Cross-reactivity of Haemophilus influenzae type a and b polysaccharides: molecular modeling and conjugate immunogenicity studies

Richardson, Nicole I; Kuttel, Michelle M.; Michael, Frank St.; Cairns, Chantelle M.; Cox, Andrew D.; Ravenscroft, Neil

doi:10.1007/s10719-021-10020-0

Cited by 6 publications

(11 citation statements)

References 56 publications

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“…Further, those we identified accounted for relatively small portions of the simulation (less than 25%). This indicates that these flexible chains behave as random coils, in common with other flexible carbohydrates that we have modeled (Richardson et al, 2021a;Richardson et al, 2021b).…”

Section: Chain Flexibility and Conformationmentioning

confidence: 60%

“…Trajectory snapshots at 50 ns intervals (shown above the graphs) illustrate the considerable diversity in the molecular conformations over all the simulations. This flexibility is an expected consequence of a linear alditol (Rib-ol-5P) with a phosphodiester linkage in the CPS backbone: modeling of Haemophilus influenzae serotypes a and b CPS, which also contain this moiety, showed similarly flexible molecules ( Richardson et al, 2021a ).…”

Section: Resultsmentioning

confidence: 99%

“…Molecular modeling is a complementary technique that can be used to correlate the conformational features of carbohydrate antigens with data on serotype cross-protection produced by immunological studies (such as serological evaluations, animal trials, human trials, or epidemiological studies) ( Zaccheus et al, 2012 ; Sarkar et al, 2013 ; Kang et al, 2014 ; Yang et al, 2017 ; Kuttel and Ravenscroft, 2018 ; Aytenfisu et al, 2019 ). Recently, we have explored the importance of the presentation of structural features or epitopes on bacterial CPS for serotype cross-protection ( Richardson et al, 2021a ; Kuttel, 2022 ). Here we apply our established molecular modeling methodology to the four primary S. pneumoniae serogroup 10 CPSs (Pn10A, Pn10B, Pn10C, and Pn10F) to establish their conformation and identify potential cross-protective epitopes.…”

Section: Introductionmentioning

confidence: 99%

“…Frontiers in Molecular Biosciences frontiersin.org Kuttel and Ravenscroft, 2018;Aytenfisu et al, 2019). Recently, we have explored the importance of the presentation of structural features or epitopes on bacterial CPS for serotype crossprotection (Richardson et al, 2021a;Kuttel, 2022). Here we apply our established molecular modeling methodology to the four primary S. pneumoniae serogroup 10 CPSs (Pn10A, Pn10B, Pn10C, and Pn10F) to establish their conformation and identify potential cross-protective epitopes.…”

Section: Introductionmentioning

confidence: 99%

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Modeling of pneumococcal serogroup 10 capsular polysaccharide molecular conformations provides insight into epitopes and observed cross-reactivity

Richardson

Kuttel²,

Ravenscroft³

2022

Front. Mol. Biosci.

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Streptococcus pneumoniae is an encapsulated gram-negative bacterium and a significant human pathogen. The capsular polysaccharide (CPS) is essential for virulence and a target antigen for vaccines. Although widespread introduction of pneumococcal conjugate vaccines (PCVs) has significantly reduced disease, the prevalence of non-vaccine serotypes has increased. On the basis of the CPS, S. pneumoniae serogroup 10 comprises four main serotypes 10A, 10B, 10C, and 10F; as well as the recently identified 10D. As it is the most prevalent, serotype 10A CPS has been included as a vaccine antigen in the next generation PCVs. Here we use molecular modeling to provide conformational rationales for the complex cross-reactivity reported between serotypes 10A, 10B, 10C, and 10F anti-sera. Although the highly mobile phosphodiester linkages produce very flexible CPS, shorter segments are conformationally defined, with exposed β-D-galactofuranose (β DGalf) side chains that are potential antibody binding sites. We identify four distinct conformational epitopes for the immunodominant β DGalf that assist in rationalizing the complex asymmetric cross-reactivity relationships. In particular, we find that strongly cross-reactive serotypes share common epitopes. Further, we show that human intelectin-1 has the potential to bind the exposed exocyclic 1,2-diol of the terminal β DGalf in each serotype; the relative accessibility of three- or six-linked β DGalf may play a role in the strength of the innate immune response and hence serotype disease prevalence. In conclusion, our modeling study and relevant serological studies support the inclusion of serotype 10A in a vaccine to best protect against serogroup 10 disease.

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Section: Chain Flexibility and Conformationmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modeling of pneumococcal serogroup 10 capsular polysaccharide molecular conformations provides insight into epitopes and observed cross-reactivity

Richardson

Kuttel²,

Ravenscroft³

2022

Front. Mol. Biosci.

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“…As there are currently no experimental data available on the molecular conformations of this group of CPS antigens, molecular modelling can provide useful information on which epitopes are exposed and thus likely to be recognized by antibodies ( Kuttel and Ravenscroft 2018 ). We have performed a range of comparative modelling investigations of microbial CPS to explain clinical findings, most recently of Haemophilus influenzae ( Richardson et al, 2021 ) and Cryptococcus neoformans ( Kuttel et al, 2020 ). Here we undertake a comparative modelling study of the Ss2, Ss1/2, Ss1 and Ss14 CPS as well as the three synthetic vaccine candidate oligosaccharides, comparing the predicted molecular flexibility and conformations to identify and contrast the probable protective epitopes for these four S. suis CPS.…”

Section: Introductionmentioning

confidence: 99%

Comparative Molecular Modelling of Capsular Polysaccharide Conformations in Streptococcus suis Serotypes 1, 2, 1/2 and 14 Identifies Common Epitopes for Antibody Binding

Kuttel

2022

Front. Mol. Biosci.

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Streptococcus suis is an encapsulated, commensal, potentially pathogenic bacterium that infects swine globally and causes sporadic life-threatening zoonotic septicemia and meningitis infections in humans. The capsular polysaccharide is a primary virulence factor for S. suis. As S. suis serotype 2 is the most prevalent serotype globally, the serotype 2 CPS is the primary target of current efforts to develop an effective glycoconjugate veterinary vaccine against S. suis. Possible cross-protection with related serotypes would broaden the coverage of a vaccine. The CPS in serotypes 2 and 1/2 differ at a single residue (Gal versus GalNAc), and both are similar to serotypes 1 and 14: all contain a terminal sialic acid on a side chain. However, despite this similarity, there is complex pattern of cross-protection for these serotypes, with varying estimations of the importance of sialic acid in a protective epitope. Further, a pentasaccharide without the terminal sialic acid has been identified as minimal epitope for serotype 2. Here we use molecular simulation to model the molecule conformations of the CPS in serotypes 2, 1/2, 1 and 14, as well as three vaccine candidate oligosaccharides. The common epitopes we identify assist in rationalizing the apparently contradictory immunological data and provide a basis for rational design of S. suis vaccines in the future.

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Semisynthetic Glycoconjugates as Potential Vaccine Candidates Against Haemophilus influenzae Type a

Kohout,

Del Bino,

Petrosilli

et al. 2024

Chemistry A European J

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Glycoconjugate vaccines are based on chemical conjugation of pathogen‐associated carbohydrates with immunogenic carrier proteins and are considered a very cost‐effective way to prevent infections. Most of the licensed glycoconjugate vaccines are composed of saccharide antigens extracted from bacterial sources. However, synthetic oligosaccharide antigens have become a promising alternative to natural polysaccharides with the advantage of being well‐defined structures providing homogeneous conjugates. Haemophilus influenzae (Hi) is responsible for a number of severe diseases. In recent years, an increasing rate of invasive infections caused by Hi serotype a (Hia) raised some concern, because no vaccine targeting Hia is currently available. The capsular polysaccharide (CPS) of Hia is constituted by phosphodiester‐linked 4‐β‐d‐glucose‐(1→4)‐d‐ribitol‐5‐(PO4→) repeating units and is the antigen for protein‐conjugated polysaccharide vaccines. To investigate the antigenic potential of the CPS from Hia, we synthesized related saccharide fragments containing up to five repeating units. Following the synthetic optimization of the needed disaccharide building blocks, they were assembled using the phosphoramidite approach for the installation of the phosphodiester linkages. The resulting CPS‐based Hia oligomers were conjugated to CRM197 carrier protein and evaluated in vivo for their immunogenic potential, showing that all glycoconjugates were capable of raising antibodies recognizing Hia synthetic fragments.

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Cross-reactivity of Haemophilus influenzae type a and b polysaccharides: molecular modeling and conjugate immunogenicity studies

Cited by 6 publications

References 56 publications

Modeling of pneumococcal serogroup 10 capsular polysaccharide molecular conformations provides insight into epitopes and observed cross-reactivity

Modeling of pneumococcal serogroup 10 capsular polysaccharide molecular conformations provides insight into epitopes and observed cross-reactivity

Comparative Molecular Modelling of Capsular Polysaccharide Conformations in Streptococcus suis Serotypes 1, 2, 1/2 and 14 Identifies Common Epitopes for Antibody Binding

Semisynthetic Glycoconjugates as Potential Vaccine Candidates Against Haemophilus influenzae Type a

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