title: Acquisition of Functional Antibodies That Block the Binding of Erythrocyte-Binding Antigen 175 and Protection Against Plasmodium falciparum Malaria in Children.
abstract: BACKGROUND
  The targets and mechanisms of human immunity to malaria are poorly understood, which poses a major barrier to malaria vaccine development. Antibodies play a key role in human immunity and may act by inhibiting receptor-binding functions of key merozoite invasion ligands. Antibodies to the major invasion ligand and vaccine candidate, erythrocyte-binding antigen 175 (EBA-175), have been linked with protection, but how these antibodies function has not been established.
  
  
  METHODS
  We developed 2 new assays that quantify the ability of antibodies to inhibit binding of EBA-175 to its erythrocyte receptor, glycophorin A, using either native or recombinant EBA-175. Binding-inhibitory antibodies were evaluated in a longitudinal cohort study of Papua New Guinean children and related to risk of malaria, age, infection status, and markers of parasite exposure.
  
  
  RESULTS
  Binding-inhibition assays (BIAs) were reproducible, and the 2 assays had a high level of agreement. Inhibitory antibodies were common among children, acquired in association with markers of increasing parasite exposure, and high in those children with active infection. Inhibitory antibodies correlated with total immunoglobulin G levels to the EBA-175 binding domain (region II). Importantly, binding-inhibitory antibodies were significantly associated with protection from symptomatic malaria when measured using either BIA.
  
  
  CONCLUSIONS
  Findings suggest that naturally acquired binding-inhibitory antibodies are an important functional mechanism that contributes to protection against malaria and further supports the potential of EBA-175 as a vaccine candidate. Identifying vaccines and approaches that induce potent binding-inhibitory antibodies may be a valuable strategy in the development of highly efficacious malaria vaccines.
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne Department of Medicine, University of Melbourne, Parkville Department of Immunology, Monash University, Melbourne.
authors.forename: Vashti
authors.initials: V
authors.lastname: Irani
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne Department of Immunology, Monash University, Melbourne Department of Surgery, Austin Health, University of Melbourne, Heidelberg, Victoria School of Biomedical Sciences, Curtin Health Innovation Research Institute-Biosciences, Curtin University, Perth, Western Australia, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ramsland
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne Department of Immunology, Monash University, Melbourne.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Guy
authors.affiliation: Papua New Guinea Institute of Medical Research, Goroka.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siba
authors.affiliation: Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia Barcelona Centre for International Health Research, Spain.
authors.forename: Ivo
authors.initials: I
authors.lastname: Mueller
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne Department of Medicine, University of Melbourne, Parkville Department of Microbiology, Monash University, Clayton, Victoria, Australia.
authors.forename: Jack S
authors.initials: JS
authors.lastname: Richards
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne Department of Medicine, University of Melbourne, Parkville Department of Microbiology, Monash University, Clayton, Victoria, Australia.
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
mesh_terms: D000293:Adolescent; D000913:Antibodies, Protozoan / Q000276:immunology*; D000953:Antigens, Protozoan / Q000276:immunology* / Q000378:metabolism*; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006021:Glycophorins / Q000378:metabolism; D006801:Humans; D007118:Immunoassay; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology*; D008137:Longitudinal Studies; D016778:Malaria, Falciparum / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D008297:Male; D052940:Merozoites / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D006021:Glycophorins; D007074:Immunoglobulin G; D015800:Protozoan Proteins; C065668:erythrocyte-binding antigen 175, Plasmodium
keywords: EBA-175; Plasmodium falciparum; antibodies; binding inhibition; malaria