Immunologic Basis for Broad Protection against Enteric Fever Salmonella

伤寒沙门氏菌、甲型副伤寒沙门氏菌和乙型副伤寒沙门氏菌的感染是全球绝大多数肠道发烧的原因，是一个主要的公共卫生问题。此外，沙门氏菌是B类病原体，有可能被用作生物恐怖武器。这项应用的总体目标是通过识别可能在保护中发挥重要作用的体液和细胞介导的免疫反应(CMI)来推动针对肠道发热的交叉保护性疫苗的开发。第二个总体目标是提供数据，以验证伤寒/副伤寒双价疫苗接种肠热病疫苗的方法。拟议的研究将利用从口服Ty21a和CVD909伤寒疫苗或减毒CVD1902S.Paratyphi A候选疫苗的受试者的外周血单核细胞和血清样本，以及来自野生型(Wt)-S挑战的受试者。伤寒和Wt-S。甲型副伤寒和流行地区的伤寒和甲型副伤寒患者。我们将利用尖端免疫学平台的力量，如质量和传统的多色流式细胞术分析和分类来表征伤寒沙门氏菌、副伤寒沙门氏菌A-和B-特异性B([Memory])(BM)、T[Memory]和T[调节性](T Reg)反应，包括 他们的细胞因子产生和归巢/趋化因子受体表达的模式使用类似系统生物学的方法。我们还将进行免疫图谱研究，以确定能引起血清抗体反应的全基因组交叉反应蛋白。具体地说，我们建议检验以下假设： (1)一组明确的CMI反应在Ty21a免疫受试者中伤寒沙门氏菌和副伤寒沙门氏菌B感染之间的交叉保护中发挥关键作用；(2)志愿者口服甲型副伤寒沙门氏菌减毒疫苗株(CVD 1902)或暴露在wt-S中。甲型副伤寒引起针对甲型副伤寒沙门氏菌抗原和与甲型副伤寒沙门氏菌和乙型副伤寒沙门氏菌交叉反应的感染细胞的一组明确的CMI反应，以及(3)口服甲型副伤寒沙门氏菌CVD 1902疫苗或暴露于wt-S。甲型副伤寒沙门氏菌(无论是在挑战研究中还是在流行地区)引起针对甲型副伤寒沙门氏菌和乙型副伤寒沙门氏菌共同抗原的血清抗体和BM、BEffector和Breguiating细胞。这些研究将通过在人类中提供新颖和独特的见解来促进针对肠道发烧和其他新出现的肠道感染的疫苗策略的开发，从而为CETR应用的总体主题做出贡献。

Infections with Salmonella enterica serovar Typhi (S. Typhi), S. Paratyphi A and S. Paratyphi B are responsible for the vast majority of enteric fevers globally and are a major public health concern. Additionally, Salmonella spp are category B pathogens that have the potential to be used as bio-terror weapons. The overall goal of this application is to advance the development of cross-protective vaccines against enteric fevers by identifying humoral and cell-mediated immune responses (CMI) which might play significant roles in protection. A secondary overall aim is to provide data to validate the S. Typhi /S. Paratyphi A bivalent vaccine approach to vaccination against enteric fevers. The proposed studies will take advantage of peripheral blood mononuclear cells and sera specimens obtained from subjects orally immunized with Ty21a and CVD 909 typhoid vaccines or with the attenuated CVD 1902 S. Paratyphi A candidate vaccine, from subjects challenged with wild-type (wt)-S. Typhi and wt-S. Paratyphi A and from typhoid and paratyphoid A patients in endemic areas. We will utilize the power of cutting edge immunologic platforms such as mass and conventional multichromatic flow cytometry analysis and sorting to characterize S. Typhi-, S. Paratyphi A-, and B-specific B([memory]) (BM), T [memory] ¿, and T [regulatory] (T reg) responses, including their patterns of cytokine production and homing/chemokine receptor expression using a systems biology like approach. We will also perform immunoprofiling studies to identify genome-wide cross-reactive proteins that elicit serum antibody responses. Specifically, we propose to test the following hypotheses: (1) a defined set of CMI responses play a key role in cross-protection between S. Typhi and S. Paratyphi B infection in Ty21a-immunized subjects, (2) oral immunization of volunteers with an attenuated S. Paratyphi A vaccine strain (CVD 1902) or exposed to wt-S. Paratyphi A elicits a defined set of CMI responses against S. Paratyphi A antigens and infected cells that cross-react with S. Typhi and S. Paratyphi B antigens, and (3) oral immunization with the attenuated S. Paratyphi A CVD 1902 vaccine or exposure to wt-S. Paratyphi A (either in challenge studies or in endemic areas) elicits serum antibodies and BM, Beffector, and Breguiatory cells specific to S. Paratyphi A, as well as against Salmonella common antigens present in S. Typhi and S. Paratyphi B. These studies will contribute to the overall theme of this CETR application by providing novel and unique insights in humans that have the potential to advance the development of vaccine strategies to enteric fevers as well as other emerging enteric infections.