Associations between prenatal malaria exposure, maternal antibodies at birth, and malaria susceptibility during the first year of life in Burkina Faso

Abstract

In this study, we investigated how different categories of prenatal malaria exposure (PME) influence levels of maternal antibodies in cord blood samples and the subsequent risk of malaria in early childhood in a birth cohort study (N = 661) nested within the COSMIC clinical trial (NCT01941264) in Burkina Faso. Plasmodium falciparum infections during pregnancy and infants' clinical malaria episodes detected during the first year of life were recorded. The levels of maternal IgG and IgG_1-4 to 15 P. falciparum antigens were measured in cord blood by quantitative suspension array technology. Results showed a significant variation in the magnitude of maternal antibody levels in cord blood, depending on the PME category, with past placental malaria (PM) more frequently associated with significant increases of IgG and/or subclass levels across three groups of antigens defined as pre-erythrocytic, erythrocytic, and markers of PM, as compared to those from the cord of non-exposed control infants. High levels of antibodies to certain erythrocytic antigens (i.e., IgG to EBA140 and EBA175, IgG1 to EBA175 and MSP1₄₂, and IgG3 to EBA140 and MSP5) were independent predictors of protection from clinical malaria during the first year of life. By contrast, high levels of IgG, IgG1, and IgG2 to the VAR2CSA DBL1-2 and IgG4 to DBL3-4 were significantly associated with an increased risk of clinical malaria. These findings indicate that PME categories have different effects on the levels of maternal-derived antibodies to malaria antigens in children at birth, and this might drive heterogeneity to clinical malaria susceptibility in early childhood.

Keywords: Plasmodium falciparum; childhood; cord blood; malaria; maternal antibodies; pregnancy; prenatal exposure; protection.

Fig 1

Maternal antibody profiles in cord blood against the selected antigens. Boxplots are shown with median and interquartile ranges for IgG (orange), IgG1 (olive green), IgG2 (green), IgG3 (blue), and IgG4 (purple). Antibody levels to Rh5 are only shown for IgG and IgG1 since the assay was not validated for IgG2, IgG3, and IgG4.

Fig 2

Maternal IgG levels in cord blood at birth according to PME categories. Boxplots comparing total IgG levels as log₁₀ of median fluorescence intensity (MFI) between the different PME groups: Non-expo, non-exposed (in green); Expo-no-PM, Exposed/no placental malaria (in orange); Past-PM, past placental malaria (in blue); Chronic-PM, chronic placental malaria (in pink); Acute-PM, acute placental malaria (in olive green). P-values were determined by Wilcoxon rank-sum test using the non-exposed group as reference: *≤0.05, **≤0.01, ***≤0.001, and ****≤0.0001. P-values were adjusted for multiple comparisons by Benjamini-Hochberg correction.

Fig 3

Kaplan-Meier survival curves showing the risk of clinical malaria during the first year of life for those maternal and infant’s covariates significant associated. (A) Risk of clinical malaria during the first year of life by malaria in pregnancy preventive treatment with Kaplan-Meier survival curves stratified by infants born to mothers who received the CSST + IPTp SP strategy (Community-based scheduled and treatment of malaria during pregnancy in addition to the standard IPTp-SP, red line) and the standard IPTp-SP alone (blue line). (B) Risk of clinical malaria during the first year of life by birth season stratified by infants born during malaria high-transmission season (July–December, red line) and low-transmission season (January–June, blue line). (C) Risk of clinical malaria during the first year of life by birth weight stratified by infants born with a birth weight ≥2,500 g (red line) and with a birth weight <2,500 g (blue line). (D and E) Risk of clinical malaria during the first year of life, by prenatal malaria exposure (any category of exposure vs non-exposure) during the first 6 months of life (D) and from 6 to 12 months of life (E), stratified by infants prenatally exposed (red line) or not (blue line) to malaria. All the Kaplan-Meier survival curves are presented with 95% confidence intervals. P-values were determined by log-rank test.

Fig 4

Kaplan-Meier survival curves assessing the effect of ratios between protective antibodies and antibodies associated with increased risk of malaria on infants’ susceptibility to malaria during the first year of life. Kaplan-Meier survival curves (including 95% confidence intervals) are stratified by infants whose ratios were >1 (red line) or equal/below 1 (blue line). (A) IgG-EBA140/IgG-DLB1-2 ratio and risk of clinical malaria. (B) IgG-EBA175/IgG-DLB1-2 ratio and risk of clinical malaria. (C) IgG1-MSP1₄₂/IgG1-DLB1-2 ratio and malaria risk. P-values were determined by log-rank test.