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

Moskovitz, R.; Burton, I.; Beutler, N.; Gonzalez-Paez, G.; Zalunardo, T.; Bick, M. V.; Ndihokubwayo, J.; Gambuzza, K.; Zhao, J.; Stanfield, R. L.; Zhu, X.; Jain, M.; Winzeler, E. A.; Emerling, D. E.; Ockenhouse, C. F.; MacGill, R. S.; Locke, E.; King, R. C.; Burton, D. R.; Rogers, T. F.; Hangartner, L.; Wilson, I. A.

doi:10.64898/2026.06.06.730512

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bioRxiv · 10.64898/2026.06.06.730512

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

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Abstract

The Plasmodium falciparum circumsporozoite protein (PfCSP) is the major surface antigen on Pf sporozoites. WHO-recommended vaccines RTS,S/AS01E and R21/Matrix-M target the PfCSP 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 {beta}-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 PfCSP epitopes modulated Fc-signaling and cellular cytotoxicity. This study provides a rationale for optimization of PfCSP-based immunogens to enhance Fc-mediated contributions to malaria vaccine efficacy.

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Moskovitz, R., Burton, I., Beutler, N., Gonzalez-Paez, G., Zalunardo, T., Bick, M. V., Ndihokubwayo, J., Gambuzza, K., Zhao, J., Stanfield, R. L., Zhu, X., Jain, M., Winzeler, E. A., Emerling, D. E., Ockenhouse, C. F., MacGill, R. S., Locke, E., King, R. C., Burton, D. R., Rogers, T. F., Hangartner, L., Wilson, I. A.. 2026-06-08. Structure and functional diversity of antibodies targeting the P. falciparum circumsporozoite protein C-terminal domain. https://doi.org/10.64898/2026.06.06.730512

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