Immune Imprinting Drives Human Norovirus Potential for Global Spread

Lisa C. Lindesmith*, Florencia A.T. Boshier, Paul D. Brewer-Jensen, Sunando Roy, Veronica Costantini, Michael L. Mallory, Mark Zweigart, Samantha R. May, Helen Conrad, Kathleen M. O’Reilly, Daniel Kelly, Cristina C. Celma, Stuart Beard, Rachel Williams, Helena J. Tutill, Sylvia Becker Dreps, Filemón Bucardo, David J. Allen, Jan Vinjé, Richard A. GoldsteinJudith Breuer, Ralph S. Baric

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)


Understanding the complex interactions between virus and host that drive new strain evolution is key to predicting the emergence potential of variants and informing vaccine development. Under our hypothesis, future dominant human norovirus GII.4 variants with critical antigenic properties that allow them to spread are currently circulating undetected, having diverged years earlier. Through large-scale sequencing of GII.4 surveillance samples, we identified two variants with extensive divergence within domains that mediate neutralizing antibody binding. Subsequent serological characterization of these strains using temporally resolved adult and child sera suggests that neither candidate could spread globally in adults with multiple GII.4 exposures, yet young children with minimal GII.4 exposure appear susceptible. Antigenic cartography of surveillance and outbreak sera indicates that continued population exposure to GII.4 Sydney 2012 and antigenically related variants over a 6-year period resulted in a broadening of immunity to heterogeneous GII.4 variants, including those identified here. We show that the strongest antibody responses in adults exposed to GII.4 Sydney 2012 are directed to previously circulating GII.4 viruses. Our data suggest that the broadening of antibody responses compromises establishment of strong GII.4 Sydney 2012 immunity, thereby allowing the continued persistence of GII.4 Sydney 2012 and modulating the cycle of norovirus GII.4 variant replacement. Our results indicate a cycle of norovirus GII.4 variant replacement dependent upon population immunity. Young children are susceptible to divergent variants; therefore, emergence of these strains worldwide is driven proximally by changes in adult serological immunity and distally by viral evolution that confers fitness in the context of immunity.

Original languageEnglish
Issue number5
Publication statusPublished - Sept 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
Copyright © 2022 Lindesmith et al.


  • antigenic cartography
  • antigenic seniority
  • epidemic
  • histo-blood group antigens
  • immune imprinting
  • neutralizing antibodies
  • norovirus
  • sequencing
  • surveillance
  • variant persistence
  • variants of concern


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