Antibody responses to Plasmodium vivax Duffy binding and Erythrocyte binding proteins predict risk of infection and are associated with protection from clinical Malaria

Abstract

Background The Plasmodium vivax Duffy Binding Protein (PvDBP) is a key target of naturally acquired immunity. However, region II of PvDBP, which contains the receptor-binding site, is highly polymorphic. The natural acquisition of antibodies to different variants of PvDBP region II (PvDBPII), including the AH, O, P and Sal1 alleles, the central region III-V (PvDBPIII-V), and P . vivax Erythrocyte Binding Protein region II (PvEBPII) and their associations with risk of clinical P . vivax malaria are not well understood. Methodology Total IgG and IgG subclasses 1, 2, and 3 that recognize four alleles of PvDBPII (AH, O, P, and Sal1), PvDBPIII-V and PvEBPII were measured in samples collected from a cohort of 1 to 3 year old Papua New Guinean (PNG) children living in a highly endemic area of PNG. The levels of binding inhibitory antibodies (BIAbs) to PvDBPII (AH, O, and Sal1) were also tested in a subset of children. The association of presence of IgG with age, cumulative exposure (measured as the product of age and malaria infections during follow-up) and prospective risk of clinical malaria were evaluated. Results The increase in antigen-specific total IgG, IgG1, and IgG3 with age and cumulative exposure was only observed for PvDBPII AH and PvEBPII. High levels of total IgG and predominant subclass IgG3 specific for PvDBPII AH were associated with decreased incidence of clinical P . vivax episodes (aIRR = 0.56–0.68, P≤0.001–0.021). High levels of total IgG and IgG1 to PvEBPII correlated strongly with protection against clinical vivax malaria compared with IgGs against all PvDBPII variants (aIRR = 0.38, P<0.001). Antibodies to PvDBPII AH and PvEBPII showed evidence of an additive effect, with a joint protective association of 70%. Conclusion Antibodies to the key parasite invasion ligands PvDBPII and PvEBPII are good correlates of protection against P . vivax malaria in PNG. This further strengthens the rationale for inclusion of PvDBPII in a recombinant subunit vaccine for P . vivax malaria and highlights the need for further functional studies to determine the potential of PvEBPII as a component of a subunit vaccine for P . vivax malaria.

Genetic diversity and neutral selection in Plasmodium vivax erythrocyte binding protein correlates with patient antigenicity

“…Similarly, an earlier study demonstrated that an IgG1 response against PvEBP domain (161-641 aa.) was dominant in an age-dependent manner in vivax patients [40]. Our study confirmed that only the IgG response against PvEBP-RIII-V (480-676 aa.)…”

“…Additionally, antibodies against PvEBP-RII were useful for serological marker of recent malaria exposure, with a half-life estimated at 734 days [42]. Anti-PvEBP-RII antibodies were predominant IgG1 and IgG3 which is similar to other PfEBAs-RII to mediate opsonic phagocytosis [39,40]. However, PvEBP-RII showed highest genetic polymorphism within pvebp-ecto domains.…”

Heterogeneity in response to serological exposure markers of recentPlasmodium vivaxinfections in contrasting epidemiological contexts

“…shown that IgG subclass profiles to P. falciparum [45] and P. vivax [46][47][48] differed among malaria antigens and that the subclass predominance is influenced by age and increasing exposure to infection. High IgG1 and IgG3 levels have been associated with long-term exposure to P. vivax [40,48].…”

Whole genome sequencing of Plasmodium vivax isolates reveals frequent sequence and structural polymorphisms in erythrocyte binding genes

“…Functional analyses indicated that region II of this gene bound to both Duffy-positive and Duffy-negative reticulocytes, although at a lower frequency compared to PvDBP, suggestive of its role in erythrocyte invasion [40]. Both PvEBP1 and PvEBP2 genes exhibit high genetic diversity and are common antibody binding targets associated with clinical protection [41,42]. Other proteins such as tryptophan-rich antigen gene (TRAg), anchored micronemal antigen (GAMA), and Rhoptry neck protein (RON) have also been suggested to play a role in red cell invasion, especially in low-density infections [43][44][45][46][47].…”