Overcoming Antigenic Diversity by Enhancing the Immunogenicity of Conserved Epitopes on the Malaria Vaccine Candidate Apical Membrane Antigen-1

PLoS Pathogens

Damien R. Drew¹  James G. Beeson¹  Michael Foley²  Xiopeng Ge²  Robin F. Anders²  Kazutoyo Miura³  Carole A. Long³  Diouf Ababacar³  Adrian H. Batchelor⁴  Meng Shi⁴  Sheetij Dutta⁴  J. David Haynes⁴  Yazmin I. Rovira⁴  Lisa S. Dlugosz⁴  J. Kathleen Moch⁴ 

[1] Burnet Institute, Melbourne, Victoria, Australia;Department of Biochemistry, La Trobe University, Victoria, Australia;Laboratory of Malaria and Vector Research, National Institutes of Health, Rockville, Maryland, United States of America;Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America

关键词: Vaccines;    Antibodies;    Enzyme-linked immunoassays;    Plasmodium;    Malaria;    Malarial parasites;    Antigens;    Monoclonal antibodies;   

DOI  :  10.1371/journal.ppat.1003840

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY