Naturally acquired Duffy-binding protein-specific binding inhibitory antibodies confer protection from blood-stage Plasmodium vivax infection

Abstract

Individuals residing in malaria-endemic regions acquire protective immunity after repeated infection with malaria parasites; however, mechanisms of protective immunity and their immune correlates are poorly understood. Blood-stage infection with Plasmodium vivax depends completely on interaction of P. vivax Duffy-binding protein (PvDBP) with the Duffy antigen on host erythrocytes. Here, we performed a prospective cohort treatment/reinfection study of children (5-14 years) residing in a P. vivax-endemic region of Papua New Guinea (PNG) in which children were cleared of blood-stage infection and then examined biweekly for reinfection for 25 weeks. To test the hypothesis that naturally acquired binding inhibitory antibodies (BIAbs) targeting PvDBP region II (PvDBPII) provide protection against P. vivax infection, we used a quantitative receptor-binding assay to distinguish between antibodies that merely recognize PvDBP and those that inhibit binding to Duffy. The presence of high-level BIAbs (>90% inhibition of PvDBPII-Duffy binding, n ‫؍‬ 18) before treatment was associated with delayed time to P. vivax reinfection diagnosed by light microscopy (P ‫؍‬ 0.02), 55% reduced risk of P. vivax reinfection (Hazard's ratio ‫؍‬ 0.45, P ‫؍‬ 0.04), and 48% reduction in geometric mean P. vivax parasitemia (P < 0.001) when compared with children with low-level BIAbs (n ‫؍‬ 148). Further, we found that stable, high-level BIAbs displayed strain-transcending inhibition by reducing reinfection with similar efficiency of PNG P. vivax strains characterized by six diverse PvDBPII haplotypes. These observations demonstrate a functional correlate of protective immunity in vivo and provide support for developing a vaccine against P. vivax malaria based on PvDBPII.Duffy antigen ͉ immunity ͉ protective antibodies P rotective immunity against malaria is acquired by residents of endemic regions over a period of years after repeated exposure to malaria parasites (1). Naturally acquired immunity to Plasmodium falciparum and Plasmodium vivax malaria does not prevent infection by these parasites completely, but limits parasite densities, reduces the frequency of clinical malaria episodes, and prevents severe disease (2). Humoral immune responses against blood-stage antigens are an important component of naturally acquired immunity to malaria (2, 3). Therefore, parasite proteins engaged in erythrocyte invasion are potential targets of protective antibody responses.Interaction between P. vivax Duffy-binding protein (PvDBP) and the Duffy antigen receptor (DA) on host erythrocytes is central to blood-stage infection by P. vivax (4, 5). Adhesion to DA is mediated by the 140-kDa PvDBP (6-8). The receptor-binding domain of PvDBP maps to the conserved, N-terminal cysteine-rich region II (PvDBPII) (9, 10). Given the complete dependence of P. vivax on the PvDBPII-Duffy interaction for blood-stage infection and recent observations that PvDBPII-specific antibodies inhibit P. vivax invasion of human erythrocytes in vitro (11), we examined the hypothesis that...

Immunological markers of Plasmodium vivax exposure and immunity: a systematic review and meta-analysis

“…Of these 18 studies, 9 were cross-sectional, 6 were cohort (4 of which also provided cross-sectional data), and 3 were case-control studies. One cohort study contributed two publications [34,35], and one publication provided data from two countries [22]. For the purpose of this review, we shall refer to each publication as a study.…”

“…The full texts of these 162 studies were examined to determine whether they complied with eligibility criteria: 114 did not meet the inclusion criteria (see Additional file 3), 7 fulfilled the inclusion and quality criteria (Figure 1), and 41 studies potentially met inclusion and quality criteria. The authors of the 41 studies that potentially met inclusion and quality criteria were contacted, yielding a further 11 studies that met inclusion and quality criteria, providing a total of 18 studies that were included in the review [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] (Figure 1). Details of these 18 studies are shown in Table 1.…”

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

“…Analysis of 676 bp within DBP-II revealed 127 polymorphic sites with nucleotide diversity varying between 0.006 and 0.0109, resulting in 193 haplotypes (35). These factors induce strain-specific protection rather than strain-transcending immunity, which leaves individuals susceptible to continued infection and disease (6,9,17,32,33,36).…”

“…Both cost-effective and efficient, vaccines are among the leading avenues of intervention, and individuals living in regions with P. vivax develop naturally acquired humoral immunity that correlates with results from in vitro functional assays (6)(7)(8)(9). A leading vaccine candidate for P. vivax is the Duffy Binding Protein (DBP) (10)(11)(12)(13)(14)(15)(16)(17)(18)(19), a parasite cell surface protein in the Erythrocyte Binding-Like (EBL) invasion protein family (14,(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

Multiple interests in structural models of DARC transmembrane protein

“…Naturally acquired antibodies to DBP seem to confer protection from blood-stage P. vivax infection, supporting the development of a vaccine against P. vivax malaria [18]. However other studies also pinpointed that produced human antibodies might have low efficiencies underlining the difficulty of vaccine design [19].…”