PROJECT SUMMARY Pneumococcal disease has a disproportional impact upon the young and elderly. Notably, advanced age and influenza A virus infection act synergistically to enhance susceptibility to pneumococcal lung infections. Indeed, older adults (>65 years old) account for 70-85% of deaths due to the combination of influenza and pneumonia. As this vulnerable population is projected to reach two billion worldwide by 2050, novel preventative approaches that boost resistance to secondary pneumococcal pneumonia, and pneumococcal disease more generally, are needed. Background: The Pfeifer group has engineered a novel vaccine formulation, termed Liposomal Encapsulation of Polysaccharides (LEPS), designed to account for both the breadth of Streptococcus pneumoniae bacterial serotypes and the unique progression profiles that complicate treatment options for pneumococcal disease. Significance/Innovation: The LEPS formulation combines both polysaccharide and protein antigens, which is an innovative approach that provides both capsule specific immunity and cross protection against other serotypes and stages of disease progression. Because this vaccine candidate has matched and exceeded the capabilities of Prevnar-13 in normal-aged mice, the enclosed application features a complementary collaboration with Dr. Elsa Bou Ghanem to test the Hypothesis that vaccination of elderly mice with the LEPS particle will induce a robust immune response relative to current pneumococcal vaccine formulations. This hypothesis will be thoroughly addressed through three specific Aims: 1) Expand Serotype Coverage with the LEPS Platform in Pneumonia Models using Aged Mice with Detailed Immunological Assessment to Reveal Mechanism; 2) Assess Secondary Bacterial Pneumonia within Aged Mice using the LEPS Platform; and 3) Test Intranasal Delivery of LEPS Formulations for Pneumococcal Disease in Mice across Age. Host survival, clinical disease score, organ-specific bacterial burden, and other indicators of infection severity (organ pathology) will be measured over time across vaccine and non-vaccine pneumococcal strains to assess serotype-specific protection as well as cross protection. Successful outcomes will include treatment effectiveness beyond current vaccine options (i.e., PPSV and PCV), in which case, we will have important preclinical data needed to support translational progression.