Importation and transmission of malaria in Zanzibar: a case study for elimination

摘要 在过去十年中，消除疟疾再次出现在全球卫生议程的首位，大多数国家 制定在20年内实现无疟疾的目标。然而，主要障碍依然存在，包括“达到 在已达到消除前状态但仍被正在进行的区域包围的区域为零 变速箱。随着这些地区接近消灭，它们往往“容易”再次感染疟疾。 附近地区和“接受者”，因为他们有正确的生态支持传播。桑给巴尔群岛 是这些地区中的一个。尽管有强有力的媒介控制和获得有效的抗疟疾治疗，但其 由于靠近坦桑尼亚大陆，消灭埃博拉病毒非常困难。具体地说，在全球消除疟疾 群岛需要更好地了解为什么以及在哪里发生进口，并理解 促进本地传播的因素。这项提案将在桑给巴尔继续进行基因组研究 消除疟疾计划(ZAMEP)被动监测和反应性病例发现(RCD)活动 确定岛屿上输入病例的疫源地(目标1A)，模拟人类旅行和寄生虫之间的关系 遗传和输入(目标1B)，根据指征病例确定二次传播的程度(目标2A)， 并显示了RCD在检测指示病例和捕获寄生虫暴发方面的局限性(目标2B)。样品将 从该群岛的每一个报告病例和坦桑尼亚大陆的10个地点收集。另外， 增强的RCD-在1周和4周后对报告的指示病例周围的家庭进行筛查-将 为捕获继发性无症状病例，包括那些感染但有专利前期的病例而进行 感染，以及在第一次RCD时尚未接种受感染蚊子的病例。我们将部署 新的高效高通量测序方法，使数千个样本能够在 全基因组的基础上。这种策略比全基因组测序便宜得多，但仍然提供了 解决方案需要使用逐个血统分析来推断高度相关的寄生虫之间的关系。 这些方法将使我们能够确定个人和社区的进口风险因素，以及 影响由进口引起的本地传播程度的可干预的风险因素。与 有关人类活动模式的地理空间数据，我们将对驱动因素有更深入的了解 输入和二次传播，这将使ZAMEP能够在地方一级量身定制干预措施。本研究 利用领先学术机构(北卡罗来纳大学、布朗大学、帝国理工学院、 MUHAS)和ZAMEP解决被列为世卫组织和其他组织最高研究优先事项的问题 指导疟疾研究的机构。因为所有疟疾流行国家都将面临疟疾的最后一英里 消除，无论是现在还是将来，我们预计这项提议中的目标的完成将有直接的 对全球疟疾政策的影响。

ABSTRACT Over the past decade, malaria elimination has re-emerged atop the global health agenda, with most countries setting goals to be malaria-free within two decades. However, major obstacles remain, including “getting to zero” in regions that have achieved pre-elimination status but remain surrounded by areas of ongoing transmission. As these regions near elimination, they are often “vulnerable” to re-introduction of malaria from nearby areas and “receptive” as they have the right ecology to support transmission. The Zanzibar Archipelago is one of these regions. Despite robust vector control and access to efficacious antimalarial treatment, its proximity to mainland Tanzania has made elimination difficult. Specifically, eliminating malaria on the archipelago requires a better understanding of why and where importation is occurring and understanding the factors that promote local transmission. This proposal will overlay genomic studies onto ongoing Zanzibar Malaria Elimination Program (ZAMEP) passive surveillance and reactive case detection (RCD) activities to identify foci of imported cases on the islands (Aim 1A), model the relationship between human travel, parasite genetics and importation (Aim 1B), determine the extent of secondary transmission from index cases (Aim 2A), and show the limits of RCD in detecting index cases and capturing parasite outbreaks (Aim 2B). Samples will be collected from every reported case on the archipelago and 10 sites on mainland Tanzania. Additionally, enhanced RCD - screening households surrounding a reported index case, both 1 and 4 weeks later - will be carried out in order to capture secondary asymptomatic cases, including those infected but with prepatent infection, as well as those yet to be inoculated by infected mosquitoes at the time of first RCD. We will deploy novel efficient high throughput sequencing methods that enable genotyping of thousands of samples on a genome-wide basis. This strategy is much cheaper than whole genome sequencing but still provides the resolution needed to use identity-by-descent analyses to infer relationships between highly related parasites. These methods will allow us to define individual and community risk factors for importation, as well as intervenable risk factors that impact the extent of local transmission arising from importation. Combined with geospatial data on human mobility patterns, we will achieve a deeper understanding of the drivers of importation and secondary transmission that will allow ZAMEP to tailor interventions at a local level. This study leverages an existing productive collaboration between leading academic institutions (UNC, Brown, Imperial, MUHAS) and ZAMEP to tackle questions cited amongst the highest research priorities for the WHO and other bodies that guide malaria research. As all malaria endemic countries will face the last mile of malaria elimination, whether now or in the future, we expect completion of the aims in this proposal to have a direct impact on global malaria policies.