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Advances in high-throughput isolation of neutralizing human monoclonal antibodies (mAbs) have enabled development of mAb-based therapeutics for many viruses (e.g., HIV-1, Ebola, SARS-CoV-2). This approach has recently been applied to isolate antimalarial human mAbs against the Plasmodium falciparum circumsporozoite protein (CSP) on sporozoites (SPZ) and reticulocyte-binding protein homolog 5 (RH5) on merozoites (MZ). CSP and RH5 are leading malaria vaccine targets because they are respectively required for the SPZ and MZ stages of malaria parasites to invade host hepatocytes and erythrocytes. CSP has three domains: an N-terminus, a central region composed of repeating NPDP/NVDP/NANP tetrapeptides, and a C-terminus. A truncated form of CSP containing 19 NANP repeats and the C-terminus is the antigenic target of the world's only approved malaria vaccine (RTS,S). RTS,S formulated with the adjuvant AS01 elicited protective CSP antibodies but was only 30-50% effective at preventing malaria in a phase III trial. The focus of this Thesis is the isolation of potent human mAbs that bind new sites of vulnerability on CSP (and RH5) in order to facilitate clinical development of promising antimalarial mAbs and improve designs of vaccines targeting these antigens. Here, and in a Report featured on the cover of Immunity, I describe the first human NVDP-specific CSP mAb (L9) that preferentially binds two adjacent NVDP repeats while cross-reacting with NANP repeats. L9 was more potently protective against SPZ challenge in mice than seven published neutralizing human NPDP- and NANP-specific CSP mAbs. Isothermal titration calorimetry and multiphoton microscopy showed that L9 and the other most protective mAbs bound CSP with a unique "two-step" binding phenotype and mediated protection by killing SPZ in the liver and preventing their egress from sinusoids to invade hepatocytes. This study defined the subdominant NVDP repeats as protective CSP epitopes not included in RTS,S, identified an in vitro correlate of mAb-mediated SPZ neutralization, and showed that the liver is an important site for CSP-specific antibodies to prevent malaria. Based on its high potency, a half-life extended version of L9 (L9LS) was clinically developed and completed Phase I testing at the NIH in December 2021 (NCT05019729). Here, and in a Report published in Cell Reports, I show that L9 lineage B cells have baseline NVDP affinity and evolve to acquire NANP reactivity. Pairing the L9 light chain with clonally-related heavy chains resulted in chimeric mAbs that preferentially bound two adjacent NVDP with high affinity, cross-reacted with NANP, and more potently neutralized SPZ compared to their original light chain. X-ray crystal structures of these chimeric mAbs revealed that they bound NANP and NVDP in a similar type-1 β-turn. These data provide insight into the ontogeny and binding mechanisms of the potent NVDP-specific mAb L9 and suggest that RTS,S might be improved by presenting ≥2 adjacent NVDP minor repeats. Here, and in a Research Article published in PLOS Pathogens, I demonstrate that combining two neutralizing "repeat" mAbs against the NPDP/NVDP/NANP tetrapeptides in the central repeat region of CSP, or combining a repeat mAb with mAbs against the C-terminus of CSP, did not provide improved protection against SPZ challenge in mice compared to a single repeat mAb. However, passive transfer of a repeat mAb (e.g., L9) into mice immunized with a RTS,S-like vaccine (which induces polyclonal antibodies against the repeat region and C-terminus of CSP) provided superior protection compared to the mAb or vaccine alone. These data show that, while combining two mAbs against the repeat region and C-terminus of CSP was ineffective at enhancing SPZ neutralization in vivo, protection was enhanced when a mAb was combined with vaccine-induced polyclonal antibodies. Given that RTS,S was recently recommended for widespread usage by the World Health Organization and CSP mAbs like L9 are scheduled to begin Phase II testing in Africa in 2022, these data suggest that combining RTS,S vaccination with passive transfer of potent CSP mAbs should provide even greater protection against malaria. Additionally, I isolated a panel of >200 human mAbs against RH5 (and its two accessory proteins, CyRPA and Ripr) from naturally infected subjects living in a malaria endemic region of Mali and from naïve subjects in the UK immunized with a RH5 vaccine. Only one study has reported the isolation of 17 RH5 human mAbs, while no CyRPA and Ripr human mAbs have been isolated to date. Determination of the epitopes bound by these mAbs, as well as their potency, is ongoing. If a potent RH5-CyRPA-Ripr-specific mAb is identified, it can potentially be combined with L9 in a multi-stage antimalarial mAb cocktail against both SPZ and MZ.