Effect of the pre-erythrocytic candidate malaria vaccine RTS,S/AS01E on blood stage immunity in young children

Abstract

Background: RTS,S/AS01(E) is the lead candidate malaria vaccine and confers pre-erythrocytic immunity. Vaccination may therefore impact acquired immunity to blood-stage malaria parasites after natural infection.

Methods: We measured, by enzyme-linked immunosorbent assay, antibodies to 4 Plasmodium falciparum merozoite antigens (AMA-1, MSP-1(42), EBA-175, and MSP-3) and by growth inhibitory activity (GIA) using 2 parasite clones (FV0 and 3D7) at 4 times on 860 children who were randomized to receive with RTS,S/AS01(E) or a control vaccine.

Results: Antibody concentrations to AMA-1, EBA-175, and MSP-1(42) decreased with age during the first year of life, then increased to 32 months of age. Anti-MSP-3 antibody concentrations gradually increased, and GIA gradually decreased up to 32 months. Vaccination with RTS,S/AS01(E) resulted in modest reductions in AMA-1, EBA-175, MSP-1(42), and MSP-3 antibody concentrations and no significant change in GIA. Increasing anti-merozoite antibody concentrations and GIA were prospectively associated with increased risk of clinical malaria.

Conclusions: Vaccination with RTS,S/AS01E reduces exposure to blood-stage parasites and, thus, reduces anti-merozoite antigen antibody concentrations. However, in this study, these antibodies were not correlates of clinical immunity to malaria. Instead, heterogeneous exposure led to confounded, positive associations between increasing antibody concentration and increasing risk of clinical malaria.

Figure 1.

A, Scatter plot of age (x axis) against AMA-1 antibody concentration with the fitted fractional polynomial: Concentration=m₁*age^−0.5 + m₂*ln(age), where m refers to coefficients fitted by the regression model. B, Scatter plot of calendar date (x axis) against AMA-1 antibody concentration with the fitted fractional polynomial: Concentration=m₁*date⁻² + m₂*date⁻² *ln(date). C, Scatter plot of calendar date (x axis) against GIA for FV0 parasites with the fitted fractional polynomial: Concentration=m₁*date⁻² + m₂*date⁻² *ln(date). D, The incidence of clinical malaria per month by calendar month.

Figure 2.

Kaplan Meier plots showing proportions of children without clinical malaria episodes according to quartile of antibody or GIA responses measured directly prior to periods of follow-up (ie, there are up to 3 observations for each individual: malaria incidence in the 2.5 months after antibody assessments at enrollment and at months 8 and 12 after the third vaccination).

Figure 3.

Maps of participants’ residences, showing the relative AMA-1 antibody concentrations by intensity of shading for the green boxes, relative to the areas with highest intensity of clinical malaria episodes shown by black circles.