Malaria Reservoir Study (MRS) II: reducing parasite diversity to break intervention resilience in Plasmodium falciparum populations at high endemicity

Malaria presents a significant health challenge in sub-Saharan Africa (SSA). It is a threat to US citizens in relation to health security, safe travel, missionary work and military operations. The relevance of malaria control and elimination in SSA to US economic opportunity and role in geopolitics cannot be underestimated. In SSA, a large fraction of the population across all ages harbors the malaria parasite Plasmodium falciparum without clinical manifestation, providing a vast infection reservoir for mosquito transmission. This asymptomatic reservoir is sustained by enormous antigenic diversity of the parasite. Our proposal addresses the hypothesis that progress toward falciparum malaria elimination should focus on reducing the number of antigenically diverse strains. Here we test this hypothesis in Ghana, a stable country in West Africa with a National Strategic Plan for malaria elimination including regions of economic and strategic importance to the US. Malaria Reservoir Study-II (MRS-II) takes advantage of enhanced intervention efforts in northern Ghana as major perturbations reducing the transmission reservoir, to address the sharp transition postulated by previous theory in both parasite diversity and infection prevalence with changes in transmission intensity. We test the importance of strain diversity to resilience of the transmission system, with a framework that combines longitudinal surveys of unprecedented depth with novel metrics for molecular surveillance of variant antigen diversity and computational models encompassing generalized and variant antigen immunity. Our three major inter-related aims are: (1) Field work for surveillance of enhanced interventions in two sites of northern Ghana differing in recent malaria control; (2) Characterization of the resilience of high-transmission systems to the major perturbation of targeted mass drug administration to children aged 3 months to 12 years in terms of changes in strain diversity; (3) Computational modeling to evaluate and predict dynamical responses to enhanced intervention in the context of the fundamental positive feedback between strain diversity and transmission intensity. The project will provide real world experience for US trainees in disease surveillance and control as well as training in quantitative tools for biomedicine. Quantitative characterization based on molecular surveillance, together with mathematical models that consider strain diversity and structure, will inform public health policy on the impact of control efforts in high-transmission regions. Current efforts are designed to reduce disease burden in children with no surveillance of the impact on the reservoir of asymptomatic infections in the community. MRS-II fills this significant gap in regions of northern Ghana with relevance to high-transmission areas of the Sahel in West Africa. More generally, our study aims to shift the paradigm in malaria epidemiology to make the parasite rather than the infected host the unit of measurement for evaluation of control and a target for elimination.