Structural basis for inhibition of Plasmodium vivax invasion by a broadly neutralizing vaccine-induced human antibody

Abstract

The most widespread form of malaria is caused by Plasmodium vivax. To replicate, this parasite must invade immature red blood cells, through a process which requires interaction of the Plasmodium vivax Duffy binding protein, PvDBP with its human receptor, the Duffy antigen receptor for chemokines, DARC. Naturally acquired antibodies that inhibit this interaction associate with clinical immunity, suggesting PvDBP as a leading candidate for inclusion in a vaccine to prevent malaria due to Plasmodium vivax. Here, we isolated a panel of monoclonal antibodies from human volunteers immunised in the first clinical vaccine trial of PvDBP. We screened their ability to prevent PvDBP from binding to DARC, and their capacity to block red blood cell invasion by a transgenic Plasmodium knowlesi parasite genetically modified to express PvDBP and to prevent reticulocyte invasion by multiple clinical isolates of Plasmodium vivax. This identified a broadly neutralising human monoclonal antibody which inhibited invasion of all tested strains of Plasmodium vivax. Finally, we determined the structure of a complex of this antibody bound to PvDBP, revealing the molecular basis for inhibition. These findings will guide future vaccine design strategies and open up possibilities for testing the prophylactic use of such an antibody.

A Humanized Mouse Model for Plasmodium vivax to Test Interventions that Block Liver Stage to Blood Stage Transition and Blood Stage Infection

“…In a recent study, ten human monoclonal antibodies (mAbs) from a PvDBP-immunized volunteer were cloned and tested for their blocking activity using the DBP-DARC interaction. One mAb potently inhibited invasion in vitro using P. knowlesi parasites expressing P. vivax DBP ( Rawlinson et al., 2019 ).…”

Malaria vaccines since 2000: progress, priorities, products

“…Both candidates induced strain-transcending functional antibodies measured in vitro. Using human mAbs generated through vaccination or natural vivax exposure, structural studies have identified functional and non-functional epitopes that will provide a rational basis to improve the design of PvDBP immunogens 103,104 .…”

Hotspots in Plasmodium and RBC Receptor-Ligand Interactions: Key Pieces for Inhibiting Malarial Parasite Invasion

“…mAb 2C6 epitope: 265 K – F 486 (dark green box), highlighting critical contact residues. mAb DB9 epitope: 476 D – E 503 (magenta box), highlighting critical contact residues [ 33 ]. mAb 3C9 epitope: 476 D – E 493 (green box), highlighting critical contact residues [ 55 ] HARBPs 1635: 398 R – G 417 (purple), 1637: 438 S – F 457 (light green) and 1639: 478 L –R 497 (apricot) located in neutralizing epitopes’ SD3 region [ 56 ].…”

“…Critical interaction regions between parasite ligands and host cell receptors have been defined from the structures of two of the most important Plasmodium species worldwide: P. falciparum and P. vivax . This has also enabled identifying functional and non-functional epitopes from ligand-neutralizing and/or inhibitory antibody (Ab) complexes [ 29 , 30 , 32 , 33 ]. Combining both approaches (receptor-ligand and antigen-antibody) highlights small ligand regions which are critical for parasite invasion, i.e., hotspots; these can be used for the rational design of future vaccines components or treatment against malaria infection.…”