Towards development of a fully synthetic conjugate vaccine: Investigation of structural analogs of Streptococcus pneumoniae serogroup 6

by Parameswar, Archana R

Serogroup 6 pneumococcal oligosaccharides as potential targets towards the development of a fully synthetic conjugate vaccine Archana R. Parameswar Doctor of Philosophy University of Missouri - St. Louis Prof. Alexei V. Demchenko, Chairperson Involvement of complex glycostructures in a variety of damaging and healing processes has already been acknowledged by development of carbohydrate-based vaccines and therapeutics. The bacteria Streptococcus pneumoniae (SPn) have become one of the most frequent causes of pneumonia, bacteremia, and meningitis in the elderly, immunocompromised, and, especially, in young children. SPn has one of the largest public health and economic impacts amongst all bacterial infectious diseases. Over 2 million children die annually worldwide due to pneumonia, accounting for almost 20% of deaths under age five with more than half of these deaths attributed to SPn. Amongst over ninety elucidated SPn serotypes, the SPn serogroup6 has been consistently ranked within the top three causes of invasive pneumococcal disease worldwide. The SPn bacterial cell is surrounded by a polysaccharide capsule and preventive vaccination is a viable tool against the bacterial invasion. Usually, serotype-specific antibodies are formed in response. Synthetic oligosaccharide components can be conjugated to a carrier Archana R. Parameswar Page 2 of 208 7/21/2008 protein with conventional coupling chemistry, to obtain semi-synthetic conjugate vaccines (glycoconjugates). This doctoral dissertation describes the application of a new glycosylation method for the synthesis of glycostructures to study immunological properties of serogroup 6. The development of an expeditious strategy to obtain synthetic saccharides of SPn6 and glycoconjugates thereof will ensure reliable and reproducible immunological studies. Consequently, by identifying the immunogenic responses of these glycoconjugates, will help target toward the development of effective vaccine candidates against SPn. Archana R. Parameswar Page 3 of 208 7/21/2008