Breadth of Functional Antibodies Is Associated With Plasmodium falciparum Merozoite Phagocytosis and Protection Against Febrile Malaria

Peripheral Merozoite Surface Proteins Are Targets of Naturally Acquired Immunity against Malaria in both India and Ghana

“…Previously, protective association of each antigen was assessed by multivariate logistic regression analysis (fitting IgG3 data as a linear covariate) (14), while in the present study IgG3 data (categorized into tertiles) were assessed by Cox proportional-hazard models. In an earlier study, two of the antigens (GLURP-R2 and cMSP3 3D7 ) from this Ghanaian subset were also found to correlate with protective immunity and opsonic phagocytosis of merozoite activity when these Ghanaian IgG preparations were assessed in an antigen-coated bead-based phagocytosis assay (26).…”

“…Most of the NAI targets identified in the present study have been previously described as targets of functional antibodies with antiparasite effects, either through neutralization of the merozoite invasion in erythrocytes or in cooperation with mononuclear cells through antibody-dependent cellular inhibition and opsonic phagocytosis (5,26,(36)(37)(38)(39). It should be noted that our experimental setup has the inherent limitation of not completely reflecting the in vivo situation since we quantified antibody levels with a multiplex assay, using recombinant proteins, rather than assessing antigen-specific antibodies in functional assays, which are likely to be better correlates of protective immunity.…”

“…Second, we assessed specific IgG reactivities toward a panel of 24 recombinant merozoite antigens using common reagents. These recombinant antigens were subdomains from different merozoite proteins selected from different subcellular compartments, most of which have been identified to play mechanistic roles in erythrocyte invasion and have been identified as targets of protective immune responses in various studies (14,15,(24)(25)(26). In both study cohorts, antibody reactivity to whole merozoites, as well as to the majority of the recombinant antigens, individually and in combination, increased with age and was higher in participants who were parasitemic at baseline, thus reinforcing the notion that an active infection boosts preexisting malarial antibodies.…”

“…In antigen-specific total IgG, subclasses or breadth score association analyses, we adjusted for age and anti-merozoite IgG levels as confounders because both of these variables are (i) a proxy for parasite exposure, (ii) correlated with malaria disease outcome, and (iii) correlated with each other. In the past, we (14,26) and others (32) have used a similar approach in antibody association studies. As published previously, bed net usage and gender were not identified as confounders (5,14).…”

Antibody effector functions in malaria and other parasitic diseases: a few needles and many haystacks

“…Opsonic phagocytosis was followed by monocyte production of tumor necrosis factor, and levels of opsonizing antibodies to whole merozoites were associated with a decreased risk of clinical malaria and high‐density parasitemia in prospective studies . When merozoite antigens were coated on beads, with THP‐1 cells as effectors, levels of opsonizing antibody to MSP1, MSP2, MSP3, RH2 and glutamate‐rich protein were associated with a decreased risk of clinical malaria in a longitudinal follow‐up study of Ghanaian children . Phagocytosis results correlated with measurement of IgG3 antibody to the same antigens, and breadth of opsonizing antibody correlated with measures of merozoite phagocytosis, suggesting that opsonizing antibodies to a range of antigens are required for merozoite opsonic clearance, which is predominantly mediated by IgG3 antibodies.…”