Evolution of protective human antibodies against Plasmodium falciparum circumsporozoite protein repeat motifs

SUMMARYCircumsporozoite protein of the human malaria parasite Plasmodium falciparum (PfCSP) is the main target of antibodies that prevent the infection and disease. Protective antibodies recognize the central PfCSP domain, but our understanding of how parasite inhibition is associated with recognition of this domain and with the evolution of potent antibodies remains scattered. Here, we characterized the epitope specificity of 200 human monoclonal PfCSP antibodies. We show that the majority of PfCSP antibodies bind to NANP and NANP-like motifs with different preferences and define the molecular basis for recognition. Epitope cross-reactivity evolved with increasing antibody affinity around a conserved (N/D)P-NANP-N(V/A) core. High affinity to this motif, but not binding to NANP-like motifs, was associated with parasite inhibition and protection. Thus, NANP drives the development of potent PfCSP antibodies independently of their cross-reactivity profile, a finding with direct implications for the design of a second-generation PfCSP-based malaria vaccine.HIGHLIGHTSThe majority of human PfCSP antibodies recognize multiple epitopesNANP affinity maturation drives the evolution of cross-reactive PfCSP antibodiesPreferential PfCSP antibody binding to a conserved core motifHigh affinity not epitope specificity is associated with PfCSP antibody potency