Malaria is a complex, mosquito-borne disease estimated to cause over 300,000 childhood deaths annually. Plasmodium falciparum (Pf), the major parasite causative of malaria, accounts for over 85% of malaria mortality, and demonstrates considerable resistance to current drug therapies. It is therefore imperative to develop a vaccine to Pf to reduce malaria morbidity and mortality. Reverse vaccinology holds promise to design effective immunogens for the development of malaria vaccines. This concept is based on interrogating the B cell repertoire of infected or vaccinated subjects to identify inhibiting antibodies that will guide immunogen design. The circumsporozoite protein (CSP) is the major surface antigen of Pf sporozoites and a leading malaria vaccine antigen. Here, we structurally and functionally characterized protective and non-protective antibodies to PfCSP from four healthy adults living in the malaria-endemic area of Lambaréné, Gabon, and from eight vaccinated European donors who underwent immunizations with aseptic, purified, cryopreserved Pf sporozoites (PfSPZ Challenge) under chloroquine prophylaxis (PfSPZ-CVac), which resulted in protection against controlled human malaria infection. Our structural delineation of protective and non-protective epitopes highlights key differences of B cell responses during natural exposure and vaccination. We provide the molecular mechanism underlying clonal selection and affinity maturation of human B cells expressing protective antibodies. Finally, we describe at the atomic level the evolution of protective human antibodies against the PfCSP repeat motifs. Collectively, these data provide the blueprints to engineer optimized antigens that can be tested as pre-erythrocytic subunit vaccines.