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Proc Natl Acad Sci U S A. 2016 May 31;113(22):6277-82. doi: 10.1073/pnas.1600488113. Epub 2016 May 18.

Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein.

Author information

1
Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110;
2
Department of Chemistry, Washington University School of Medicine in St. Louis, St. Louis, MO 63110;
3
Global Health Infectious Disease Research, Department of Global Health, College of Public Health, University of South Florida, Tampa, FL 33620;
4
Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110 tolia@wustl.edu.

Abstract

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.

KEYWORDS:

Duffy Binding Protein; Plasmodium vivax; broadly neutralizing; epitopes; malaria

PMID:
27194724
PMCID:
PMC4896725
DOI:
10.1073/pnas.1600488113
[Indexed for MEDLINE]
Free PMC Article

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