Program for Resistance, Immunology, Surveillance & Modeling of Malaria in Uganda (PRISM) Renewal

摘要/摘要 疟疾仍然是最重要的全球卫生挑战之一，估计有2.15亿病例， 每年有43.8万人死亡。疟疾对撒哈拉以南非洲的影响尤为严重，那里88%的病例 90%的死亡发生在最近，控制干预措施的规模急剧扩大 减少非洲疟疾的负担。然而，进展并不均匀，事实上， 在负担最重的国家，如乌干达，进展最慢。我们的“棱镜”计划 总部设在乌干达，代表东非地区的国际疟疾卓越中心 研究网络。乌干达是高负担国家所面临挑战的象征， 监测系统不足以评估疟疾负担的趋势或监测 控制干预。通过PRISM，我们实施了一项全面的疟疾监测计划， 包括在三个地区加强基于卫生设施的监测和详细的纵向研究， 不同的传输强度。补充性的实验室研究包括监测 抗疟药物和杀虫剂抗药性以及疟疾暴露的血清学测量。这些研究 极大地提高了我们对乌干达疟疾流行病学和控制效果的认识， 干预措施。在这次更新申请中，我们建议继续我们疟疾监测的关键组成部分， 工作，但要扩大我们的范围，以解决更根本的问题之间的相互作用 寄生虫、蚊媒和人类宿主。将进行更深入的纵向评价， 将增加尖端分子研究，以更好地测量感染性叮咬的暴露;更敏感地 确定血流感染;表征影响感染的寄生虫、媒介和人类遗传因素， 疟疾;并评估这些因素对传染性和传播的影响。该计划将包括三个 研究项目以综合方式联系在一起，以最大限度地提高科学发现。研究项目1 （抗性项目）将使用在多个地点收集的样本， 药物和杀虫剂抗性的表型和基因型标记，并评估这些标记的影响 关于疟疾传播。研究项目2（流行病学项目）将使用队列的纵向样本 为了表征决定子孢子接种是否导致血液建立的因素 阶段感染和影响血液感染的持续时间、密度和临床后果的特征因素 分期感染研究项目3（传输项目）将使用队列样本来确定因素 与配子体的产生和发育有关，评估人类宿主对蚊子的感染性 载体，并表征人类传染性储库。这些高度相关的项目将在 在疟疾流行病学不同和人口水平不同的情况下， 在乌干达，需要提供优化控制和最终消除疟疾战略所需的信息。

Summary/Abstract Malaria remains one of the most important global health challenges, with an estimated 215 million cases and 438 thousand deaths each year. Malaria disproportionately affects sub-Saharan Africa, where 88% of cases and 90% of deaths occur. There has recently been a dramatic increase in the scale up of control interventions and reduction in the burden of malaria across Africa. However, progress has not been uniform, and in fact has been slowest in countries with the highest burden, such as Uganda. Our program called “PRISM” has been based in Uganda, representing the East African region for the International Centers of Excellence for Malaria Research network. Uganda is emblematic of the challenges faced by high burden countries, where routine surveillance systems are inadequate to assess trends in the burden of malaria or to monitor the impact of control interventions. Through PRISM we have implemented a comprehensive malaria surveillance program including enhanced health facility-based surveillance and detailed longitudinal studies in three regions with differing transmission intensities. Complementary laboratory-based studies include surveillance for markers of antimalarial drug and insecticide resistance and serologic measures of malaria exposure. These studies have greatly improved our understanding of the epidemiology of malaria in Uganda and of the impact of control interventions. In this renewal application we propose to continue key components of our malaria surveillance work, but to expand our scope to address more fundamental questions about interactions between the parasite, mosquito vector, and human host. More intensive longitudinal evaluations will be conducted and cutting edge molecular studies will be added to better measure exposure to infective bites; more sensitively identify bloodstream infections; characterize parasite, vector, and human genetic factors that impact on malaria; and assess impacts of these factors on infectivity and transmission. The program will consist of three research projects linked together in an integrated manner to maximize scientific discovery. Research project 1 (Resistance project) will use samples collected over time at multiple sites to characterize the evolution of phenotypic and genotypic markers of drug and insecticide resistance and assess the impacts of these markers on malaria transmission. Research project 2 (Epidemiology project) will use longitudinal samples from cohorts to characterize factors that determine whether sporozoite inoculation results in the establishment of blood stage infection and characterize factors affecting the duration, density, and clinical consequences of blood stage infections. Research project 3 (Transmission project) will use cohort samples to determine factors associated with gametocyte production and development, evaluate infectivity of the human host to mosquito vectors, and characterize the human infectious reservoir. These highly interrelated projects will be conducted in settings with varied malaria epidemiology and differing population level control intervention to provide critical information needed to optimize strategies for the control and ultimate elimination of malaria in Uganda.