A Common Solution to Group 2 Influenza Virus Neutralization

Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):445-50. doi: 10.1073/pnas.1319058110. Epub 2013 Dec 11.

Abstract

The discovery and characterization of broadly neutralizing antibodies (bnAbs) against influenza viruses have raised hopes for the development of monoclonal antibody (mAb)-based immunotherapy and the design of universal influenza vaccines. Only one human bnAb (CR8020) specifically recognizing group 2 influenza A viruses has been previously characterized that binds to a highly conserved epitope at the base of the hemagglutinin (HA) stem and has neutralizing activity against H3, H7, and H10 viruses. Here, we report a second group 2 bnAb, CR8043, which was derived from a different germ-line gene encoding a highly divergent amino acid sequence. CR8043 has in vitro neutralizing activity against H3 and H10 viruses and protects mice against challenge with a lethal dose of H3N2 and H7N7 viruses. The crystal structure and EM reconstructions of the CR8043-H3 HA complex revealed that CR8043 binds to a site similar to the CR8020 epitope but uses an alternative angle of approach and a distinct set of interactions. The identification of another antibody against the group 2 stem epitope suggests that this conserved site of vulnerability has great potential for design of therapeutics and vaccines.

Keywords: X-ray crystallography; antibody recognition; electron microscopy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies / chemistry
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Viral / chemistry
  • Antibodies, Viral / immunology*
  • Chromatography, Gel
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / chemistry
  • Female
  • Hemagglutinin Glycoproteins, Influenza Virus / chemistry
  • Humans
  • Immunologic Memory
  • Influenza A virus / chemistry*
  • Influenza Vaccines / chemistry
  • Influenza Vaccines / immunology
  • Kinetics
  • Mice
  • Mice, Inbred BALB C
  • Microscopy, Electron
  • Models, Molecular
  • Molecular Conformation
  • Species Specificity

Substances

  • Antibodies
  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Epitopes
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Influenza Vaccines

Associated data

  • PDB/4NM4
  • PDB/4NM8