菌疫苗株进行工程改造，以从其他腹泻病原体中传递抗原。

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