Abstract Malaria remains a great public health challenge that has resisted world-wide control efforts. The malaria parasite's intracellular life-cycle inside red blood cells (RBC) and its ability for antigenic variation have thwarted vaccine development. Immunity to malaria is short-lived and requires constant exposure to the parasite. Naturally acquired immunity is gained by residents in malaria endemic areas, which protects them from severe malaria and reduces the risk of reinfection. All adaptive arms of the immune system, namely T and B cells can contribute to clinical immunity against different stages of the parasite cycle, both in humans and in mouse models of malaria. Passive transfer of serum from clinically immune individual can protect susceptible patients, establishing the importance to antibody responses in protection. Yet, how protective antibody responses are achieved is unknown. Current vaccines against the deadliest form of the malaria parasite, Plasmodium falciparum (Pf), are only partially protective and confer only limited protection over time. This proposal builds on the study of a cohort of African patients that allowed us to capture varied levels of clinical immunity. Using high throughput unsupervised analysis of peripheral blood mononuclear cells and plasma from clinically protected versus susceptible patients, we discovered the presence of an expanded subset of memory CD4+ T cells. Frequencies of these cells also correlated with higher plasma parasite-specific opsonizing Abs. We hypothesize that the memory CD4+ T cells are essential for long-lived immunity against malaria by promoting optimal protective Ab responses. The current proposal will explore the functional attributes of these memory CD4+ T cells and establish the characteristics of these highly protective Abs that develop in clinically protected patients.