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Abstract
Streptococcus pneumoniae (Spn) bacteria is a major human pathogen and a threat to public health with its ability to cause invasive pneumococcal diseases (IPD). Currently, there are over 100 different serotypes of Spn characterized by their differences in capsular polysaccharide (CPS). These CPS are targeted for inclusion in glycoconjugate vaccines to combat infections. Glycoconjugates are comprised of carrier protein covalently linked with the CPS of different bacteria serotypes. The current vaccine on the market, PCV13, has seen great success in curving disease; however, limited effects have been observed in the elderly and immunocompromised populations. This demonstrates a need for continued research into conjugate vaccine design, mechanism of immune activation and novel methods for fighting IPD. In this dissertation, we provide evidence for adaptive immune activation by glycoconjugates utilizing the MHCII pathway. Additionally, a new design for glycoconjugates utilizing carrier peptides linked with defined lengths of oligosaccharides over the traditional full protein linked to full polysaccharide. We defined a set of human derived carrier peptides discovered from clinically relevant carrier proteins to be used in conjugate strategies. Finally, we elucidated the mechanism of action for the glycoside hydrolase Pn3Pase to aid in its use as a therapeutic against highly virulent type 3 Spn infections. These studies increase our knowledge and understanding of the mechanism of action of glycoconjugate vaccines to aid in new therapeutics and knowledge based vaccine design to help battle IPD.