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Synthetic Vaccine Against Human Pathogenic Bacteria


Shigella dysenteriae type 1 is a Gram-negative human pathogen that causes endemic and epidemic dysentery worldwide. In spite of its discovery a century ago, there is still no licensed vaccine against this bacterium that is resistant to most of the available antibiotics in many parts of the world. An experimental vaccine consisting of a protein conjugate of the O-SP of this organism elicited significant anti-O-SP antibody levels that may confer protection. We surmized that an improved vaccine might be constructed from chemically defined oligosaccharide fragments of the O-SP.

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Starting from monosaccharides that carry orthogonal protecting and activating groups, a building block was constructed that corresponds to a complete repeating unit. Iterative combination of this building blocks afforded di-, tri- and tetramers of the repeating unit corresponding to octa-, dodeca- and hexadeca-saccharide portions of the native O-SP. These oligosaccharides were covalently attached to a carrier protein.The protein conjugates of the synthetic oligosaccharides elicited significant anti-O-SP IgG antibody levels in mice. These experiments established that the immunogenicity of the neoglycoconjugates are determined not only by the length of the oligosaccharide but also by the amount of the saccharide chains attached to the protein: An intermediate loading induced higher antibody response than either lower or higher loadings. The highest antibody levels were induced by the dodeca- and hexadeca-saccharide conjugates having an average of nine oligosaccharide chains per HSA molecule. A new technique was developed for the synthesis of higher-membered oligosaccharides. An essential feature of this approach is the use of lipophilic protecting groups in the building blocks, that could be exploited to facilitate the isolation of the targeted oligosaccharides in pure form. The technique essentially eliminates a conventional chromatographic procedure in the most demanding part of the oligosaccharide synthesis that used silica gel as the chromatographic material and organic solvents in our previous syntheses. These are replaced by a reverse-phase adsorbent and environmentally friendly solvents as eluents. With this technique large-scale preparation of our synthetic vaccines will be feasible without the previous uncertainties in the isolation/purification steps of the syntheses of higher- membered oligosaccharide intermediates.

Pozsgay, Vince
DHHS/NIH - National Institute of Child Health and Human Development
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