Synthetically defined glycoprotein vaccines: current status and future directions

Abstract

Primary examples in vaccine design have shown good levels of carbohydrate-specific antibody generation when raised using extracted or fully synthetic capsular polysaccharide glycans covalently coupled to a protein carrier. Herein, we cover recent clinical developments of carbohydrate-based vaccines and describe how novel cutting-edge methodology for the total synthesis of oligosaccharides and for the precise placement of carbohydrates at pre-determined sites within a protein may be used to further improve the safety and efficacy of glycovaccines.

Fig. 1. Illustration of a classical approach to the design of a carbohydrate-based vaccine using polysaccharides extracted from biological sources; (A) direct conjugation to carrier protein; (B) polysaccharide sizing followed by end terminal conjugation of generated oligosaccharides.

Fig. 2. Illustration of commonly employed strategies for the conjugation of carbohydrate antigens (P = polysaccharide) to carrier proteins (protein) in licensed vaccines. These strategies often result in a mixture of glycoproteins due to the heterogeneity of the carbohydrate haptens and the variability of the attachment points onto the protein.

Fig. 3. One-pot oligosaccharide assembly strategies (PG: protecting group, LG: leaving group, [LG]: latent leaving group).

Fig. 4. Streamlined automated solid-phase oligosaccharide synthesis (PG′: protecting group labile to hydrogenolysis).

Fig. 5. Total synthesis of (glyco)proteins using chemical ligation strategies.

Fig. 6. Chemoenzymatic (remodelling) and chemical strategies for the in vitro production of homogeneous glycoproteins. GHs = glycoside hydrolases and GTs = glycosyltransferases.