Does treating low density malaria infections reduce malaria transmission?

摘要 现在有强有力的证据表明，无症状携带者是南亚地区大部分疟疾传播的原因。 撒哈拉非洲占全球疟疾负担的95%。在高、低传输中均是如此 设置.在疟疾控制工作取得一些成功和传播下降的地区， 如果不针对无症状感染宿主进行干预，可能很难取得进一步进展。 自2018年以来，我们一直在坦桑尼亚沿海的巴加莫约农村地区工作， 水库和进行蚊子喂养研究，以更好地了解人与蚊子的传播， 低密度疟疾感染（LMI）。这项工作涉及直接皮肤喂养测定，以测量 > 500名儿童和成人对冈比亚按蚊的感染性，正在进行的分析 配子体血症和其他协变量与传播可能性（传染性）的关系， 蚊子感染率。现在，与加州大学旧金山弗朗西斯科和伊法卡拉大学合作， 卫生研究所，我们有机会利用这些数据来了解如何治疗LMI， 在儿童中定期发现活跃病例可导致配子体携带减少， 水库"坦桑尼亚儿童低密度疟疾感染（LMI）试验"（U01AI155315，PI：Hsiang 和Olotu）将评估治疗儿童LMI是否会对长期健康产生临床益处。两个多 2000年，巴加莫约区的200名儿童随机接受分子标记的疟疾活动病例检测， 将每年筛查3次（在一年两次的传播高峰期间和第二次结束时） 峰值），并接受抗疟治疗，如果阳性。他们也将遵循 每月一次，如果他们出现发烧，并在快速测试中呈阳性，则按照标准被动病例进行治疗 检测（PCD）。在对照组中，200名儿童将仅接受PCD。在这个项目中，我们将 从每月监测样本中测量配子体血症，以确定积极治疗的效果。 每个研究组中配子体患病率和配子体AUC（曲线下面积）的LMI（目标1）。以来 配子体携带的减少将不可避免地转化为个体间传递性的降低， 根据年龄、症状状态和季节性等因素，我们将使用来自巴加莫约皮肤饲料的数据 一个队列来模拟配子体血症的减少如何转化为人-蚊传播的减少 在两个研究组中（目标2）。我们假设，主动检测LMI病例将减少配子体携带 和儿童的传染性天数比单独PCD更大程度地减少。拟议工作 将量化使用超灵敏诊断积极检测和 治疗非洲儿童的LMI。研究结果对政策制定者来说很重要，并推动了努力背后的科学 以阻断传播并实现消灭疟疾。

ABSTRACT Evidence is now robust that asymptomatic carriers contribute to the bulk of malaria transmission in Sub- Saharan Africa, where 95% of the global malaria burden resides. This is true in both high and low transmission settings. In areas where malaria control efforts have achieved some success and transmission has declined, it may be hard to make further progress without interventions targeting the asymptomatic infectious reservoir. We have worked in rural Bagamoyo district in coastal Tanzania since 2018, characterizing the asymptomatic reservoir and performing mosquito feeding studies to better understand human-to-mosquito transmission from low density malaria infections (LMI). This work has involved direct skin feeding assays to measure the infectivity of > 500 children and adults to Anopheles gambiae, with ongoing analyses examining the relationship of gametocytemia and other covariates to the likelihood of transmission (infectiousness) and mosquito infection rates. Now, in conjunction with the University of California San Francisco and the Ifakara Health Institute, we have the opportunity to leverage this data to understand how treatment of LMI through periodic active case detection in children can lead to a reduction in gametocyte carriage and the infectious reservoir. The “Low-density malaria infection (LMI) trial among children in Tanzania” (U01AI155315, PI: Hsiang and Olotu) will assess whether treating LMI in children results in clinical benefits on long-term health. Over two years, 200 children in Bagamoyo district randomized to undergo malaria active case detection with molecular testing (ACDm) will be screened 3 times each year (during biannual transmission peaks and at end of second peak) using an ultrasensitive PCR, and receive antimalarial therapy if positive. They will also be followed monthly and treated if they present with fever and are positive on a rapid test, as per standard passive case detection (PCD). In the comparator arm, 200 children will receive PCD only. In this proposed project, we will measure gametocytemia from monthly surveillance samples to determine the effects of proactive treatment of LMI on gametocyte prevalence and gametocyte AUC (area under the curve) in each study arm (Aim 1). Since reductions in gametocyte carriage will variably translate into reduced transmissibility across individuals based on factors such as age, symptom status, and seasonality, we will use data from our Bagamoyo skin feed cohort to model how reductions in gametocytemia translates to a reduction in human-to-mosquito transmission in both study arms (Aim 2). We hypothesize that active case detection of LMI will reduce gametocyte carriage and days of infectiousness in children to a greater extent than that achieved by PCD alone. The proposed work will quantify the potential transmission-reducing benefit of using ultrasensitive diagnostics to actively detect and treat LMI in African children. Findings will be important to policymakers and advance the science behind efforts to interrupt transmission and achieve malaria elimination.