New preprint! Structural basis for synergistic antibody protection against the essential malaria invasion complex protein RIPR

New preprint! Structural basis for synergistic antibody protection against the essential malaria invasion complex protein RIPR

12 January 2026

We're very excited to share our latest pre-print where we unpick the structural basis for synergistic antibody protection against the malaria vaccine candidate RIPR. 

Plasmodium falciparum invades red-blood cells through a complex series of interactions, many of which are redundant. A notable exception is the parasite’s RH5 protein which forms an essential, non-redundant interaction with basigin (BSG/CD147). RH5 forms a hetero-pentameric complex with CyRPA, RIPR, PTRAMP, and CSS, collectively referred to as the “PCRCR-complex”. Each component of this complex is essential for merozoite invasion and therefore represents a promising vaccine target. We have previously identified RIPREGF (5-8) as the target of neutralising anti-RIPR antibodies, and developed a new blood-sage malaria, “R78C”, which comprises RIPR epidermal growth factor (EGF)-like domains 7-8 (RIPREGF (7-8)) fused to CyRPA1. However, no potent anti-RIPR monoclonals have been identified and the mechanisms by which anti-RIPR antibodies inhibit parasite invasion remained unclear.

In this new work2, we investigate a panel of 83 human IgG mAbs from RIPR-vaccinated Kymouse platform mice. We show that single mAbs have minimal neutralising activity, whereas pools of antibodies targeting the RIPR-Tail region work together to interfere malaria invasion. In collaboration with the Scripps Institute, and the Oxford Protein Informatics group; we combined a comprehensive mAb neutralisation screen, single-particle Cryo-EM (image below), and course-grained molecular dynamics simulations. Together, these approaches reveal that cooperative binding of mAbs restricts RIPR-Tail conformations and disrupts essential protein–protein interactions. Finally, we demonstrate that the addition of a number of RIPR domains may improve the R78C vaccine leading to a next generation blood stage vaccine.

Read the new pre-print on VeriXiv!

 

 

1. Williams, B. G., King, L. D., Pulido, D., Quinkert, D., Lias, A. M., Silk, S. E., ... & Draper, S. J. (2024). Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex. Nature Communications, 15(1), 4857.
2. Williams BG, Barrett JR, Bartholdson Scott J et al. Structural basis for synergistic antibody protection against the essential malaria invasion complex protein RIPR [version 1]. VeriXiv 2025, 2:434 (https://doi.org/10.12688/verixiv.2585.1)