Naturally Acquired Immunity to Malaria during the Epidemiologic Transition in Ken

肯恩流行病学转变期间对疟疾的自然获得免疫力

• 批准号: 8486389
• 负责人: James Walter Kazura
• 金额: $ 61.4万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8486389
• 关键词: Accounting; Address; Adult; Affect; Africa; Africa South of the Sahara; African; Age; Alleles; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; Binding; Blood; C-terminal; Cellular biology; Child; Childhood; Clinical; Clinical Trials; Cohort Studies; Conduct Clinical Trials; Development; Disease; Enzyme-Linked Immunosorbent Assay; Epidemiology; Epitopes; Erythrocytes; Exposure to; Frequencies; Funding; Genomics; Goals; Growth; Homologous Protein; Immune; Immunity; Immunoglobulin G; Insecticides; Interferons; Interleukin-10; Intervention; Kenya; Life; Ligands; Maintenance; Malaria; Measurable; Measures; Memory; Memory B-Lymphocyte; Merozoite Surface Protein 1; Morbidity - disease rate; Orthologous Gene; Outcomes Research; Parasitemia; Parasites; Phase III Clinical Trials; Phenotype; Plasma; Plasmodium falciparum; Predictive Value; Predisposition; Prevalence; Proteins; Public Health; Relative (related person); Research; Reticulocytes; Risk; Role; Rupture; Serine; Staging; Surface; T cell response; T memory cell; T-Lymphocyte; Tertiary Protein Structure; Time; Transgenic Organisms; Vaccines; Work; acquired immunity; age related; antigen binding; apical membrane; asexual; base; circumsporozoite protein; cohort; cytokine; density; design; insight; memory CD4 T lymphocyte; novel; response; transmission process; vaccine candidate; vaccine development; vector

DESCRIPTION (provided by applicant): The long term goals of the proposed work are to understand how anti-malaria antibodies and T-cell and B-cell memory contribute to protection against asexual blood stage Plasmodium falciparum and the impact of vector interventions that are now decreasing malaria transmission in Africa on immune memory and malaria susceptibility. Our previous research in western Kenya has been concerned with elucidating the mechanisms underlying age-related naturally acquired immunity, with a focus on antibody and T-cell responses to the 42 kDa C-terminal region of Merozoite Surface Protein 1. This earlier work was done when malaria transmission was higher than at present and before a clinical trial of MSP1 in Kenyan children showed no efficacy. Accordingly, our research strategy has been modified to address the impact of reduced malaria exposure on acquired immunity and stalled progress toward development of a blood stage vaccine. The Specific Aims are to: 1: Identify a repertoire of merozoite invasion ligands important in protection against parasitemia and clinical malaria. Antibodies from well characterized historic cohorts of children and adults (2000-09) will be used to identify merozoite proteins credentialed as biologically significant by their established role for progression of merozoites through the erythrocyte cycle (MSP1, AMA1, EBA175, EBA140, Reticulocyte-binding homolog (Rh) proteins, SERA5) and other targets that are (presently) not well characterized (6-cys proteins, MSP6, MSP7). 2: Examine how T-cell memory to credentialed merozoite antigens contributes to age-related malaria immunity. CD4 T-cell memory subsets and cytokines implicated to have a protective role (IFN-() and counter- regulatory function on IFN-( (IL-10, TGF-¿) from historic and new (2012-14) child and adult cohorts will be evaluated and compared. 3: Evaluate the relationship of B-cell memory to the development and maintenance of acquired immunity. The frequency of circulating Ag-specific memory B-cells will be quantified and correlated with the magnitude and durability of antibody responses, incident parasitemia, and clinical malaria. These responses will be evaluated in the context of B-cell memory phenotypes stratified according to age and clinical malaria status. Measurable outcomes from this research will identify and validate new malaria antigens as vaccine candidates and contribute to understanding the mechanisms and impact of decreasing transmission on the age profile and durability of naturally acquired immunity against malaria.

描述(申请人提供)：拟议工作的长期目标是了解抗疟疾抗体和T细胞和B细胞记忆如何有助于预防无性血液期恶性疟原虫，以及媒介干预措施对免疫记忆和疟疾易感性的影响目前正在减少非洲的疟疾传播。我们之前在肯尼亚西部的研究一直致力于阐明与年龄相关的自然获得性免疫的机制，重点是针对裂殖子表面蛋白1 42 kDa C末端区域的抗体和T细胞反应。这项早期工作是在疟疾传播比目前更高的时候完成的，在肯尼亚儿童中进行的MSP1临床试验显示无效之前。因此，我们的研究战略已经修改，以解决疟疾暴露减少对获得性免疫的影响，以及血液期疫苗开发的停滞进展。具体目标是：1：确定在预防寄生虫血症和临床疟疾方面重要的裂殖子入侵配体的保留体系。来自具有良好特征的儿童和成人历史队列(2000-09年)的抗体将被用于鉴定裂殖子蛋白(MSP1、AMA1、EBA175、EBA140、网织红细胞结合同源物(Rh)蛋白、SERA5)和其他(目前)不具良好特征的靶标(6-CyS蛋白、MSP6、MSP7)，这些蛋白被证明具有生物学意义，因为它们在红细胞周期中对裂殖子的进展起到了作用。2：研究T细胞对获得证书的裂殖子抗原的记忆如何有助于年龄相关的疟疾免疫。将评估和比较历史和新的(2012-14)儿童和成人队列中的CD4T细胞记忆亚群和细胞因子对干扰素-(IL-10，转化生长因子-β)的保护作用和反向调节功能。3：探讨B细胞记忆与获得性免疫发生和维持的关系。循环中的抗原特异性记忆B细胞的频率将被量化，并与抗体反应的大小和持久性、发生的寄生虫血症和临床疟疾相关。这些反应将在根据年龄和临床疟疾状况分层的B细胞记忆表型的背景下进行评估。这项研究的可衡量结果将确定和验证新的疟疾抗原作为候选疫苗，并有助于理解减少传播对年龄分布和自然获得的疟疾免疫持久性的影响的机制和影响。