Development of novel conjugate vaccines against Salmonella

Abstract

Various Salmonella enterica serovars can cause human diseases that range in severity from a mild gastroenteritis to a severe systemic infection known as typhoid fever. The emergence of antibiotic re- sistance in S. enterica strains poses a major problem in treatment of patients in many regions of the world. Currently, two licensed vaccines exist, conferring protection against S. enterica serovar Ty- phi, the causative agent of human typhoid. Unfortunately, these typhoid vaccines are only moderately immunogenic in infants and young children and revaccination is required every few years. Therefore, new vaccines are needed, which not only confer long- term protection against S. Typhi but also other harmful S. enterica serovars. Conjugate vaccines are among the most effective and safe vac- cines against bacterial diseases and have been used in humans for over 30 years. They are composed of an antigenic cell surface polysaccharide, purified from the pathogen, chemically coupled to a carrier protein. Several clinical trials have shown that glyco- conjugates are promising vaccine candidates to prevent Salmonella infections. However, manufacturing of conjugate vaccines is a complex, multi-step process. An alternative approach to produce glycoconjugates is based on the bacterial N-linked protein glyco- sylation system first described in Campylobacter jejuni. This pro- tein modification system was functionally transferred into E. coli, enabling production of customized recombinant glycoproteins in vivo. In this dissertation, the possibilities of using the in vivo con- jugation technology for production of conjugate vaccines against various S. enterica serovars causing human diseases were explored.