Bacterial polysaccharides as major surface antigens: interest in O-acetyl substitutions

Mulard, Laurence A.

doi:10.1039/9781788010641-00071

Cited by 14 publications

(15 citation statements)

References 85 publications

(191 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The contribution of O-acetylation in the functional immune response to licensed bacterial polysaccharide-based vaccines was shed to light in various instances as exemplified for Salmonella typhi Vi or Neisseria meningitidis serogroup A, but not in others, indicating a case-to-case specificity. 81,82 As outlined, 80 while not specifically quantified at the pmLPS-rEPA conjugate stage and a priori not particularly controlled although possibly affected in the course of the production process, 80,83 these non-carbohydrate substitutions are present in the first generation of SF2a conjugate vaccine candidates. In contrast, O-acetylation is absent in Flexyn2a, the bioconjugate vaccine candidate that has gone into clinical trial.…”

Section: Bioconjugates Versus Detoxified Lps-based Conjugates: O-acetmentioning

confidence: 99%

Classical and novel strategies to develop aShigellaglycoconjugate vaccine: from concept to efficacy in human

Barel

Mulard

2019

Human Vaccines & Immunotherapeutics

Self Cite

View full text Add to dashboard Cite

Shigella are gram-negative bacteria that cause severe diarrhea and dysentery, with a high level of antimicrobial resistance. Disease-induced protection against reinfection in Shigella -endemic areas provides convincing evidence on the feasibility of a vaccine and on the importance of Shigella lipopolysaccharides as targets of the host humoral protective immune response against disease. This article provides an overview of the original and current strategies toward the development of a Shigella glycan-protein conjugate vaccine that would cover the most commonly detected strains. Going beyond pioneering “lattice”-type polysaccharide-protein conjugates, progress, and challenges are addressed with focus on promising alternatives, which have reached phases I and II clinical trial. Glycoengineered bioconjugates and “sun”-type conjugates featuring well-defined synthetic carbohydrate antigens are discussed with insights on the molecular parameters governing the rational design of a cost-effective glycoconjugate vaccine efficacious in preventing diseases caused by Shigella in the most at risk populations, young children living in endemic areas.

show abstract

Section: Bioconjugates Versus Detoxified Lps-based Conjugates: O-acetmentioning

confidence: 99%

Classical and novel strategies to develop aShigellaglycoconjugate vaccine: from concept to efficacy in human

Barel

Mulard

2019

Human Vaccines & Immunotherapeutics

Self Cite

View full text Add to dashboard Cite

show abstract

“…A Phase I clinical trial of a MenA oligosaccharide (OS) with an average chain length of 6 to 10 repeating units (RUs) conjugated to the diphtheria toxoid CRM 197 showed it to be both safe and immunogenic (27). In contrast to many surface PSs, including those from Shigella spp and other meningococcal serogroups (28), O-acetylation has been hypothesized to play a critical role in MenA PS immunogenicity (29). Antibodies from immunized subjects were shown to preferentially recognize O-acetylated moieties, while de-O-acetylated PS conjugate resulted in a marked reduction of immunogenicity and, crucially, of the ability to induce bactericidal antibodies in murine models (30).…”

Section: Significancementioning

confidence: 99%

Structure of a protective epitope reveals the importance of acetylation of Neisseria meningitidis serogroup A capsular polysaccharide

Henriques

Iacono

Gimeno

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Meningococcal meningitis remains a substantial cause of mortality and morbidity worldwide. Until recently, countries in the African meningitis belt were susceptible to devastating outbreaks, largely attributed to serogroup A Neisseria meningitidis (MenA). Vaccination with glycoconjugates of MenA capsular polysaccharide led to an almost complete elimination of MenA clinical cases. To understand the molecular basis of vaccine-induced protection, we generated a panel of oligosaccharide fragments of different lengths and tested them with polyclonal and monoclonal antibodies by inhibition enzyme-linked immunosorbent assay, surface plasmon resonance, and competitive human serum bactericidal assay, which is a surrogate for protection. The epitope was shown to optimize between three and six repeating units and to be O-acetylated. The molecular interactions between a protective monoclonal antibody and a MenA capsular polysaccharide fragment were further elucidated at the atomic level by saturation transfer difference NMR spectroscopy and X-ray crystallography. The epitope consists of a trisaccharide anchored to the antibody via the O- and N-acetyl moieties through either H-bonding or CH–π interactions. In silico docking showed that 3-O-acetylation of the upstream residue is essential for antibody binding, while O-acetate could be equally accommodated at three and four positions of the other two residues. These results shed light on the mechanism of action of current MenA vaccines and provide a foundation for the rational design of improved therapies.

show abstract

“…Recent advances in carbohydrate chemistry has opened the way to a third-generation of polysaccharide vaccines, based on the use of synthetic oligosaccharides conjugated to carrier protein. The breakthrough in synthetic vaccines was carried out for H. influenzae type b in 2004, when the Vérez Bencomo research team in Cuba synthesized the first synthetic conjugate vaccine currently available under the trade name Quimi-Hib [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , ...…”

Section: Discussionmentioning

confidence: 99%

“…In addition to these promising findings, the influence of O -acetylation of S. flexneri 2a O-Ag fragments on antigenicity was studied by Mulard group [ 21 ]. Polysaccharide O -acetylation has been shown to play a key role for many pathogens in inducing functional Ab responses [ 22 , 23 , 24 ]. In particular, three diversely O -acetylated S. flexneri 2a O-Ag decasaccharides were synthesized in homogeneous form and their binding to five different protective mAbs was studied, showing some differences in the recognition patterns.…”

Section: Shigellamentioning

confidence: 99%

Recent Advances in the Synthesis of Glycoconjugates for Vaccine Development

2018

View full text Add to dashboard Cite

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.

show abstract

Bacterial polysaccharides as major surface antigens: interest in O-acetyl substitutions

Cited by 14 publications

References 85 publications

Classical and novel strategies to develop aShigellaglycoconjugate vaccine: from concept to efficacy in human

Classical and novel strategies to develop aShigellaglycoconjugate vaccine: from concept to efficacy in human

Structure of a protective epitope reveals the importance of acetylation of Neisseria meningitidis serogroup A capsular polysaccharide

Recent Advances in the Synthesis of Glycoconjugates for Vaccine Development

Contact Info

Product

Resources

About