Program for Resistance, Immunology, Surveillance & Modeling of Malaria in Uganda

描述（由申请人提供）：尽管扩大了控制努力，但疟疾每年仍夺去100多万人的生命。迫切需要疟疾疫苗，但由于我们对疟疾免疫机制的了解有限以及缺乏可靠的体外保护相关物，这一目标的进展受到阻碍。最近，采用子孢子疫苗接种的实验性攻击模型揭示了对保护性免疫重要的宿主防御机制，突出了疟疾特异性T细胞的关键作用。这些有趣的结果表明，在具有不同免疫力的人群中仔细研究T细胞对疟疾的反应可能会深入了解保护所需的免疫机制，为疫苗的合理设计提供指导。但不 目前还不清楚疫苗诱导免疫的机制是否与自然获得性免疫的机制相同。迄今为止，在自然接触人群中进行的抗疟免疫研究没有得出明确和一致的免疫保护相关性，但这种努力受到疟疾发病率的次优措施以及无法控制接触强度和年龄的混淆的阻碍。使用通过正在进行的ICEMR队列研究收集的样本和数据，我们有一个独特的机会对一个大型儿童队列中的疟疾特异性T细胞反应进行详细分析，这些儿童将被纵向跟踪，并仔细测量疟疾发病率和家庭水平的暴露强度。这一队列是基于乌干达的一个地区，具有非常高的全年传播强度，包括儿童6个月。至10岁，跨越发育期，在此期间通常观察到临床免疫的自然获得。拟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来表征对疟疾的免疫反应，并确定这种反应与疟疾发病率之间的关系，同时控制年龄和家庭一级的接触强度。这些研究将大大提高我们对儿童期获得疟疾天然免疫力以及负责保护的免疫机制的理解。

DESCRIPTION (provided by applicant): 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.