Towards an oligosaccharide-based glycoconjugate Vaccine against Shigella dysenteriae type 1

This review summarizes the authors' studies in the past decade aimed at developing a synthetic oligosaccharide-based glycoconjugate vaccine to prevent a serious human disease caused by the Gram negative bacterium Shigelladysenteriae type 1. Starting from simple monosaccharides, oligosaccharides as large as a 24 monosaccharide-containing linear polymer, were assembled. Under suitable conditions, oligosaccharides containing 4 to 16 hexopyranose residues were covalently attached to an immunogenic protein. The serum response to the synthetic glycoconjugates depends, both on the size of the oligosaccharides, and on the molar ratio of the oligosaccharides to the carrier protein. Also reviewed are studies of the fine specificities of the interaction between oligosaccharides and anti-polysaccharide monoclonal antibodies as well as conformational studies of the synthetic oligosaccharides. 1 Polysaccharide-Based Vaccines 1.1 Surface Polysaccharides of Bacteria 1.2 Immunologic Properties of Polysaccharides 1.3 Polysaccharide-Protein Conjugates 1.3.1 Methods for the Conjugation of Polysaccharides to Proteins 1.3.2 Immunogenicity of Polysaccharide-Protein Conjugates 1.4 Synthetic Oligosaccharides Can be Superior to Natural Polysaccharides for Glycoconjugate Vaccines 1.5 Potentials of the O-Specific Polysaccharides of Shigellae for Vaccine Development 2 Chemical Synthesis of Oligosaccharides Related to the O-Specific Polysaccharide of S. dysenteriae Type 1 2.1 General Strategy 2.2 Synthesis of the Monosaccharide Building Blocks 2.2.1 The L-Rhamnose Moiety 2.2.2 The D-Galactose Moiety 2.2.3 The D-Glucosamine Synthons 2.3 Synthesis of a Complete Repeating Unit 2.4 Construction of Extended Oligosaccharides 2.5 The Lipophilic Protecting Group-Based Approach to Oligosaccharides 3 Covalent Attachment of the Oligosaccharides to Human Serum Albumin 3.1 Conjugation through a Secondary Spacer, Using Reductive Amination 3.2 Conjugation through Diels-Alder Cycloaddition Reactions 4 The Molecular Specificity of the Non-Covalent Binding between O-Specific Polysaccharide-Specific Antibodies and Oligosaccharides Related to the O-Specific Polysaccharide 5 Conformational Studies 6 Immunogenicity of the Protein Conjugates of the Synthetic Oligosaccharides in Mice 7 Conclusions and Future Prospects.