title: Human antibodies fix complement to inhibit Plasmodium falciparum invasion of erythrocytes and are associated with protection against malaria.
abstract: Antibodies play major roles in immunity to malaria; however, a limited understanding of mechanisms mediating protection is a major barrier to vaccine development. We have demonstrated that acquired human anti-malarial antibodies promote complement deposition on the merozoite to mediate inhibition of erythrocyte invasion through C1q fixation and activation of the classical complement pathway. Antibody-mediated complement-dependent (Ab-C') inhibition was the predominant invasion-inhibitory activity of human antibodies; most antibodies were non-inhibitory without complement. Inhibitory activity was mediated predominately via C1q fixation, and merozoite surface proteins 1 and 2 were identified as major targets. Complement fixation by antibodies was very strongly associated with protection from both clinical malaria and high-density parasitemia in a prospective longitudinal study of children. Ab-C' inhibitory activity could be induced by human immunization with a candidate merozoite surface-protein vaccine. Our findings demonstrate that human anti-malarial antibodies have evolved to function by fixing complement for potent invasion-inhibitory activity and protective immunity.
authors.affiliation: The Burnet Institute for Medical Research and Public Health, 85 Commercial Road, Melbourne, VIC 3004, Australia; Department of Medical Biology, University of Melbourne, Royal Parade, Melbourne, VIC 3010, Australia.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Boyle
authors.affiliation: The Burnet Institute for Medical Research and Public Health, 85 Commercial Road, Melbourne, VIC 3004, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Reiling
authors.affiliation: The Burnet Institute for Medical Research and Public Health, 85 Commercial Road, Melbourne, VIC 3004, Australia.
authors.forename: Gaoqian
authors.initials: G
authors.lastname: Feng
authors.affiliation: The Burnet Institute for Medical Research and Public Health, 85 Commercial Road, Melbourne, VIC 3004, Australia.
authors.forename: Christine
authors.initials: C
authors.lastname: Langer
authors.affiliation: Centre for Geographic Medicine Research, Kenya Medical Research Institute, Coast, PO Box 230, 80108 Kilifi, Kenya.
authors.forename: Faith H
authors.initials: FH
authors.lastname: Osier
authors.affiliation: London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E7HT, UK.
authors.forename: Harvey
authors.initials: H
authors.lastname: Aspeling-Jones
authors.affiliation: The Burnet Institute for Medical Research and Public Health, 85 Commercial Road, Melbourne, VIC 3004, Australia; Department of Medical Biology, University of Melbourne, Royal Parade, Melbourne, VIC 3010, Australia.
authors.forename: Yik Sheng
authors.initials: YS
authors.lastname: Cheng
authors.affiliation: The Burnet Institute for Medical Research and Public Health, 85 Commercial Road, Melbourne, VIC 3004, Australia.
authors.forename: Janine
authors.initials: J
authors.lastname: Stubbs
authors.affiliation: London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E7HT, UK.
authors.forename: Kevin K A
authors.initials: KK
authors.lastname: Tetteh
authors.affiliation: London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E7HT, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Conway
authors.affiliation: QIMR Berghofer Medical Research Institute, University of Queensland, 300 Herston Road, Herston, QLD 4006, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: McCarthy
authors.affiliation: Walter and Eliza Hall Institute, Royal Parade, Melbourne, VIC 3050, Australia.
authors.forename: Ivo
authors.initials: I
authors.lastname: Muller
authors.affiliation: Centre for Geographic Medicine Research, Kenya Medical Research Institute, Coast, PO Box 230, 80108 Kilifi, Kenya.
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.affiliation: Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia.
authors.forename: Robin F
authors.initials: RF
authors.lastname: Anders
authors.affiliation: The Burnet Institute for Medical Research and Public Health, 85 Commercial Road, Melbourne, VIC 3004, Australia; Department of Microbiology, Monash University, Clayton, VIC 3800, Australia. Electronic address: beeson@burnet.edu.au.
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
mesh_terms: D000293:Adolescent; D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis*; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D015922:Complement C1q / Q000378:metabolism*; D003168:Complement Fixation Tests; D003171:Complement Pathway, Classical; D004912:Erythrocytes / Q000276:immunology / Q000469:parasitology; D005260:Female; D015870:Gene Expression; D054884:Host-Pathogen Interactions; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D008297:Male; D020066:Merozoite Surface Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D052940:Merozoites / Q000276:immunology*; D018512:Parasitemia / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D010963:Plasmodium falciparum / Q000276:immunology*; D011446:Prospective Studies; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D007074:Immunoglobulin G; D017780:Malaria Vaccines; D020066:Merozoite Surface Protein 1; D015800:Protozoan Proteins; C065974:merozoite surface protein 2, Plasmodium; D015922:Complement C1q