An engineered vaccine of the Plasmodium vivax Duffy binding protein enhances induction of broadly neutralizing antibodies

Abstract

Plasmodium vivax invasion into human reticulocytes is a complex process. The Duffy binding protein (DBP) dimerization with its cognate receptor is vital for junction formation in the invasion process. Due to its functional importance, DBP is considered a prime vaccine candidate, but variation in B-cell epitopes at the dimer interface of DBP leads to induction of strain-limited immunity. We believe that the polymorphic residues tend to divert immune responses away from functionally conserved epitopes important for receptor binding or DBP dimerization. As a proof of concept, we engineered the vaccine DEKnull to ablate the dominant Bc epitope to partially overcome strain-specific immune antibody responses. Additional surface engineering on the next generation immunogen, DEKnull-2, provides an immunogenicity breakthrough to conserved protective epitopes. DEKnull-2 elicits a stronger broadly neutralizing response and reactivity with long-term persistent antibody responses of acquired natural immunity. By using novel engineered DBP immunogens, we validate that the prime targets of protective immunity are conformational epitopes at the dimer interface. These successful results indicate a potential approach that can be used generally to improve efficacy of other malaria vaccine candidates.

Immunization with Recombinant Plasmodium falciparum Erythrocyte Membrane Protein 1 CIDRα1 Domains Induces Domain Subtype Inhibitory Antibodies

“…These results indicate that inhibitory antibodies targeting the immunogens are readily elicited and that epitopes recognized by crossvariant inhibitory antibodies, while dependent on amino acid similarity, predominantly are conformational. Further characterization of the epitopes recognized by functional and nonfunctional monoclonal antibodies may aid design of engineered immunogens eliciting a broadly reactive functional IgG, similar to what has been achieved for engineered versions of the closely related Plasmodium vivax Duffy binding proteins (28).…”

Blood-stage Plasmodium vivax antibody dynamics in a low transmission setting: A nine year follow-up study in the Amazon region

“…vivax reticulocyte invasion pathway [ 22 ]. Since DBPII induces both strain-specific and strain-transcending antibody responses [ 23 , 24 ], we included in this study recombinant proteins corresponding to common variants circulating in the Amazon area (DBPII-Sal1 and DBPII-Brz1), as well as a novel engineered DBPII construct (DEKnull-2) associated with broad DBPII antibody responses [ 25 ]. During the 9-year period of our cross-sectional surveys, the level of malaria transmission in the study area fluctuated significantly, allowing us to characterize and associate the varying antibody profiles observed with different transmission intensities.…”

On the Evolution and Function of Plasmodium vivax Reticulocyte Binding Surface Antigen (pvrbsa)

“…For instance, the Duffy antigen, which is not present in P. falciparum , is essential for P. vivax invasion ( Chitnis and Miller, 1994 ). PvDBP-conserved epitopes can trigger strong neutralizing antibodies; it has therefore been suggested as one of the main P. vivax vaccine candidates ( Chen et al, 2016 ; Ntumngia et al, 2017 ).…”