title: Overcoming antigenic diversity by enhancing the immunogenicity of conserved epitopes on the malaria vaccine candidate apical membrane antigen-1.
abstract: Malaria vaccine candidate Apical Membrane Antigen-1 (AMA1) induces protection, but only against parasite strains that are closely related to the vaccine. Overcoming the AMA1 diversity problem will require an understanding of the structural basis of cross-strain invasion inhibition. A vaccine containing four diverse allelic proteins 3D7, FVO, HB3 and W2mef (AMA1 Quadvax or QV) elicited polyclonal rabbit antibodies that similarly inhibited the invasion of four vaccine and 22 non-vaccine strains of P. falciparum. Comparing polyclonal anti-QV with antibodies against a strain-specific, monovalent, 3D7 AMA1 vaccine revealed that QV induced higher levels of broadly inhibitory antibodies which were associated with increased conserved face and domain-3 responses and reduced domain-2 response. Inhibitory monoclonal antibodies (mAb) raised against the QV reacted with a novel cross-reactive epitope at the rim of the hydrophobic trough on domain-1; this epitope mapped to the conserved face of AMA1 and it encompassed the 1e-loop. MAbs binding to the 1e-loop region (1B10, 4E8 and 4E11) were ∼10-fold more potent than previously characterized AMA1-inhibitory mAbs and a mode of action of these 1e-loop mAbs was the inhibition of AMA1 binding to its ligand RON2. Unlike the epitope of a previously characterized 3D7-specific mAb, 1F9, the 1e-loop inhibitory epitope was partially conserved across strains. Another novel mAb, 1E10, which bound to domain-3, was broadly inhibitory and it blocked the proteolytic processing of AMA1. By itself mAb 1E10 was weakly inhibitory but it synergized with a previously characterized, strain-transcending mAb, 4G2, which binds close to the hydrophobic trough on the conserved face and inhibits RON2 binding to AMA1. Novel inhibition susceptible regions and epitopes, identified here, can form the basis for improving the antigenic breadth and inhibitory response of AMA1 vaccines. Vaccination with a few diverse antigenic proteins could provide universal coverage by redirecting the immune response towards conserved epitopes.
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Sheetij
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Dlugosz
authors.affiliation: Burnet Institute, Melbourne, Victoria, Australia.
authors.forename: Damien R
authors.initials: DR
authors.lastname: Drew
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Ge
authors.affiliation: Department of Biochemistry, La Trobe University, Victoria, Australia.
authors.forename: Xiopeng
authors.initials: X
authors.lastname: Ge
authors.affiliation: Laboratory of Malaria and Vector Research, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Diouf
authors.initials: D
authors.lastname: Ababacar
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Yazmin I
authors.initials: YI
authors.lastname: Rovira
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: J Kathleen
authors.initials: JK
authors.lastname: Moch
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Meng
authors.initials: M
authors.lastname: Shi
authors.affiliation: Laboratory of Malaria and Vector Research, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Carole A
authors.initials: CA
authors.lastname: Long
authors.affiliation: Department of Biochemistry, La Trobe University, Victoria, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Foley
authors.affiliation: Burnet Institute, Melbourne, Victoria, Australia.
authors.forename: James G
authors.initials: JG
authors.lastname: Beeson
authors.affiliation: Department of Biochemistry, La Trobe University, Victoria, Australia.
authors.forename: Robin F
authors.initials: RF
authors.lastname: Anders
authors.affiliation: Laboratory of Malaria and Vector Research, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Miura
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: J David
authors.initials: JD
authors.lastname: Haynes
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Adrian H
authors.initials: AH
authors.lastname: Batchelor
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D000940:Antigenic Variation / Q000235:genetics / Q000276:immunology; D000953:Antigens, Protozoan / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D017124:Conserved Sequence / Q000276:immunology; D018604:Epitope Mapping; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D056724:Immunity, Humoral; D017780:Malaria Vaccines / Q000737:chemistry / Q000276:immunology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D010962:Plasmodium berghei / Q000235:genetics / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology*; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000953:Antigens, Protozoan; D000939:Epitopes; D017780:Malaria Vaccines; D008565:Membrane Proteins; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; C090077:apical membrane antigen I, Plasmodium