Structure and functional diversity of antibodies targeting the P. falciparum circumsporozoite protein C-terminal domain

The Plasmodium falciparum circumsporozoite protein ( Pf CSP) is the major surface antigen on Pf sporozoites. WHO-recommended vaccines RTS,S/AS01 _E and R21/Matrix-M target the Pf CSP major repeat region and C-terminal domain (ctCSP). Although multiple studies associated protection with antibody responses to ctCSP, only a few ctCSP-specific monoclonal antibodies (mAbs) have been characterized. Here, crystal structures of 11 Fab-ctCSP complexes reveal how mAbs against the conserved β-epitope region achieve diverse modes of strain-transcending recognition, in contrast to mAbs to the hypervariable ⍺-epitope. Consistent with previous studies, ctCSP on sporozoites could be unmasked by mAbs that bind CSP repeats, with unmasking dependent on the mAb fine-specificity and binding mode. In vitro, ctCSP mAbs promoted stronger Fc-receptor signaling, cellular cytotoxicity, and phagocytosis than repeat region mAbs, while mAb combinations targeting distinct Pf CSP epitopes modulated Fc-signaling and cellular cytotoxicity. This study provides a rationale for optimization of Pf CSP-based immunogens to enhance Fc-mediated contributions to malaria vaccine efficacy.