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Molecular modeling of bacterial polysaccharide antigens to inform future vaccine development
Polysaccharide conjugate vaccines have been pivotal in reducing the prevalence and severity of bacterial infectious diseases worldwide, preventing countless deaths. The effectiveness of a vaccine can be extended if the selected vaccine strains in a multivalent vaccine cross-protect against non-vacci...
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| Format: | Thesis |
| Language: | English |
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Department of Chemistry
2021
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| _version_ | 1867614323044515840 |
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| access_status_str | Open Access |
| author | Hlozek, Jason |
| author2 | Ravenscroft, Neil |
| author_browse | Hlozek, Jason Ravenscroft, Neil |
| author_facet | Ravenscroft, Neil Hlozek, Jason |
| author_sort | Hlozek, Jason |
| collection | Thesis |
| description | Polysaccharide conjugate vaccines have been pivotal in reducing the prevalence and severity of bacterial infectious diseases worldwide, preventing countless deaths. The effectiveness of a vaccine can be extended if the selected vaccine strains in a multivalent vaccine cross-protect against non-vaccine strains. Detailed knowledge of antigen structure and conformation is required for vaccine components to be rationally selected. However, experimental methods may not be able to ascertain the conformations of polysaccharide chains. To address this, molecular dynamics simulations can provide key theoretical insights on molecular conformation to rationalize cross-protection data and inform vaccine development. In this work, we use molecular dynamics to investigate the conformations of glycan antigens of Neisseria meningitidis and Shigella flexneri bacteria - causative agents of meningitis and diarrheal disease. For N. meningitidis, our modeling indicates that serogroup A is unlikely to cross-protect against serogroup X infection, justifying the inclusion of serogroup X in future multivalent meningococcal vaccines. We also find that a chemically-stable carba-analogue of serogroup A has significant conformational differences to the native serogroup A chain, which does not support its use as a suitable serogroup A vaccine replacement. Our simulations of S. flexneri glycan antigens (serogroups Y, 2, 3, and 5) identify heuristics for the effects of substitution on backbone conformation and supports a proposed vaccine containing serotypes 2a (with O-acetylation) and 3a that will provide broad crossprotection. These findings can guide the rational selection of vaccine components to result in next-generation vaccines with greater cost-effectiveness and improved disease coverage. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/33811 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:50:12.840Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2021 |
| publishDateRange | 2021 |
| publishDateSort | 2021 |
| publisher | Department of Chemistry |
| publisherStr | Department of Chemistry |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/33811 Molecular modeling of bacterial polysaccharide antigens to inform future vaccine development Hlozek, Jason Ravenscroft, Neil Kuttel, Michelle Chemistry Polysaccharide conjugate vaccines have been pivotal in reducing the prevalence and severity of bacterial infectious diseases worldwide, preventing countless deaths. The effectiveness of a vaccine can be extended if the selected vaccine strains in a multivalent vaccine cross-protect against non-vaccine strains. Detailed knowledge of antigen structure and conformation is required for vaccine components to be rationally selected. However, experimental methods may not be able to ascertain the conformations of polysaccharide chains. To address this, molecular dynamics simulations can provide key theoretical insights on molecular conformation to rationalize cross-protection data and inform vaccine development. In this work, we use molecular dynamics to investigate the conformations of glycan antigens of Neisseria meningitidis and Shigella flexneri bacteria - causative agents of meningitis and diarrheal disease. For N. meningitidis, our modeling indicates that serogroup A is unlikely to cross-protect against serogroup X infection, justifying the inclusion of serogroup X in future multivalent meningococcal vaccines. We also find that a chemically-stable carba-analogue of serogroup A has significant conformational differences to the native serogroup A chain, which does not support its use as a suitable serogroup A vaccine replacement. Our simulations of S. flexneri glycan antigens (serogroups Y, 2, 3, and 5) identify heuristics for the effects of substitution on backbone conformation and supports a proposed vaccine containing serotypes 2a (with O-acetylation) and 3a that will provide broad crossprotection. These findings can guide the rational selection of vaccine components to result in next-generation vaccines with greater cost-effectiveness and improved disease coverage. 2021-08-24T01:29:20Z 2021-08-24T01:29:20Z 2021 2021-08-23T23:53:34Z Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/33811 eng application/pdf Department of Chemistry Faculty of Science |
| spellingShingle | Chemistry Hlozek, Jason Molecular modeling of bacterial polysaccharide antigens to inform future vaccine development |
| thesis_degree_str | Doctoral |
| title | Molecular modeling of bacterial polysaccharide antigens to inform future vaccine development |
| title_full | Molecular modeling of bacterial polysaccharide antigens to inform future vaccine development |
| title_fullStr | Molecular modeling of bacterial polysaccharide antigens to inform future vaccine development |
| title_full_unstemmed | Molecular modeling of bacterial polysaccharide antigens to inform future vaccine development |
| title_short | Molecular modeling of bacterial polysaccharide antigens to inform future vaccine development |
| title_sort | molecular modeling of bacterial polysaccharide antigens to inform future vaccine development |
| topic | Chemistry |
| url | http://hdl.handle.net/11427/33811 |
| work_keys_str_mv | AT hlozekjason molecularmodelingofbacterialpolysaccharideantigenstoinformfuturevaccinedevelopment |