Protective Immunity to Human Cholera in Bangladesh

孟加拉国对人类霍乱的保护性免疫力

• 批准号: 6960345
• 负责人: STEPHEN B. CALDERWOOD
• 金额: $ 44.84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-05 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6960345
• 关键词: B lymphocyte; Vibrio cholerae; bacterial proteins; bactericidal immunity; biopsy; biotechnology; blood tests; cholera; cholera vaccine; clinical research; cooperative study; disease /disorder prevention /control; feces analysis; gene expression; gene expression profiling; high throughput technology; human subject; human therapy evaluation; immune response; immunologic memory; longitudinal human study; microarray technology; mucosal immunity; proteomics; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): This project is a collaboration between Massachusetts General Hospital-Harvard Medical School and the International Centre for Diarrheal Disease Research in Bangladesh (ICDDR,B), focused on defining protective immunity to V. cholerae infection and developing an improved cholera vaccine. The central hypothesis of this project is that V. cholerae expresses specific proteins during early infection, which generate immune responses that are protective on subsequent exposure; an ancillary hypothesis is that these proteins are not adequately expressed during colonization with available vaccine strains, and that these differences may explain the lessened efficacy of current vaccines. There are five specific aims in this project. In Specific Aim 1, the investigators will determine the genes and proteins expressed during human infection with V. cholerae in Bangladesh, utilizing gene expression profiling by microarray in samples of stool and vomit, as well as proteomic analysis of these samples. In Specific Aim 2, the investigators will identify proteins that are immunogenic following human infection with V. cholerae, as well as following vaccination with cholera vaccine strain Peru-15, in order to determine whether differences in gene expression between wild-type V. cholerae and Peru-15 may be correlated with differences in specific immune responses. In Specific Aim 3, the investigators will assess the duration of immunity to key cholera antigens following both cholera and Peru-15 vaccination over a 1-year followup period. The duration of immunity will be evaluated in serum, feces, and duodenal biopsies, as well as with a newly described methodology for measuring circulating, antigen-specific memory B cells. In Specific Aim 4, the investigators will examine which of the immune responses to in vivo-expressed proteins are protective following exposure to V. cholerae in household contacts utilizing: baseline antibody liters to key antigens in serum and feces; the increase in baseline to day 3 immunologic responses (as a marker of an anamnestic response), and the number of circulating, antigen-specific memory B cells at baseline. In Specific Aim 5, the investigators will evaluate selected host factors for correlation with development of immune responses following cholera or Peru-15 vaccination, as well as with susceptibility to symptomatic cholera following exposure in household contacts. The long term goals of this project are to develop the theoretical underpinnings for an improved vaccine for prevention of cholera, and to accomplish substantial technology transfer and capacity building at the ICDDR,B.

描述（由申请人提供）：该项目是马萨诸塞州总医院-哈佛大学医学院和孟加拉国国际腹泻病研究中心 (ICDDR,B) 之间的合作项目，重点是确定对霍乱弧菌感染的保护性免疫力并开发改进的霍乱疫苗。该项目的中心假设是，霍乱弧菌在早期感染期间表达特定的蛋白质，这些蛋白质产生免疫反应，对随后的接触提供保护。一个辅助假设是，这些蛋白质在现有疫苗株的定殖过程中没有充分表达，这些差异可能解释了当前疫苗功效降低的原因。该项目有五个具体目标。在具体目标 1 中，研究人员将利用粪便和呕吐物样本中的微阵列基因表达谱以及对这些样本的蛋白质组分析，确定孟加拉国人类感染霍乱弧菌期间表达的基因和蛋白质。在具体目标 2 中，研究人员将鉴定人类感染霍乱弧菌以及接种霍乱疫苗株 Peru-15 后具有免疫原性的蛋白质，以确定野生型霍乱弧菌和 Peru-15 之间基因表达的差异是否可能与特异性免疫反应的差异相关。在具体目标 3 中，研究人员将在 1 年的随访期内评估霍乱和 Peru-15 疫苗接种后对关键霍乱抗原的免疫力持续时间。免疫持续时间将通过血清、粪便和十二指肠活检以及新描述的测量循环抗原特异性记忆 B 细胞的方法进行评估。在具体目标 4 中，研究人员将检查家庭接触者接触霍乱弧菌后，哪些对体内表达蛋白的免疫反应具有保护性，利用： 针对血清和粪便中关键抗原的基线抗体升；基线至第 3 天免疫反应的增加（作为记忆反应的标志），以及基线时循环的抗原特异性记忆 B 细胞的数量。在具体目标 5 中，研究人员将评估选定的宿主因素与霍乱或 Peru-15 疫苗接种后免疫反应发展的相关性，以及与家庭接触者接触后对症状性霍乱的易感性的相关性。 The long term goals of this project are to develop the theoretical underpinnings for an improved vaccine for prevention of cholera, and to accomplish substantial technology transfer and capacity building at the ICDDR,B.