Immune Protection from Malaria: Age, Exposure Intensity, and the T Cell Response

尽管加大了控制力度，疟疾每年仍夺走100万人的生命。一种疟疾疫苗迫在眉睫 这是必要的，但由于我们对机制的了解有限，实现这一目标的进展受到阻碍 对疟疾的潜在免疫力和缺乏可靠的体外保护相关性。最近，试验性的 采用子孢子疫苗的挑战模型揭示了宿主防御机制的重要意义 对于保护性免疫，突出了疟疾特异性T细胞的关键作用。这些耐人寻味的结果表明 对不同免疫力个体队列中T细胞对疟疾反应的仔细研究 可提供对保护所需的免疫机制的洞察，为理性 疫苗的设计。然而，目前尚不清楚疫苗诱导的机制是否 免疫力与潜在的自然获得性免疫力是相同的。到目前为止，基于人口的研究 自然暴露的个体中的抗疟疾免疫没有产生明确和一致的免疫 保护的关联性，但这种努力因疟疾发病率的次优措施而受到阻碍 以及无法控制暴露强度和年龄的混杂。使用样本和数据 通过正在进行的ICEMR队列研究收集的数据，我们有一个独特的机会来执行详细的 纵向追踪大量儿童中疟疾特异性T细胞反应的分析 对疟疾发病率和家庭暴露强度进行仔细测量。这群人是 总部设在乌干达一个全年传播强度特别高的地区，包括儿童 6个月至10岁，跨越临床自然习得的发育期 免疫力通常是遵守的。建议的研究将利用多参数流式细胞术，基因 表达微阵列和多重细胞因子分析，以表征对疟疾和 确定这种反应与疟疾发病率之间的关系，控制年龄和 家庭水平的暴露强度。这些研究将极大地提高我们对收购的理解 儿童时期对疟疾的自然免疫力以及负责保护的免疫机制。

Despite expanding control efforts, malaria still claims >1 million lives each year. A malaria vaccine is urgently needed, but progress toward this goal has been hindered by our limited understanding of the mechanisms underlying immunity to malaria and a lack of reliable in vitro correlates of protection. Recently, experimental challenge models employing sporozoite vaccination have shed light on host defense mechanisms important for protective immunity, highlighting a critical role for malaria-specific T cells. These intriguing results suggest that careful study of the T cell response to malaria in cohorts of individuals with varying degrees of immunity may offer insight into the immune mechanisms required for protection, providing guidance for the rational design of vaccines. However, it is not known whether the mechanisms responsible for vaccine-induced immunity are identical to those underlying naturally acquired immunity. To date, population-based studies of antimalarial immunity among naturally exposed individuals have yielded no clear and consistent immune correlates of protection, but such efforts have been hindered by suboptimal measures of malaria incidence as well as the inability to control for confounding by exposure intensity and age. Using samples and data collected through an ongoing ICEMR cohort study, we have a unique opportunity to perform detailed analyses of malaria-specific T cell responses in a large cohort of children who will be followed longitudinally with careful measures of both malaria incidence and household-level exposure intensity. This cohort is based in a region of Uganda with exceptionally high year-round transmission intensity, and includes children 6 mos to 10 yrs of age, spanning the developmental period during which the natural acquisition of clinical immunity is normally observed. The proposed studies will utilize multiparameter flow cytometry, gene expression microarrays, and multiplex cytokine analysis to characterize the immune response to malaria and determine the relationship between this response and malaria incidence, controlling for both age and household-level exposure intensity. These studies will greatly enhance our understanding of the acquisition of natural immunity to malaria during childhood and the immune mechanisms responsible for protection.