OVERALL RESEARCH STRATEGY ABSTRACT/SUMMARY Despite significant progress to reduce global malaria incidence and related deaths over the past 20 years, this positive trend is now in a state of decline. Data from 2021 indicated that the global milestones set out in WHO's global technical strategy for malaria 2016-30 (GTS) were not met, with both case and mortality targets being off track by 48%. Increasing insecticide and drug resistance, limited sensitivity of field diagnostic tools and declining investments are urgent contributory factors to the decline in coverage and effectiveness of routine control interventions. To date, the true contribution of non-falciparum malaria (NFM) – often presenting as asymptomatic infection – to the global disease burden remains underappreciated. While P. vivax (Pv) has risen in research priority over the past 10 years, research into the fundamental epidemiology and transmission dynamics of of P. ovale (Po wallikeri [Pow] and Po curtisi [Poc]) and P. malariae (Pm) has been largely neglected. Quantifying the asymptomatic malaria reservoir in human populations has been a priority topic for current ICEMR programs, yet deeper insight into this issue is elusive. A concurrent biological threat to malaria control is the invasion and spread of Anopheles stephensi Liston (AS) into the Horn of Africa and movement westward into Central and West Africa, presenting a serious concern to control efforts across the continent. Sympatric Pv and AS will change the dynamics of malaria control, as not only is AS a competent vector for Pf/Pv where both are endemic (e.g., South Asia), it has also demonstrated preference for similar breeding habitats as the urban dengue vector Aedes aegypti, risking a return of malaria into highly dense, urbanized cities and towns throughout SSA. How the expansion of AS to areas with different climates and ecologies will affect malaria transmission remains to be seen. Tackling existing obstacles to achieving global malaria elimination goals thus remains only partly, if not poorly addressed. The West-Central Africa Enhancing Malaria Epidemiology Research through Genomics & Translational Systems biology (Émergents [fr.]) ICEMR program leverages successful, well- established collaborations, unique advanced research and training infrastructures, and an extensive Sub- Saharan Africa (SSA) research network to address emerging and challenging issues in malaria transmission in the region. Émergents ICEMR is built on a proven research platform and consortium of World Bank, Wellcome Trust-, African Academy of Sciences-, and NIH/CDC-funded centers of excellence in Cameroon and Nigeria. This Émergents ICEMR program will focus research in Nigeria and Cameroon, proposing three interwoven programmatic packages (PP): PP1. Genomic Epidemiological Mapping (GEM) of non-falciparum malaria (NFM; Pv, Po, and P. malariae [Pm]) to quantify the parasite reservoir, measure transmissibility to mosquitoes and evaluate the insecticide resistance status of mosquitoes with NFM parasite infections; PP2. Bionomics, Ecology, & Control of An. stephensi (BECA) against the background of endemic primary and secondary anopheline vectors; PP3. Advancing Clinical and Entomological Surveillance (ACES) through emergent diagnostic and translational systems biology platforms to address emerging issues viz. asymptomatic malaria and non-falciparum malaria transmission in the context of Malaria Elimination and Eradication (MEE). To date, there has been no ICEMR program in the Central-West Africa nexus, which appears to be the leading edge of two new invasive species to Sub-Saharan Africa, namely Pv and An. stephensi in two bordering countries with high malaria burden (Nigeria and Cameroon). Émergents ICEMR directly fills this unmet public health vacuum. Considering the established network of collaborations westward to Ghana and southwards to the Democratic Republic of Congo, the Émergents ICEMR can serve as an effective springboard to support and advance malaria research and training in an expansive region representing diverse malaria burden, eco-epidemiological landscapes, and emerging risk to the invasive species.

OVERALL RESEARCH STRATEGY PROJECT NARRATIVE Increasing insecticide and drug resistance, limited sensitivity of field diagnostic tools and declining investments are urgent contributory factors to the decline in coverage and effectiveness of routine control interventions for malaria control and elimination. Moreover, the true contribution of non-falciparum malaria (NFM) – often presenting as asymptomatic infection – to the global disease burden remains underappreciated. The West- Central Africa Enhancing Malaria Epidemiology Research through Genomics & Translational Systems biology (Émergents [fr.]) ICEMR program is built on a proven research platform and consortium of World Bank, Wellcome Trust, African Academy of Sciences-, and NIH/CDC-funded centers of excellence in Cameroon and Nigeria, and will leverage this expertise to focus on (a) Genomic Epidemiological Mapping (GEM) of non-falciparum malaria (NFM) to quantify the parasite reservoir, measure transmissibility to mosquitoes and evaluate the insecticide resistance status of mosquitoes with NFM parasite infections; (b) Bionomics, Ecology, & Control of Anopheles stephensi (BECA) against the background of endemic primary and secondary anopheline vectors; and (c) Advancing Clinical and Entomological Surveillance (ACES) through emergent diagnostic and translational systems biology platforms to address emerging issues viz. asymptomatic malaria and non-falciparum malaria transmission.