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导致胃肠炎，但多重耐药 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。这份翻译研究提案测试了 适当改造鼠伤寒沙门氏菌减毒株的假说 和肠炎，带有Guaba(编码鸟嘌呤核苷酸生物合成酶)的弱化突变。 而DPx(编码ATPase)或DPP(编码蛋白酶)，都可以在疫苗接种中发挥重要作用 通过以下方式对抗这些NTS血清型：1)允许更安全、高产量地制备纯化O多糖(OPS) 和用于制造结合疫苗的鞭毛蛋白(DPP和c/px突变体超表达鞭毛)，以及2)通过 它们在异种粘膜基础/肠外加强免疫策略中的应用，在该策略中，给予小鼠 随后，口服减毒鼠伤寒沙门氏菌和肠炎沙门氏菌 B组沙门氏菌和D组OPS共价连接到第一期鞭毛的结合疫苗 鼠伤寒沙门氏菌和肠炎杆菌的蛋白质。我们假设这一战略将显著扩大 免疫反应引发并增强了对什么的保护(在小鼠的口服激发研究中进行了测试) 可以通过口服疫苗或单独使用结合物来实现。我们希望SLGA抗体和细胞介导的 活疫苗激发的免疫(CMI)与血清中抗OPS抗体的协同作用 肠外结合疫苗激发的杀菌抗体和抗鞭毛抗体。 已构建的两株甲型副伤寒沙门氏菌，基因类型为guaBAc/pX和guaBA.dpP， 将在赠款第一年的第一阶段临床试验中提供给志愿者，以获得对这些项目的初步评估 在人类中的衰减(尽管是在甲型副伤寒背景中)以及它们可能适合于减弱NTS。 由于鼠伤寒杆菌和肠炎是最常见的NTS血清型，与侵袭性和 严重的胃肠道NTS临床疾病在美国(和全球)，这项研究可以为 研制一种合理、高效、广谱的NTS疫苗。如果双价疫苗 对其他B&D群血清型的交叉保护，如果(未来)C1或C2群结合物是 此外，还将为绝大多数与侵入性疾病相关的NTS提供保险 和严重的疾病在美国和世界各地。

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.