Protective Immunity by Shigella vaccines in humans

描述(由申请人提供)：本提案中提出的研究的总体目标是确定免疫机制，以有效预防接种疫苗后的志贺氏菌病和自然感染志贺氏菌。志贺氏菌是一种全球性感染，在拥挤和卫生条件不佳的环境中迅速传播。鉴于成功控制这种感染的现有公共卫生措施的缺陷、耐药性的出现以及对其在生物恐怖主义中的潜在用途的担忧，迫切需要开发安全有效的疫苗来预防志贺氏菌1、福氏2a志贺菌和宋内氏志贺氏菌。然而，由于缺乏保护性免疫的特定决定因素的信息，志贺氏菌疫苗的开发一直受到阻碍。因此，了解人类对志贺氏菌的免疫学保护相关性。是非常重要的。我们的工作假设是，在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，细胞介导的免疫和抗体反应在保护志愿者免受志贺氏菌病方面发挥着核心作用。 具体地说，用志贺氏菌、宋内氏志贺氏菌或福氏2a志贺氏菌免疫志愿者或用野生型志贺氏菌(zlstxA株)、宋内氏志贺氏菌或福氏2a志贺菌攻击的志愿者的血清、粪便和外周血单核细胞标本，我们建议检验以下假设：(1)志贺氏菌免疫或攻击后，干扰素-γ和其他细胞因子对参与细胞侵袭的关键志贺氏菌蛋白(如IPAB、IPAC和iPad)的分泌是由CD4T细胞介导的，并受到II类主要组织相容性复合体分子的限制；(2)志贺氏菌免疫或激发志愿者在循环中出现特异性细胞毒性T淋巴细胞：(3)对志贺氏菌的保护性CMI依赖于一组确定的志贺氏菌抗原的免疫优势表位；(4)志贺氏菌免疫或攻击可在血清和粪便中出现针对内毒素的抗体，也可针对志贺氏菌侵袭的关键分子，如IPAB、IPAC、iPad和其他志贺氏菌蛋白；(5)志贺氏菌免疫或攻击可在循环中出现(A)表达肠道归巢分子(如整合素α4beta7)的特异性T和B淋巴细胞，(B)扩增效应器(TEff)和外周记忆T细胞池(TEM)。

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.