Spatial Scales of Plasmodium Falciparum Generations; Implications for Elimination

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Project Summary Malaria is a major public health problem, with an estimated 198 million cases occurring world-wide in 2013. Effective strategies to reduce malaria transmission and disease have been highly successful leading to a 40% reduction in malaria cases in sub-Saharan Africa since 2000. It has been observed that infections cluster geographically and such clustering becomes more pronounced as transmission declines. The science of identifying `hotspots' of infection or foci of transmission is a growing area that promises to help target interventions more effectively. However, it has not been shown whether infected individuals in close physical proximity (i.e. in the same household) are jointly infected due to simply living in a risky place, or because an infected household member is a risk factor for nearby susceptible individuals. If the former, then targeting hotspots should focus on reducing environmental risk factors in the area around a hotpsot. If the latter, then interventions to identify and treat `transmitters' will reduce transmission and reduce the incidence of new cases. Therefore, we need to understand the spatial scale of malaria transmission to predict the impact of community case detection and hotspot targeting. To shed light on this important issue, we propose two scientific objectives. First, we will measure the genetic relatedness of infections within the same household compared to the relatedness of infections at further distances. We will determine whether this relationship differs in fever `hotspots' (geographic clusters of high fever incidence) and fever `coldspots'. Parasite DNA from dried blood spots collected from a moderate endemic study area in western Kenya (approximately 15 km by 28 km encompassing more than 80 villages) will be sequenced at a moderately polymorphic gene using deep sequencing techniques. This will provide evidence for local, focal transmission if nearby infections are more closely related or will point to mixed transmission whereby infections only begin to differ as you reach the distance of mosquito flying ranges. Our second objective is to trap malaria mosquito vectors and identify infected mosquitoes. We will determine the source of the mosquito's infection by sequencing parasites in the mosquito salivary glands and comparing to parasite genotypes in humans. By doing so, we can find out whether infections are being transmitted at a household scale or transmission is `well mixed' geographically and only limited by the range of the mosquito. If successful, this will be the first report of linking individual infections in mosquitoes to their human source. The ability to track infections from human to mosquito and back again would allow us to understand the dynamics and scale of transmission in a way that has not previously been possible. We expect to scale up this approach to larger populations in subsequent studies. These results will provide insight into the expected impact of interventions designed to target hotspots.