Immunogenetic determinants of influenza B virus susceptibility and vaccine response: current evidence, gaps, and future directions

Influenza B virus (IBV) remains an important but comparatively underexamined contributor to seasonal influenza burden, particularly in children, adolescents, and older adults. Although IBV lacks the broad animal reservoir and pandemic potential of influenza A virus, its epidemiology, evolutionary dynamics, and contribution to variable vaccine effectiveness remain clinically and biologically important. Recent surveillance has further changed the field: no confirmed naturally circulating B/Yamagata-lineage viruses have been detected since March 2020, and current influenza B activity is overwhelmingly attributable to B/Victoria-lineage viruses. An important but still insufficiently developed dimension of IBV biology is immunogenetics. Variation in antigen presentation, innate sensing pathways, interferon responsiveness, and host dependency or restriction factors may contribute to heterogeneity in susceptibility, disease severity, cross-lineage immunity, and vaccine responsiveness. However, the strength of evidence varies across these domains, and much of the proposed framework still relies on inference from broader influenza literature rather than direct IBV-specific human data. In this review, we evaluate current evidence for immunogenetic determinants of IBV susceptibility and vaccine response, while distinguishing direct IBV findings from conclusions extrapolated from influenza A virus or general antiviral immunology. Available evidence identifies antigenic match, antigenic drift, age, exposure history, and baseline immunity as the best-supported non-genetic determinants of vaccine performance, whereas IBV-specific host-genetic predictors of susceptibility and vaccine response remain incompletely defined. We further highlight the major evidence gaps that limit predictive models of IBV immune control and vaccine performance, and outline priorities for future research, including integrated studies linking host genotype, immune phenotyping, and lineage-resolved virologic outcomes.