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Synlett 2003(6): 0743-0767
DOI: 10.1055/s-2003-38724
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© Georg Thieme Verlag Stuttgart ˙ New York

Towards an Oligosaccharide-Based Glycoconjugate Vaccine Against Shigella dysenteriae Type 1

Vince Pozsgay*a, Bruce Coxona, Cornelis P. J. Glaudemansb, Rachel Schneersona, John B. Robbinsa
a National Institute of Child Health and Human Development, National Institute of Health, 6 Center Dr., MSC 2720, Bethesda, MD 20892-2720, USA
Fax: +1(301)2951435; e-Mail: vipo@helix.nih.gov;
b National Institute of Diabetes, Digestive, and Kidney Diseases, National Institute of Health, 6 Center Dr., MSC 2720, Bethesda, MD 20892-2720, USA
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Publication History

Received 31 May 2002
Publication Date:
17 April 2003 (online)

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Abstract

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 Shigella dysenteriae 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

Key words

polysaccharide - oligosaccharides - monosaccharides - antibodies

62

Anonymous referee 2002.

64

Berkin, A.; Pozsgay, V. In preparation.