Abstract
Influenza B viruses (IBV) can cause severe disease and death much like influenza A viruses (IAV), with a disproportionate number of infections in children. Despite moving to a quadrivalent vaccine to include strains from both the B/Victoria and B/Yamagata lineages, vaccine effectiveness rates continue to be variable and low in many past seasons. To develop more effective influenza B virus vaccines, three novel IBV hemagglutinin (HA) vaccines were designed using a computationally optimized broadly reactive antigen (COBRA) methodology. These IBV HA proteins were expressed on the surface of a virus-like particle (VLP) and used to vaccinate ferrets that were pre-immune to historical B/Victoria or B/Yamagata lineage viruses. Ferrets vaccinated with B-COBRA HA vaccines had neutralizing antibodies with high titer HAI titer against all influenza B viruses regardless of pre-immunization history. Conversely, VLPs expressing wild-type IBV HA antigens preferentially boosted titers against viruses from the same lineage and there was little-to-no seroprotective antibodies detected in ferrets with mismatched IBV pre-immune infections. Overall, a single IBV HA developed using the COBRA methodology elicited protective broadly-reactive antibodies against current and future drifted IBVs from both lineages.