Highlighted Text:
Show |
Hide
Full text loading...
Chapter 11 : Conjugation Chemistry
Authors:
Andrew Lees1,
Velupillai Puvanesarajah2,
Carl E. Frasch3
VIEW AFFILIATIONS
HIDE AFFILIATIONS
Affiliations:
1: Fina BioSolutions LLC, 9610 Medical Center Dr., Suite 200, Rockville, MD 20850;
2: Sanofi-Aventis, Swiftwater, PA 18370;
3: Frasch Biologics Consulting, P.O. Box 986, Martinsburg, WV 25402
Content Type: Monograph
Publication Year:
2008
Category: Bacterial Pathogenesis; Immunology
Book DOI:
10.1128/9781555815820
Chapter DOI:
10.1128/9781555815820.ch11
MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
Preview this chapter:
Conjugation Chemistry, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555815820/9781555814083_Chap11-1.gif /docserver/preview/fulltext/10.1128/9781555815820/9781555814083_Chap11-2.gif
Abstract:
Most bacteria that cause invasive disease, especially those that cause bacteremia, are protected from innate host immunity because they express polysaccharides (PSs) on their cell surfaces. The bacterial capsular PSs are composed of thousands of carbohydrate repeat units resulting in polydisperse polymers that can have molecular masses into the millions of daltons. Multivalent pneumococcal conjugate vaccines present additional complexities with regard to their syntheses, as each serotype is chemically distinct, effectively requiring the optimization of the manufacture of seven or more individual vaccines. Various proteins and peptide molecules have been demonstrated, in preclinical studies, to be effective carriers for PSs and oligosaccharides, but only a small number of protein carriers have been investigated in humans. Surface-exposed proteins and toxins from human pathogenic bacteria have been used as carriers, as they contain one or more of the T-cell epitopes. In order to convert PSs into T-cell-dependent antigens, the protein must be chemically linked to the carbohydrate; that is, there must be covalent links between the two components. Protein solubility at the required pH, concentration, and temperature is an important determinant of the suitability of a protein for use in a particular conjugation scheme. The conjugation step is generally the slowest chemical step and risks damage to the components. Efforts should be made to improve conjugation efficiencies to levels at which the residual unconjugated components, especially free PSs, do not interfere with inductions of protective immune responses. The use of efficient, mild conjugation chemistry would allow for higher yields of vaccine.
Citation:
Lees A, Puvanesarajah V, Frasch C.
2008.
Conjugation Chemistry,
p 163-174.
In
Siber G, Klugman K, Mäkelä P (ed),
Pneumococcal Vaccines.
ASM Press, Washington, DC.
doi: 10.1128/9781555815820.ch11
Figures
Conjugation Chemistry
[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815820.ch11-1,webId=/content/author/10.1128/9781555815820.ch11-1,properties={foaf_givenname=Andrew, foaf_name=Andrew Lees, foaf_surname=Lees, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815820.ch11-aff1]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815820.ch11-2,webId=/content/author/10.1128/9781555815820.ch11-2,properties={foaf_givenname=Velupillai, foaf_name=Velupillai Puvanesarajah, foaf_surname=Puvanesarajah, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815820.ch11-aff2]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815820.ch11-3,webId=/content/author/10.1128/9781555815820.ch11-3,properties={foaf_givenname=Carl E., foaf_name=Carl E. Frasch, foaf_surname=Frasch, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815820.ch11-aff3]]}]]
Citation:
Lees A, Puvanesarajah V, Frasch C.
2008.
Conjugation Chemistry,
p 163-174.
In
Siber G, Klugman K, Mäkelä P (ed),
Pneumococcal Vaccines.
ASM Press, Washington, DC.
doi: 10.1128/9781555815820.ch11
/content/10.1128/9781555815820.ch11.ch11fig01
Figure 1
General overview of the protein (Pr)-PS conjugation process.
10.1128/9781555815820/f0166-01_thmb.gif
10.1128/9781555815820/f0166-01.gif
Figure 1
General overview of the protein (Pr)-PS conjugation process.
Citation:
Lees A, Puvanesarajah V, Frasch C.
2008.
Conjugation Chemistry,
p 163-174.
In
Siber G, Klugman K, Mäkelä P (ed),
Pneumococcal Vaccines.
ASM Press, Washington, DC.
doi: 10.1128/9781555815820.ch11
/content/10.1128/9781555815820.ch11.ch11fig02
Figure 2
Reaction schemes for reductive amination (A) and cyanylation (B) using CDAP. Prot, protein.
10.1128/9781555815820/f0169-01_thmb.gif
10.1128/9781555815820/f0169-01.gif
Figure 2
Reaction schemes for reductive amination (A) and cyanylation (B) using CDAP. Prot, protein.
Citation:
Lees A, Puvanesarajah V, Frasch C.
2008.
Conjugation Chemistry,
p 163-174.
In
Siber G, Klugman K, Mäkelä P (ed),
Pneumococcal Vaccines.
ASM Press, Washington, DC.
doi: 10.1128/9781555815820.ch11
References
/content/book/10.1128/9781555815820.ch11
1.
Akkoyunlu, M.,, H. Janson,, M. Ruan, and, A. Forsgren. 1996. Biological activity of serum antibodies to a nonacylated form of lipoprotein D of Haemophilus influenzae. Infect. Immun. 64 : 4586– 4592.
2.
Anderson, P. W.,, M. E. Pichichero,, E. C. Stein,, S. Porcelli,, R. F. Betts,, D. M. Connuck,, D. Korones,, R. A. Insel,, J. M. Zahradnik, and, R. Eby. 1989. Effect of oligosaccharide chain length, exposed terminal group, and hapten loading on the antibody response of human adults and infants to vaccines consisting of Haemophilus influenzae type b capsular antigen unterminally coupled to the diphtheria protein CRM197. J. Immunol. 142 : 2464– 2468.
3.
Bernatoniene, J., and, A. Finn. 2005. Advances in pneumococcal vaccines: advantages for infants and children. Drugs 65 : 229– 255.
4.
Berry, D. S.,, F. Lynn,, C. H. Lee,, C. E. Frasch, and, M. C. Bash. 2002. Effect of O acetylation of Neisseria meningitidis serogroup A capsular polysaccharide on development of functional immune responses. Infect. Immun. 70 : 3707– 3713.
5.
Briles, D. E.,, S. K. Hollingshead,, J. King,, A. Swift,, P. A. Braun,, M. K. Park,, L. M. Ferguson,, M. H. Nahm, and, G. S. Nabors. 2000. Immunization of humans with recombinant pneumococcal surface protein A (rPspA) elicits antibodies that passively protect mice from fatal infection with Streptococcus pneumoniae bearing heterologous PspA. J. Infect. Dis. 182 : 1694– 1701.
6.
Constantino, P. May 2005. Capsular polysaccharide solubilization and combination vaccines. U.S. patent application 10/481,457.
7.
Daum, R. S.,, D. Hogerman,, M. B. Rennels,, K. Bewley,, F. Malinoski,, E. Rothstein,, K. Reisinger,, S. Block,, H. Keyserling, and, M. Steinhoff. 1997. Infant immunization with pneumococcal CRM197 vaccines: effect of saccharide size on immunogenicity and interactions with simultaneously administered vaccines. J. Infect. Dis. 176 : 445– 455.
8.
Dick, W. E., Jr., and, M. Beurret. 1989. Glycoconjugates of bacterial carbohydrate antigens. A survey and consideration of design and preparation factors. Contrib. Microbiol. Immunol. 10 : 48– 114.
9.
Fattom, A.,, Y. H. Cho,, C. Chu,, S. Fuller,, L. Fries, and, R. Naso. 1999. Epitopic overload at the site of injection may result in suppression of the immune response to combined capsular polysaccharide conjugate vaccines. Vaccine 17 : 126– 133.
10.
Fattom, A.,, C. Lue,, S. C. Szu,, J. Mestecky,, G. Schiffman,, D. Bryla,, W. F. Vann,, D. Watson,, L. M. Kimzey,, J. B. Robbins, et al. 1990. Serum antibody response in adult volunteers elicited by injection of Streptococcus pneumoniae type 12F polysaccharide alone or conjugated to diphtheria toxoid. Infect. Immun. 58 : 2309– 2312.
11.
Fusco, P. C.,, E. K. Farley,, C. H. Huang,, S. Moore, and, F. Michon. 2007. Protective meningococcal capsular polysaccharide epitopes and the role of O acetylation. Clin. Vaccine Immunol. 14 : 577– 584.
12.
Goebel, W. F., and, A. T. Avery. 1929. Chemo-immunological studies on conjugated carbohydrate-proteins. II. Immunological specifity of synthethic sugar-protein antigens. J. Exp. Med. 50 : 533– 550.
13.
Jansen, W. T., and, H. Snippe. 2004. Short-chain oligosaccharide protein conjugates as experimental pneumococcal vaccines. Indian J. Med. Res. 119(Suppl.) : 7– 12.
14.
Jennings, H. J. 1990. Capsular polysaccharides as vaccine candidates. Curr. Top. Microbiol. Immunol. 150 : 97– 127.
15.
Jones, C.,, X. Lemercinier,, D. T. Crane,, C. K. Gee, and, S. Austin. 2000. Spectroscopic studies of the structure and stability of glycoconjugate vaccines. Dev. Biol. ( Basel) 103 : 121– 136.
16.
Kamerling, J. P. 2000. Pneumococcal polysaccharides: a chemical view, p. 81–114. In A. Tomadz (ed.), Streptococcus pneumoniae, Molecular Biology and Mechanisms of Disease. Mary Ann Liebert, Inc., Larchmont, NY.
17.
Kim, J. S.,, E. R. Laskowich,, R. G. Arumugham,, R. E. Kaiser, and, G. J. MacMichael. 2005. Determination of saccharide content in pneumococcal polysaccharides and conjugate vaccines by GC-MSD. Anal. Biochem. 347 : 262– 274.
18.
Kim, J. S.,, E. R. Laskowich,, F. Michon,, R. E. Kaiser, and, R. G. Arumugham. 2006. Monitoring activation sites on polysaccharides by GC–MS. Anal. Biochem. 358 : 136– 142.
19.
Kniskern, P. J., and, S. Marburg. 1994. Conjugation: design, chemistry, and analysis, p. 37–67. In R. W. Ellis and D. M. Granoff (ed.), Development and Clinical Uses of Haemophilus b Conjugate Vaccines, vol. 11. Marcel Dekker, New York, NY.
20.
Kniskern, P. J. M.,, J. William,, A. Hagopian,, C. C. Ip,, J. P. Hennessey, Jr., D. J. Kubek, and, P. D. Burke. 1998. Process for making capsular polysaccharides from Streptococcus pneumoniae. U.S. patent 5,847,112.
21.
Kohn, J., and, M. Wilchek. 1984. The use of cyanogen bromide and other novel cyanylating agents for the activation of polysaccharide resins. Appl. Biochem. Biotechnol. 9 : 285– 305.
22.
Kuo, J.,, M. Douglas,, H. K. Ree, and, A. A. Lindberg. 1995. Characterization of a recombinant pneumolysin and its use as a protein carrier for pneumococcal type 18C conjugate vaccines. Infect. Immun. 63 : 2706– 2713.
23.
Laferriere, C. A., and, J. Poolman. September 2005. Vaccine. U.S. patent application no. 10/498,900.
24.
Laferriere, C. A.,, R. K. Sood,, J. M. de Muys,, F. Michon, and, H. J. Jennings. 1998. Streptococcus pneumoniae type 14 polysaccharide-conjugate vaccines: length stabilization of opsonophagocytic conformational polysaccharide epitopes. Infect. Immun. 66 : 2441– 2446.
25.
Laferriere, C. A.,, R. K. Sood,, J. M. de Muys,, F. Michon, and, H. J. Jennings. 1997. The synthesis of Streptococcus pneumoniae polysaccharide-tetanus toxoid conjugates and the effect of chain length on immunogenicity. Vaccine 15 : 179– 186.
26.
Lee, C.-H. R., and, C. E. Frasch. February 2005. Polysaccharide-Protein Conjugate Vaccines. International patent WO/2005/014037.
27.
Lee, C. J.,, T. R. Wang, and, S. S. Tai. 1997. Immunologic epitope, gene, and immunity involved in pneumococcal glycoconjugate. Crit. Rev. Microbiol. 23 : 121– 142.
28.
Lees, A., and, J. J. Mond. June 2001. Process for preparing conjugate vaccines including free protein and the conjugate vaccines, immunogens and immunogenic reagents produced by this process. U.S. patent 6,248,334.
29.
Lees, A.,, B. L. Nelson, and, J. J. Mond. 1996. Activation of soluble polysaccharides with 1-cyano-4-dimethylaminopyridinium tetrafluoroborate for use in protein-polysaccharide conjugate vaccines and immunological reagents. Vaccine 14 : 190– 198.
30.
Lees, A.,, G. Sen, and, A. LopezAcosta. 2006. Versatile and efficient synthesis of protein-polysaccharide conjugate vaccines using aminooxy reagents and oxime chemistry. Vaccine 24 : 716– 729.
31.
McMaster, R. 2000. Purification of polysaccharide-protein conjugate vaccines by ultrafiltration with ammonium sulfate solutions. U.S. patent 6,146,902.
32.
McNeely, T. B.,, J. M. Staub,, C. M. Rusk,, M. J. Blum, and, J. J. Donnelly. 1998. Antibody responses to capsular polysaccharide backbone and O-acetate side groups of Streptococcus pneumoniae type 9V in humans and rhesus macaques. Infect. Immun. 66 : 3705– 3710.
33.
Michon, F.,, P. C. Fusco,, C. A. Minetti,, M. Laude-Sharp,, C. Uitz,, C. H. Huang,, A. J. D'Ambra,, S. Moore,, D. P. Remeta,, I. Heron, and, M. S. Blake. 1998. Multivalent pneumococcal capsular polysaccharide conjugate vaccines employing genetically detoxified pneumolysin as a carrier protein. Vaccine 16 : 1732– 1741.
34.
Michon, F. B., and, M. Blake. December 2001. Procedures for the extraction and isolation of bacterial capsular polysaccharides for use as vaccines or linked to proteins as conjugate vaccines. U.S. patent application no. 09/884,367.
35.
Nurkka, A.,, J. Joensuu,, I. Henckaerts,, P. Peeters,, J. Poolman,, T. Kilpi, and, H. Kayhty. 2004. Immunogenicity and safety of the eleven valent pneumococcal polysaccharide-protein D conjugate vaccine in infants. Pediatr. Infect. Dis. J. 23 : 1008– 1014.
36.
Peeters, C. C.,, A. M. Tenbergen-Meekes,, D. E. Evenberg,, J. T. Poolman,, B. J. Zegers, and, G. T. Rijkers. 1991. A comparative study of the immunogenicity of pneumococcal type 4 polysaccharide and oligosaccharide tetanus toxoid conjugates in adult mice. J. Immunol. 146 : 4308– 4314.
37.
Peeters, C. C.,, A. M. Tenbergen-Meekes,, J. T. Poolman,, B. J. Zegers, and, G. T. Rijkers. 1992. Immunogenicity of a Streptococcus pneumoniae type 4 polysaccharide-protein conjugate vaccine is decreased by admixture of high doses of free saccharide. Vaccine 10 : 833– 840.
38.
Prymula, R.,, P. Peeters,, V. Chrobok,, P. Kriz,, E. Novakova,, E. Kaliskova,, I. Kohl,, P. Lommel,, J. Poolman,, J. P. Prieels, and, L. Schuerman. 2006. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study. Lancet 367 : 740– 748.
39.
Puumalainen, T.,, N. Ekstrom,, R. Zeta-Capeding,, J. Ollgren,, K. Jousimies,, M. Lucero,, H. Nohynek, and, H. Kayhty. 2003. Functional antibodies elicited by an 11-valent diphtheria-tetanus toxoid-conjugated pneumococcal vaccine. J. Infect. Dis. 187 : 1704– 1708.
40.
Richmond, P.,, R. Borrow,, J. Findlow,, S. Martin,, C. Thornton,, K. Cartwright, and, E. Miller. 2001. Evaluation of de-O-acetylated meningococcal C polysaccharide-tetanus toxoid conjugate vaccine in infancy: reactogenicity, immunogenicity, immunologic priming, and bactericidal activity against O-acetylated and de-O-acetylated serogroup C strains. Infect. Immun. 69 : 2378– 2382.
41.
Rodriguez, M. E.,, G. P. van den Dobbelsteen,, L. A. Oomen,, O. de Weers,, L. van Buren,, M. Beurret,, J. T. Poolman, and, P. Hoogerhout. 1998. Immunogenicity of Streptococcus pneumoniae type 6B and 14 polysaccharide-tetanus toxoid conjugates and the effect of uncoupled polysaccharide on the antigen-specific immune response. Vaccine 16 : 1941– 1949.
42.
Ruan, M. R.,, M. Akkoyunlu,, A. Grubb, and, A. Forsgren. 1990. Protein D of Haemophilus influenzae. A novel bacterial surface protein with affinity for human IgD. J. Immunol. 145 : 3379– 3384.
43.
Schneerson, R.,, O. Barrera,, A. Sutton, and, J. B. Robbins. 1980. Preparation, characterization, and immunogenicity of Haemophilus influenzae type b polysaccharide-protein conjugates. J. Exp. Med. 152 : 361– 376.
44.
Sorensen, U. B., and, J. Henrichsen. 1984. C-polysaccharide in a pneumococcal vaccine. Acta. Pathol. Microbiol. Immunol. Scand. C 92 : 351– 356.
45.
Sorensen, U. B.,, J. Henrichsen,, H. C. Chen, and, S. C. Szu. 1990. Covalent linkage between the capsular polysaccharide and the cell wall peptidoglycan of Streptococcus pneumoniae revealed by immunochemical methods. Microb. Pathog. 8 : 325– 334.
46.
Steinhoff, M. C.,, K. Edwards,, H. Keyserling,, M. L. Thoms,, C. Johnson,, D. Madore, and, D. Hogerman. 1994. A randomized comparison of three bivalent Streptococcus pneumoniae glycoprotein conjugate vaccines in young children: effect of polysaccharide size and linkage characteristics. Pediatr. Infect. Dis. J. 13 : 368– 372.
47.
Szu, S. C.,, X. R. Li,, A. L. Stone, and, J. B. Robbins. 1991. Relation between structure and immunologic properties of the Vi capsular polysaccharide. Infect. Immun. 59 : 4555– 4561.
48.
Tai, S. S. 2006. Streptococcus pneumoniae protein vaccine candidates: properties, activities and animal studies. Crit. Rev. Microbiol. 32 : 139– 153.
49.
Talaga, P.,, L. Bellamy, and, M. Moreau. 2001. Quantitative determination of C-polysaccharide in Streptococcus pneumoniae capsular polysaccharides by use of high-performance anion-exchange chromatography with pulsed amperometric detection. Vaccine 19 : 2987– 2994.
50.
Thaysen-Andersen M. J. S.,, E. S. Wilhelmsen,, J. W. Petersen, and, P. Hojrup. 2007. Investigation of the detoxification mechanism of formaldehyde-treated tetanus toxin. Vaccine 25 : 2213– 2227.
51.
World Health Organization. 2005. Technical Report Series, annex 2, vol. 927. World Health Organization, Geneva, Switzerland.
52.
Xu, Q.,, C. Abeygunawardana,, A. S. Ng,, A. W. Sturgess,, B. J. Harmon, and, J. P. Hennessey, Jr., 2005. Characterization and quantification of C-polysaccharide in Streptococcus pneumoniae capsular polysaccharide preparations. Anal. Biochem. 336 : 262– 272.
53.
Yu, J.,, D. E. Briles,, J. A. Englund,, S. K. Hollingshead,, W. P. Glezen, and, M. H. Nahm. 2003. Immunogenic protein contaminants in pneumococcal vaccines. J. Infect. Dis. 187 : 1019– 1023.
54.
Yu, X.,, Y. Sun,, C. Frasch,, N. Concepcion, and, M. H. Nahm. 1999. Pneumococcal capsular polysaccharide preparations may contain non-C-polysaccharide contaminants that are immunogenic. Clin. Diagn. Lab. Immunol. 6 : 519– 524.
Tables
Conjugation Chemistry
[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815820.ch11-1,webId=/content/author/10.1128/9781555815820.ch11-1,properties={foaf_givenname=Andrew, foaf_name=Andrew Lees, foaf_surname=Lees, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815820.ch11-aff1]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815820.ch11-2,webId=/content/author/10.1128/9781555815820.ch11-2,properties={foaf_givenname=Velupillai, foaf_name=Velupillai Puvanesarajah, foaf_surname=Puvanesarajah, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815820.ch11-aff2]]}], com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555815820.ch11-3,webId=/content/author/10.1128/9781555815820.ch11-3,properties={foaf_givenname=Carl E., foaf_name=Carl E. Frasch, foaf_surname=Frasch, pub_isAffiliatedWith=[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/affiliation/10.1128/9781555815820.ch11-aff3]]}]]
Citation:
Lees A, Puvanesarajah V, Frasch C.
2008.
Conjugation Chemistry,
p 163-174.
In
Siber G, Klugman K, Mäkelä P (ed),
Pneumococcal Vaccines.
ASM Press, Washington, DC.
doi: 10.1128/9781555815820.ch11
/content/10.1128/9781555815820.ch11.ch11tab01
Table 1
Comparison of conjugation methods that have been used for PCV
Table 1
Comparison of conjugation methods that have been used for PCV
Citation:
Lees A, Puvanesarajah V, Frasch C.
2008.
Conjugation Chemistry,
p 163-174.
In
Siber G, Klugman K, Mäkelä P (ed),
Pneumococcal Vaccines.
ASM Press, Washington, DC.
doi: 10.1128/9781555815820.ch11