A novel CSP C-terminal epitope targeted by an antibody with protective activity against Plasmodium falciparum

<jats:p>Potent and durable vaccine responses will be required for control of malaria caused by <jats:italic>Plasmodium falciparum (Pf)</jats:italic>. RTS,S/AS01 is the first, and to date, the only vaccine that has demonstrated significant reduction of clinical and severe malaria in endemic cohorts in Phase 3 trials. Although the vaccine is protective, efficacy declines over time with kinetics paralleling the decline in antibody responses to the <jats:italic>Pf</jats:italic> circumsporozoite protein (<jats:italic>Pf</jats:italic>CSP). Although most attention has focused on antibodies to repeat motifs on <jats:italic>Pf</jats:italic>CSP, antibodies to other regions may play a role in protection. Here, we expressed and characterized seven monoclonal antibodies to the C-terminal domain of CSP (ctCSP) from volunteers immunized with RTS,S/AS01. Competition and crystal structure studies indicated that the antibodies target two different sites on opposite faces of ctCSP. One site contains a polymorphic region (denoted α-ctCSP) and has been previously characterized, whereas the second is a previously undescribed site on the conserved β-sheet face of the ctCSP (denoted β-ctCSP). Antibodies to the β-ctCSP site exhibited broad reactivity with a diverse panel of ctCSP peptides whose sequences were derived from field isolates of <jats:italic>P</jats:italic>. <jats:italic>falciparum</jats:italic> whereas antibodies to the α-ctCSP site showed very limited cross reactivity. Importantly, an antibody to the β-site demonstrated inhibition activity against malaria infection in a murine model. This study identifies a previously unidentified conserved epitope on CSP that could be targeted by prophylactic antibodies and exploited in structure-based vaccine design.</jats:p>