title: Evidence for erythrocyte-binding antigen 175 as a component of a ligand-blocking blood-stage malaria vaccine.
abstract: The ligands that pathogens use to invade their target cells have often proven to be good targets for vaccine development. However, Plasmodium falciparum has redundant ligands that mediate invasion of erythrocytes. The first requirement for the development of a successful ligand-blocking malaria vaccine is the demonstration that antibodies induced to each ligand can block the erythrocyte invasion of parasites with polymorphic sequences. Because of P. falciparum's redundancy in erythrocyte invasion, each ligand needs to be studied under artificial conditions in which parasite invasion is restricted in its use of alternative pathways. Here we investigate the role of erythrocyte-binding antigen 175 (EBA-175), a parasite ligand that binds to sialic acid on glycophorin A, in the invasion of erythrocytes by 10 P. falciparum clones under conditions in which invasion is partially limited to the EBA-175-glycophorin A pathway, using chymotrypsin-treated erythrocytes. We show that the ability to invade erythrocytes for both sialic acid-independent and sialic acid-dependent pathways requires the EBA-175-glycophorin A pathway for erythrocyte invasion. Importantly, antibodies against region II of EBA-175 from the 3D7 clone blocked invasion of chymotrypsin-treated erythrocytes by >50% by all parasite clones studied, including those with multiple different mutations described in the literature. The one exception was FCR3, which had a similar sequence to 3D7 but only 30% inhibition of invasion of chymotrypsin-treated erythrocytes, indicating alternative pathways for invasion of chymotrypsin-treated erythrocytes. Our findings suggest that antibodies to region II of EBA-175, as one component of a ligand-blocking malaria vaccine, are largely unaffected by polymorphism in EBA-175.
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA. ljiang@niaid.nih.gov
authors.forename: Lubin
authors.initials: L
authors.lastname: Jiang
authors.forename: Deepak
authors.initials: D
authors.lastname: Gaur
authors.forename: Jianbing
authors.initials: J
authors.lastname: Mu
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Carole A
authors.initials: CA
authors.lastname: Long
authors.forename: Louis H
authors.initials: LH
authors.lastname: Miller
mesh_terms: D000913:Antibodies, Protozoan / Q000494:pharmacology*; D000953:Antigens, Protozoan / Q000276:immunology* / Q000378:metabolism; D002918:Chymotrypsin; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D006021:Glycophorins / Q000378:metabolism*; D006790:Host-Parasite Interactions / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008288:Malaria / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000276:immunology* / Q000378:metabolism; D015800:Protozoan Proteins / Q000276:immunology* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D006021:Glycophorins; D007074:Immunoglobulin G; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C065668:erythrocyte-binding antigen 175, Plasmodium; D002918:Chymotrypsin