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: 7433766
• 负责人: STEPHEN B. CALDERWOOD
• 金额: $ 62.2万
• 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/7433766
• 关键词: Age; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; Bangladesh; Biopsy; Blood; Blood typing procedure; Cholera; Cholera Toxin; Cholera Vaccine; Clinical; Collaborations; Condition; Development; Diarrhea; Disease; Enrollment; Exposure to; Feces; Fimbriae Proteins; Funding; Gene Expression; Gene Expression Profiling; Gene Proteins; General Hospitals; Genes; Goals; Half-Life; Household; Human; Immune response; Immunity; Immunoglobulin-Secreting Cells; Immunologic Memory; Immunologics; In Vitro; Infection; Integration Host Factors; Longevity; Massachusetts; Measurement; Measures; Memory B-Lymphocyte; Messenger RNA; Methodology; Mucosal Immune Responses; Numbers; Nutritional status; Oral; Organism; Patients; Peru; Predisposition; Prevention; Proteins; Proteomics; Range; Research; Research Personnel; Sampling; Serum; Techniques; Technology Transfer; Tissues; Vaccination; Vaccines; Vibrio cholerae; Virulence Factors; Vitamin A; Vomiting; Week; Zinc; base; blood group; day; follow-up; immunogenic; improved; in vivo; international center; lipopolysaccharide B; medical schools; programs; response; sex

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-哈佛医学院与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和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蛋白质，从而产生免疫反应，对随后的接触具有保护作用；一个辅助假设是，这些蛋白质在现有疫苗株定植过程中没有充分表达，这些差异可能解释了当前疫苗效力降低的原因。这个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这些样本的蛋白质组学分析，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Specific Aim 2中，研究人员将鉴定人类感染霍乱弧菌以及秘鲁-15霍乱疫苗株接种后的免疫原性蛋白，以确定野生型霍乱弧菌和秘鲁-15霍乱疫苗株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，调查人员将在1年的随访期内评估霍乱和秘鲁-15疫苗接种后对关键霍乱抗原的免疫持续时间。免疫持续时间将在血清、粪便和十二指肠活检中进行评估，并采用一种新描述的方法来测量循环中抗原特异性记忆B细胞。在特异性目标4中，研究人员将检查在家庭接触者暴露于霍乱弧菌后，对体内表达蛋白的哪些免疫反应具有保护作用：血清和粪便中关键抗原的基线抗体升数；基线至第3天免疫应答的增加（作为遗忘反应的标志），以及基线时循环抗原特异性记忆B细胞的数量。在具体目标5中，调查人员将评估选定的宿主因素与霍乱或秘鲁-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。该项目的长期目标是为改进预防霍乱的疫苗奠定理论基础，并在国际疾病预防与发展中心(B)完成大量技术转让和能力建设。