title: Chondroitin sulfate A-adhering Plasmodium falciparum-infected erythrocytes express functionally important antibody epitopes shared by multiple variants.
abstract: Acquired protection from Plasmodium falciparum placental malaria, a major cause of maternal, fetal, and infant morbidity, is mediated by IgG specific for the P. falciparum erythrocyte membrane protein 1 variant VAR2CSA. This protein enables adhesion of P. falciparum-infected erythrocytes to chondroitin sulfate A in the intervillous space. Although interclonal variation of the var2csa gene is lower than that among var genes in general, VAR2CSA-specific Abs appear to target mainly polymorphic epitopes. This has raised doubts about the feasibility of VAR2CSA-based vaccines. We used eight human monoclonal IgG Abs from affinity-matured memory B cells of P. falciparum-exposed women to study interclonal variation and functional importance of Ab epitopes among placental and peripheral parasites from East and West Africa. Most placental P. falciparum isolates were labeled by several mAbs, whereas peripheral isolates from children were essentially nonreactive. The mAb reactivity of peripheral isolates from pregnant women indicated that some were placental, whereas others had alternative sequestration foci. Most of the mAbs were comparable in their reactivity with bound infected erythrocytes (IEs) and recombinant VAR2CSA and interfered with IE and/or VAR2CSA binding to chondroitin sulfate A. Pair-wise mAb combinations were more inhibitory than single mAbs, and all of the mAbs together was the most efficient combination. Each mAb could opsonize IEs for phagocytosis, and a combination of the eight mAbs caused phagocytosis similar to that of plasma IgG-opsonized IEs. We conclude that functionally important Ab epitopes are shared by the majority of polymorphic VAR2CSA variants, which supports the feasibility of VAR2CSA-based vaccines against placental malaria.
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology, and Microbiology, University of Copenhagen, Denmark.
authors.forename: Lea
authors.initials: L
authors.lastname: Barfod
authors.forename: Tina
authors.initials: T
authors.lastname: Dobrilovic
authors.forename: Pamela
authors.initials: P
authors.lastname: Magistrado
authors.forename: Pongsak
authors.initials: P
authors.lastname: Khunrae
authors.forename: Firmine
authors.initials: F
authors.lastname: Viwami
authors.forename: Jonas
authors.initials: J
authors.lastname: Bruun
authors.forename: Madeleine
authors.initials: M
authors.lastname: Dahlbäck
authors.forename: Nadia L
authors.initials: NL
authors.lastname: Bernasconi
authors.forename: Michal
authors.initials: M
authors.lastname: Fried
authors.forename: Davis
authors.initials: D
authors.lastname: John
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Duffy
authors.forename: Ali
authors.initials: A
authors.lastname: Salanti
authors.forename: Antonio
authors.initials: A
authors.lastname: Lanzavecchia
authors.forename: Chwee Teck
authors.initials: CT
authors.lastname: Lim
authors.forename: Nicaise Tuikue
authors.initials: NT
authors.lastname: Ndam
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Higgins
authors.forename: Lars
authors.initials: L
authors.lastname: Hviid
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000913:Antibodies, Protozoan / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D002809:Chondroitin Sulfates / Q000276:immunology*; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D004912:Erythrocytes / Q000276:immunology* / Q000469:parasitology; D005260:Female; D006801:Humans; D017780:Malaria Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D016778:Malaria, Falciparum / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D008297:Male; D010920:Placenta / Q000276:immunology / Q000469:parasitology; D010963:Plasmodium falciparum / Q000235:genetics / Q000276:immunology*; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000235:genetics / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000913:Antibodies, Protozoan; D000939:Epitopes; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum; D002809:Chondroitin Sulfates