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Design and immunogenicity of a novel synthetic antigen based on the ligand domain of the Plasmodium vivax duffy binding protein.

Abstract

The Duffy binding protein is considered a leading vaccine candidate against asexual blood-stage Plasmodium vivax. The interaction of P. vivax merozoites with human reticulocytes through Duffy binding protein (DBP) and its cognate receptor is vital for parasite infection. The ligand domain of DBP (DBPII) is polymorphic, showing a diversity characteristic of selective immune pressure that tends to compromise vaccine efficacy associated with strain-specific immunity. A previous study resolved that a polymorphic region of DBPII was a dominant B-cell epitope target of human inhibitory anti-DBP antibodies, which we refer to as the DEK epitope for the amino acids in the SalI allele. We hypothesized that the polymorphic residues, which are not functionally important for erythrocyte binding but flank the receptor binding motif of DBPII, comprise variant epitopes that tend to divert the immune response away from more conserved epitopes. In this study, we designed, expressed, and evaluated the immunogenicity of a novel artificial DBPII allele, termed DEKnull, having nonpolar amino acids in the naturally occurring polymorphic charged residues of the DEK epitope. The DEKnull antigen retained erythrocyte-binding activity and elicited antibodies to shared epitopes of SalI DBPII from which it was derived. Our results confirmed that removal of the dominant variant epitope in the DEKnull vaccine lowered immunogenicity of DBPII, but inhibitory anti-DBPII antibodies were elicited against shared neutralizing epitopes on SalI. Focusing immune responses toward more conserved DBP epitopes may avoid development of a strain-specific immunity and enhance functional inhibition against broader range of DBPII variants.

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  • Authors

    Ntumngia FB, Adams JH

    Institution

    Global Health Infectious Disease Research, Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, USA.

    Source

    Clinical and vaccine immunology : CVI 19:1 2012 Jan pg 30-6

    MeSH

    Amino Acid Sequence
    Animals
    Antibodies, Neutralizing
    Antibodies, Protozoan
    Antigens, Protozoan
    Enzyme-Linked Immunosorbent Assay
    Epitopes, B-Lymphocyte
    Erythrocytes
    Humans
    Immunoblotting
    Immunodominant Epitopes
    Malaria Vaccines
    Molecular Sequence Data
    Plasmodium vivax
    Protein Binding
    Protozoan Proteins
    Rats
    Receptors, Cell Surface
    Vaccines, Synthetic

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    22116684