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保护免受无性血液阶段恶性疟原虫的侵害，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。我们以前在肯尼亚西部的研究一直关注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的42 kDa C末端区域的反应。这项早期的工作是在疟疾传播率高于目前的情况下进行的，而且在肯尼亚儿童的MSP 1临床试验没有显示出疗效之前。因此，我们的研究策略已经修改，以解决减少疟疾暴露对获得性免疫的影响，并阻止了血液阶段疫苗的开发。具体目的是：1：鉴定在对抗寄生虫血症和临床疟疾中重要的裂殖子侵入配体的库。将使用来自儿童和成人（2000-09年）的充分表征的历史队列的抗体来鉴定裂殖子蛋白质，所述裂殖子蛋白质通过其在裂殖子通过红细胞周期的进展中的既定作用而被确认为具有生物学意义（MSP 1，AMA 1，EBA 175，EBA 140，网织红细胞结合同源物（Rh）蛋白，SERA 5）和（目前）未充分表征的其它靶标（6-cys蛋白、MSP 6、MSP 7）。第2章：研究T细胞对裂殖子抗原的记忆如何有助于与年龄相关的疟疾免疫。将评估和比较来自历史和新的（2012-14）儿童和成人组群的涉及对IFN-α（IL-10，TGF-β）具有保护作用（IFN-α）和反调节功能的CD 4 T细胞记忆亚群和细胞因子。3：评估B细胞记忆与获得性免疫的发展和维持的关系。将对循环Ag特异性记忆B细胞的频率进行定量，并将其与抗体应答、偶发寄生虫血症和临床疟疾的幅度和持久性相关联。这些反应将在根据年龄和临床疟疾状态分层的B细胞记忆表型的背景下进行评价。 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，并有助于了解减少传播对年龄分布和自然获得的抗疟疾免疫力持久性的机制和影响。

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.