Browsing by Author "Hlozek, Jason"

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    Molecular modeling of bacterial polysaccharide antigens to inform future vaccine development
    (2021) Hlozek, Jason; Ravenscroft, Neil; Kuttel, Michelle
    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.
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    Molecular Modeling of the Shigella flexneri Serogroup 3 and 5 O-Antigens and Conformational Relationships for a Vaccine Containing Serotypes 2a and 3a
    (2020-11-02) Hlozek, Jason; Owen, Sara; Ravenscroft, Neil; Kuttel, Michelle M.
    The pathogenic bacterium Shigella flexneri is a leading global cause of diarrheal disease. The O-antigen is the primary vaccine target and distinguishes the 30 serotypes reported. Except for serotype 6, all S. flexneri serotypes have a common backbone repeating unit (serotype Y), with variations in substitution creating the various serotypes. A quadrivalent vaccine containing serotypes 2a and 3a (as well as 6 and Shigella sonnei) is proposed to provide broad protection against non-vaccine S. flexneri serotypes through shared epitopes and conformations. Here we model the O-antigen (O-Ag) conformations of serogroups 3 and 5: a continuation of our ongoing systematic study of the S. flexneri O-antigens that began with serogroup 2. Our simulations show that S. flexneri serogroups 2, 3, and 5 all have flexible O-Ags, with substitutions of the backbone altering the chain conformations in different ways. Our analysis suggests three general heuristics for the effects of substitution on the Shigella O-Ag conformations: (1) substitution on rhamnose C reduces the extension of the O-Ag chain; (2) substitution at O-3 of rhamnose A restricts the O-Ags to predominantly helical conformations, (3) substitution at O-3 of rhamnose B has only a slight effect on conformation. The common O-Ag conformations across serotypes identified in this work support the assumption that a quadrivalent vaccine containing serotypes 2a and 3a could provide coverage against S. flexneri serotype 3b and serogroup 5.
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    Molecular Modeling of the Shigella flexneri Serogroup 3 and 5 O-Antigens and Conformational Relationships for a Vaccine Containing Serotypes 2a and 3a
    (2020-11-02) Hlozek, Jason; Owen, Sara; Ravenscroft, Neil; Kuttel, Michelle M
    The pathogenic bacterium Shigella flexneri is a leading global cause of diarrheal disease. The O-antigen is the primary vaccine target and distinguishes the 30 serotypes reported. Except for serotype 6, all S. flexneri serotypes have a common backbone repeating unit (serotype Y), with variations in substitution creating the various serotypes. A quadrivalent vaccine containing serotypes 2a and 3a (as well as 6 and Shigella sonnei) is proposed to provide broad protection against non-vaccine S. flexneri serotypes through shared epitopes and conformations. Here we model the O-antigen (O-Ag) conformations of serogroups 3 and 5: a continuation of our ongoing systematic study of the S. flexneri O-antigens that began with serogroup 2. Our simulations show that S. flexneri serogroups 2, 3, and 5 all have flexible O-Ags, with substitutions of the backbone altering the chain conformations in different ways. Our analysis suggests three general heuristics for the effects of substitution on the Shigella O-Ag conformations: (1) substitution on rhamnose C reduces the extension of the O-Ag chain; (2) substitution at O-3 of rhamnose A restricts the O-Ags to predominantly helical conformations, (3) substitution at O-3 of rhamnose B has only a slight effect on conformation. The common O-Ag conformations across serotypes identified in this work support the assumption that a quadrivalent vaccine containing serotypes 2a and 3a could provide coverage against S. flexneri serotype 3b and serogroup 5.