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

摘要 在过去十年中，消除疟疾再次成为全球卫生议程的首要任务，大多数国家 设定在20年内实现无疟疾的目标。然而，主要障碍仍然存在，包括“获得 在已达到消除前状态但仍被正在进行的地区包围的地区， 传输随着这些地区接近消灭疟疾，它们往往“容易”从非洲重新引入疟疾。 附近的地区和“接受”，因为他们有合适的生态支持传播。桑给巴尔群岛 就是这些地区之一。尽管有强有力的病媒控制和有效的抗疟治疗， 由于靠近坦桑尼亚大陆，很难消灭。具体而言，消除疟疾的 群岛需要更好地了解进口的原因和地点， 促进本地传播的因素。这项提议将把基因组研究覆盖到正在进行的桑给巴尔 消除疟疾方案的被动监测和反应性病例检测活动， 确定岛屿上的输入性病例疫源地（目标1A），建立人类旅行、寄生虫 遗传学和输入（目标1B），确定指示病例的二次传播程度（目标2A）， 并显示RCD在检测指示病例和捕获寄生虫爆发方面的局限性（目标2B）。样本将 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。此外，本发明还 将加强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- 开展这项工作的目的是捕捉继发性无症状病例，包括那些感染但有先兆的病例。 感染者，以及在第一次RCD时尚未被受感染蚊子接种的人。我们将部署 新的高效高通量测序方法，能够对数千个样品进行基因分型， 全基因组基础这种策略比全基因组测序便宜得多，但仍然提供了 解决需要使用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输入的个人和社区风险因素，以及 影响由输入引起的本地传播程度的可干预风险因素。结合 地理空间数据的人类流动模式，我们将实现更深入的了解的驱动因素， 这将使ZAMEP能够在地方一级采取有针对性的干预措施。本研究 利用领先的学术机构之间现有的富有成效的合作（麻省理工学院，布朗，帝国， MUHAS）和ZAMEP解决世界卫生组织和其他组织最优先研究的问题。 指导疟疾研究的机构。由于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，我们希望完成这项建议中的目标， 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.