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. 1992 Sep;60(9):3528–3532. doi: 10.1128/iai.60.9.3528-3532.1992

Synthesis of a conjugate vaccine composed of pneumococcus type 14 capsular polysaccharide bound to pertussis toxin.

R Schneerson 1, L Levi 1, J B Robbins 1, D M Bryla 1, G Schiffman 1, T Lagergard 1
PMCID: PMC257356  PMID: 1500160

Abstract

Type 14 is one of the common types isolated from patients of all ages with infections caused by Streptococcus pneumoniae. Its capsular polysaccharide (Pn14) is composed of a neutrally charged tetrasaccharide repeat unit. Pn14 does not elicit protective levels of antibodies in infants and children and is a less than optimal immunogen of the 23-valent vaccine for adults. Pertussis toxin (PT) is both a virulence factor and protective antigen of Bordetella pertussis: it is not soluble at neutral pH and forms insoluble complexes with acidic polysaccharides. Both Pn14 and PT are potential components of vaccines for infants and children. Accordingly, a synthetic scheme was devised to prepare a conjugate of Pn14 and PT. An adipic acid hydrazide derivative of Pn14 was bound to PT at pH 3.9 by carbodiimide-mediated condensation. The conjugation procedure inactivated the PT as assayed by CHO cell and histamine-sensitizing activity. The Pn14-PT conjugate elicited antibodies in mice to Pn14 at levels estimated to be protective in humans and elicited neutralizing antibodies to PT. We plan to evaluate Pn14-PT clinically.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson P., Betts R. Human adult immunogenicity of protein-coupled pneumococcal capsular antigens of serotypes prevalent in otitis media. Pediatr Infect Dis J. 1989 Jan;8(1 Suppl):S50–S53. [PubMed] [Google Scholar]
  2. Austrian R., Howie V. M., Ploussard J. H. The bacteriology of pneumococcal otitis media. Johns Hopkins Med J. 1977 Sep;141(3):104–111. [PubMed] [Google Scholar]
  3. Austrian R. Some observations on the pneumococcus and on the current status of pneumococcal disease and its prevention. Rev Infect Dis. 1981 Mar-Apr;3 (Suppl):S1–17. doi: 10.1093/clinids/3.supplement_1.s1. [DOI] [PubMed] [Google Scholar]
  4. Beuvery E. C., van Rossum F., Nagel J. Comparison of the induction of immunoglobulin M and G antibodies in mice with purified pneumococcal type 3 and meningococcal group C polysaccharides and their protein conjugates. Infect Immun. 1982 Jul;37(1):15–22. doi: 10.1128/iai.37.1.15-22.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bolan G., Broome C. V., Facklam R. R., Plikaytis B. D., Fraser D. W., Schlech W. F., 3rd Pneumococcal vaccine efficacy in selected populations in the United States. Ann Intern Med. 1986 Jan;104(1):1–6. doi: 10.7326/0003-4819-104-1-1. [DOI] [PubMed] [Google Scholar]
  6. Broome C. V., Fraser D. W. Pertussis in the United States, 1979: a look at vaccine efficacy. J Infect Dis. 1981 Aug;144(2):187–190. doi: 10.1093/infdis/144.2.187. [DOI] [PubMed] [Google Scholar]
  7. Burns D. L., Kenimer J. G., Manclark C. R. Role of the A subunit of pertussis toxin in alteration of Chinese hamster ovary cell morphology. Infect Immun. 1987 Jan;55(1):24–28. doi: 10.1128/iai.55.1.24-28.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chu C., Schneerson R., Robbins J. B., Rastogi S. C. Further studies on the immunogenicity of Haemophilus influenzae type b and pneumococcal type 6A polysaccharide-protein conjugates. Infect Immun. 1983 Apr;40(1):245–256. doi: 10.1128/iai.40.1.245-256.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Churchill A. E. A potency test for inactivated small animal parvovirus vaccines using chicks. J Biol Stand. 1982 Jan;10(1):1–8. doi: 10.1016/s0092-1157(82)80042-5. [DOI] [PubMed] [Google Scholar]
  10. Fattom A., Lue C., Szu S. C., Mestecky J., Schiffman G., Bryla D., Vann W. F., Watson D., Kimzey L. M., Robbins J. B. Serum antibody response in adult volunteers elicited by injection of Streptococcus pneumoniae type 12F polysaccharide alone or conjugated to diphtheria toxoid. Infect Immun. 1990 Jul;58(7):2309–2312. doi: 10.1128/iai.58.7.2309-2312.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Granström M., Granström G., Gillenius P., Askelöf P. Neutralizing antibodies to pertussis toxin in whooping cough. J Infect Dis. 1985 Apr;151(4):646–649. doi: 10.1093/infdis/151.4.646. [DOI] [PubMed] [Google Scholar]
  12. Granström M., Olinder-Nielsen A. M., Holmblad P., Mark A., Hanngren K. Specific immunoglobulin for treatment of whooping cough. Lancet. 1991 Nov 16;338(8777):1230–1233. doi: 10.1016/0140-6736(91)92101-7. [DOI] [PubMed] [Google Scholar]
  13. Kolb J. P., Genot E., Petit-Koskas E., Paul-Eugene N., Dugas B. Effect of bacterial toxins on human B cell activation. I. Mitogenic activity of pertussis toxin. Eur J Immunol. 1990 May;20(5):969–976. doi: 10.1002/eji.1830200504. [DOI] [PubMed] [Google Scholar]
  14. Kong A. S., Morse S. I. The effect of Bordetella pertussis on the antibody response in mice to type III pneumococcal polysaccharide. J Immunol. 1976 Apr;116(4):989–993. [PubMed] [Google Scholar]
  15. Landesman S. H., Schiffman G. Assessment of the antibody response to pneumococcal vaccine in high-risk populations. Rev Infect Dis. 1981 Mar-Apr;3 (Suppl):S184–S197. doi: 10.1093/clinids/3.supplement_1.s184. [DOI] [PubMed] [Google Scholar]
  16. Lindberg B., Lönngren J., Powell D. A. Structural studies on the specific type-14 pneumococcal polysaccharide. Carbohydr Res. 1977 Sep;58(1):177–186. doi: 10.1016/s0008-6215(00)83413-8. [DOI] [PubMed] [Google Scholar]
  17. Morse J. H., Kong A. S., Lindenbaum J., Morse S. I. The mitogenic effect of the lymphocytosis promoting factor from Bordetella pertussis on human lymphocytes. J Clin Invest. 1977 Sep;60(3):683–692. doi: 10.1172/JCI108820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Morse S. I., Morse J. H. Isolation and properties of the leukocytosis- and lymphocytosis-promoting factor of Bordetella pertussis. J Exp Med. 1976 Jun 1;143(6):1483–1502. doi: 10.1084/jem.143.6.1483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mäkelä O., Pasanen V. J., Sarvas H., Lehtonen M. A gene of the immunoglobulin H-chain cluster controls the murine antibody response to pneumococcal polysaccharide type 14. Scand J Immunol. 1980;12(2):155–158. doi: 10.1111/j.1365-3083.1980.tb00052.x. [DOI] [PubMed] [Google Scholar]
  20. Mäkelä P. H., Sibakov M., Herva E., Henrichsen J., Luotonen J., Timonen M., Leinonen M., Koskela M., Pukander J., Pöntynen S. Pneumococcal vaccine and otitis media. Lancet. 1980 Sep 13;2(8194):547–551. doi: 10.1016/s0140-6736(80)91989-3. [DOI] [PubMed] [Google Scholar]
  21. Oda M., Cowell J. L., Burstyn D. G., Manclark C. R. Protective activities of the filamentous hemagglutinin and the lymphocytosis-promoting factor of Bordetella pertussis in mice. J Infect Dis. 1984 Dec;150(6):823–833. doi: 10.1093/infdis/150.6.823. [DOI] [PubMed] [Google Scholar]
  22. Olin P., Storsaeter J., Romanus V. The efficacy of acellular pertussis vaccine. JAMA. 1989 Jan 27;261(4):560–560. [PubMed] [Google Scholar]
  23. Paton J. C., Lock R. A., Lee C. J., Li J. P., Berry A. M., Mitchell T. J., Andrew P. W., Hansman D., Boulnois G. J. Purification and immunogenicity of genetically obtained pneumolysin toxoids and their conjugation to Streptococcus pneumoniae type 19F polysaccharide. Infect Immun. 1991 Jul;59(7):2297–2304. doi: 10.1128/iai.59.7.2297-2304.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Peeters C. C., Tenbergen-Meekes A. M., Evenberg D. E., Poolman J. T., Zegers B. J., Rijkers G. T. A comparative study of the immunogenicity of pneumococcal type 4 polysaccharide and oligosaccharide tetanus toxoid conjugates in adult mice. J Immunol. 1991 Jun 15;146(12):4308–4314. [PubMed] [Google Scholar]
  25. Pittman M. Determination of the histamine sensitizing unitage of pertussis vaccine. J Biol Stand. 1975;3(2):185–191. doi: 10.1016/0092-1157(75)90046-3. [DOI] [PubMed] [Google Scholar]
  26. Pittman M. Pertussis toxin: the cause of the harmful effects and prolonged immunity of whooping cough. A hypothesis. Rev Infect Dis. 1979 May-Jun;1(3):401–412. doi: 10.1093/clinids/1.3.401. [DOI] [PubMed] [Google Scholar]
  27. Porro M., Costantino P., Fabbiani S., Pellegrini V., Viti S. A semi-synthetic glycoconjugate antigen prepared by chemical glycosilation of pertussis toxin by a meningococcal group C oligosaccharide hapten. Dev Biol Stand. 1985;61:525–530. [PubMed] [Google Scholar]
  28. Robbins J. B., Austrian R., Lee C. J., Rastogi S. C., Schiffman G., Henrichsen J., Mäkelä P. H., Broome C. V., Facklam R. R., Tiesjema R. H. Considerations for formulating the second-generation pneumococcal capsular polysaccharide vaccine with emphasis on the cross-reactive types within groups. J Infect Dis. 1983 Dec;148(6):1136–1159. doi: 10.1093/infdis/148.6.1136. [DOI] [PubMed] [Google Scholar]
  29. Robbins J. B., Schneerson R. Polysaccharide-protein conjugates: a new generation of vaccines. J Infect Dis. 1990 May;161(5):821–832. doi: 10.1093/infdis/161.5.821. [DOI] [PubMed] [Google Scholar]
  30. Sato H., Sato Y. Bordetella pertussis infection in mice: correlation of specific antibodies against two antigens, pertussis toxin, and filamentous hemagglutinin with mouse protectivity in an intracerebral or aerosol challenge system. Infect Immun. 1984 Nov;46(2):415–421. doi: 10.1128/iai.46.2.415-421.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schiffman G., Douglas R. M., Bonner M. J., Robbins M., Austrian R. A radioimmunoassay for immunologic phenomena in pneumococcal disease and for the antibody response to pneumococcal vaccines. I. Method for the radioimmunoassay of anticapsular antibodies and comparison with other techniques. J Immunol Methods. 1980;33(2):133–144. doi: 10.1016/s0022-1759(80)80004-4. [DOI] [PubMed] [Google Scholar]
  32. Sekura R. D., Fish F., Manclark C. R., Meade B., Zhang Y. L. Pertussis toxin. Affinity purification of a new ADP-ribosyltransferase. J Biol Chem. 1983 Dec 10;258(23):14647–14651. [PubMed] [Google Scholar]
  33. Sekura R. D., Zhang Y. L., Roberson R., Acton B., Trollfors B., Tolson N., Shiloach J., Bryla D., Muir-Nash J., Koeller D. Clinical, metabolic, and antibody responses of adult volunteers to an investigational vaccine composed of pertussis toxin inactivated by hydrogen peroxide. J Pediatr. 1988 Nov;113(5):806–813. doi: 10.1016/s0022-3476(88)80005-2. [DOI] [PubMed] [Google Scholar]
  34. Shapiro E. D., Berg A. T., Austrian R., Schroeder D., Parcells V., Margolis A., Adair R. K., Clemens J. D. The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med. 1991 Nov 21;325(21):1453–1460. doi: 10.1056/NEJM199111213252101. [DOI] [PubMed] [Google Scholar]
  35. Verheul A. F., Versteeg A. A., De Reuver M. J., Jansze M., Snippe H. Modulation of the immune response to pneumococcal type 14 capsular polysaccharide-protein conjugates by the adjuvant Quil A depends on the properties of the conjugates. Infect Immun. 1989 Apr;57(4):1078–1083. doi: 10.1128/iai.57.4.1078-1083.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Zackrisson G., Taranger J., Trollfors B. History of whooping cough in nonvaccinated Swedish children, related to serum antibodies to pertussis toxin and filamentous hemagglutinin. J Pediatr. 1990 Feb;116(2):190–194. doi: 10.1016/s0022-3476(05)82873-2. [DOI] [PubMed] [Google Scholar]
  37. van de Wijgert J. H., Verheul A. F., Snippe H., Check I. J., Hunter R. L. Immunogenicity of Streptococcus pneumoniae type 14 capsular polysaccharide: influence of carriers and adjuvants on isotype distribution. Infect Immun. 1991 Aug;59(8):2750–2757. doi: 10.1128/iai.59.8.2750-2757.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]

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