Influenza B virus (IBV), in conjunction with Influenza A virus (IAV), results in yearly epidemics. While IAV is a well-studied pathogen, IBV lags in understanding of its pathology, replication mechanics, and vaccination use strategies. For example, smoking is a known risk factor for IAV, but little is known regarding its effects on IBV infections and pathology. Second, the IBV nucleoprotein (BNP) fulfills a critical role during replication, but its associated host factors remain largely unclear. Last, live virus vaccinations for IAV during pandemics are considered a potential risk due to the possibility the vaccine virus will reassort with circulating IAV, restoring virulence and exposing a naïve population to a pathogenic virus unintentionally. To fill these gaps, we set out to understand: a) what are the impacts of cigarette smoke on IBV infections b) what host factors are interacting with BNP and how are they involved in replication and c) whether we could attenuate recombinant IBVs (rIBVs) expressing the IAV HA by progressive mutations to the IAV ectodomain. To these ends, we developed an animal model to study the impact of cigarette smoke extract on IBV infections in mice not previously available. We found that low concentration of CSE increased IFN- production in spleenocyte of infected mice, and high concentrations of CSE resulted in lower humoral responses to infection and lower survival rates. Additionally, we confirmed that BNP interacts with the host protein IMPα4, a nuclear import adaptor protein, through yeast-two-hybrid and Co-IP analysis. Further, knockout of IMPα4 expression reduced IBV replication. Finally, progressive mutation of IAV ectodomain using IBV coding sequence did result in attenuation of replication ex vivo, and these candidates could elicit significant humoral and neutralizing responses that protected mice from lethal challenge with homologous strains of IAVs. Together, each of these studies represent a necessary step forward in understanding how lifestyle factors impact IBV infections, the potential specific host-viral protein interactions that could be drug therapeutic targets of the future, and necessary development of innately safe and efficacious live vaccines for use in pandemic scenarios.