Brendan Farrell

Dynamic hinge-motion of PfRIPR revealed by malaria invasion inhibitory antibodies The PfPCRCR complex is essential for invasion of human erythrocytes by the deadliest malaria parasite, Plasmodium falciparum . Antibodies against each subunit of PfPCRCR prevent erythrocyte invasion and the PfRH5 component is currently the most advanced blood-stage malaria vaccine. Central within PfPCRCR is PfRIPR. This complex molecule contains a core and a flexible tail and allows PfPCRCR to bridge the parasite and erythrocyte during invasion. In this study, we generated a small panel of human monoclonal antibodies against PfRIPR. We structurally characterised four PfRIPR tail-binding antibodies in complex with PfRIPR fragments. We show that growth-inhibitory antibody RP.012 induces a kink in the PfRIPR tail while non-inhibitory antibodies do not. Furthermore, we show that these four antibodies modulate each other, either through antagonism or by acting synergistically. These studies have implications for the design of PfRIPR-based vaccine immunogens and indicate that the tail of PfRIPR undergoes essential conformational changes during erythrocyte invasion. ### Competing Interest Statement J.T., A.C., and L.T.W. are coinventors on a provisional patent filed on the human mAbs described in this study (63/777,850). The other authors have no competing interests. Wellcome Trust, https://ror.org/029chgv08, 220797/Z/20/Z Medical Research Council, MR/Z505687/1 Gates Foundation, INV-078815

A lovely collaboration with Josh Tan's group at NIH. Thanks to everyone on the team for their hard work!

Read our preprint here:
www.biorxiv.org/content/10.6...

How do antibodies against PfRIPR act to impede erythrocyte invasion? In our latest study, we isolate and structurally characterise a panel of human antibodies and the growth inhibitory antibody RP.012, revealing an unexpected story of synergy and antagonism that has consequences for vaccine design.

Erythrocyte invasion in malaria: from molecular mechanisms to rational vaccines Nature Reviews Microbiology, Published online: 15 September 2025; doi:10.1038/s41579-025-01235-1If erythrocyte invasion is blocked during the blood stage of infection by Plasmodium parasites, malaria can be prevented. In this Review, structural insights on erythrocyte invasion by the merozoite form of Plasmodium are discussed in the context of rational design of a blood-stage malaria vaccine.

New online! Erythrocyte invasion in malaria: from molecular mechanisms to rational vaccines

Extremely happy to share the first paper of my postdoc work with @parasitematt.

It is the product of a great collaboration with Akihito Sakoguchi, Hisashi Arase and Shiroh Iwanaga at Osaka University as well as Marcus Widdess and Mike Dustin here in Oxford.

rdcu.be/eqx2J

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