title: Immunoglobulin G subclass-specific responses against Plasmodium falciparum merozoite antigens are associated with control of parasitemia and protection from symptomatic illness.
abstract: 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.
authors.affiliation: Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Australia.
authors.forename: Danielle I
authors.initials: DI
authors.lastname: Stanisic
authors.forename: Jack S
authors.initials: JS
authors.lastname: Richards
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: McCallum
authors.forename: Pascal
authors.initials: P
authors.lastname: Michon
authors.forename: Christopher L
authors.initials: CL
authors.lastname: King
authors.forename: Sonja
authors.initials: S
authors.lastname: Schoepflin
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gilson
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Murphy
authors.forename: Robin F
authors.initials: RF
authors.lastname: Anders
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood / Q000276:immunology*; D000953:Antigens, Protozoan / Q000097:blood / Q000276:immunology*; D000962:Antimalarials / Q000627:therapeutic use; D037621:Artemisinins / Q000627:therapeutic use; D000077332:Artesunate; D002648:Child; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology*; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology; D020066:Merozoite Surface Protein 1 / Q000276:immunology; D052940:Merozoites / Q000276:immunology; D018512:Parasitemia / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D000962:Antimalarials; D037621:Artemisinins; D007074:Immunoglobulin G; D008565:Membrane Proteins; D020066:Merozoite Surface Protein 1; D015800:Protozoan Proteins; C090077:apical membrane antigen I, Plasmodium; C065974:merozoite surface protein 2, Plasmodium; D000077332:Artesunate