Major Advances in the Development of Synthetic Oligosaccharide-Based Vaccines

Because of their involvement in a variety of different biological processes and their occurrence onto pathogens and malignant cell surface, carbohydrates have been identified as ideal candidates for vaccine formulation. However, as free oligosaccharides are poorly immunogenic and do not induce immunological memory in the most at risk population (infants and young children, elderly and immunocompromised patients), glycoconjugate vaccines containing the same carbohydrate antigen covalently linked to an immunogenic carrier protein have gained a prominent role. Accordingly, a number of glycoconjugate vaccines mostly directed against infections caused by bacterial pathogens have been licensed and are currently available on the market. However, also glycoconjugate vaccines suffer from significant drawbacks. The challenging procedures required for the isolation and purification of the carbohydrate antigen from its natural source often lead to poor homogeneity and presence of biological contaminants, resulting in batch-to-batch variability. Moreover, in some cases, the overwhelming immunogenicity of the carrier protein may induce the carbohydrate epitope suppression, causing hyporesponsiveness. The development of synthetic oligosaccharide-based vaccine candidates, characterized by the presence of pure and well-defined synthetic oligosaccharide structures, is expected to meet the requirement of homogeneous and highly reproducible preparations. In the present chapter, we report on the major advances in the development of synthetic carbohydrate-based vaccines. First of all, we describe different strategies developed during the last years to circumvent the inherent difficulties of classical oligosaccharide synthesis, such as the one-pot glycosylation and the solid-phase synthesis, and their application to the preparation of carbohydrate antigens apt to conjugation with protein carriers. Next, we discuss the most representative methodologies employed for the chemical ligation of oligosaccharide structures to proteins. Finally, in the last section, we report significant examples of fully synthetic vaccines exploiting the multivalency effect. These constructs are based on the concept that the conjugation of multiple copies of synthetic oligosaccharide antigens to multivalent scaffolds, such as dendrimers, (cyclo)peptides, gold nanoparticles, and calixarenes, raises cooperative interactions between carbohydrates and immune receptors, leading to strong enhancement of the saccharide antigen immunogenicity.