Abstract The goal of this proposal is to develop a safe and powerful mucosal adjuvant to substantially improve influenza (flu) vaccines in the elderly. The elderly not only are particularly vulnerable to flu viral infection but also suffer from severe diseases and high mortality. Despite wide-spread vaccination programs, flu- related complications disproportionally affect the elderly, because of immune senescence. Growing evidence in both humans and animal models suggests that CD8+ or cytotoxic T lymphocyte (CTL) responses, not neutralizing antibodies, are correlated better with viral clearance and reduced morbidity of the elderly, especially when the vaccine and circulating viral strains are mismatched. As the number of persons over 65 years of age has increased steadily and is projected to reach more than 1 billion by 2030 worldwide, there is a desperate need to create more effective flu vaccines for the elderly. We develop a novel mucosal adjuvant capable of vigorously stimulating not only humoral but also CD8+ T cell responses in the lung, in marked contrast to the current flu vaccines that evoke primarily humoral immunity. The adjuvant, named PS-GMNP, is based on encapsulation of an agonist cGAMP of the stimulator of IFN genes (STING) into pulmonary surfactant-nanoparticles. While stimulating robust protective immune responses, the novel adjuvant provoked little lung inflammation, which is critical to the elderly who are prone to lung inflammation. PS-GMNP-adjuvanted flu vaccine conferred strong protection against lethal challenges of matched and mismatched flu A viruses after a single intranasal vaccination in both young and aged mice. Under similar conditions, the flu vaccine alone or the vaccine emulsified with MF59 adjuvant exhibited low or no protection at all. In this proposal, we will monitor the kinetic CD8+ T cell response in the respiratory system and correlate the response with protection against diverse flu A viruses in aged mice. We will investigate whether a combination of two heterosubtypic flu vaccines can further enhance the breadth of the cross-protection and how long the cross-protection can be sustained in aged mice. Secondly, we will explore whether cGAMP-mediated activation of alveolar epithelia cells (AEC) is pivotal to overcome age-related alterations of dendritic cells (DCs) and/or alveolar macrophages (aM?) and to strenghten CD8+ T cell respopnses in aged mice. Finally, we will validate PS-GMNP?s adjuvanticity in human peripheral blood mononuclear cells (PBMC) and corroborate whether cGAMP-activated DCs can sufficiently bolster the expansion of aged CD8+ T cells ex vivo. The study, if successful, would have immediate and profound impact on the overall health and quality of the aged population.