Identification of an Immunogenic Broadly Inhibitory Surface Epitope of the Plasmodium vivax Duffy Binding Protein Ligand Domain

Abstract

The Plasmodium vivax Duffy binding protein region II (DBPII) is a vital ligand for the parasite’s invasion of reticulocytes, thereby making this molecule an attractive vaccine candidate against vivax malaria. However, strain-specific immunity due to DBPII allelic variation in Bc epitopes may complicate vaccine efficacy, suggesting that an effective DBPII vaccine needs to target conserved epitopes that are potential targets of strain-transcending neutralizing immunity. The minimal epitopes reactive with functionally inhibitory anti-DBPII monoclonal antibody (MAb) 3C9 and noninhibitory anti-DBPII MAb 3D10 were mapped using phage display expression libraries, since previous attempts to deduce the 3C9 epitope by cocrystallographic methods failed. Inhibitory MAb 3C9 binds to a conserved conformation-dependent epitope in subdomain 3, while noninhibitory MAb 3D10 binds to a linear epitope in subdomain 1 of DBPII, consistent with previous studies. Immunogenicity studies using synthetic linear peptides of the minimal epitopes determined that the 3C9 epitope, but not the 3D10 epitope, could induce functionally inhibitory anti-DBPII antibodies. Therefore, the highly conserved binding-inhibitory 3C9 epitope offers the potential as a component in a broadly inhibitory, strain-transcending DBP subunit vaccine. IMPORTANCE Vivax malaria is the second leading cause of malaria worldwide and the major cause of non-African malaria. Unfortunately, efforts to develop antimalarial vaccines specifically targeting Plasmodium vivax have been largely neglected, and few candidates have progressed into clinical trials. The Duffy binding protein is considered a leading blood-stage vaccine candidate because this ligand’s recognition of the Duffy blood group reticulocyte surface receptor is considered essential for infection. This study identifies a new target epitope on the ligand’s surface that may serve as the target of vaccine-induced binding-inhibitory antibody (BIAb). Understanding the potential targets of vaccine protection will be important for development of an effective vaccine.

Extensive genetic diversity of Plasmodium vivax dbp-II in Rio de Janeiro Atlantic Forest and Brazilian Amazon Basin: evidence of positive selection

“…The frequency of these SNPs was similar to this study, as in the case of Thailand [18], Myanmar [19], Sudan [21], and Papua New Guinea [17], or smaller as in the case of Sri-Lanka [22]. These data reinforce the idea that pvdbp-II diversity seems to occur independently of the malaria endemicity levels [23,24]. Further, eight SNPs were exclusively detected in AF, and, interestingly, two of them (K371N and E385Q/K) had been previously found in AF areas of Santa Catarina state [25].…”

Dynamics of IgM and IgG responses to the next generation of engineered Duffy binding protein II immunogen: Strain-specific and strain-transcending immune responses over a nine-year period

“…In the case of P. vivax MSP1, antibody response to different regions of the protein appeared distinct, with the N-terminal portion predominantly associated with IgM antibodies and C-terminal with IgG response [54][55][56][57]. In the case of DBPII, several studies have mapped functional immunoreactive B cell epitopes associated with broadly neutralizing IgG antibody response [12,14,15,18], but no data is available about IgM response.…”

“…Duffy binding protein II (DBPII) is a leading P. vivax malaria vaccine candidate that binds the Duffy antigen receptor for chemokines (DARC) on reticulocytes is critical for reticulocyte invasion [9,10]. Although naturally acquired DBPII antibodies tend to be biased towards strain-specific responses [11][12][13], our project identified the epitope targets of protective neutralizing IgG antibody response to overlap conserved residues essential for receptor binding and DBP dimerization [12,[14][15][16][17][18][19]. Individuals able to produce these broadly binding-inhibitory antibodies (BIAb) to DBPII present reduced risk of clinical P. vivax malaria [20,21].…”

UsingPlasmodium knowlesias a model for screeningPlasmodium vivaxblood-stage malaria vaccine targets reveals new candidates

“…Clearly PvDBP has been the subject of decades of work, meaning that there are multiple lines of evidence supporting its candidacy. The limitations of this target are also well known, specifically the challenge of strain-specific antibody responses, which may be able to be overcome with epitope engineering (28,(66)(67)(68). One question in weighing up the candidacy of any vaccine antigen is whether the gene that encodes it is essential for parasite growth, as targeting a non-essential gene would seem likely to select for parasites that do not rely on the gene product, and so are able to escape the vaccine.…”