Whereas the genome of P. vivax contains more than 5000 genes encoding proteins, only a handful of proteins have been investigated as targets of naturally acquired immunity against this parasite. A comprehensive and systematic characterization of antibody responses to P. vivax antigens in exposed populations is thus urgently needed. In this work, we investigated antibody responses to a library of 34 P. vivax entire ectodomain proteins known or predicted to be involved in merozoite invasion in two Asia-Pacific populations, analyzing the relationship of antibody levels with markers of current and cumulative malaria exposure, socio-economic and clinical indicators.
IgG recognition by samples collected from Solomon Islanders differed significantly between proteins, and 29 proteins were considered immunogenic (P < 0.001-0.018). Significant increases in IgG levels with age were observed for most proteins (P < 0.001-0.027). However, IgG responses to only a few proteins were significantly higher in the setting of concurrent asymptomatic PCR- or microscopy-detected P. vivax infections. These results suggest that IgG responses to these proteins relate more to cumulative lifetime rather than concurrent exposure to P. vivax.
In samples collected at the start of 16 months of follow-up of 264 1-3 years old children from an area of high malaria endemicity in Papua New Guinea (PNG), we identified a strong association between reduced risk of clinical disease and high antibody levels to P12, P41, and a novel hypothetical protein not previously studied, PVX_081550 (incidence rate ratio [IRR] 0.46- 0.74, P < 0.001-0.041). These data emphasize the benefits of an unbiased screening approach in identifying new antigenic targets of natural immunity against malaria. Further molecular/functional characterization is necessary to define whether P12, P41 and PVX_081550 are interesting candidates for vaccine development, or whether antibodies to these proteins act only as biomarkers of acquired immunity.
Elimination of Plasmodium vivax malaria would be greatly facilitated by the development of an effective vaccine. A comprehensive and systematic characterization of antibodies to P. vivax antigens in exposed populations is useful in guiding rational vaccine design.
In this study, we investigated antibodies to a large library of P. vivax entire ectodomain merozoite proteins in 2 Asia-Pacific populations, analysing the relationship of antibody levels with markers of current and cumulative malaria exposure, and socioeconomic and clinical indicators. 29 antigenic targets of natural immunity were identified. Of these, 12 highly-immunogenic proteins were strongly associated with age and thus cumulative lifetime exposure in Solomon Islanders ( P<0.001–0.027). A subset of 6 proteins, selected on the basis of immunogenicity and expression levels, were used to examine antibody levels in plasma samples from a population of young Papua New Guinean children with well-characterized individual differences in exposure. This analysis identified a strong association between reduced risk of clinical disease and antibody levels to P12, P41, and a novel hypothetical protein that has not previously been studied, PVX_081550 (IRR 0.46–0.74; P<0.001–0.041).
These data emphasize the benefits of an unbiased screening approach in identifying novel vaccine candidate antigens. Functional studies are now required to establish whether PVX_081550 is a key component of the naturally-acquired protective immune response, a biomarker of immune status, or both.
Plasmodium vivax is now the predominant malaria parasite outside Africa. Because P. vivax can remain dormant in the liver for months, identifying and treating P. vivax in asymptomatic individuals is difficult. Additionally, current widely-used vector control measures are less efficient against mosquitoes that transmit P. vivax. An effective vaccine would therefore immensely facilitate P. vivax elimination. Unfortunately, little is known about P. vivax biology and only a few proteins have been investigated as targets for vaccine development. To address these knowledge gaps, we measured antibody levels to 34 entire ectodomain proteins predicted to be involved in P. vivax invasion of erythrocytes, in samples from individuals living in 2 malaria-endemic Asia-Pacific countries. We found that antibodies in malaria-exposed Solomon Islanders were reactive to the majority of proteins in our panel, and that antibodies to 12 of these proteins strongly reflected cumulative life-time exposure to P. vivax. In samples from Papua New Guinea children, we identified an association between antibodies to 3 proteins and protection against clinical malaria. Our results demonstrate that screening antibodies to a large number of P. vivax proteins is a useful approach in identifying novel targets of immunity. Functional studies are now required to establish whether these proteins are biomarkers of an individual’s immune status, potential vaccine candidates that warrant further development, or both.