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Synlett 2003(6): 0743-0767
DOI: 10.1055/s-2003-38724
ACCOUNT
© 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
Further Information

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

    References

  • 1 For a concise overview of polysaccharide-based antibacterial vaccines and a review of oligosaccharide-protein conjugates as vaccine candidates see: Pozsgay V. Adv. Carbohydr. Chem. Biochem.  2001,  56:  153 
    Google Scholar
  • 2 Robbins JB. Schneerson R. Anderson P. Smith DH. J. Am. Med. Assoc.  1996,  276:  1181 
    CrossrefGoogle Scholar
  • 3 Sutton A. Schneerson R. Kendallmorris S. Robbins JB. Infect. Immun.  1982,  35:  95 
    Google Scholar
  • 4 Liang-Takasaki CJ. Grossman N. Leive L. J. Immunol.  1983,  130:  1867 
    Google Scholar
  • 5 Robbins JB. Chu C. Schneerson R. Clin. Infect. Dis.  1992,  15:  346 
    Google Scholar
  • 6 Robbins JB. Schneerson R. Szu SC. J. Infect. Dis.  1995,  171:  1387 
    Google Scholar
  • 7 Fothergill LD. Wright J. J. Immunol.  1933,  24:  273 
    Google Scholar
  • 8 Goldschneider I. Gotschlich EC. Artenstein MS. J. Exp. Med.  1969,  129:  1307 
    CrossrefGoogle Scholar
  • 9 Schneerson R. Robbins JB. N: Engl. J. Med.  1975,  292:  1093 
    Google Scholar
  • 10 Robbins JB. Schneerson R. Glode MP. Vann WF. Schiffer MS. Liu T.-Y. Parke JC. Huntley C. J. Allergy Clin. Immunol.  1975,  56:  141 
    Google Scholar
  • 11 Robbins JB. Schneerson R. Gotschlich EC. Pediatr. Infect. Dis. J.  2000,  19:  945 
    Google Scholar
  • 12 Landsteiner K. The Specificity of Serological Reactions   Harvard University Press; Cambridge MA: 1945. 
    Google Scholar
  • 13 Goebel WF. Avery OT. J. Exp. Med.  1929,  50:  521 
    CrossrefGoogle Scholar
  • 14 Goebel WF. J. Exp. Med.  1939,  69:  353 
    Google Scholar
  • 15 Goebel WF. J. Exp. Med.  1940,  72:  33 
    Google Scholar
  • 16 Peeters CCAM. Lagerman PR. de Weers O. Ooemn LA. Hoogerhout P. Beurret M. Poolman JT. In Vaccine Protocols   Robinson A. Farrar G. Wiblin C. Humana Press Inc.; Totowa N.J.: 1996.  p.111-133 
    Google Scholar
  • 17 Dick WE. Beurret M. Contrib. Microbiol. Immunol.  1989,  10:  48 
    Google Scholar
  • 18 Jennings HJ. Sood R. In K. Neoglycoconjugates. Preparation and Applications   Lee YC. Lee RT. Academic Press; New York: 1994.  p.325-371  
    Google Scholar
  • 19 Chu C. Liu B. Watson D. Szu S. Bryla D. Shiloach J. Schneerson R. Robbins JB. Infect. Immun.  1991,  59:  4450 
    Google Scholar
  • 20 Bethell GS. Ayers JS. Hancock WS. Hearn MTW. J. Biol. Chem.  1979,  254:  2572 
    Google Scholar
  • 21 Marburg S. Jorn D. Tolman RL. Arison B. McCauley J. Kniskern PJ. Hagopian A. Vella PP. J. Am. Chem. Soc.  1986,  108:  5282 
    CrossrefGoogle Scholar
  • 22 Egan W. Ann. Rep. Med. Chem.  1993,  28:  257 
    Google Scholar
  • 23 Gray GR. Arch. Biochem. Biophys.  1974,  163:  426 
    Google Scholar
  • 24 Paoletti LC. Kasper DL. Michon F. DiFabio JL. Holme K. Jennings HJ. Wessels M. J. Biol. Chem.  1990,  265:  18278 
    Google Scholar
  • 25 Paulsen H. Paal M. Carbohydr. Res.  1983,  113:  203 
    CrossrefGoogle Scholar
  • 26 Roy R. Katzenellenbogen E. Jennings HJ. Can. J. Biochem. Cell Biol.  1984,  62:  270 
    Google Scholar
  • 27 Liu XC. Dordick JS. J. Am. Chem. Soc.  1999,  121:  466 
    CrossrefGoogle Scholar
  • 28 Constantino P. Viti S. Podda A. Velmonte MA. Nencioni L. Rappuoli R. Vaccine  1992,  10:  691 
    CrossrefGoogle Scholar
  • 29 Arakatsu Y. Ashwell G. Kabat EA. J. Immunol.  1966,  97:  858 
    Google Scholar
  • 30 Schneerson R. Barrera O. Sutton A. Robbins JB. J. Exp. Med.  1980,  152:  361 
    CrossrefGoogle Scholar
  • 31 Black S. Shinefield H. Fireman B. Lewis E. Ray P. Hansen JR. Elvin L. Ensor KM. Hackell J. Siber G. Malinoski F. Madore D. Chang I. Kohberger R. Watson W. Austrian R. Edwards K. Pediatr. Infect. Dis. J.  2000,  19:  187 
    Google Scholar
  • 32 Lagergard T. Shiloach J. Robbins JB. Schneerson R. Infect. Immun.  1990,  58:  687 
    Google Scholar
  • 33 Lin FYC. Ho VA. Khiem HB. Trach DD. Bay PV. Thanh TC. Kossaczka Z. Bryla DA. Shiloach J. Robbins JB. Schneerson R. Szu SC. Lanh MN. Hunt S. Trinh L. Kaufman JB. N. Engl. J. Med.  2001,  344:  1263 
    CrossrefGoogle Scholar
  • 34 Shinefield H. Black S. Fattom A. Horwith G. Rasgon S. Ordonez J. Yeoh H. Law D. Robbins JB. Schneerson R. Muenz L. Naso R. N. Engl. J. Med.  2002,  346:  491 
    CrossrefGoogle Scholar
  • 35 Svenson SB. Lindberg AA. Infect. Immun.  1981,  32:  490 
    Google Scholar
  • 36 Anderson PW. Pichichero ME. Insel RA. Betts R. Eby R. Smith DH. J. Immunol.  1986,  137:  1181 
    Google Scholar
  • 37 Laferriere CA. Sood RK. deMuys JM. Michon F. Jennings HJ. Vaccine  1997,  15:  179 
    CrossrefGoogle Scholar
  • 38 Pichichero ME. Porcelli S. Treanor J. Anderson P. Vaccine  1998,  16:  83 
    CrossrefGoogle Scholar
  • 39 Glaudemans CPJ. Chem. Rev.  1991,  91:  25 
    CrossrefGoogle Scholar
  • 40 Lindberg AA. Pal T. Vaccine  1993,  11:  168 
    CrossrefGoogle Scholar
  • 41 Iversen ER. Colding H. Petersen L. Ngetich R. Shanks GD. Trans. R. Soc. Trop. Med. Hyg.  1998,  92:  30 
    Google Scholar
  • 42 Iwalokun BA. Gbenle GO. Smith SI. Ogunledun A. Akinsinde KA. Omonigbehin EA. J. Health Popul. Nutr.  2001,  19:  183 
    Google Scholar
  • 43 Lindberg AA. Karnell A. Weintraub A. Rev. Infect. Dis.  1991,  13:  S279 
    Google Scholar
  • 44 Passwell JH. Harlev E. Ashkenazi S. Chu CY. Miron D. Ramon R. Farzan N. Shiloach J. Bryla DA. Majadly F. Roberson R. Robbins JB. Schneerson R. Infect. Immun.  2001,  69:  1351 
    Google Scholar
  • 45 Konadu EY. Lin FYC. Ho VA. Thuy NTT. Bay PV. Thanh TC. Khiem HB. Trach DD. Karpas AB. Li J. Bryla DA. Robbins JB. Szu SC. Infect. Immun.  2000,  68:  1529 
    CrossrefGoogle Scholar
  • 46 Pozsgay V. Angew. Chem. Int. Ed.  1998,  37:  138 
    Google Scholar
  • 47 Pozsgay V. J. Org. Chem.  1998,  63:  5983 
    Google Scholar
  • 48 Pozsgay V. Coxon B. Yeh H. Bioorg. Med. Chem.  1993,  1:  237 
    Google Scholar
  • 49 Pozsgay V. Pannell L. Carbohydr. Res.  1994,  258:  105 
    CrossrefGoogle Scholar
  • 50 Pozsgay V. Glaudemans CPJ. Robbins JB. Schneerson R. Carbohydr. Res.  1993,  244:  259 
    Google Scholar
  • 51 Pozsgay V. J. Am. Chem. Soc.  1995,  117:  6673-6681  
    Google Scholar
  • 52 Pozsgay V. Tetrahedron: Asymmetry  2000,  11:  151 
    Google Scholar
  • 53 Pozsgay V. Coxon B. Carbohydr. Res.  1994,  257:  189 
    CrossrefGoogle Scholar
  • 54 Pozsgay V. Jennings HJ. Carbohydr. Res.  1988,  179:  61 
    CrossrefGoogle Scholar
  • 55 Schmidt RR. Jung K.-H. In Carbohydrates in Chemistry and Biology   Vol 1:  Ernst B. Hart GW. Sinaӱ P. Wiley-VCH; Weinheim: 2000.  p.5-59  
    Google Scholar
  • 56 Pozsgay V. Glaudemans CPJ. Robbins JB. Schneerson R. Tetrahedron  1992,  48:  10249 
    CrossrefGoogle Scholar
  • 57 Pozsgay V. J. Org. Chem.  1999,  64:  7277 
    Google Scholar
  • 58 Pozsgay V. J. Carbohydr. Chem.  2001,  71:  659 
    Google Scholar
  • 59 Pedretti V. Veyrières A. Sinaӱ P. Tetrahedron  1990,  46:  77 
    CrossrefGoogle Scholar
  • 60 Evans ME. Parrish FW. Carbohydr. Res.  1977,  54:  105 
    CrossrefGoogle Scholar
  • 61 For a comprehensive review of solid phase-based oligosaccharide synthesis, see: Solid Support Oligosaccharide Synthesis and Combinatorial Carbohydrate Libraries   Seeberger PH. Wiley-Interscience; New York: 2002. 
    Google Scholar
  • 63 Pozsgay V. Org. Lett.  1999,  1:  477 
    Google Scholar
  • 65 Vaino AR. Szarek WA. Adv. Carbohydr. Chem. Biochem.  2001,  56:  9 
    Google Scholar
  • 66 Pozsgay V. Vieira NE. Yergey A. Org. Lett.  2002,  4:  3191 
    Google Scholar
  • 67 Hudlicky T. Koszyk FJ. Kutchan TM. Sheth JP. J. Org. Chem.  1980,  45:  5020 
    Google Scholar
  • 68 Pavliak V. Nashed EM. Pozsgay V. Kovac P. Karpas A. Chu CY. Schneerson R. Robbins JB. Glaudemans CPJ. J. Biol. Chem.  1993,  268:  25797 
    Google Scholar
  • 69 Miller CE. Karpas A. Schneerson R. Huppi K. Kovac P. Pozsgay V. Glaudemans CP. J. Molec. Immun.  1996,  33:  1217 
    Google Scholar
  • 70 Pozsgay V. Glaudemans CPJ. Robbins JB. Schneerson R. Bioorg. Med. Chem. Lett.  1992,  2:  255 
    Google Scholar
  • 71 Pozsgay V. Sari N. Coxon B. Carbohydr. Res.  1998,  308:  229 
    Google Scholar
  • 72 Coxon B. Sari N. Batta G. Pozsgay V. Carbohydr. Res.  2000,  324:  53 
    CrossrefGoogle Scholar
  • 73 Nyholm P.-G. Mulard LA. Miller CE. Olin R. Glaudemans CPJ. Glycocobiology  2001,  11:  945 
    Google Scholar
  • 74 Pozsgay V. Chu C. Pannell L. Wolfe J. Robbins JB. Schneerson R. Proc. Natl. Acad. Sci. U.S.A.  1999,  96:  5194 
    CrossrefGoogle Scholar
62

Anonymous referee 2002.

64

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