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Abstract
Influenza B viruses (FLUBVs) contribute significantly to seasonal influenza epidemics, co-circulating with influenza A viruses and disproportionately affecting children and other vulnerable populations. Unlike influenza A, which infects multiple species, FLUBVs are uniquely restricted to humans and have evolved into two antigenically distinct lineages, Victoria and Yamagata, which have continuously diverged since the 1970s. In recent years, particularly since 2015, contemporary FLUBVs have undergone further divergence, driven by distinct evolutionary mechanisms that have contributed to increased endemic activity.Despite their global impact, critical gaps remain in our understanding of FLUBV receptor specificity, immune interactions, and mechanisms of cross-protection between lineages. Using novel glycan microarrays designed to mimic the human respiratory tract, we comprehensively characterized the receptor binding profiles of ancestral and contemporary FLUBVs from both lineages. Our findings reveal that glycosylation at a critical hemagglutinin (HA) residue (N196) modulates receptor binding, influencing host adaptation and viral evolution. Additionally, we investigated lineage-specific differences in immunity using animal models, demonstrating that infection with Victoria lineage viruses elicits robust cross-protective neuraminidase (NA)-specific antibodies, whereas Yamagata infectionprovides limited immunity against Victoria viruses. These results offer a mechanistic explanation for the recent disappearance of Yamagata viruses from circulation and highlight the importance of NA-targeted immunity in vaccine design. Further, comparative analysis of innate immune responses to FLUBV infection in ferrets revealed that Victoria and Yamagata viruses exhibit distinct cytokine kinetics and gene expression patterns. Notably, Yamagata viruses induce an early antiviral response through SOCS1 upregulation, while Victoria viruses delay innate immune activation, potentially enhancing viral replication and immune evasion. Together, these studies provide new insights into the molecular and immunological differences between FLUBV lineages, with implications for vaccine strategies and influenza B virus control.