ABSTRACT Despite significant gains in the control of Plasmodium falciparum (PF) globally, Plasmodium ovale (PO) and Plasmodium vivax (PV) may be expanding to fill the niche left behind. These malaria species are more difficult to control due to early commitment to transmissible life cycle stages (gametocytes), allowing transmission prior to treatment, and by the formation of dormant liver stages (hypnozoites) which are resistant to blood stage antimalarial drugs and can cause recurrent infection at a later date (relapse). PO and PV are more prevalent in Africa than previously recognized. PO, known to be endemic, is a rising cause of malaria infections in multiple countries. PV, long thought absent from Africa, has persisted despite the dogma that the lack of Duffy protein, the main red cell (RBC) invasion ligand, renders Africans immune to infection. Despite the growing evidence of their increased burden, almost nothing is known about key biologic parameters that govern PO and PV transmission in Africa. Largely due to the lack of field diagnostics and molecular tools, studies of PO and PV in most of Africa have almost exclusively been limited to cross-sectional prevalence surveys or convenience sampling from clinics, without any attempt to gain a deeper understanding of the basic transmission biology and relapse patterns of these species. This proposal leverages technical advances in the field, including field deployable molecular diagnostics, high throughput genotyping and single cell sequencing, to provide the first robust studies of these fundamental knowledge gaps in PO and PV biology in Africa. Through community and clinic-based surveillance, we will identify PO and PV infected individuals in Dschang Cameroon, a site co- endemic for all 4 major species of human malaria in Africa and which has the most extensive epidemiologic data concerning PV infection in Central Africa. By combining human, vector and genomic studies, the proposal will provide key information about transmission biology (Aim 1), relapse patterns (Aim 2) and, for PV, the ability to overcome the mechanisms that restrict RBC invasion (Aim 3). Filling in these gaps will lead to the design of more appropriate interventions for relapsing malaria by defining the infectious reservoir and the contribution of relapse to the reservoir (Aim 1A, 2A and 2B), as well as defining vectors for targeted intervention (Aim 1B). This work will provide insight into the mechanisms by which PV and PO in Africa may prove resilient in the face of continued elimination efforts targeting PF and at the same time generate tools (e.g. point-of-care diagnostics and diversity markers) to track these species. Together, these findings will help shape the design of new malaria control strategies for relapsing malarias.