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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Veröffentlicht in:Cell Jg. 161; H. 5; S. 1026 - 1034
Hauptverfasser: 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
Sprache:Englisch
Veröffentlicht: United States 21.05.2015
Schlagworte:
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
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Abstract 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.
AbstractList 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.
Author Schmidt, Aaron G
Stewart, Shaun
Harrison, Stephen C
Kepler, Thomas B
Haynes, Barton F
Moody, M Anthony
Liao, Hua-Xin
Therkelsen, Matthew D
Author_xml – sequence: 1
  givenname: Aaron G
  surname: Schmidt
  fullname: Schmidt, Aaron G
  organization: Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
– sequence: 2
  givenname: Matthew D
  surname: Therkelsen
  fullname: Therkelsen, Matthew D
  organization: Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
– sequence: 3
  givenname: Shaun
  surname: Stewart
  fullname: Stewart, Shaun
  organization: Novartis Vaccines and Diagnostics, Cambridge MA, USA
– sequence: 4
  givenname: Thomas B
  surname: Kepler
  fullname: Kepler, Thomas B
  organization: Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA
– sequence: 5
  givenname: Hua-Xin
  surname: Liao
  fullname: Liao, Hua-Xin
  organization: Duke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710, USA
– sequence: 6
  givenname: M Anthony
  surname: Moody
  fullname: Moody, M Anthony
  organization: Duke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710, USA
– sequence: 7
  givenname: Barton F
  surname: Haynes
  fullname: Haynes, Barton F
  organization: Duke Human Vaccine Institute, Duke University Medical School, Durham, NC 27710, USA
– sequence: 8
  givenname: Stephen C
  surname: Harrison
  fullname: Harrison, Stephen C
  email: harrison@crystal.harvard.edu
  organization: Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA. Electronic address: harrison@crystal.harvard.edu
BackLink https://www.ncbi.nlm.nih.gov/pubmed/25959776$$D View this record in MEDLINE/PubMed
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Snippet Vaccines for rapidly evolving pathogens will confer lasting immunity if they elicit antibodies recognizing conserved epitopes, such as a receptor-binding site...
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SubjectTerms 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
Title Viral receptor-binding site antibodies with diverse germline origins
URI https://www.ncbi.nlm.nih.gov/pubmed/25959776
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