Naturally Acquired Immunity to Malaria during the Epidemiologic Transition in Ken

描述（由申请人提供）：拟议工作的长期目标是了解抗疟疾抗体以及 T 细胞和 B 细胞记忆如何有助于预防无性血期恶性疟原虫，以及目前正在减少非洲疟疾传播的媒介干预措施对免疫记忆和疟疾易感性的影响。我们之前在肯尼亚西部进行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，重点是抗体和 T 细胞对裂殖子表面蛋白 1 42 kDa C 末端区域的反应。这项早期工作是在疟疾传播率高于目前的情况下完成的，并且在 MSP1 在肯尼亚儿童中的临床试验显示没有效果之前完成。因此，我们的研究策略进行了修改，以解决疟疾暴露减少对获得性免疫的影响以及血液阶段疫苗开发进展停滞的问题。具体目标是： 1：鉴定对于预防寄生虫血症和临床疟疾很重要的裂殖子入侵配体库。来自已充分表征的儿童和成人历史群体 (2000-09) 的抗体将用于鉴定裂殖子蛋白，这些蛋白因其在红细胞周期中裂殖子进展中的既定作用而被证明具有生物学意义（MSP1、AMA1、EBA175、EBA140、网织红细胞结合同源 (Rh) 蛋白、SERA5）和其他（目前）尚未充分表征的靶标（6-cys 蛋白、 MSP6、MSP7)。 2：检查 T 细胞对经过验证的裂殖子抗原的记忆如何有助于与年龄相关的疟疾免疫。将评估和比较历史和新 (2012-14) 儿童和成人队列中具有保护作用的 CD4 T 细胞记忆亚群和细胞因子 (IFN-() 和 IFN-(IL-10、TGF-�) 的反调节功能。3：评估 B 细胞记忆与获得性免疫的发展和维持的关系。循环 Ag 特异性记忆 B 细胞的频率将被量化，并与抗体的大小和持久性相关联。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，该研究的可测量结果将识别和验证新的疟疾抗原作为候选疫苗，并有助于了解减少传播对年龄特征和自然获得性疟疾免疫力的持久性的影响。

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.