Substantial evidence indicates that
antibodies to Plasmodium falciparum merozoite
antigens play a role in protection from
malaria, although the precise targets and mechanisms mediating immunity remain unclear. Different
malaria antigens induce distinct
immunoglobulin G (
IgG) subclass responses, but the importance of different responses in protective immunity from
malaria is not known and the factors determining subclass responses in vivo are poorly understood. We examined
IgG and
IgG subclass responses to the merozoite
antigens MSP1-19 (the 19-kDa C-terminal region of
merozoite surface protein 1), MSP2 (merozoite
surface protein 2), and AMA-1 (apical membrane
antigen 1), including different polymorphic variants of these
antigens, in a longitudinal cohort of children in Papua New Guinea.
IgG1 and
IgG3 were the predominant subclasses of
antibodies to each
antigen, and all antibody responses increased in association with age and exposure without evidence of increasing polarization toward one subclass. The profiles of
IgG subclasses differed somewhat for different alleles of MSP2 but not for different variants of AMA-1. Individuals did not appear to have a propensity to make a specific subclass response irrespective of the
antigen. Instead, data suggest that subclass responses to each
antigen are generated independently among individuals and that
antigen properties, rather than host factors, are the major determinants of
IgG subclass responses. High levels of AMA-1-specific
IgG3 and MSP1-19-specific
IgG1 were strongly predictive of a reduced risk of symptomatic
malaria and high-density P. falciparum
infections. However, no antibody response was significantly associated with protection from parasitization per se. Our findings have major implications for understanding human immunity and for
malaria vaccine development and evaluation.