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.
|Publication status||Published - Sept 2022|
Bibliographical noteFunding Information:
We thank the Microscopy Services Laboratory, Department of Pathology and Laboratory Medicine, University of North Carolina Chapel Hill, and Shilpi Sheth, LSHTM, for her support of the genomics work through retrieval of specimens and preparation and testing of nucleic acid extracts. The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Funding was provided by the Wellcome Trust [203268/Z/16/Z], and the National Institute of Allergy and Infectious Disease R01 AI148260 and R01AI127845.
Funding was provided by the Wellcome Trust [203268/Z/16/Z], and the National Institute of Allergy and Infectious Disease R01 AI148260 and R01AI127845.
Copyright © 2022 Lindesmith et al.
- antigenic cartography
- antigenic seniority
- histo-blood group antigens
- immune imprinting
- neutralizing antibodies
- variant persistence
- variants of concern