Xiao, X.; Zhou, Q.; Marapana, D. F.; McLean, T. C.; Chan, R. W. B.; Shakeel, S.; Leis, A.; Lim, P. S.; Jung, N. C.; Naung, M.; Lopaticki, S.; Dixon, M. W. A.; Barry, A. E.; Cowman, A. F.; Scally, S. W.

Plasmodium falciparum causes the majority of severe malaria, and merozoite invasion of erythrocytes is a vulnerable, antibody-accessible step of the blood-stage cycle. PfRipr is an essential component of the PCRCR invasion complex, yet the structural basis for antibody-mediated neutralisation remains unclear. Here, we map inhibitory and non-inhibitory epitopes across PfRipr and show that all potent inhibitors localise to the tail region (EGF6-8). Crystal structures reveal that inhibitory antibodies restrict the flexibility surrounding EGF7. Indeed, EGF7 buried surface area correlates strongly with inhibitory potency, identifying this domain as the principal invasion inhibitory determinant. Pairwise antibody combinations revealed unexpected synergy, with non-inhibitory mAbs potentiating anti-Rh5 activity. Conditional deletion, sequence replacement or positional swapping of EGF6-8 abolished invasion, demonstrating that both sequence and spatial arrangement are indispensable. These data define EGF7 as a conserved, functionally essential vulnerability and provide a blueprint for rational EGF6-8 immunogen design capable of eliciting P. falciparum strain-transcending protection against blood-stage malaria.