The Plasmodium vivax vaccine candidate Duffy Binding Protein (DBP) is a protein
necessary for P. vivax invasion of reticulocytes. The polymorphic nature of DBP
induces strain-specific immune responses that pose unique challenges for vaccine
development. DEKnull is a synthetic DBP based antigen that has been engineered
through mutation to enhance induction of blocking inhibitory antibodies. We
determined the x-ray crystal structure of DEKnull to identify if any
conformational changes had occurred upon mutation. Computational and
experimental analyses assessed immunogenicity differences between DBP and
DEKnull epitopes. Functional binding assays with monoclonal antibodies were used
to interrogate the available epitopes in DEKnull. We demonstrate that DEKnull is
structurally similar to the parental Sal1 DBP. The DEKnull mutations do not
cause peptide backbone shifts within the polymorphic loop, or at either the DBP
dimerization interface or DARC receptor binding pockets, two important
structurally conserved protective epitope motifs. All B-cell epitopes, except
for the mutated DEK motif, are conserved between DEKnull and DBP. The DEKnull
protein retains binding to conformationally dependent inhibitory antibodies.
DEKnull is an iterative improvement of DBP as a vaccine candidate. DEKnull has
reduced immunogenicity to polymorphic regions responsible for strain-specific
immunity while retaining conserved protein folds necessary for induction of
strain-transcending blocking inhibitory antibodies.
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