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

DOI: 10.1038/s41564-019-0462-1 DOI Help

Authors: Thomas. A. Rawlinson (Jenner Institute, University of Oxford) , Natalie M. Barber (University of Oxford) , Franziska Mohring (London School of Hygiene and Tropical Medicine) , Jee Sun Cho (Jenner Institute, University of Oxford) , Varakorn Kosaisavee (Mahidol University) , Samuel F. Gerard (University of Oxford) , Daniel G. W. Alanine (Jenner Institute, University of Oxford) , Geneviève M. Labbé (Jenner Institute, University of Oxford) , Sean C. Elias (Jenner Institute, University of Oxford) , Sarah E. Silk (Jenner Institute, University of Oxford) , Doris Quinkert (Jenner Institute, University of Oxford) , Jing Jin (Jenner Institute, University of Oxford) , Jennifer M. Marshall (Jenner Institute, University of Oxford) , Ruth O. Payne (Jenner Institute, University of Oxford) , Angela M. Minassian (Jenner Institute, University of Oxford) , Bruce Russell (University of Otago) , Laurent Rénia (A*STAR) , François H. Nosten (University of Oxford; Mahidol University) , Robert W. Moon (London School of Hygiene and Tropical Medicine) , Matthew K. Higgins (University of Oxford) , Simon J. Draper (Jenner Institute, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Microbiology , VOL 6

State: Published (Approved)
Published: May 2019
Diamond Proposal Number(s): 18069

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 requiring interaction of the P. vivax Duffy binding protein (PvDBP) with its human receptor, the Duffy antigen receptor for chemokines. 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 P. vivax. Here, we isolated a panel of monoclonal antibodies from human volunteers immunized in a clinical vaccine trial of PvDBP. We screened their ability to prevent PvDBP from binding to the Duffy antigen receptor for chemokines, 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 P. vivax. This identified a broadly neutralizing human monoclonal antibody that inhibited invasion of all tested strains of P. vivax. Finally, we determined the structure of a complex of this antibody bound to PvDBP, indicating 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.

Journal Keywords: Humoral immunity; Parasitology; Vaccines; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography