title: Induction of strain-transcending antibodies against Group A PfEMP1 surface antigens from virulent malaria parasites.
abstract: Sequence diversity in pathogen antigens is an obstacle to the development of interventions against many infectious diseases. In malaria caused by Plasmodium falciparum, the PfEMP1 family of variant surface antigens encoded by var genes are adhesion molecules that play a pivotal role in malaria pathogenesis and clinical disease. PfEMP1 is a major target of protective immunity, however, development of drugs or vaccines based on PfEMP1 is problematic due to extensive sequence diversity within the PfEMP1 family. Here we identified the PfEMP1 variants transcribed by P. falciparum strains selected for a virulence-associated adhesion phenotype (IgM-positive rosetting). The parasites transcribed a subset of Group A PfEMP1 variants characterised by an unusual PfEMP1 architecture and a distinct N-terminal domain (either DBLα1.5 or DBLα1.8 type). Antibodies raised in rabbits against the N-terminal domains showed functional activity (surface reactivity with live infected erythrocytes (IEs), rosette inhibition and induction of phagocytosis of IEs) down to low concentrations (<10 µg/ml of total IgG) against homologous parasites. Furthermore, the antibodies showed broad cross-reactivity against heterologous parasite strains with the same rosetting phenotype, including clinical isolates from four sub-Saharan African countries that showed surface reactivity with either DBLα1.5 antibodies (variant HB3var6) or DBLα1.8 antibodies (variant TM284var1). These data show that parasites with a virulence-associated adhesion phenotype share IE surface epitopes that can be targeted by strain-transcending antibodies to PfEMP1. The existence of shared surface epitopes amongst functionally similar disease-associated P. falciparum parasite isolates suggests that development of therapeutic interventions to prevent severe malaria is a realistic goal.
authors.affiliation: Centre for Immunity, Infection and Evolution, Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ashfaq
authors.initials: A
authors.lastname: Ghumra
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Semblat
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ataide
authors.forename: Carolyne
authors.initials: C
authors.lastname: Kifude
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Adams
authors.forename: Antoine
authors.initials: A
authors.lastname: Claessens
authors.forename: Damian N
authors.initials: DN
authors.lastname: Anong
authors.forename: Peter C
authors.initials: PC
authors.lastname: Bull
authors.forename: Clare
authors.initials: C
authors.lastname: Fennell
authors.forename: Monica
authors.initials: M
authors.lastname: Arman
authors.forename: Alfred
authors.initials: A
authors.lastname: Amambua-Ngwa
authors.forename: Michael
authors.initials: M
authors.lastname: Walther
authors.forename: David J
authors.initials: DJ
authors.lastname: Conway
authors.forename: Lalla
authors.initials: L
authors.lastname: Kassambara
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.forename: Ahmed
authors.initials: A
authors.lastname: Raza
authors.forename: J Alexandra
authors.initials: JA
authors.lastname: Rowe
mesh_terms: D017954:Africa South of the Sahara; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology*; D000953:Antigens, Protozoan / Q000276:immunology*; D004912:Erythrocytes / Q000276:immunology / Q000469:parasitology; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000276:immunology* / Q000517:prevention & control; D008297:Male; D010963:Plasmodium falciparum / Q000276:immunology*; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000276:immunology*; D011817:Rabbits
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D015800:Protozoan Proteins; C085731:erythrocyte membrane protein 1, Plasmodium falciparum