Viral receptor-binding site antibodies with diverse germline origins

Vaccines for rapidly evolving pathogens will confer lasting immunity if they elicit antibodies recognizing conserved epitopes, such as a receptor-binding site (RBS). From characteristics of an influenza-virus RBS-directed antibody, we devised a signature motif to search for similar antibodies. We id...

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Bibliographic Details
Published in:Cell Vol. 161; no. 5; pp. 1026 - 1034
Main Authors: Schmidt, Aaron G, Therkelsen, Matthew D, Stewart, Shaun, Kepler, Thomas B, Liao, Hua-Xin, Moody, M Anthony, Haynes, Barton F, Harrison, Stephen C
Format: Journal Article
Language:English
Published: United States 21.05.2015
Subjects:
Amino Acid Sequence
Antibodies, Viral - chemistry
Antibodies, Viral - immunology
Complementarity Determining Regions
Humans
Immunoglobulin Heavy Chains - genetics
Immunoglobulin Variable Region - genetics
Influenza Vaccines - immunology
Models, Molecular
Molecular Mimicry
Molecular Sequence Data
Receptors, Virus - chemistry
ISSN:1097-4172
Online Access:Get more information
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Summary:Vaccines for rapidly evolving pathogens will confer lasting immunity if they elicit antibodies recognizing conserved epitopes, such as a receptor-binding site (RBS). From characteristics of an influenza-virus RBS-directed antibody, we devised a signature motif to search for similar antibodies. We identified, from three vaccinees, over 100 candidates encoded by 11 different VH genes. Crystal structures show that antibodies in this class engage the hemagglutinin RBS and mimic binding of the receptor, sialic acid, by supplying a critical dipeptide on their projecting, heavy-chain third complementarity determining region. They share contacts with conserved, receptor-binding residues but contact different residues on the RBS periphery, limiting the likelihood of viral escape when several such antibodies are present. These data show that related modes of RBS recognition can arise from different germline origins and mature through diverse affinity maturation pathways. Immunogens focused on an RBS-directed response will thus have a broad range of B cell targets.
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ISSN:1097-4172
DOI:10.1016/j.cell.2015.04.028