Protective Immunity by Shigella vaccines in humans

描述（由申请方提供）：本提案中所述研究的总体目标是确定介导疫苗接种和自然感染志贺氏菌后有效预防志贺氏菌病的免疫学机制。 志贺氏菌是一种全球性传染病，在拥挤和卫生设施不足的环境中迅速传播。鉴于现有的公共卫生措施的缺点，成功地控制这种感染，耐药性的出现和担心其在生物恐怖主义的潜在用途，安全有效的疫苗，以S。sp. flexneri 2a和S.宋内急需。然而，志贺氏菌疫苗的开发一直受到相当大的缺乏保护性免疫的具体决定因素的信息。因此，了解人类对志贺氏菌的免疫保护相关性。非常重要。我们的工作假设是，细胞介导的免疫和抗体应答在保护志愿者接种减毒志贺氏菌候选疫苗或感染野生型志贺氏菌后免受志贺氏菌感染方面发挥着核心作用。 具体地说，使用血清，粪便和外周血单个核细胞标本获得的志愿者免疫与减毒株的S。Aesthacteriae，S. sonnei或S. flexneri 2a或用野生型S. zlstxA菌株）、S. sonnei或S. flexneri 2a，我们提出测试以下假设：（1）干扰素-γ和其它细胞因子分泌到参与细胞侵袭的关键志贺氏菌蛋白（例如，志贺氏菌免疫或攻击后的免疫应答（如：I paB、I paC和I paD）是由CD 4 + T细胞介导的，并受II类主要组织相容性复合物分子的限制;（2）志贺氏菌免疫或攻击后的免疫应答促进了特异性细胞毒性T淋巴细胞在循环中的出现;（3）志贺氏菌保护性CMI依赖于一组确定的志贺氏菌抗原的免疫显性表位;（4）用志贺氏菌对志愿者进行免疫或攻击，使血清和粪便中出现不仅针对LPS，而且针对参与志贺氏菌侵袭的关键分子的抗体，IpaB、IpaC、iPad和其它志贺氏菌蛋白，和（5）用志贺氏菌免疫或攻击志愿者，使得（a）表达肠道归巢分子（例如，整联蛋白α 4 β 7）和（B）扩增效应子（Teff）和外周记忆T细胞（TEM）库。

DESCRIPTION (provided by applicant): The overall goal of the studies presented in this proposal is to identify the immunological mechanisms that mediate effective protection from shigellosis following vaccination and natural infection with Shigella. Shigella is a global infection that disseminates rapidly in settings where there is crowding and inadequate sanitation. Given the shortcomings of available public health measures to successfully control this infection, the appearance of drug resistance and concerns about its potential use in bioterrorism, the development of safe and effective vaccines to S. dysenteriae 1, S. flexneri 2a and S. sonnei is urgently needed. However, Shigella vaccine development has been hampered by a considerable lack of information of the specific determinants of protective immunity. Thus, the understanding of the immunological correlates of protection in humans to Shigella spp. is of great importance. Our working hypothesis is that both cell-mediated immunity and antibody responses play a central role in protection of volunteers from shigellosis following immunization with attenuated Shigella vaccine candidates or infection with wild-type Shigella. Specifically, using serum, stool and peripheral blood mononuclear cell specimens obtained from volunteers immunized with attenuated strains of S. dysenteriae, S. sonnei or S. flexneri 2a or challenged with wild-type S. dysenteriae (zlstxA strain), S. sonnei or S. flexneri 2a, we propose to test the following hypotheses: (1) secretion of interferon-gamma, and other cytokines to key Shigella proteins involved in cell invasion (e.g., IpaB, IpaC and IpaD) following immunization or challenge of volunteers with Shigella is mediated by CD4 + T cells and restricted by class II major histocompatibility complex molecules; (2) immunization or challenge of volunteers with Shigella elicits the appearance in circulation of specific cytotoxic T lymphocytes; (3) protective CMI against Shigella depends on a defined set of immunodominant epitopes derived from Shigella antigens; (4) immunization or challenge of volunteers with Shigella elicits the appearance in serum and stools of antibodies directed not only to LPS, but also to key molecules involved in Shigella invasion, e.g., IpaB, IpaC, IpaD and other Shigella proteins and (5) immunization or challenge of volunteers with Shigella elicits the appearance in circulation of (a) specific T and B lymphocytes expressing gut homing molecules (e.g., integrin alpha4beta7)and (b) expanded effector (Teff) and peripheral memory T cell (TEM)pools.