Vaccine strategy for broad spectrum protection agains non-typhoidal salmonell

虽然非伤寒沙门氏菌（NTS）长期以来一直被认为会引起胃肠炎，但多重耐药沙门氏菌（NTS） 高毒力菌株正在成为侵袭性菌血症和局部感染的重要原因 在美国和全球，导致住院和死亡。本翻译研究提案测试 适当工程化的减毒鼠伤寒沙门氏菌菌株 和肠杆菌，在guaBA（编码鸟嘌呤核苷酸生物合成酶）中具有减毒突变 以及dpX（编码ATP酶）或dpP（编码蛋白酶），可以在疫苗接种中发挥重要作用 针对这些NTS血清型，通过：1）允许更安全、高产率地制备纯化的O多糖（OPS）， 和鞭毛蛋白用于制备缀合疫苗（dpP和c/pX突变体超表达鞭毛），和2）通过 它们在异源粘膜初免/胃肠外加强免疫策略中的用途， 减毒沙门氏菌鼠伤寒沙门氏菌（S.经肠给药，随后用 由沙门氏菌属B和D OPS组共价连接至I相鞭毛组成的缀合物疫苗 鼠伤寒沙门氏菌或肠杆菌的蛋白质。我们假设，这一战略将显着扩大 免疫反应引发并增强保护（在小鼠口服攻击研究中测试）， 可以用口服疫苗或单独的缀合物来实现。我们预期SIgA抗体和细胞介导的 活疫苗刺激的免疫力（CMI）与血清IgG抗OPS协同作用 杀菌抗体和抗鞭毛抗体。 两个S已经构建的甲型副伤寒菌株，基因型guaBAc/pX和guaBA.dpP， 将在第一个资助年的第一阶段临床试验中喂给志愿者，以获得对这些药物的初步评估。 在人类中的减毒（尽管在甲型副伤寒背景下）和它们对于减毒NTS的可能适用性。 由于鼠伤寒和肠杆菌是与侵袭性和 严重的胃肠道NTS临床疾病在美国（和全球），这项研究可以铺平道路， 研制合理、高效、广谱的NTS疫苗。如果二价疫苗 交叉保护对抗其他B & D组血清型，并且如果（将来）C1或C2组缀合物 补充说，覆盖范围将提供对绝大多数与侵入性相关的NTS， 在美国和世界范围内的严重疾病。

While non-typhoidal Salmonella (NTS) have long been known to cause gastroenteritis, multiple antibioticresistant highly virulent strains are emerging as important causes of invasive bacteremia and focal infections in the USA and globally, resulting in hospitalizations and deaths. This translational research proposal tests the hypothesis that appropriately engineered attenuated strains of Salmonella enterica serovar Typhimurium and Enteritidis, with attenuating mutations in guaBA (encoding guanine nucleotide biosynthesis enzymes) and either dpX (encoding ATPase) or dpP (encoding a protease), can play an important role in vaccinating against these NTS serovars by: 1) allowing safer, high yield preparation of purified O polysaccharide (OPS) and flagella protein for making conjugate vaccines (dpP and c/pX mutants hyper-express flagella), and 2) by their use in a heterologous mucosal prime/parenteral boost immunization strategy in which mice given the attenuated strains of S. Typhimurium and S. Enteritidis orally are subsequently boosted parenterally with conjugate vaccines consisting of Salmonella Group B and D OPS covalently linked to Phase 1 flagella protein of Typhimurium or Enteritidis, respectively. We hypothesize that this strategy will markedly broaden the immune responses elicited and enhance protection (tested in oral challenge studies in mice) over what can be achieved with either oral vaccines or conjugates alone. We expect SlgA antibodies and cellmediated immunity (CMI) stimulated by the live vaccine to synergize with the serum IgG anti-OPS bactericidal antibodies and anti-flagella antibodies stimulated by the parenteral conjugate vaccines. Two S. Paratyphi A strains, genotypes guaBAc/pXand guaBA.dpP, that have already been constructed, will be fed to volunteers in a Phase 1 clinical trial in grant-year 1 to obtain a preliminary assessment of these attenuations in humans (albeit in Paratyphi A background) and their likely suitability for attenuating NTS. Since Typhimurium and Enteritidis are the most common NTS serovars associated with invasive and severe gastrointestinal NTS clinical disease in the USA (and globally), this research can pave the way for development of a rational, highly effective, broad spectrum vaccine against NTS. If the bivalent vaccines cross protect against other Group B & D serovars and if (in the future) either a group C1 or C2 conjugate is added, coverage will then be provided against the overwhelming majority of NTS associated with invasive and severe disease in the USA and worldwide.