Influenza A virus (IAV) is a major cause of serious respiratory illness and has been responsible for significant morbidity and mortality in humans worldwide. The virus leads to approximately 200,000 hospitalizations and up to 36,000 deaths annually in the United States during non-pandemic years. Given the disease severity, the associated economic costs and the recent appearance of novel IAV strains within the US, there has been a renewed interest in developing novel and efficacious “universal” influenza vaccination strategies to combat this significant global public health threat. Importantly recent studies have highlighted the fact that immunizations that generate local (i.e. nasal mucosa and lung) tissue-resident memory T and B memory cells in addition to systemic immunity offer the greatest protection against future IAV encounters. The currently approved IAV- vaccines are designed to largely induce IAV-specific antibodies, and by their design, do not induce lung resident memory T and B cells that occur during natural IAV infections. Thus our long-term goal is to develop a protective vaccine against IAV that induces lung resident T and B cells without the toxicity that occurs with natural infection. To this end we have recently developed a nanoparticle based IAV vaccine (IAV-nanovax) that mimics, without the pathology associated with IAV infections, many of the key attributes thought to be important for lung resident T and B cell induction and maintenance. Importantly this IAV nanoparticle vaccine, breaks the cold chain, is needle free, and is biocompatible. This IAV-nanovax has shown promising efficacy in protection against homologous and heterologous IAV infections and the ability to induce T cell and B cell responses in the lungs in our preliminary studies. Therefore, this proposal will use the combined expertise of the Co-PIs and Co-Investigators to determine if a nanoparticle-based approach will allow for the induction of durable, IAV-specific, lung-resident T and B cell responses and therein provide robust protection against homologous and heterologous IAV strains using the following Specific Aims: 1) Determine the vaccine formulation that induces optimal immunity and protection against homologous and heterologous virus challenges, 2) Determine the vaccine formulation that induces optimal protection against virus challenge in outbred populations. At the end of the project, we will have extended our findings into translationally relevant outbred populations, established protective immune correlates that can be used to assess the efficacy of future vaccination strategies, and delivered a protective preclinical nanovaccine.