Neuraminidase-specific antibodies drive differential cross-protection between contemporary FLUBV lineages

The two influenza B virus (FLUBV) lineages have continuously diverged from each other since the 1980s, with recent (post-2015) viruses exhibiting accelerated evolutionary rates. Emerging data from human studies and epidemiological models suggest that increased divergence in contemporary viruses may drive differential cross-protection, where infection with Yamagata lineage viruses provides limited immunity against Victoria lineage viruses. Here, we developed animal models to investigate the mechanisms behind asymmetric cross-protection between contemporary FLUBV lineages. Our results show that contemporary Victoria immunity provides robust cross-protection against the Yamagata lineage, whereas Yamagata immunity offers limited protection against the Victoria lineage. This differential cross-protection is driven by Victoria-elicited neuraminidase (NA)–specific antibodies, which show cross-lineage reactivity, unlike those from Yamagata infections. These findings identify a phenomenon in contemporary FLUBV that may help explain the recent disappearance of the Yamagata lineage from circulation, highlighting the crucial role of targeting NA in vaccination strategies to enhance cross-lineage FLUBV protection.