Glycan repositioning of influenza hemagglutinin stem facilitates the elicitation of protective cross-group antibody responses

Nat Commun. 2020 Feb 7;11(1):791. doi: 10.1038/s41467-020-14579-4.

Abstract

The conserved hemagglutinin (HA) stem has been a focus of universal influenza vaccine efforts. Influenza A group 1 HA stem-nanoparticles have been demonstrated to confer heterosubtypic protection in animals; however, the protection does not extend to group 2 viruses, due in part to differences in glycosylation between group 1 and 2 stems. Here, we show that introducing the group 2 glycan at Asn38HA1 to a group 1 stem-nanoparticle (gN38 variant) based on A/New Caledonia/20/99 (H1N1) broadens antibody responses to cross-react with group 2 HAs. Immunoglobulins elicited by the gN38 variant provide complete protection against group 2 H7N9 virus infection, while the variant loses protection against a group 1 H5N1 virus. The N38HA1 glycan thus is pivotal in directing antibody responses by controlling access to group-determining stem epitopes. Precise targeting of stem-directed antibody responses to the site of vulnerability by glycan repositioning may be a step towards achieving cross-group influenza protection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Viral / immunology
  • Antibody Specificity
  • Asparagine / chemistry
  • Asparagine / metabolism
  • Broadly Neutralizing Antibodies / immunology
  • Cross Reactions
  • Epitopes / immunology
  • Female
  • Glycosylation
  • Hemagglutinin Glycoproteins, Influenza Virus / chemistry*
  • Hemagglutinin Glycoproteins, Influenza Virus / immunology*
  • Hemagglutinin Glycoproteins, Influenza Virus / metabolism
  • Immunoglobulins / immunology
  • Influenza A Virus, H7N9 Subtype / pathogenicity
  • Influenza Vaccines / immunology*
  • Mice, Inbred BALB C
  • Nanoparticles / chemistry*
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / prevention & control
  • Polysaccharides / chemistry*

Substances

  • Antibodies, Viral
  • Broadly Neutralizing Antibodies
  • Epitopes
  • H1N1 virus hemagglutinin
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Immunoglobulins
  • Influenza Vaccines
  • Polysaccharides
  • Asparagine