Naturally Acquired Immune Responses to P. vivax Merozoite Surface Protein 3α and Merozoite Surface Protein 9 Are Associated with Reduced Risk of P. vivax Malaria in Young Papua New Guinean Children

Abstract

Background Plasmodium vivax is the most geographically widespread human malaria parasite. Cohort studies in Papua New Guinea have identified a rapid onset of immunity against vivax-malaria in children living in highly endemic areas. Although numerous P. vivax merozoite antigens are targets of naturally acquired antibodies, the role of many of these antibodies in protective immunity is yet unknown.Methodology/Principal FindingsIn a cohort of children aged 1–3 years, antibodies to different regions of Merozoite Surface Protein 3α (PvMSP3α) and Merozoite Surface Protein 9 (PvMSP9) were measured and related to prospective risk of P. vivax malaria during 16 months of active follow-up. Overall, there was a low prevalence of antibodies to PvMSP3α and PvMSP9 proteins (9–65%). Antibodies to the PvMSP3α N-terminal, Block I and Block II regions increased significantly with age while antibodies to the PvMSP3α Block I and PvMSP9 N-terminal regions were positively associated with concurrent P. vivax infection. Independent of exposure (defined as the number of genetically distinct blood-stage infection acquired over time (molFOB)) and age, antibodies specific to both PvMSP3α Block II (adjusted incidence ratio (aIRR) = 0.59, p = 0.011) and PvMSP9 N-terminus (aIRR = 0.68, p = 0.035) were associated with protection against clinical P. vivax malaria. This protection was most pronounced against high-density infections. For PvMSP3α Block II, the effect was stronger with higher levels of antibodies.ConclusionsThese results indicate that PvMSP3α Block II and PvMSP9 N-terminus should be further investigated for their potential as P. vivax vaccine antigens. Controlling for molFOB assures that the observed associations are not confounded by individual differences in exposure.

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

“…Although PvMSP-3α antibodies appeared to be a marker of P. vivax infection in cross-sectional data from Stanisic et al [36], cohort data from the same study showed a 47% reduction in the risk of symptomatic P. vivax for PvMSP-3α RII IgG responders and around a 20% risk reduction for IgG responders to PvMSP-3α NT , PvMSP-3α RI and PvMSP-3α CT (Figure 6). …”

“…Lima-Junior et al [25] showed around a 60% reduction in the odds of P. vivax infection in IgG responders to PvMSP-3α full-length (MSP-3α FL ), PvMSP-3α NT , PvMSP-3α RI , and around a 35% reduction for PvMSP-3α RII and PvMSP-3α CT compared with non-responders ( Figure 6). Conversely, Stanisic et al [36] showed fold increases of between Figure 5 Forest plot of the association of PvMSP-1 N-terminus IgG responses with Plasmodium vivax outcomes. Estimates represent the estimate of P. vivax infection in IgG responders compared with non-responders.…”

“…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.…”

“…One cross-sectional study in Brazil by Lima-Junior et al [25] and one cohort study in PNG by Stanisic et al [36] (which contributed both cross-sectional and cohort data) investigated the association between antibody responses to regions of PvMSP-3α and P. vivax outcomes. The two cross-sectional studies gave opposing results and were not combined (I 2 > 75% and/or P < 0.01).…”

“…All estimates are unadjusted, with the exception of estimates from cohort data from Stanisic et al [36], which were adjusted for age, season, spatial variation, and individual differences in exposure. Meta-analysis of responses to PvMSP-3α NT , PvMSP-3α RI , PvMSP-3α RII , and PvMSP-3α CT , and odds of P. vivax infection (estimates from cross-sectional studies) showed a high degree of heterogeneity (I 2 > 75% and/or P < 0.1) so estimates were not pooled.…”