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Special Issue "Conjugate Vaccines from Carbohydrate Antigens"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (31 May 2018)

Special Issue Editors

Guest Editor
Dr. Paul Kovac

NIDDK, LBC, National Institutes of Health, Bethesda, MD 20892-0815, USA
Website | E-Mail
Phone: 301-496-3569
Interests: organic chemistry; carbohydrate chemistry; synthetic oligosaccharides; development of conjugate vaccines from synthetic and bacterial carbohydrate antigens
Guest Editor
Dr. Peng Xu

NIDDK, LBC, National Institutes of Health, Bethesda, MD 20892-0815, USA
Website | E-Mail
Interests: neoglycoconjugate vaccine; conjugation chemistry; chemical glycosylation; oligosaccharide synthesis; lipopolysaccharide; O-specific polysaccharide
Guest Editor
Dr. Helene Pfister

NIDDK, LBC, National Institutes of Health, Bethesda, MD 20892-0815, USA
Website | E-Mail
Interests: carbohydrate chemistry; oligosaccharides synthesis; conjugation chemistry; glycoproteins; glycopolymers; glycoconjugate vaccines

Special Issue Information

Dear Colleagues,

Vaccines are one of the most cost-effective way to control infectious diseases. In addition to protein antigens, cell surface carbohydrates are widely used as antigenic components of vaccines. Since the preparation and clinical use of the first carbohydrate–protein conjugate vaccine in the 1980s, the advantages of this class of vaccines, such as longer shelf life and protective immunity, fewer undesirable side-effects, and better protection in children, have been largely recognized. Glycoconjugate vaccines are composed of carbohydrate antigens, covalently linked to a carrier moiety, usually a non-toxic protein. The carbohydrate moiety is normally an oligosaccharide or polysaccharide of bacterial origins. However, several glycoconjugate vaccines from synthetic oligosaccharides are in development. While immunogenic proteins, such as tetanus toxoid are generally used as carriers of antigens, recent advances in the field showed the potential of immunogenic peptides for the same purpose.

This Special Issue is dedicated to the design, synthesis, and antigenicity/immunogenicity studies of glycoconjugate vaccines. In addition, we welcome contributions on conjugation methodology, synthesis of conjugation-ready oligosaccharides related to protective antigens, and purification and characterization of bacterial polysaccharides.

Dr. Paul Kovac
Dr. Peng Xu
Dr. Helene Pfister
Guest Editors

Manuscript Submission Information

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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. Molecules 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 1800 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

  • glycoconjugates
  • neoglycoconjugate
  • conjugation methodology
  • immunogens
  • carbohydrate antigens
  • bacterial carbohydrates
  • vaccines

Published Papers (10 papers)

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Research

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Open AccessArticle Structure-Immunogenicity Relationship of α- and β-Tetrasaccharide Glycoforms from Bacillus anthracis Exosporium and Fragments Thereof
Molecules 2018, 23(8), 2079; https://doi.org/10.3390/molecules23082079
Received: 12 July 2018 / Revised: 1 August 2018 / Accepted: 17 August 2018 / Published: 20 August 2018
PDF Full-text (1939 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The tetrasaccharide (2-O-methyl-4-(3-hydroxy-3-methylbutamido)-4,6-dideoxy-α-d-glucopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→2)-l-rhamnopyranose) from the major exosporium protein (BclA) of Bacillus anthracis has been proposed as a target for development of diagnostics and immune therapy or prophylaxis. While the immunodominant character of the
[...] Read more.
The tetrasaccharide (2-O-methyl-4-(3-hydroxy-3-methylbutamido)-4,6-dideoxy-α-d-glucopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→2)-l-rhamnopyranose) from the major exosporium protein (BclA) of Bacillus anthracis has been proposed as a target for development of diagnostics and immune therapy or prophylaxis. While the immunodominant character of the anthrose residue has been previously elucidated, the role of the stereochemical configuration of the downstream rhamnose is unknown. Because the linkage of this residue to the GlcNAc bridging the glycan and the protein is lost during isolation of the tetrasaccharide, its α- and β-glycoforms have been synthesized. Herein, we prepared neoglycoconjugates from a series of fragments of the tetrasaccharide, including the complete α- and β-tetrasaccharide glycoforms, a 2-demethoxylated version of the α-tetrasaccharide, and the α- and β-trirhamnosides and CRM197. By immunization of mice, we showed that the anti α- and β-tetrasaccharide serum equally recognized both glycoforms. In contrast the sera produced following immunization with the α- and β-trirhamnoside fragments exhibited higher recognition for their own antigens than for their anomeric counterparts. The anti α- and β-tetrasaccharide sera recognized Sterne spores in a comparable fashion. ΔBclA spores not expressing the major exosporium protein were also recognized by the same sera, while mutants that produced the carbohydrate antigen with deletion of either rhamnose or anthrose were not. The tetrasaccharide could, therefore, be expressed in proteins other than BlcA. This work proves that α- and β-tetrasaccharide are equally potent immunogens. Full article
(This article belongs to the Special Issue Conjugate Vaccines from Carbohydrate Antigens)
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Open AccessArticle A Three Component Synthetic Vaccine Containing a β-Mannan T-Cell Peptide Epitope and a β-Glucan Dendritic Cell Ligand
Molecules 2018, 23(8), 1961; https://doi.org/10.3390/molecules23081961
Received: 30 May 2018 / Revised: 29 July 2018 / Accepted: 3 August 2018 / Published: 6 August 2018
PDF Full-text (2897 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Glycoconjugates prepared from the capsular polysaccharide of several pathogenic bacteria and carrier proteins, such as CRM 197 or tetanus toxoid, have been one of the most successful public health measures to be implemented in the last quarter century. A crucial element in the
[...] Read more.
Glycoconjugates prepared from the capsular polysaccharide of several pathogenic bacteria and carrier proteins, such as CRM 197 or tetanus toxoid, have been one of the most successful public health measures to be implemented in the last quarter century. A crucial element in the success of conjugate vaccines has been the recruitment of T-cell help and systematic induction of a secondary immune response. The seminal discovery, that degraded polysaccharide fragments with attached peptide are presented to the T-cell receptor of carbohydrate specific T-cells by MHC-II molecules that bind to the peptide component of degraded vaccine, suggests potentially novel designs for conjugate vaccines. A fully synthetic conjugate vaccine was constructed from a 1,2-linked β-mannose trisaccharide conjugated to a T-cell peptide, previously shown to afford protection against Candida albicans. This combined B- and T-cell epitope was synthesized with a C-terminal azidolysine residue for subsequent conjugation by click chemistry. Four copies of a β-1,3 linked hexaglucan dendritic cell epitope were conjugated to an asymmetric dendrimer bearing an alkyne terminated tether. Click chemistry of these two components created a conjugate vaccine that induced antibodies to all three epitopes of the fully synthetic construct. Full article
(This article belongs to the Special Issue Conjugate Vaccines from Carbohydrate Antigens)
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Open AccessArticle Immunogenicity and Induction of Functional Antibodies in Rabbits Immunized with a Trivalent Typhoid-Invasive Nontyphoidal Salmonella Glycoconjugate Formulation
Molecules 2018, 23(7), 1749; https://doi.org/10.3390/molecules23071749
Received: 21 May 2018 / Revised: 12 July 2018 / Accepted: 14 July 2018 / Published: 17 July 2018
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Abstract
Typhoid fever due to Salmonella Typhi and invasive nontyphoidal Salmonella (iNTS) infections caused by serovars Enteritidis (SE) and Typhimurium (STm) are major pediatric health problems in sub-Saharan Africa. Typhoid has high complication rates, and iNTS infections have high case fatality rates; moreover, emerging
[...] Read more.
Typhoid fever due to Salmonella Typhi and invasive nontyphoidal Salmonella (iNTS) infections caused by serovars Enteritidis (SE) and Typhimurium (STm) are major pediatric health problems in sub-Saharan Africa. Typhoid has high complication rates, and iNTS infections have high case fatality rates; moreover, emerging antimicrobial resistance is diminishing treatment options. Vi capsule-based typhoid conjugate vaccine (Typbar-TCV™), licensed in India and pre-qualified by the World Health Organization, elicits durable immunity when administered to infants, but no iNTS vaccines are licensed or imminent. We have developed monovalent SE and STm glycoconjugate vaccines based on coupling lipopolysaccharide-derived core-O polysaccharide (COPS) to phase 1 flagellin protein (FliC) from the homologous serovar. Herein, we report the immunogenicity of multivalent formulations of iNTS COPS:FliC conjugates with Typbar-TCV™. Rabbits immunized with the trivalent typhoid-iNTS glycoconjugate vaccine generated high titers of serum IgG antibody to all three polysaccharide antigens for which anti-COPS IgG antibodies were directed primarily against serogroup-specific OPS epitopes. Responses to SE and STm FliC were lower relative to anti-COPS titers. Post-vaccination rabbit sera mediated bactericidal activity in-vitro, and protected mice after passive transfer against challenge with virulent SE or STm Malian blood isolates. These results support accelerated progression to clinical trials. Full article
(This article belongs to the Special Issue Conjugate Vaccines from Carbohydrate Antigens)
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Review

Jump to: Research

Open AccessFeature PaperReview Chemical Synthesis of Rare, Deoxy-Amino Sugars Containing Bacterial Glycoconjugates as Potential Vaccine Candidates
Molecules 2018, 23(8), 1997; https://doi.org/10.3390/molecules23081997
Received: 10 July 2018 / Revised: 4 August 2018 / Accepted: 8 August 2018 / Published: 10 August 2018
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Abstract
Bacteria often contain rare deoxy amino sugars which are absent in the host cells. This structural difference can be harnessed for the development of vaccines. Over the last fifteen years, remarkable progress has been made toward the development of novel and efficient protocols
[...] Read more.
Bacteria often contain rare deoxy amino sugars which are absent in the host cells. This structural difference can be harnessed for the development of vaccines. Over the last fifteen years, remarkable progress has been made toward the development of novel and efficient protocols for obtaining the rare sugar building blocks and their stereoselective assembly to construct conjugation ready bacterial glycans. In this review, we discuss the total synthesis of a variety of rare sugar containing bacterial glycoconjugates which are potential vaccine candidates. Full article
(This article belongs to the Special Issue Conjugate Vaccines from Carbohydrate Antigens)
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Open AccessReview Anomeric O-Functionalization of Carbohydrates for Chemical Conjugation to Vaccine Constructs
Molecules 2018, 23(7), 1742; https://doi.org/10.3390/molecules23071742
Received: 25 June 2018 / Revised: 12 July 2018 / Accepted: 13 July 2018 / Published: 17 July 2018
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Abstract
Carbohydrates mediate a wide range of biological interactions, and understanding these processes benefits the development of new therapeutics. Isolating sufficient quantities of glycoconjugates from biological samples remains a significant challenge. With advances in chemical and enzymatic carbohydrate synthesis, the availability of complex carbohydrates
[...] Read more.
Carbohydrates mediate a wide range of biological interactions, and understanding these processes benefits the development of new therapeutics. Isolating sufficient quantities of glycoconjugates from biological samples remains a significant challenge. With advances in chemical and enzymatic carbohydrate synthesis, the availability of complex carbohydrates is increasing and developing methods for stereoselective conjugation these polar head groups to proteins and lipids is critically important for pharmaceutical applications. The aim of this review is to provide an overview of commonly employed strategies for installing a functionalized linker at the anomeric position as well as examples of further transformations that have successfully led to glycoconjugation to vaccine constructs for biological evaluation as carbohydrate-based therapeutics. Full article
(This article belongs to the Special Issue Conjugate Vaccines from Carbohydrate Antigens)
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Open AccessFeature PaperReview Recent Advances in the Synthesis of Glycoconjugates for Vaccine Development
Molecules 2018, 23(7), 1712; https://doi.org/10.3390/molecules23071712
Received: 8 June 2018 / Revised: 9 July 2018 / Accepted: 11 July 2018 / Published: 13 July 2018
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Abstract
During the last decade there has been a growing interest in glycoimmunology, a relatively new research field dealing with the specific interactions of carbohydrates with the immune system. Pathogens’ cell surfaces are covered by a thick layer of oligo- and polysaccharides that are
[...] Read more.
During the last decade there has been a growing interest in glycoimmunology, a relatively new research field dealing with the specific interactions of carbohydrates with the immune system. Pathogens’ cell surfaces are covered by a thick layer of oligo- and polysaccharides that are crucial virulence factors, as they mediate receptors binding on host cells for initial adhesion and organism invasion. Since in most cases these saccharide structures are uniquely exposed on the pathogen surface, they represent attractive targets for vaccine design. Polysaccharides isolated from cell walls of microorganisms and chemically conjugated to immunogenic proteins have been used as antigens for vaccine development for a range of infectious diseases. However, several challenges are associated with carbohydrate antigens purified from natural sources, such as their difficult characterization and heterogeneous composition. Consequently, glycoconjugates with chemically well-defined structures, that are able to confer highly reproducible biological properties and a better safety profile, are at the forefront of vaccine development. Following on from our previous review on the subject, in the present account we specifically focus on the most recent advances in the synthesis and preliminary immunological evaluation of next generation glycoconjugate vaccines designed to target bacterial and fungal infections that have been reported in the literature since 2011. Full article
(This article belongs to the Special Issue Conjugate Vaccines from Carbohydrate Antigens)
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Open AccessFeature PaperReview Recent Advances in Toll Like Receptor-Targeting Glycoconjugate Vaccines
Molecules 2018, 23(7), 1583; https://doi.org/10.3390/molecules23071583
Received: 11 June 2018 / Revised: 25 June 2018 / Accepted: 28 June 2018 / Published: 29 June 2018
PDF Full-text (3227 KB) | HTML Full-text | XML Full-text
Abstract
Many malignant cell surface carbohydrates resulting from abnormal glycosylation patterns of certain diseases can serve as antigens for the development of vaccines against these diseases. However, carbohydrate antigens are usually poorly immunogenic by themselves, thus they need to be covalently coupled with immunologically
[...] Read more.
Many malignant cell surface carbohydrates resulting from abnormal glycosylation patterns of certain diseases can serve as antigens for the development of vaccines against these diseases. However, carbohydrate antigens are usually poorly immunogenic by themselves, thus they need to be covalently coupled with immunologically active carrier molecules to be functional. The most well established and commonly used carriers are proteins. In recent years, the use of toll-like receptor (TLR) ligands to formulate glycoconjugate vaccines has gained significant attention because TLR ligands can serve not only as carrier molecules but also as built-in adjuvants to form fully synthetic and self-adjuvanting conjugate vaccines, which have several advantages over carbohydrate-protein conjugates and formulated mixtures with external adjuvants. This article reviews recent progresses in the development of conjugate vaccines based on TLR ligands. Two major classes of TLR ligands, lipopeptides and lipid A derivatives will be covered with more focus on monophosohoryl lipid A (MPLA) and related analogs, which are TLR4 ligands demonstrated to be able to provoke T cell-dependent, adaptive immune responses. Corresponding conjugate vaccines have shown promising application potentials to multiple diseases including cancer. Full article
(This article belongs to the Special Issue Conjugate Vaccines from Carbohydrate Antigens)
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Open AccessReview Protein Carriers for Glycoconjugate Vaccines: History, Selection Criteria, Characterization and New Trends
Molecules 2018, 23(6), 1451; https://doi.org/10.3390/molecules23061451
Received: 22 May 2018 / Revised: 8 June 2018 / Accepted: 13 June 2018 / Published: 15 June 2018
Cited by 1 | PDF Full-text (686 KB) | HTML Full-text | XML Full-text
Abstract
Currently licensed glycoconjugate vaccines are composed of a carbohydrate moiety covalently linked to a protein carrier. Polysaccharides are T-cell independent antigens able to directly stimulate B cells to produce antibodies. Disease burden caused by polysaccharide-encapsulated bacteria is highest in the first year of
[...] Read more.
Currently licensed glycoconjugate vaccines are composed of a carbohydrate moiety covalently linked to a protein carrier. Polysaccharides are T-cell independent antigens able to directly stimulate B cells to produce antibodies. Disease burden caused by polysaccharide-encapsulated bacteria is highest in the first year of life, where plain polysaccharides are not generally immunogenic, limiting their use as vaccines. This limitation has been overcome by covalent coupling carbohydrate antigens to proteins that provide T cell epitopes. In addition to the protein carriers currently used in licensed glycoconjugate vaccines, there is a search for new protein carriers driven by several considerations: (i) concerns that pre-exposure or co-exposure to a given carrier can lead to immune interference and reduction of the anti-carbohydrate immune response; (ii) increasing interest to explore the dual role of proteins as carrier and protective antigen; and (iii) new ways to present carbohydrates antigens to the immune system. Protein carriers can be directly coupled to activated glycans or derivatized to introduce functional groups for subsequent conjugation. Proteins can be genetically modified to pre-determine the site of glycans attachment by insertion of unnatural amino acids bearing specific functional groups, or glycosylation consensus sequences for in vivo expression of the glycoconjugate. A large portion of the new protein carriers under investigation are recombinant ones, but more complex systems such as Outer Membrane Vesicles and other nanoparticles are being investigated. Selection criteria for new protein carriers are based on several aspects including safety, manufacturability, stability, reactivity toward conjugation, and preclinical evidence of immunogenicity of corresponding glycoconjugates. Characterization panels of protein carriers include tests before conjugation, after derivatization when applicable, and after conjugation. Glycoconjugate vaccines based on non-covalent association of carrier systems to carbohydrates are being investigated with promising results in animal models. The ability of these systems to convert T-independent carbohydrate antigens into T-dependent ones, in comparison to traditional glycoconjugates, needs to be assessed in humans. Full article
(This article belongs to the Special Issue Conjugate Vaccines from Carbohydrate Antigens)
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Open AccessReview Role of O-Acetylation in the Immunogenicity of Bacterial Polysaccharide Vaccines
Molecules 2018, 23(6), 1340; https://doi.org/10.3390/molecules23061340
Received: 8 May 2018 / Revised: 21 May 2018 / Accepted: 30 May 2018 / Published: 2 June 2018
Cited by 1 | PDF Full-text (640 KB) | HTML Full-text | XML Full-text
Abstract
The incidence of infectious diseases caused by several bacterial pathogens such as Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis, has been dramatically reduced over the last 25 years through the use of glycoconjugate vaccines. The structures of the bacterial
[...] Read more.
The incidence of infectious diseases caused by several bacterial pathogens such as Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis, has been dramatically reduced over the last 25 years through the use of glycoconjugate vaccines. The structures of the bacterial capsular polysaccharide (CPS) antigens, extracted and purified from microbial cultures and obtained with very high purity, show that many of them are decorated by O-acetyl groups. While these groups are often considered important for the structural identity of the polysaccharides, they play a major role in the functional immune response to some vaccines such as meningococcal serogroup A and Salmonella typhi Vi, but do not seem to be important for many others, such as meningococcal serogroups C, W, Y, and type III Group B Streptococcus. This review discusses the O-acetylation status of CPSs and its role in the immunological responses of these antigens. Full article
(This article belongs to the Special Issue Conjugate Vaccines from Carbohydrate Antigens)
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Open AccessReview Epitopes of MUC1 Tandem Repeats in Cancer as Revealed by Antibody Crystallography: Toward Glycopeptide Signature-Guided Therapy
Molecules 2018, 23(6), 1326; https://doi.org/10.3390/molecules23061326
Received: 1 May 2018 / Revised: 20 May 2018 / Accepted: 22 May 2018 / Published: 31 May 2018
Cited by 1 | PDF Full-text (4257 KB) | HTML Full-text | XML Full-text
Abstract
Abnormally O-glycosylated MUC1 tandem repeat glycopeptide epitopes expressed by multiple types of cancer have long been attractive targets for therapy in the race against genetic mutations of tumor cells. Glycopeptide signature-guided therapy might be a more promising avenue than mutation signature-guided therapy.
[...] Read more.
Abnormally O-glycosylated MUC1 tandem repeat glycopeptide epitopes expressed by multiple types of cancer have long been attractive targets for therapy in the race against genetic mutations of tumor cells. Glycopeptide signature-guided therapy might be a more promising avenue than mutation signature-guided therapy. Three O-glycosylated peptide motifs, PDTR, GSTA, and GVTS, exist in a tandem repeat HGVTSAPDTRPAPGSTAPPA, containing five O-glycosylation sites. The exact peptide and sugar residues involved in antibody binding are poorly defined. Co-crystal structures of glycopeptides and respective monoclonal antibodies are very few. Here we review 3 groups of monoclonal antibodies: antibodies which only bind to peptide portion, antibodies which only bind to sugar portion, and antibodies which bind to both peptide and sugar portions. The antigenicity of peptide and sugar portions of glyco-MUC1 tandem repeat were analyzed according to available biochemical and structural data, especially the GSTA and GVTS motifs independent from the most studied PDTR. Tn is focused as a peptide-modifying residue in vaccine design, to induce glycopeptide-binding antibodies with cross reactivity to Tn-related tumor glycans, but not glycans of healthy cells. The unique requirement for the designs of antibody in antibody-drug conjugate, bi-specific antibodies, and chimeric antigen receptors are also discussed. Full article
(This article belongs to the Special Issue Conjugate Vaccines from Carbohydrate Antigens)
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