Effect of the nonreducing end of
            <i>Shigella dysenteriae</i>
            type 1 O-specific oligosaccharides on their immunogenicity as conjugates in mice

Pozsgay, Vince; Kübler-Kiełb, Joanna; Schneerson, Rachel; Robbins, John B.

doi:10.1073/pnas.0706969104

Cited by 52 publications

(39 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Besides, the increased protective capacity of [AB(E)CD] 3 -TT over [AB(E)CD] 2 -TT parallels data reported for H. influenzae b (41), and the corresponding increased immunogenicity supports data described for S. dysenteriae 1 (40). Alternative options toward additional increase of the protective anti-LPS 2a Ab response will be investigated (42). Indeed, in direct support to our observations, protection against shigellosis is thought to be correlated to the level of anti-LPS Abs (17,18), although the threshold of the anti-LPS Ab response required to ensure protection is yet unknown.…”

Section: Discussionsupporting

confidence: 64%

A Synthetic Carbohydrate-Protein Conjugate Vaccine Candidate against Shigella flexneri 2a Infection

Phalipon

Tanguy

Grandjean

et al. 2009

The Journal of Immunology

123

108

View full text Add to dashboard Cite

The protective Ag of Shigella, the Gram-negative enteroinvasive bacterium causing bacillary dysentery, or shigellosis, is its O-specific polysaccharide (O-SP) domain of the LPS, the major bacterial surface component. As an alternative to the development of detoxified LPS-based conjugate vaccines, recent effort was put into the investigation of neoglycoproteins encompassing synthetic oligosaccharides mimicking the protective Ags of the O-SP. We previously reported that when coupled to tetanus toxoid via single point attachment, a synthetic pentadecasaccharide representing three biological repeating units of the O-SP of Shigella flexneri 2a (SF2a), one of the most common Shigella serotypes, elicits a better serum anti-LPS 2a Ab response in mice than shorter synthetic O-SP sequences. In this study, we show that the pentadecasaccharide-induced anti-LPS 2a Abs protect passively administered naive mice from Shigella infection. Therefore, this three repeating units sequence, which is recognized by anti-SF2a sera from infected patients, acts as a functional mimic of the native polysaccharide Ag. Analyses of parameters influencing immunogenicity revealed that an investigational SF2a vaccine displaying a pentadecasaccharide:tetanus toxoid molar loading of 14:1 triggers a high and sustained anti-LPS Ab response, without inducing anti-linker Ab, when administered four times at a dose corresponding to 1 g of carbohydrate. In addition, the profile of the anti-LPS Ab response, dominated by IgG1 production (Th2-type response), mimics that observed in human upon natural SF2a infection. This synthetic carbohydrate-based conjugate may be a candidate for a SF2a vaccine.

show abstract

Section: Discussionsupporting

confidence: 64%

A Synthetic Carbohydrate-Protein Conjugate Vaccine Candidate against Shigella flexneri 2a Infection

Phalipon

Tanguy

Grandjean

et al. 2009

The Journal of Immunology

123

108

View full text Add to dashboard Cite

show abstract

“…On the basis of these data we propose to evaluate clinically the O-SPC protein conjugates. The finding that the identity of the sugar residue positioned at the nonreducing end of the synthetic S. dysentariae type 1 oligosaccharide conjugates is an important variable for the immunogenicity of these conjugates (14) points to the importance of the end groups in general in the immune response and may provide an explanation for the superior immunogenicity of the O-SPC and synthetic oligosaccharide conjugates over O-SP conjugates; the former have more end groups. The importance of the terminal saccharide was also demonstrated for Bordetellae conjugates prepared the same way, where the terminal reducing end was immunodominant (11).…”

Section: Discussionmentioning

confidence: 98%

Synthesis, characterization, and immunogenicity in mice of Shigella sonnei O-specific oligosaccharide-core-protein conjugates

Robbins

Kübler-Kiełb

Vinogradov

et al. 2009

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

Self Cite

View full text Add to dashboard Cite

Shigellosis, an enteric disease, is on the World Health Organization's priority prevention list. In one study, the Shigella sonnei O-specific polysaccharide (O-SP)-protein conjugate showed 72% protection against disease in Israeli army recruits exposed to high rates (8 -14%) of infection. The protection was related to vaccineinduced IgG anti-O-SP levels. Synthetic oligosaccharides of Shigella dysenteriae type 1, bound by their reducing ends to a carrier protein (''sun''-type configuration), induced significantly higher antibody levels than the native O-SP bound to protein by multiplepoint attachments (''lattice''-type configuration). Attempts to synthesize the S. sonnei O-SP based oligosaccharides were not successful. Here, we describe the isolation, characterization, and conjugation of low-molecular-mass O-SP-core (O-SPC) fragments. The O-SPC fragments were bound by their reducing ends similar to the preparation of the synthetic S. dysenteriae type 1 conjugates. The O-SPC conjugates used oxime linkages between the terminal Kdo residues at the reducing ends of the S. sonnei saccharides and aminooxy linkers bound to BSA or a recombinant diphtheria toxin. The coupling reaction was carried out at a neutral pH and room temperature. IgG antibody levels induced in young outbred mice by the S. sonnei O-SPC conjugates were significantly higher then those elicited by the O-SP conjugates. Accordingly, we propose to evaluate clinically these conjugates.lipopolysaccharide ͉ glycoconjugate ͉ vaccine ͉ Kdo ͉ IgG

show abstract

“…Other variables reported to influence the immunogenicity of conjugates were the number of OS chains per protein molecule and the identity of the nonreducing end molecule (17,18,22,27,28). In the present study, the range of optimal chain density was wide, with an average number of chains between 8 and 17.…”

Section: Discussionmentioning

confidence: 76%

“…pertussis and B. bronchiseptica core OS have low molecular weights and require covalent binding to a protein to be immunogenic. The conjugate-induced antibody levels are a function of the saccharide chain length, their loading on the protein, and the structure of the nonreducing terminal monosaccharide (17,18). To evaluate these variables, we prepared conjugates of B. pertussis and B. bronchiseptica OS isolated from native and genetically modified strains (B. bronchiseptica RBA2b OS differed from that of B. pertussis in the OS chain length by producing multiples of band A terminal trisaccharide, and B. bronchiseptica RBB1a OS had ∼50% of GlcNAc replaced by GalNAc at the nonreducing end) and studied their chemical, serological, and immunological properties as an addition to pertussis vaccine.…”

mentioning

confidence: 99%

Oligosaccharide conjugates of Bordetella pertussis and bronchiseptica induce bactericidal antibodies, an addition to pertussis vaccine

Kübler-Kiełb

Vinogradov

Lagergård

et al. 2011

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

Self Cite

View full text Add to dashboard Cite

Pertussis is a highly contagious respiratory disease that is especially dangerous for infants and children. Despite mass vaccination, reported pertussis cases have increased in the United States and other parts of the world, probably because of increased awareness, improved diagnostic means, and waning vaccine-induced immunity among adolescents and adults. Licensed vaccines do not kill the organism directly; the addition of a component inducing bactericidal antibodies would improve vaccine efficacy. We investigated Bordetella pertussis and Bordetella bronchiseptica LPS-derived core oligosaccharide (OS) protein conjugates for their immunogenicity in mice. B. pertussis and B. bronchiseptica core OS were bound to aminooxylated BSA via their terminal Kdo residues. The two conjugates induced similar anti-B. pertussis LPS IgG levels in mice. B. bronchiseptica was investigated because it is easier to grow than B. pertussis. Using B. bronchiseptica genetically modified strains deficient in the O-specific polysaccharide, we isolated fractions of core OS with one to five repeats of the terminal trisaccharide, having at the nonreducing end a GlcNAc or GalNAc, and bound them to BSA at different densities. The highest antibody levels in mice were elicited by conjugates containing an average of 8-17 OS chains per protein and with one repeat of the terminal trisaccharide. Conjugate-induced antisera were bactericidal against B. pertussis, and the titers correlated with ELISA-measured antibody levels (r = 0.74). Such conjugates are easy to prepare and standardize; added to a recombinant pertussis toxoid, they may induce antibacterial and antitoxin immunity.hydroxylamine | Gram-negative

show abstract

Effect of the nonreducing end of Shigella dysenteriae type 1 O-specific oligosaccharides on their immunogenicity as conjugates in mice

Abstract: The highest anti-LPS levels were elicited by conjugates having N-acetylglucosamine (10-mer) or galactose residues (7-and 11-mers) at their nonreducing termini.vaccine ͉ glycoconjugate ͉ oligosaccharide synthesis ͉ bioconjugation ͉ dysentery

Cited by 52 publications

References 39 publications

A Synthetic Carbohydrate-Protein Conjugate Vaccine Candidate against Shigella flexneri 2a Infection

A Synthetic Carbohydrate-Protein Conjugate Vaccine Candidate against Shigella flexneri 2a Infection

Synthesis, characterization, and immunogenicity in mice of Shigella sonnei O-specific oligosaccharide-core-protein conjugates

Oligosaccharide conjugates of Bordetella pertussis and bronchiseptica induce bactericidal antibodies, an addition to pertussis vaccine

Contact Info

Product

Resources

About