Exposure of an occluded hemagglutinin epitope drives selection of a class of cross-protective influenza antibodies

Nat Commun. 2019 Aug 28;10(1):3883. doi: 10.1038/s41467-019-11821-6.


Germinal center (GC) B cells at viral replication sites acquire specificity to poorly immunogenic but conserved influenza hemagglutinin (HA) epitopes. Here, high-throughput epitope mapping of local GC B cells is used to identify conserved HA epitope selecting cross-reactive antibodies that mediate heterosubtypic protection. A distinct feature of this epitope is an occlusion in the naive trimeric HA structure that is exposed in the post-fusion HA structure to occur under low pH conditions during viral replication. Importantly, systemic immunization by the post-fusion HA antigen results in GC B cells targeting the occluded epitope, and induces a class of protective antibodies that have cross-group specificity and afford protection independent of virus neutralization activity. Furthermore, this class of broadly protective antibodies develops at late time points and persists. Our results identify a class of cross-protective antibodies that are selected at the viral replication site, and provide insights into vaccine strategies using the occluded epitope.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Viral / immunology*
  • B-Lymphocytes / immunology*
  • Cross Reactions
  • Epitope Mapping
  • Epitopes / immunology*
  • Germinal Center / cytology
  • Germinal Center / immunology
  • Hemagglutinin Glycoproteins, Influenza Virus / immunology*
  • Humans
  • Immunization
  • Influenza A virus / immunology*
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Virus Replication


  • Antibodies, Viral
  • Epitopes
  • Hemagglutinin Glycoproteins, Influenza Virus