Synthetic Glycoconjugates as Human Vaccines

Jennings, Harold J.; Sood, Ramesh K.

doi:10.1016/b978-0-12-440585-1.50013-9

Cited by 48 publications

(36 citation statements)

References 128 publications

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“…Propionyl group is only one carbon longer than acetyl group, so there is a relatively small structural difference between Neu5Pr and natural Neu5Ac. However, a similar structural change was found in previous studies to substantially improve the immunogenicity of polysialic acid [27,28]. It is thus of interest to us to examine the immunological properties of Neu5Pr.…”

Section: Synthesis Of Sialic Acids and Their Protein Conjugatessupporting

confidence: 75%

“…Second, synthetic vaccines must be able to induce sufficient immune responses. In principle, synthetic carbohydrates, including artificial sialooligosaccharide analogs, are more immunogenic than natural counterparts [26][27][28][29][30]. However, there has been no systematic study of how different functional groups affect the immunological properties of sialic acids.…”

Section: Introductionmentioning

confidence: 99%

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Preparation and immunological studies of protein conjugates of N-acylneuraminic acids

et al. 2003

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The overexpression of N-acetylneuraminic acid (Neu5Ac) is closely correlated with malignant transformations. Thus, Neu5Ac is an important target in the design of cancer vaccines. To study the influence of chemical modifications of Neu5Ac on its immunological properties, the α-allyl glycosides of five differently N-acylated neuraminic acid derivatives were prepared. Following selective ozonolysis of their allyl group to form an aldehyde functionality, they were coupled to keyhole limpet hemocyanin (KLH) via reductive amination. Resultant glycoconjugates were studied in C57BL/6 mice. The N-propionyl, N-iso-butanoyl and N-phenylacetyl derivatives of neuraminic acid provoked robust immune responses of various antibody isotypes, including IgM, IgG1, IgG2a and IgG3, whereas N-trifluoropropionylneuraminic acid and natural Neu5Ac were essentially nonimmunogenic. Moreover, the N-phenylacetyl and N-iso-butanoyl derivatives mainly induced IgG responses that are desirable for antitumor applications. These results raise the promise of formulating effective glycoconjugate cancer vaccines via derivatizing sialic acid residues of sialooligosaccharides.

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Section: Synthesis Of Sialic Acids and Their Protein Conjugatessupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Preparation and immunological studies of protein conjugates of N-acylneuraminic acids

et al. 2003

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“…The S. pneumoniae CPS contain repeating oligomeric units, some of which are characterized by glucuronic acid and/or galacturonic acid residues, which may be substituted with O-acetyl, pyruvate acetyl, and glycerol phosphate groups (29,33). It is generally accepted that the capsule enables the bacteria to escape recognition by phagocytic cells.…”

Section: Interaction Of S Pneumoniae Polysaccharides With C-type Lecmentioning

confidence: 99%

Recognition of Bacterial Surface Polysaccharides by Lectins of the Innate Immune System and Its Contribution to Defense against Infection: the Case of Pulmonary Pathogens

et al. 2008

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5Many pathogenic bacterial species are classified into serological types, distinguished by their carbohydrate-rich surface antigens. These antigens are referred to as serotypic epitopes or glycoepitopes. Glycoepitopes are most commonly associated with capsular polysaccharides (CPS) or the O-antigen domains of bacterial lipopolysaccharides (LPS).The association of specific bacterial serotypes of a given genus with defined clinical infections is a common phenomenon that applies to a variety of gram-negative bacteria and gram-positive bacteria. As discussed below, of the 77 distinct capsular serotypes in the species Klebsiella pneumoniae, only 25 account for most pulmonary and blood infections (12). Likewise, of the more than 90 capsular serotypes of Streptococcus pneumoniae, only 23 account for most infections, and these are included in the current capsular vaccine (25).The surfaces of the pulmonary pathogens Klebsiella pneumoniae and Streptococcus pneumoniae are coated with a variety of glycoconjugates that confer specific properties. For example, the polysaccharide capsules enable these pathogens to resist phagocytosis. In a few cases, it has been argued that serotype-associated differences in capsular size contribute to virulence and the high frequency of isolation. However, there is no satisfactory explanation why only a limited number of capsular serotypes are responsible for most infections (12,25).Because lectins are important components of the lung's innate immune system, it is reasonable to hypothesize that differences in the frequencies of isolation of specific serotypes in the setting of pneumonia are in part determined by the recognition, or the lack of recognition, of their corresponding glycoepitopes by lectins. We propose that the lack of recognition of glycoconjugates by one or more lectins of the lung contributes to the high frequency of isolation from pneumonia patients of the pulmonary pathogens bearing reactive glycoepitopes. Conversely, lectins that recognize serotype-specific glycoepitopes contribute to the eradication of these serotypes, resulting in a lower frequency of their isolation from clinical samples.In this review, we first correlate the sugar specificities of several types of lung lectins with the glycoconjugates on the surfaces of selected pulmonary pathogens. We then briefly describe in vitro data that suggest mechanisms through which the lung C-type lectins contribute to the elimination of specific glycoepitope-bearing serotypes. Finally, we review available evidence supporting our hypothesis that the high frequency of isolation of serotypes bearing a specific glycoepitope results from the ability of these serotypes to evade recognition by lectins of the innate immune system. PULMONARY LECTINS OF THE INNATE IMMUNE SYSTEMDuring the last 3 decades, there has been intensive research on animal lectins (59, 90). Although lung lectins play a variety of homeostatic roles (38, 89), considerable research has focused on the contributions of several lectins to the innate, natural defense s...

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“…This bond is cleaved by mild acid hydrolysis (Fig. 1) to release a polysaccharide bearing a Kdo residue at its reducing end (22). The use of the carboxylic group of the Kdo moiety for polysaccharide-protein coupling results in a saccharide with a single terminal active site for conjugation.…”

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confidence: 99%

“…The use of the carboxylic group of the Kdo moiety for polysaccharide-protein coupling results in a saccharide with a single terminal active site for conjugation. This single-end activated pmLPS has a high potential for use as a vaccine: (i) the O139 specific antigenic determinant(s) are conserved; (ii) it is the simplest conjugate configuration in which polysaccharide chains radiate from the protein carriers; (iii) the coupling procedure is the easiest to control, producing well-defined non-cross-linked, water-soluble conjugate molecules of known configuration (22).…”

mentioning

confidence: 99%

Preparation, Immunogenicity, and Protective Efficacy, in a Murine Model, of a Conjugate Vaccine Composed of the Polysaccharide Moiety of the Lipopolysaccharide of Vibrio cholerae O139 Bound to Tetanus Toxoid

et al. 2001

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The epidemic and pandemic potential of Vibrio cholerae O139 is such that a vaccine against this newly emerged serogroup of V. cholerae is required. A conjugate made of the polysaccharide moiety (O-specific polysaccharide plus core) of the lipopolysaccharide (LPS) of V. cholerae O139 (pmLPS) was prepared by derivatization of the pmLPS with adipic acid dihydrazide and coupling to tetanus toxoid (TT) by carbodiimidemediated condensation. The immunologic properties of the conjugate were tested using BALB/c mice injected subcutaneously three times at 2 weeks interval and then a fourth time 4 weeks later. Mice were bled 7 days after each injection and then once each month for the following 6 months. LPS and TT antibody levels were determined by enzyme-linked immunosorbent assay using immunoplates coated with either O139 LPS or TT. Both pmLPS and pmLPS-TT conjugate elicited low levels of immunoglobulin M (IgM), peaking 5 weeks after the first immunization. The conjugate elicited high levels of IgG antibodies, peaking 3 months after the first immunization and declining slowly during the following 5 months. TT alone, or as a component of conjugate, induced mostly IgG antibodies. Antibodies elicited by the conjugate recognized both capsular polysaccharide and LPS from V. cholerae O139 and were vibriocidal. They were also protective in the neonatal mouse model of cholera infection. The conjugation of the O139 pmLPS, therefore, enhanced its immunogenicity and conferred T-dependent properties to this polysaccharide.Since the appearance of Vibrio cholerae O139 in the suburb of Madras, India, in October 1992, epidemic cholera caused by this strain has spread rapidly throughout the Indian subcontinent (1). Clinical illness associated with V. cholerae O139 infection appears to be virtually identical to that due to V. cholerae O1 E1 Tor infections. However, in contrast to infection with V. cholerae O1, V. cholerae O139 infection has largely affected the adult population in areas of V. cholerae O1 endemicity, indicating a lack of protective immunity against this newly evolved strain (1). Presumably, there are differences between the immune responses against O1 and O139 strains, which may be of considerable importance in terms of protection (33). A quiescent period followed the appearance of V. cholerae O139, and it was thought that it was a one-time event. However, there was an upsurge of cases in Calcutta, India, in 1996, and the O139 serogroup again became the dominant serogroup causing cholera in India by September 1996 (32). The O139 serogroup has remained present in India and Bangladesh since this last outbreak (15) and requires careful monitoring.It has been suggested that the emergence of V. cholerae O139 is the result of a complex chromosomal rearrangement involving the horizontal transfer of genes encoding enzymes involved in O-specific polysaccharide (O-SP) biosynthesis (3,8,14,43). Indeed, the major differences between V. cholerae O1 and V. cholerae O139 reside in their cell surface components. V. cholerae O139, unlike ...

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Synthetic Glycoconjugates as Human Vaccines

Cited by 48 publications

References 128 publications

Preparation and immunological studies of protein conjugates of N-acylneuraminic acids

Preparation and immunological studies of protein conjugates of N-acylneuraminic acids

Recognition of Bacterial Surface Polysaccharides by Lectins of the Innate Immune System and Its Contribution to Defense against Infection: the Case of Pulmonary Pathogens

Preparation, Immunogenicity, and Protective Efficacy, in a Murine Model, of a Conjugate Vaccine Composed of the Polysaccharide Moiety of the Lipopolysaccharide of Vibrio cholerae O139 Bound to Tetanus Toxoid

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