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Vaccines
Special Issues
Carbohydrate Immunogens in Vaccines
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Carbohydrate Immunogens in Vaccines

A special issue of Vaccines (ISSN 2076-393X).

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 21703

Special Issue Editor

Prof. Dr. Mario A. Monteiro

E-Mail Website
Guest Editor
Department of Chemistry, University of Guelph, Guelph, ON, Canada
Interests: vaccines; saccharides; conjugates; bacteria; infectious diseases

Special Issue Information

Dear Colleagues,

The rate-determining-step in developing new subunit vaccines is the discovery of molecular targets that will serve as the protective immunogen. In particular, bacterial pathogens expose complex polysaccharides that make attractive vaccine targets, such as those in the sucessful pneumococcal and meningococcal vaccines. An important branch of ongoing vaccine research focus on specie-specific polysaccharides produced by antibiotic resistant microbes, such as Mycobacterium tuberculosis, Clostridia and Staphylococcus species and enteric food borne pathogens. This Special Issue of Vaccines aims at divulging carbohydrate-based vaccine targets and their application in prophylatic and therapeutic vaccines against diseases caused by such bacterial pathogens. The research/review articles will focus on (i) physico-chemical approaches used in the characterization of polysaccharide targets produced by clinical-important pathogens; (ii) polysaccharide-protein conjugation methodology and (iii) cGMP manufacturing of polysaccharide-conjugate vaccines.

Prof. Dr. Mario A. Monteiro
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Vaccines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Vaccines
  • Bacterial Polysaccharides
  • Viral Oligosaccharides
  • Cancer-Associated Glycans
  • Immunogens

Published Papers (5 papers)

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Research

18 pages, 3130 KiB  
Article
Activation of Soluble Polysaccharides with 1-Cyano-4-Dimethylaminopyridine Tetrafluoroborate (CDAP) for Use in Protein–Polysaccharide Conjugate Vaccines and Immunological Reagents. III Optimization of CDAP Activation
by Andrew Lees, Jackson F. Barr and Samson Gebretnsae
Vaccines 2020, 8(4), 777; https://doi.org/10.3390/vaccines8040777 - 18 Dec 2020
Cited by 16 | Viewed by 5609
Abstract
CDAP (1-cyano-4-dimethylaminopyridine tetrafluoroborate) is employed in the synthesis of conjugate vaccines as a cyanylating reagent. In the published method, which used pH 9 activation at 20 °C (Vaccine, 14:190, 1996), the rapid reaction made the process difficult to control. Here, we [...] Read more.
CDAP (1-cyano-4-dimethylaminopyridine tetrafluoroborate) is employed in the synthesis of conjugate vaccines as a cyanylating reagent. In the published method, which used pH 9 activation at 20 °C (Vaccine, 14:190, 1996), the rapid reaction made the process difficult to control. Here, we describe optimizing CDAP activation using dextran as a model polysaccharide. CDAP stability and reactivity were determined as a function of time, pH and temperature. While the rate of dextran activation was slower at lower pH and temperature, it was balanced by the increased stability of CDAP, which left more reagent available for reaction. Whereas maximal activation took less than 2.5 min at pH 9 and 20 °C, it took 10–15 min at 0 °C. At pH 7 and 0 °C, the optimal time increased to >3 h to achieve a high level of activation. Many buffers interfered with CDAP activation, but DMAP could be used to preadjust the pH of polysaccharide solutions so that the pH only needed to be maintained. We found that the stability of the activated dextran was relatively independent of pH over the range of pH 1–9, with the level of activation decreased by 40–60% over 2 h. The use of low temperature and a less basic pH, with an optimum reaction time, requires less CDAP, improving activation levels while making the process more reliable and easier to scale up. Full article
(This article belongs to the Special Issue Carbohydrate Immunogens in Vaccines)
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17 pages, 3264 KiB  
Article
Molecular Modeling of the Shigella flexneri Serogroup 3 and 5 O-Antigens and Conformational Relationships for a Vaccine Containing Serotypes 2a and 3a
by Jason Hlozek, Sara Owen, Neil Ravenscroft and Michelle M. Kuttel
Vaccines 2020, 8(4), 643; https://doi.org/10.3390/vaccines8040643 - 02 Nov 2020
Cited by 6 | Viewed by 2387
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Carbohydrate Immunogens in Vaccines)
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18 pages, 2152 KiB  
Article
Recognition of Dimeric Lewis X by Anti-Dimeric Lex Antibody SH2
by Sinthuja Jegatheeswaran, Ari Asnani, Adam Forman, Jenifer L. Hendel, Christopher J. Moore, Ali Nejatie, An Wang, Jo-Wen Wang and France-Isabelle Auzanneau
Vaccines 2020, 8(3), 538; https://doi.org/10.3390/vaccines8030538 - 17 Sep 2020
Cited by 4 | Viewed by 3767
Abstract
The carbohydrate antigen dimeric Lewis X (DimLex), which accumulates in colonic and liver adenocarcinomas, is a valuable target to develop anti-cancer therapeutics. Using the native DimLex antigen as a vaccine would elicit an autoimmune response against the Lex antigen [...] Read more.
The carbohydrate antigen dimeric Lewis X (DimLex), which accumulates in colonic and liver adenocarcinomas, is a valuable target to develop anti-cancer therapeutics. Using the native DimLex antigen as a vaccine would elicit an autoimmune response against the Lex antigen found on normal, healthy cells. Thus, we aim to study the immunogenic potential of DimLex and search internal epitopes displayed by DimLex that remain to be recognized by anti-DimLex monoclonal antibodies (mAbs) but no longer possess epitopes recognized by anti-Lex mAbs. In this context, we attempted to map the epitope recognized by anti-DimLex mAb SH2 by titrations and competitive inhibition experiments using oligosaccharide fragments of DimLex as well as Lex analogues. We compare our results with that reported for anti-Lex mAb SH1 and anti-polymeric Lex mAbs 1G5F6 and 291-2G3-A. While SH1 recognizes an epitope localized to the non-reducing end Lex trisaccharide, SH2, 1G5F6, and 291-2G3-A have greater affinity for DimLex conjugates than for Lex conjugates. We show, however, that the Lex trisaccharide is still an important recognition element for SH2, which (like 1G5F6 and 291-2G3-A) makes contacts with all three sugar units of Lex. In contrast to mAb SH1, anti-polymeric Lex mAbs make contact with the GlcNAc acetamido group, suggesting that epitopes extend further from the non-reducing end Lex. Results with SH2 show that this epitope is only recognized when DimLex is presented by glycoconjugates. We have reported that DimLex adopts two conformations around the β-d-GlcNAc-(1→3)-d-Gal bond connecting the Lex trisaccharides. We propose that only one of these conformations is recognized by SH2 and that this conformation is favored when the hexasaccharide is presented as part of a glycoconjugate such as DimLex-bovine serum albumin (DimLex-BSA). Proper presentation of the oligosaccharide candidate via conjugation to a protein or lipid is essential for the design of an anti-cancer vaccine or immunotherapeutic based on DimLex. Full article
(This article belongs to the Special Issue Carbohydrate Immunogens in Vaccines)
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17 pages, 3469 KiB  
Article
GMMA and Glycoconjugate Approaches Compared in Mice for the Development of a Vaccine against Shigella flexneri Serotype 6
by Maria Michelina Raso, Gianmarco Gasperini, Renzo Alfini, Fabiola Schiavo, Maria Grazia Aruta, Martina Carducci, Maria Concetta Forgione, Silvia Martini, Paola Cescutti, Francesca Necchi and Francesca Micoli
Vaccines 2020, 8(2), 160; https://doi.org/10.3390/vaccines8020160 - 03 Apr 2020
Cited by 36 | Viewed by 5549
Abstract
Shigella infections are one of the top causes of diarrhea throughout the world, with Shigella flexneri being predominant in developing countries. Currently, no vaccines are widely available and increasing levels of multidrug-resistance make Shigella a high priority for vaccine development. The serotype-specific O-antigen [...] Read more.
Shigella infections are one of the top causes of diarrhea throughout the world, with Shigella flexneri being predominant in developing countries. Currently, no vaccines are widely available and increasing levels of multidrug-resistance make Shigella a high priority for vaccine development. The serotype-specific O-antigen moiety of Shigella lipopolysaccharide has been recognized as a key target for protective immunity, and many O-antigen based candidate vaccines are in development. Recently, the Generalized Modules for Membrane Antigens (GMMA) technology has been proposed as an alternative approach to traditional glycoconjugate vaccines for O-antigen delivery. Here, these two technologies are compared for a vaccine against S. flexneri serotype 6. Genetic strategies for GMMA production, conjugation approaches for linkage of the O-antigen to CRM197 carrier protein, and a large panel of analytical methods for full vaccine characterization have been put in place. In a head-to-head immunogenicity study in mice, GMMA induced higher anti-O-antigen IgG than glycoconjugate administered without Alhydrogel. When formulated on Alhydrogel, GMMA and glycoconjugate elicited similar levels of persistent anti-O-antigen IgG with bactericidal activity. Glycoconjugates are a well-established bacterial vaccine approach, but can be costly, particularly when multicomponent preparations are required. With similar immunogenicity and a simpler manufacturing process, GMMA are a promising strategy for the development of a vaccine against Shigella. Full article
(This article belongs to the Special Issue Carbohydrate Immunogens in Vaccines)
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19 pages, 1472 KiB  
Article
In Vitro Production and Immunogenicity of a Clostridium difficile Spore-Specific BclA3 Glycopeptide Conjugate Vaccine
by Annie Aubry, Wei Zou, Evguenii Vinogradov, Dean Williams, Wangxue Chen, Greg Harris, Hongyan Zhou, Melissa J. Schur, Michel Gilbert, Gillian R. Douce and Susan M. Logan
Vaccines 2020, 8(1), 73; https://doi.org/10.3390/vaccines8010073 - 07 Feb 2020
Cited by 6 | Viewed by 3625
Abstract
The BclA3 glycoprotein is a major component of the exosporangial layer of Clostridium difficile spores and in this study we demonstrate that this glycoprotein is a major spore surface associated antigen. Here, we confirm the role of SgtA glycosyltransferase (SgtA GT) in BclA3 [...] Read more.
The BclA3 glycoprotein is a major component of the exosporangial layer of Clostridium difficile spores and in this study we demonstrate that this glycoprotein is a major spore surface associated antigen. Here, we confirm the role of SgtA glycosyltransferase (SgtA GT) in BclA3 glycosylation and recapitulate this process by expressing and purifying SgtA GT fused to MalE, the maltose binding protein from Escherichia coli. In vitro assays using the recombinant enzyme and BclA3 synthetic peptides demonstrated that SgtA GT was responsible for the addition of β-O-linked GlcNAc to threonine residues of each synthetic peptide. These peptide sequences were selected from the central, collagen repeat region of the BclA3 protein. Following optimization of SgtA GT activity, we generated sufficient glycopeptide (10 mg) to allow conjugation to KLH (keyhole limpet hemocyanin) protein. Glycosylated and unglycosylated versions of these conjugates were then used as antigens to immunize rabbits and mice. Immune responses to each of the conjugates were examined by Enzyme Linked Immunosorbent Assay ELISA. Additionally, the BclA3 conjugated peptide and glycopeptide were used as antigens in an ELISA assay with serum raised against formalin-killed spores. Only the glycopeptide was recognized by anti-spore polyclonal immune serum demonstrating that the glycan moiety is a predominant spore-associated surface antigen. To determine whether antibodies to these peptides could modify persistence of spores within the gut, animals immunized intranasally with either the KLH-glycopeptide or KLH-peptide conjugate in the presence of cholera toxin, were challenged with R20291 spores. Although specific antibodies were raised to both antigens, immunization did not provide any protection against acute or recurrent disease. Full article
(This article belongs to the Special Issue Carbohydrate Immunogens in Vaccines)
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