The RH5-CyRPA-Ripr Complex as a Malaria Vaccine Target

Abstract

Despite ongoing efforts, a highly effective vaccine against Plasmodium falciparum remains elusive. Vaccines targeting the pre-erythrocytic stages of the P. falciparum life cycle are the most advanced to date, affording moderate levels of efficacy in field trials. However, the discovery that the members of the merozoite PfRH5-PfCyRPA-PfRipr (RCR) complex are capable of inducing strain-transcendent neutralizing antibodies has renewed enthusiasm for the possibility of preventing disease by targeting the parasite during the blood stage of infection. With Phase I/II clinical trials now underway using first-generation vaccines against PfRH5, and more on the horizon for PfCyRPA and PfRipr, this review explores the rationale and future potential of the RCR complex as a P. falciparum vaccine target.

Keywords: CyRPA; Plasmodium falciparum; RH5; Ripr; erythrocyte invasion; malaria vaccine.

Figure 1

Mapping the Critical PfRH5 Epitopes on the RCR Complex. (A) An illustration of the RCR complex binding basigin on the human erythrocyte based on the cryo-EM structure (EMD-9192, PDB: 6MPV) and crystal structure of PfRH5:basigin (PDB: 4U0Q). (B) RCR bound to basigin. (C) RCR binding basigin-blocking Fabs QA1 (PDB: 4U1G) and R5.004 (PDB: 6RCU). (D) RCR bound to basigin proximal Fabs R5.016 (PDB: 6RCU) and 9AD4 (PDB: 4U0R). (E) RCR bound to synergistic noninhibitory Fab R5.011 (PDB: 6RCV). The basigin binding site on PfRH5 has been coloured blue where basigin is absent in the lower panels. Figure produced using Chimera [87]. Abbreviations: cryo-EM, cryoelectron microscopy; RCR, PfRH5-PfCyRPA-PfRipr; PDB, protein data bank.

Figure 2

Mapping the Critical PfCyRPA Epitopes on the RCR Complex Bound to Basigin. PDB IDs: RCR complex (6MPV), PfRH5:basigin (PDB: 4U0Q), PfCyRPA:c12 Fab (PDB: 5EZO), and PfCyRPA:8A7 Fab (PDB: 5TIH). Figure produced using Chimera [87]. Abbreviations: RCR, PfRH5-PfCyRPA-PfRipr; PDB, protein data bank.