Abstract
Synthetic cell-surface glycans are promising vaccine candidates against Clostridium difficile. The complexity of large, highly antigenic and immunogenic glycans is a synthetic challenge. Less complex antigens providing similar immune responses are desirable for vaccine development. Based on molecular-level glycan-antibody interaction analyses, we here demonstrate that the C. difficile surface polysaccharide-I (PS-I) can be resembled by multivalent display of minimal disaccharide epitopes on a synthetic scaffold that does not participate in binding. We show that antibody avidity as a measure of antigenicity increases by about five orders of magnitude when disaccharides are compared with constructs containing five disaccharides. The synthetic, pentavalent vaccine candidate containing a peptide T-cell epitope elicits weak but highly specific antibody responses to larger PS-I glycans in mice. This study highlights the potential of multivalently displaying small oligosaccharides to achieve antigenicity characteristic of larger glycans. The approach may result in more cost-efficient carbohydrate vaccines with reduced synthetic effort.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Bacterial / blood
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Antibodies, Bacterial / immunology
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Antibody Formation / immunology
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Antigens, Bacterial / immunology
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Blotting, Western
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Clostridioides difficile / immunology*
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Clostridioides difficile / physiology
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Disaccharides / chemistry
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Disaccharides / immunology*
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Disaccharides / metabolism
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Enterocolitis, Pseudomembranous / blood
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Enterocolitis, Pseudomembranous / immunology
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Enterocolitis, Pseudomembranous / microbiology
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Epitopes, T-Lymphocyte / chemistry
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Epitopes, T-Lymphocyte / immunology*
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Epitopes, T-Lymphocyte / metabolism
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Female
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Glycoconjugates / chemistry
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Glycoconjugates / immunology
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Glycoconjugates / metabolism
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Host-Pathogen Interactions / immunology
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Immunization / methods
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Mice, Inbred C57BL
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Molecular Structure
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Polysaccharides / chemistry
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Polysaccharides / immunology*
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Polysaccharides / metabolism
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Vaccines, Synthetic / administration & dosage
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Vaccines, Synthetic / immunology
Substances
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Antibodies, Bacterial
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Antigens, Bacterial
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Disaccharides
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Epitopes, T-Lymphocyte
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Glycoconjugates
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Polysaccharides
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Vaccines, Synthetic