Modelling the contribution of relapse infections to the epidemiology and control of Plasmodium vivax malaria

间日疟原虫是世界上分布最广泛的疟疾种类，有近30亿人生活在高危国家，估计每年有1亿至4亿临床病例，主要发生在亚洲和南美洲。尽管间日疟原虫给公共卫生带来了巨大负担，但与恶性疟原虫（导致非洲大多数疟疾病例的寄生虫物种）相比，间日疟原虫的研究被忽视了。间日疟的一个主要特征是复发性感染，在所有形式的疟疾中都没有见过，即感染者在从初次感染中恢复后几周到几个月再次感染。这种现象在从亚洲和南美回来的英国和欧洲游客身上偶尔会出现。尽管在旅行期间每天服用抗疟疾药片，一些旅行者在返回时仍会复发感染，并可能在一年后出现可能致命的临床疟疾发作。相比之下，生活在间日疟流行国家的人们经常发生复发感染。然而，在实践中，在世界上间日疟原虫持续传播的区域，很难将这些复发与蚊虫叮咬引起的新感染区分开来。复发性感染是由间日疟原虫引起的，这些寄生虫在肝脏中处于休眠状态，并在以后重新激活。复发感染的触发因素仍然知之甚少，解释范围从其他疾病引起的发烧，暴露于随后的蚊子叮咬，以及复发感染的生物钟。在这个项目中，我的目标是通过使用模拟模型来分析巴布亚新几内亚，所罗门群岛，泰国和巴西试验中暴露于间日疟原虫感染的大约4,000人的数据，探索导致感染复发的原因。随着感染复发的理解，我将开发一个模拟模型，研究间日疟原虫是如何在人与蚊子之间传播的，并利用这个模型来研究如何扩大疟疾控制干预措施，以控制或消除流行国家的间日疟原虫。间日疟原虫可以通过使用杀虫剂处理过的蚊帐来杀死受感染的蚊子，或者使用抗疟疾药物来杀死人体内的寄生虫来预防。大多数抗疟疾药物只针对血液阶段的感染，而不触及肝脏中的寄生虫。一个值得注意的例外是伯氨喹，它既针对血液中的寄生虫，也针对肝脏中休眠的寄生虫。一个世纪的疟疾控制经验表明，药物治疗和媒介控制可以减少间日疟原虫疟疾病例，然而，这些干预措施对人群水平传播的影响一直难以预测。我将使用间日疟原虫传播的模拟模型来比较针对寄生虫生命周期不同阶段的药物治疗方案如何通过防止进一步传播来保护受感染的个体和更广泛的社区。在国家疟疾控制规划努力加强间日疟控制并在某些情况下消除间日疟时，来自这些模型的见解将有助于为选择疟疾控制干预措施的最佳组合提供所需的证据基础。

Plasmodium vivax is the most widely distributed species of malaria across the world, with almost 3 billion people living in at-risk countries, and an estimated 100 - 400 million clinical cases every year, mostly in Asia and South America. Despite the enormous burden to public health, research into P. vivax is neglected compared to P. falciparum (the parasite species responsible for the majority of cases of malaria in Africa). A key feature of P. vivax malaria not seen in all forms of malaria is the occurrence of relapse infections, where infected individuals become re-infected weeks to months after recovering from their initial infection. This is a phenomenon occasionally seen in British and European travellers returning from Asia and South America. Despite taking daily anti-malarial tablets during their trip, some travellers suffer relapse infections upon their return and may experience a potentially fatal episode of clinical malaria, often up to a year later. In contrast, relapse infections are a regular occurrence for people living in countries with P. vivax malaria. However in practice, in regions of the world where P. vivax is continuously transmitted it is difficult to distinguish these relapses from new infections arising from mosquito bites.Relapse infections arise from P. vivax parasites that lie dormant in the liver and re-activate at a later date. The triggers for relapse infections are still poorly understood, with explanations ranging from fever due to other diseases, exposure to subsequent mosquito bites, and a biological clock for relapse infections. In this project, I aim to explore what causes infections to relapse by using simulation models to analyse data from approximately 4,000 people exposed to P. vivax infection in trials in Papua New Guinea, the Solomon Islands, Thailand and Brazil. With an understanding of how infections relapse, I will develop a simulation model of how P. vivax is transmitted between humans and mosquitoes, and use this to investigate how scaling up malaria control interventions can be used to control or eliminate P. vivax from endemic countries. P. vivax can be prevented by using insecticide treated nets to kill infected mosquitoes, or anti-malarial drugs to kill the parasites inside humans. Most anti-malarial drugs only target blood-stage infection and leave parasites in the liver untouched. A notable exception is primaquine which targets both parasites in the blood and dormant parasites in the liver. A century of experience of malaria control has shown that drug treatment and vector control reduce cases of P. vivax malaria, however the impact of these interventions on population level transmission has been difficult to predict. I will use a simulation model of the transmission of P. vivax to compare how treatment programmes with drugs targeting different stages in the parasite's lifecycle can protect the infected individual, and the wider community by preventing onward transmission. Insights from these models will contribute to the evidence base required to choose optimal combinations of malaria control interventions as national malaria control programmes strive for increased P. vivax control and in some cases, elimination.