Emergence of a novel GII.17 variant is associated with immune evasion rather than an altered HBGA-binding profile

The epidemiology of noroviruses, a major cause of gastroenteritis in humans, is shaped by their continuous evolution. Novel genotypes and variants periodically emerge, replacing previously dominant strains. In 2024, a novel GII.17 variant led to an increased number of notified outbreaks, becoming the dominant genotype detected in Europe. To investigate if this surge in GII.17 detection is attributable to changes in the binding and antigenicity of this novel variant, we compared properties of a GII.17 2024 strain with representative GII.17 strains from 2005 (Clade B), 2014 (Clade C), and 2015 (Clade D), and the epidemic GII.4 Sydney 2012 variant. Norovirus virus-like particles (VLPs) were used to assess binding to saliva samples and human intestinal tissues with different histo-blood group antigen (HBGA) profiles. Binding specificity to individual glycans was determined using synthetic HBGAs. Additionally, VP1-NanoLuc (NLuc) fusion proteins were used in binding blocking assays to evaluate the antigenic properties of the variants using 75 sera from healthy adults that were collected during different time periods of GII.17 circulation (the winters of 2009-2010, 2015 and 2024). Compared with other GII.17 variants, the 2024 strain exhibited amino acid substitutions in the P2 domain, which contains both antigenic sites and the HBGA binding site. Binding-blocking assays with human sera confirmed that the 2024 variant is antigenically distinct from the 2005 and 2015 GII.17 strains but closely related to the 2014 variant. All post-2005 GII.17 strains showed a broader HBGA binding profile compared to the GII.17 2005 strain, likely contributing to their more successful spread. These findings show that the recent re-emergence of GII.17 coincided with antigenic drift, enabling it to escape from pre-existing immunity, but not with major changes in HBGA binding specificity. Understanding the factors influencing norovirus emergence is essential for the development of preventive strategies against future norovirus epidemics.