Protective Immunity by Shigella vaccines in humans

志贺氏菌疫苗对人类的保护性免疫力

• 批准号: 7066091
• 负责人: Marcelo B. Sztein
• 金额: $ 51.38万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7066091
• 关键词: B lymphocyte; MHC class II antigen; Shigella; Shigella vaccines; T lymphocyte; active immunization; antibacterial antibody; bacillary dysentery; bacteria infection mechanism; bacterial antigens; bacterial proteins; bactericidal immunity; bioterrorism /chemical warfare; cell mediated lymphocytolysis test; cellular immunity; clinical research; cytokine; enzyme linked immunosorbent assay; feces; flow cytometry; human tissue; interferon gamma; leukocytes; microarray technology; serum; tissue /cell culture

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.

描述（由申请人提供）：该提案中提出的研究的总体目标是确定疫苗接种和自然感染志贺氏病后有效保护免受Shigellosis的免疫学机制。 Shigella是一种全球感染，在拥挤和卫生不足的环境中迅速传播。鉴于可用的公共卫生措施成功控制了这种感染，耐药性的出现以及其在生物恐怖主义中的潜在用途的担忧，因此迫切需要向S. dysenteriae 1，S。flexneri2a和S. sonnei开发安全有效的疫苗。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受到了阻碍。因此，对人类保护的免疫学相关性与志贺氏菌的理解。非常重要。我们的工作假设是，细胞介导的免疫力和抗体反应在保护志愿者免受志赛病后的志愿者中的核心作用起着至关重要的作用，并通过降低的志贺氏菌疫苗候选物或野生型志贺氏菌感染了志愿者。 具体而言，使用血清，粪便和外周血单核细胞样本从志愿者获得的志愿者获得，并用s. dysenteriae，S。s。sonnei或S. flexneri 2a的减毒菌株进行免疫，或者用野生型S. dysenteriae（Zlstxa菌株）（Zlstxa菌株），S。s. sotnei或S. flexnei或S. flexnei s. prefney test test test（我们提出测试）：干扰素 - 伽马和其他细胞因子对参与细胞侵袭的关键志贺氏蛋白（例如，IPAB，IPAC和IPAD）在免疫或志愿者的挑战后，志贺氏菌的挑战是由CD4 + T细胞介导的，并受到II类主要的MARIGE HAVILAIBLE REMITATIBLY REMPASSIBITION COMPPPOLINIAL SOMPALLISIOS REMPACTIBLES的限制； （2）具有志贺氏菌的志愿者的免疫或挑战引起了特定细胞毒性T淋巴细胞循环的出现； （3）针对志贺氏菌的保护性CMI取决于源自志贺氏菌抗原的一组定义的免疫主导表位； （4）具有志贺氏菌的志愿者的免疫或挑战引起了不仅针对LP的抗体的血清和粪便中的出现表达肠道归巢分子（例如整联蛋白alpha4beta7）和（b）膨胀效应子（TEFF）和外周记忆T细胞（TEM）池的淋巴细胞（例如整合素α4Beta7）。