Rational Antigen Selection and Delivery Technology for Development of Next Generation Pneumococcal Vaccines
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Vaccines represent one of the most effective disease prevention methods available. The efficacy of a vaccine is highly dependent upon the type of antigen and delivery vector as both can have a distinct impact on the type and potency of the resulting immune response.However, selection of the proper antigen can be challenging due to the ever-changing nature of bacterial transcriptomics, particularly during biofilm formation. As such, the phenotypes during biofilm formation must be carefully considered when developing comprehensive bacterial vaccines. It is also essential to consider the antigen delivery process when developing an immunization strategy. While naked protein antigen administration will elicit some form of immunological response,a heightened response can be achieved through the coupling of the antigen to a delivery vector. Thus in the work presented herein, two novel protein antigens for S. pneumoniae, GlpO and PncO,are identified based on defined set of qualifications: surface accessibility, protein homology thorough the strains, and gene upregulation during biofilm release.Furthermore, two antigen delivery strategies are described herein. The first, a hybrid biological-biomaterial antigen delivery vector (the hybrid vector), was optimized by localizing protein antigen accumulation to the cytoplasm of the Escherichia coli which comprises the core of the delivery vehicle. The second delivery technique, the liposomal encapsulation of polysaccharides(LEPS) used affinity binding to co-localize pneumococcal protein and polysaccharide antigens. Formulations of both strategies out performed industry standards in pneumococcal disease models. In summary, this dissertation presents a road map for the identification of protein antigens for biofilm forming bacteria as well as two strategies to enhance the efficacy of protein antigens.