Differential Cross-Protective Immunity is Elicited by Infection with Contemporary Influenza B Lineage Viruses

Influenza B virus (FLUBV) significantly contributes to the influenza disease burden and has complicated vaccine development and efficacy, yet remains understudied compared to its counterpart, influenza A virus (FLUAV). Since its isolation in 1940, FLUBV has diverged into two antigenically distinct lineages: Victoria (B/Vic) and Yamagata (B/Yam). Recent human studies and epidemiological modeling reveal differences in immunity elicited by each FLUBV lineage, contributing to higher reinfection rates following B/Yam infection. To investigate disparities in FLUBV lineage cross-protection and immunity, we examined the effects of lineage-specific prior immunity on FLUBV reinfection dynamics. Mice were infected with representative B/Vic and B/Yam viruses from evolutionary distinct clades and subsequently reinfected with heterolineal viruses (i.e., B/Vic → B/Yam and B/Yam → B/Vic) to assess the extent of protection elicited between the lineages. Using this validated challenge model, we explored potential mechanisms underlying the asymmetric reinfection dynamics observed between the lineages. Our findings align with human observations, indicating that contemporary B/Vic viruses confer cross-protection against contemporary B/Yam infections, whereas contemporary B/Yam viruses do not provide the same degree of protection. Furthermore, we demonstrated that serum antibodies elicited by hemagglutinin vaccination cannot account for the observed heterolineal protection. Rather, antibodies targeting the viral neuraminidase (NA) may play a significant role in eliciting cross-protection to subsequent FLUBV infection. Our findings define asymmetric cross-protection resulting from contemporary FLUBV infection and suggest NA as a potential significant contributor to heterolineal FLUBV protection. This asymmetric immunity may also help explain the proposed extinction of B/Yam viruses since the COVID-19 pandemic.