Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 22, Pages 6277-6282Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1600488113
Keywords
malaria; Plasmodium vivax; Duffy Binding Protein; broadly neutralizing; epitopes
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Funding
- US Department of Energy [DE-AC02-05CH11231]
- Rheumatic Diseases Core Center [under National Institutes of Health (NIH)] [P30 AR048335]
- NIH [R56 AI080792, HHSN272201400018C, R01 AI064478, T32 AI007172]
- Burroughs Wellcome Fund [1013514]
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Plasmodium vivax Duffy Binding Protein (PvDBP) is the most promising vaccine candidate for P. vivax malaria. The polymorphic nature of PvDBP induces strain-specific immune responses, however, and the epitopes of broadly neutralizing antibodies are unknown. These features hamper the rational design of potent DBP-based vaccines and necessitate the identification of globally conserved epitopes. Using X-ray crystallography, small-angle X-ray scattering, hydrogen-deuterium exchange mass spectrometry, and mutational mapping, we have defined epitopes for three inhibitory mAbs (mAbs 2D10, 2H2, and 2C6) and one noninhibitory mAb (3D10) that engage DBP. These studies expand the currently known inhibitory epitope repertoire by establishing protective motifs in subdomain three outside the receptor-binding and dimerization residues of DBP, and introduce globally conserved protective targets. All of the epitopes are highly conserved among DBP alleles. The identification of broadly conserved epitopes of inhibitory antibodies provides critical motifs that should be retained in the next generation of potent vaccines for P. vivax malaria.
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