biostudies-literatureUnknown11(13)Page CKThe 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-Science advanceseadu3344https://www.ebi.ac.uk/biostudies/studies/S-EPMC11952091biostudies-literatureNeuraminidase-specific antibodies drive differential cross-protection between contemporary FLUBV lineages.PMC11952091Shepard JDRowe-Haas DKPage CKRodriguez AJTompkins SMAkinpelu JYJacob JCHertz THan JRay SDFerguson JAFriedman LMWard ABfalseNeuraminidase-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-2025-01-01T00:00:00Z2025 Mar2025-06-25T03:04:35.22Z2025-06-25T03:04:35.22ZS-EPMC119520914015349910.1126/sciadv.adu3344