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. ImportanceInfluenza B viruses (FLUBV) consist of two divergently evolving lineages, Victoria (B/Vic) and Yamagata (B/Yam). Contemporary isolates from these lineages exhibit increased endemic activity and higher evolutionary rates while utilizing distinct mechanisms for evolutionary success. This is exemplified by novel seasonal infection dynamics with Influenza A viruses, differences in cross-protection elicited between the FLUBV lineages, and the potential extinction of B/Yam following the COVID-19 pandemic. We explore FLUBV infection dynamics utilizing contemporary viruses to define the asymmetric immunity elicited between the lineages. Contemporary Yamagata viruses are unable to confer the same breadth of protection as Victoria viruses. This may help explain the higher reinfection rates for Yamagata viruses and suggest a potential contributor to the extinction of this lineage.