Breadth of anti-merozoite antibody responses is associated with the genetic diversity of asymptomatic Plasmodium falciparum infections and protection against clinical malaria

Abstract

Background: Elucidating the mechanisms of naturally acquired immunity to Plasmodium falciparum infections would be highly valuable for malaria vaccine development. Asymptomatic multiclonal infections have been shown to predict protection from clinical malaria in a transmission-dependent manner, but the mechanisms underlying this are unclear. We assessed the breadth of antibody responses to several vaccine candidate merozoite antigens in relation to the infecting parasite population and clinical immunity.

Methods: In a cohort study in Tanzania, 320 children aged 1-16 years who were asymptomatic at baseline were included. We genotyped P. falciparum infections by targeting the msp2 gene using polymerase chain reaction and capillary electrophoresis and measured antibodies to 7 merozoite antigens using a multiplex assay. We assessed the correlation between the number of clones and the breadth of the antibody response, and examined their effects on the risk of malaria during 40 weeks of follow-up using age-adjusted multivariate regression models.

Results: The antibody breadth was positively correlated with the number of clones (RR [risk ratio], 1.63; 95% confidence interval [CI], 1.32-2.02). Multiclonal infections were associated with a nonsignificant reduction in the risk of malaria in the absence of antibodies (RR, 0.83; 95% CI, .29-2.34). The breadth of the antibody response was significantly associated with a reduced risk of malaria in the absence of infections (RR, 0.25; 95% CI, .09-.66). In combination, these factors were associated with a lower risk of malaria than they were individually (RR, 0.14; 95% CI, .04-.48).

Conclusions: These data suggest that malaria vaccines mimicking naturally acquired immunity should ideally induce antibody responses that can be boosted by natural infections.

Keywords: antibodies; immunity; malaria; merozoite surface antigens; multiclonal infections.

Figures

Figure 1.

Age distribution of the proportion of individuals with malaria episodes, number of clones, and the breadth of antibody responses. Age distribution of the proportion of individuals with clinical malaria during follow-up (A); the distribution of the number of clones (B, mean ± SEM on y-axis), and the breadth of antibody responses (C; mean ± SEM on y-axis).

Figure 2.

Relationship between the number of Plasmodium falciparum clones and the breadth of antibody responses at baseline. Bar graphs show the proportion of individuals with the corresponding breadth of antibody responses and number of clones. An increase in the number of clones was associated with an increase in the breadth of antibody responses (risk ratio, 1.63; 95% confidence interval, 1.32–2.02).