Project Summary/Abstract One of the major problems of the great burden of Streptococcus pneumoniae infections is the acquisition of antimicrobial resistance and the global spread of resistant clones. This problems get enhanced by the major disadvantages of the current capsular polysaccharide based vaccines, such as cost, serotype specificity, and the resulting incomplete coverage. While the use of polysaccharide vaccines, specially the conjugate vaccine, had significantly reduced the amount of invasive disease caused Spn, it only has reduced that of the represented serotypes. This occurs mainly because of disease being caused by serotypes not present in the vaccine (maximum of 23 of the >97 capsule types, only 13 in the conjugate vaccine) and replacement carriage. Our rationale is that development of a subunit based vaccine utilizing novel conserved antigenic proteins in conjunction with novel polyphosphazene (PPZ) adjuvants, proven to induce adaptive immunity will deepen the current toolkit to prevent pneumococcal disease without serotype limitations. Thus, we hypothesize that addition of conserved immunogenic proteins to the PPZ molecule will provide the groundwork for the development of a broadly protective pneumococcal subunit based vaccine. The gaps in knowledge we aim to bridge are to define and characterize novel pneumococcal antigenic proteins and polyelectrolyte adjuvants formulations that will initiate adaptive immune responses and lead to protection against disease in a serotype independent manner. The proposed work is significant due to the high incidence serotype replacement that current polysaccharide based vaccines are prone to, which leads to increase susceptibility of children and the elderly to Spn carriage and severe infections (e.g. pneumonia, bacteremia, and meningitis); and innovative since it will use novel formulations of antigenic and conserved pneumococcal proteins to induce potent adaptive immune responses, that will not be serotype dependent.