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Glycoconjugate vaccines have contributed enormously to reducing and controlling encapsulated bacterial infections for over thirty years. Glycoconjugate vaccines are based on a carbohydrate antigen that is covalently linked to a carrier protein; this is necessary to cause T cell responses for optimal immunogenicity, and to protect young children. Many interdependent parameters affect the immunogenicity of glycoconjugate vaccines, including the size of the saccharide antigen. Here, we examine and discuss the impact of glycan chain length on the efficacy of glycoconjugate vaccines and report the methods employed to size polysaccharide antigens, while highlighting the underlying reaction mechanisms. A better understanding of the impact of key parameters on the immunogenicity of glycoconjugates is critical to developing a new generation of highly effective vaccines.

Carbohydrates are ubiquitous molecules expressed on the surface of nearly all living cells, and their interaction with carbohydrate-binding proteins is critical to many immunobiological processes. Carbohydrates are utilized as antigens in many licensed vaccines against bacterial pathogens. More recently, they have also been considered as adjuvants. Interestingly, unlike other types of vaccines, adjuvants have improved immune response to carbohydrate-based vaccine in humans only in a few cases. Furthermore, despite the discovery of many new adjuvants in the last years, aluminum salts, when needed, remain the only authorized adjuvant for carbohydrate-based vaccines. In this review, we highlight historical and recent advances on the use of glycans either as vaccine antigens or adjuvants, and we review the use of currently available adjuvants to improve the efficacy of carbohydrate-based vaccines. A better understanding of the mechanism of carbohydrate interaction with innate and adaptive immune cells will benefit the design of a new generation of glycan-based vaccines and of immunomodulators to fight both longstanding and emerging diseases.

The Novartis Vaccines Institute for Global Health (NVGH) is working on the development of a bivalent glycoconjugate vaccine against nontyphoidal Salmonellae (NTS) covering the main serovars S. Typhimurium and S. Enteritidis causing invasive disease in Africa. The vaccine is based on the conjugation of the lipopolysaccharide O antigen, the main surface polysaccharide of NTS, with CRM197 as carrier protein. In this contest, my PhD project has been focused in three related aspects: 1) Structural and biological characterization of NTS O antigen purified from different S. Typhimurium and S. Enteritidis strains. 2) Synthesis, characterization and immunological evaluation of a panel of NTS glycoconjugate vaccine variants (OAg source, conjugation chemistry, OAg/protein ratio) to better understand the key factors in glycoconjugate vaccine design required for optimal antibody-mediated immunity. 3) Design of new efficient glycoconjugation methodologies which allow the synthesis of structurally highly-defined glycoconjugate vaccines and simplify the conjugation process.