IgG antibodies to synthetic GPI are biomarkers of immune-status to both Plasmodium falciparum and Plasmodium vivax malaria in young children

Abstract

Background: Further reduction in malaria prevalence and its eventual elimination would be greatly facilitated by the development of biomarkers of exposure and/or acquired immunity to malaria, as well as the deployment of effective vaccines against Plasmodium falciparum and Plasmodium vivax. A better understanding of the acquisition of immunity in naturally-exposed populations is essential for the identification of antigens useful as biomarkers, as well as to inform rational vaccine development.

Methods: ELISA was used to measure total IgG to a synthetic form of glycosylphosphatidylinositol from P. falciparum (PfGPI) in a cohort of 1-3 years old Papua New Guinea children with well-characterized individual differences in exposure to P. falciparum and P. vivax blood-stage infections. The relationship between IgG levels to PfGPI and measures of recent and past exposure to P. falciparum and P. vivax infections was investigated, as well as the association between antibody levels and prospective risk of clinical malaria over 16 months of follow-up.

Results: Total IgG levels to PfGPI were low in the young children tested. Antibody levels were higher in the presence of P. falciparum or P. vivax infections, but short-lived. High IgG levels were associated with higher risk of P. falciparum malaria (IRR 1.33-1.66, P = 0.008-0.027), suggesting that they are biomarkers of increased exposure to P. falciparum infections. Given the cross-reactive nature of antibodies to PfGPI, high IgG levels were also associated with reduced risk of P. vivax malaria (IRR 0.65-0.67, P = 0.039-0.044), indicating that these antibodies are also markers of acquired immunity to P. vivax.

Conclusions: This study highlights that in young children, IgG to PfGPI might be a useful marker of immune-status to both P. falciparum and P. vivax infections, and potentially useful to help malaria control programs to identify populations at-risk. Further functional studies are necessary to confirm the potential of PfGPI as a target for vaccine development.

Keywords: Biomarker of exposure; Clinical malaria; Exposure; GPI; Glycosylphosphatidylinositol; IgG antibody; Malaria elimination; Plasmodium falciparum; Plasmodium vivax; Protection.

Fig. 1

IgG to PfGPI and clinical symptoms in Papua New Guinean children. a Scatterplot of total IgG levels (optical density at 450 nm) versus haemoglobin levels (g/dL) (n = 223) with a Lowess smoothed fitted curve. P values and rho are from Spearman’s rank correlation. Box plots show median IgG levels (black bar), minimum and maximum (whiskers) and outliers (open circles) by b presence of enlarged spleen (n = 59); c current clinical episode of any density by P. falciparum (n = 65) or P. vivax (n = 70); d Gerbich blood type 1 = wild-type (n = 83), 2 = heterozygote (n = 111), 3 = homozygote (n = 29). P values are from ANOVA or 2 sample t tests

Fig. 2

IgG to PfGPI and risk of falciparum and vivax-malaria in Papua New Guinean children. Data are plotted as incidence rate ratios and 95% confidence intervals over 16 months of follow-up, adjusted for age, season, village of residency, haemoglobin levels and Gerbich blood type (n = 223). Black and white circles represent children with medium and high antibody levels, respectively. Clinical malaria was defined as axillary temperature ≥ 37.5 °C or history of fever in the preceding 48 h with a current P. falciparum parasitemia of > 2500 (n = 383); > 10,000 (n = 315); and > 50,000 parasites/μL (n = 175); and P. vivax > 500 (n = 301); > 2000 (n = 207); and > 10,000 parasites/μL (n = 90). IRR, 95% confidence intervals and P values are from negative binomial GEE models