Sera Antibody Repertoire Analyses Reveal Mechanisms of Broad and Pandemic Strain Neutralizing Responses after Human Norovirus Vaccination

Immunity. 2019 Jun 18;50(6):1530-1541.e8. doi: 10.1016/j.immuni.2019.05.007.


Rapidly evolving RNA viruses, such as the GII.4 strain of human norovirus (HuNoV), and their vaccines elicit complex serological responses associated with previous exposure. Specific correlates of protection, moreover, remain poorly understood. Here, we report the GII.4-serological antibody repertoire-pre- and post-vaccination-and select several antibody clonotypes for epitope and structural analysis. The humoral response was dominated by GII.4-specific antibodies that blocked ancestral strains or by antibodies that bound to divergent genotypes and did not block viral-entry-ligand interactions. However, one antibody, A1431, showed broad blockade toward tested GII.4 strains and neutralized the pandemic GII.P16-GII.4 Sydney strain. Structural mapping revealed conserved epitopes, which were occluded on the virion or partially exposed, allowing for broad blockade with neutralizing activity. Overall, our results provide high-resolution molecular information on humoral immune responses after HuNoV vaccination and demonstrate that infection-derived and vaccine-elicited antibodies can exhibit broad blockade and neutralization against this prevalent human pathogen.

Keywords: antigenic seniority; epitope mapping; human monoclonal antibodies; imprinting; neutralizing antibodies; norovirus; original antigen sin; serological repertoire; vaccination; x-ray crystallography.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Viral / chemistry
  • Antibodies, Viral / immunology*
  • Caliciviridae Infections / epidemiology
  • Caliciviridae Infections / immunology*
  • Caliciviridae Infections / prevention & control*
  • Caliciviridae Infections / virology
  • Cell Line
  • Conserved Sequence
  • Epitopes / chemistry
  • Epitopes / immunology
  • Humans
  • Immunoglobulin G / immunology
  • Models, Molecular
  • Norovirus / classification
  • Norovirus / immunology*
  • Protein Binding
  • Protein Conformation
  • Recombinant Proteins / immunology
  • Vaccination
  • Viral Vaccines / immunology*


  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Epitopes
  • Immunoglobulin G
  • Recombinant Proteins
  • Viral Vaccines