Influenza is a common and potentially life threatening infection. The constant evolution of the virus poses challenges on the cross-reactive response of the immune system, and emergence of new strains renders the antibody-mediated protection insufficient. Cellmediated immunity (CMI) may attenuate the severity of illness and provide better heterosubtypic coverage. A myriad of underlying comorbidities affect the outcomes of influenza infection; however, such known risk factors fail to explain a significant proportion of severe influenza infections. To investigate cross reactive antibody and cell-mediated responses and predictors of disease severity we employed several projects and distinct cohorts- after natural infection; live- attenuated vaccine and inactivated vaccine. The main contributions of this project were the development of assays to measure antibody responses to multiple influenza strains, using a microbead based assay and application of phenotypic and functional assays to the study of influenza specific responses. Using these methods in healthy volunteers it was shown that repeated vaccination using a recurring strain failed to elicit increased antibody or cytotoxic T cell (CTL) responses. The administration of live attenuated influenza vaccine (LAIV) resulted in generation of measurable cross-reactive antibody responses. The study showed that even in a vaccine naïve adult population, LAIV resulted in limited generation of CD4 or CD8 responses. Furthermore, the microbead assay was applied to the study of prevalence rates of 2009 H1N1 pandemic during the first wave, demonstrating acceptable specificity with increased sensitivity along with the added benefits of high throughput and ability to simultaneously study responses to multiple strains of influenza. The study of severe influenza infection during II the 2009 pandemic was able to characterize the profile of several pro-inflammatory cytokines and chemokines that trended towards higher concentrations in those individuals that succumbed to pandemic H1N1 infection. This adds to the accumulating evidence suggesting that a cytokine storm together with inability to contain it are involved in determining the outcome of pandemic H1N1 infection. This may potentially aid in early identification of patients with poor prognosis and provide targets for tailored antiinflammatory interventions. In addition the study identified, for the first time, the association between CCR5 deletion and pandemic influenza severity, illustrating the importance of this polymorphism beyond HIV and flaviviral infections.