Does treating low density malaria infections reduce malaria transmission?

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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.