Vaccine Design pp 673-694 | Cite as

Haemophilus influenzae Type b Conjugate Vaccines

  • Peter J. Kniskern
  • Stephen Marburg
  • Ronald W. Ellis
Part of the Pharmaceutical Biotechnology book series (PBIO, volume 6)

Abstract

Haemophilus influenzae, a gram-negative rod-shaped bacterium, is a major human pathogen that causes a range of diseases in infants, children, and adults. There are six antigenic types of H. influenzae, termed a-f, whose antigenic specificity is provided by the capsular Polysaccharide (Ps). There also are nontypeable strains which lack a capsular Ps. H. influenzae type b (Hib) is the most pathogenic H. influenzae strain for infants and young children and a major cause of invasive bacterial infections. Until the 1990s, Hib caused an estimated 10,000 cases of meningitis per year in children 2 months to 5 years of age in the United States (Vadheim and Ward, 1994). The mortality rate is up to 5% in developed countries, and up to 35% of survivors may develop permanent neurological sequelae. Other invasive Hib infections include cellulitis, empyema, endocarditis, endophthalmitis, epididymitis, epiglottitis, osteomyelitis, pericarditis, pneumonia, septic arthritis, and tracheitis (Kaplan, 1994). While the total incidence of such Hib infections was approximately equal to that of Hib meningitis in the United States, these diseases vary significantly in relative incidence elsewhere in the world. As a result of the development and widespread use of Hib conjugate vaccines in several developed countries, the incidence of invasive Hib diseases has decreased by about 95% in the United States (M.M.W.R., 1994) and 60–80% in other countries (Vadheim and Ward, 1994).

Keywords

Lysine Oligosaccharide Schiff Measle Osteomyelitis 

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References

  1. Alexander, H. E., Ellis, C., and Leidy, G., 1943, Treatment of type-specific Haemophilus influenzae infections in infancy and childhood, J. Pediatr. 20:673–698.Google Scholar
  2. Alexander, H. E., Heidelberger, M., and Leidy, G., 1944, The protective or curative element in type b H. influenzae rabbit serum, Yale J. Biol. Med. 16:425–440.PubMedGoogle Scholar
  3. Anderson, G., 1994, Progress toward elimination of Haemophilus influenzae type b diseases among infants and children — 1987–1993, Morbid. Mortal. Weekly Rep. 48:144–188.Google Scholar
  4. Anderson, P. W., and Eby, R., 1990, Immunogenic Conjugates, U.S. Patent No. 4,902,506.Google Scholar
  5. Anderson, P. W., and Smith, D. H., 1977, Immunogenicity in weanling rabbits of a polyribophosphate complex from Haemophilus influenzae type b, J. Infect. Dis. 136 (Suppl.):S63–S70.PubMedCrossRefGoogle Scholar
  6. Anderson, P. W., Pitt, J., and Smith, D. H., 1976, Synthesis and release of polyribophosphate by Haemophilus influenzae type b in vitro, Infect. Immun. 13:581–589.PubMedGoogle Scholar
  7. Anderson, P., Smith, D. H., Ingram, D. L., Wilkins, J., Wehrle, P. F., and Howie, V. M., 1977, Antibody to polyribophosphate of Haemophilus influenzae type b in infants and children: Effect of immunization with polyribophosphate, J. Infect. Dis. 136 (Suppl):S57–S62.PubMedCrossRefGoogle Scholar
  8. Anderson, P. W., Pichichero, M. E., Stein, E. C., Porcelli, S., Betts, R. E., Connuck, D. M., Korones, D., Insel, R. A., Zahradnik, J. M, and Eby, R., 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 uniterminally coupled to the diphtheria protein CRM197, J. Immunol. 142:2464–2468.PubMedGoogle Scholar
  9. Baker, P. J., 1975, Homeostatic control of antibody responses: A model based on recognition of cell-associated antibody by regulatory T cells, Transplant. Rev. 26:3–20.PubMedGoogle Scholar
  10. Black, S. B., Shinefield, H. R., Fireman, B., Hiatt, R., Polen, M., Vittinghoff, E., and the Northern California Kaiser Permanente Study Center Pediatrics Group, 1991, Efficacy in infancy of Oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine in a United States population of 61,080 children, Pediatr. Infect. Dis. J. 10:97–104.PubMedCrossRefGoogle Scholar
  11. Chu, C. Y., Schneerson, R., Robbins, J. B., and Rastogi, S. C., 1983, Further studies on the immunogenicity of Haemophilus influenzae type b and pneumococcal type 6A polysaccharide-protein conjugates, Infect. Immun. 40:245–256.PubMedGoogle Scholar
  12. Clemens, J. D., Ferreccio, C., Levine, M. M, Horowitz, I., Rao, M. R., Eng, M., Edwards, K. M. and Fritzell, B., 1992, Impact of Haemophilus influenzae type b polysaccharide-tetanus protein conjugate vaccine to concurrently administered diphtheria-tetanus-pertussis vaccine, J. Am. Med. Assoc. 267:673–678.CrossRefGoogle Scholar
  13. Code of Federal Regulations, 1991, 21CFR 610.13.Google Scholar
  14. Code of Federal Regulations, 1991, 21CFR 610.11.Google Scholar
  15. Colombatti, M., Dell’Arciprete, L., Rappuoli, R., and Tridente, G., 1989, Selective immunotoxins prepared with mutant diphtheria toxins coupled to monoclonal antibodies, Methods Enzymol. 178:404–422.PubMedCrossRefGoogle Scholar
  16. Crisel, R. M., Baker, R. S., and Dorman, D. E., 1975, Capsular polymer of Haemophilus influenzae type b. I. Structural characterization of the capsular polymer of strain Egan, J. Biol. Chem. 250:4926–4930.PubMedGoogle Scholar
  17. Daum, R. S., and Granoff, D. M, 1994, Lessons from the evaluation of immunogenicity, in: Development and Clinical Use of Haemophilus b Conjugate Vaccines (R. Ellis and D. M. Granoff, eds.), Dekker, New York, pp. 291–312.Google Scholar
  18. Decker, M. D., Edwards, K. M., Bradley, R., and Palmer, P., 1992, Comparative trial in infants of four conjugate Haemophilus influenzae type b vaccines, J. Pediatr. 120:184–189.PubMedCrossRefGoogle Scholar
  19. Dick, W. E., and Bevrett, M., 1989, Glycoconjucates of bacterial carbohydrate antigens: a survey and consideration of design and preparation factors, Conjugate Vaccines (J. M. Cruise and R. E. Lewis, eds.), Karger, Basel, p. 48.Google Scholar
  20. Drug Information for the Health Care Professional, USP DI, Vol. IA, The U.S. Pharmacopeal Convention, Inc. (1992).Google Scholar
  21. Ellman, G. L., 1959, Tissue sulfhydryl groups, Arch. Biochem. Biophys. 82:70–77.PubMedCrossRefGoogle Scholar
  22. Eskola, J., Käyhty, H., Takala, A. K., Peltola, H., Rönnberg, P.-R., Kela, E., Pekkanen, E., McVerry, P., and Mäkelä, P. H., 1990a, A randomized, prospective field trial of a conjugate vaccine in the protection of infants and young children against invasive Haemophilus influenzae type b disease, N. Engl. J. Med. 323:1381–1387.PubMedCrossRefGoogle Scholar
  23. Eskola, J., Peltola, H., Takala, A., Palmgren, J., and Mäkelä, P. H., 1990b, Protective efficacy of the Haemophilus influenzae type b conjugate vaccine HbOC in Finnish infants, Program and Abstracts of the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, October 1990, American Society for Microbiology, Washington, DC (Abstract No. 60).Google Scholar
  24. Fothergill, L. D., Le Roy, D., and Wright, J., 1933, Influenzal meningitis: The relation of age incidence to the bactericidal power of blood against the causal organism, J. Immunol. 24:273–284.Google Scholar
  25. Frasch, C. E., 1994, Regulatory perspectives in vaccine licensure, in: Development and Clinical Use of Haemophilus b Conjugate Vaccines (R. Ellis and D. M. Granoff, eds.), Dekker, New York, pp. 435–453.Google Scholar
  26. Fritzell, B., and Plotkin, S., 1992, Efficacy and safety of a Haemophilus influenzae type b capsular polysaccharide-tetanus protein conjugate vaccine, J. Pediatr. 121:355–362.PubMedCrossRefGoogle Scholar
  27. Goebel, W. F., and Avery, O. T., 1931, Chemo-immunological studies on conjugated carbohydrate-protein. V. The immunological specificity of an antigen prepared by combining one capsular Polysaccharide of type 3 pneumococcus with foreign protein, J. Exp. Med. 54:431–437.PubMedCrossRefGoogle Scholar
  28. Gordon, L. K., 1986, Polysaccharide Endotoxoid Conjugate Vaccines, 1986, U.S. Patent No. 4,619,828.Google Scholar
  29. Granoff, D. M., Anderson, E. L., Osterholm, M. T., Holmes, S. J., McHugh, J. E., Belshe, R. B., Medley, F., and Murphy, T. V., 1992, Differences in the immunogenicity of three Haemophilus influenzae type b conjugate vaccines in infants, J. Pediatr. 121:187–194.PubMedCrossRefGoogle Scholar
  30. Granoff, D. M., Holmes, S. J., Belshe, R. B., and Anderson, E. L., 1993, The effect of carrier priming on the anticapsular antibody response to Haemophilus influenzae type b conjugate vaccines, Pediatr. Res. 33 (No.4, Part 2):169A.Google Scholar
  31. Gray, B. M., 1990, Opsonophagocidal activity in sera from infants and children immunized with Haemophilus influenzae type b conjugate vaccine (meningococcal protein conjugate), Pediatrics 85 (Apr. Suppl.):694–697.PubMedGoogle Scholar
  32. Hennessey, J. P., Bednar, B., and Manam, V., 1993, Molecular size analysis of Haemophilus influenzae type b capsular Polysaccharide, J. Liquid Chromatogr. 16:1715–1729.CrossRefGoogle Scholar
  33. Jennings, H. J., Lugowski, C., and Kasper, D. L., 1981, Conformational aspects critical to the immunospecificity of the type 3 group B streptococcal Polysaccharide, Biochemistry 20:4511–4518.PubMedCrossRefGoogle Scholar
  34. Kaplan, S. L., 1994, Pathogenesis and treatment of infants and children, in: Development and Clinical Use of Haemophilus b Conjugate Vaccines (R. Ellis and D. M. Granoff, eds.), Dekker, New York, pp. 371–388.Google Scholar
  35. Käyhty, H., Peltola, H., Karanko, V., and Mäkelä, P. H., 1983, The protective level of serum antibodies to the capsular Polysaccharide of Haemophilus influenzae type b, J. Infect. Dis. 147:1100–1105.PubMedCrossRefGoogle Scholar
  36. Kniskern, P. J., and Marburg, S., 1994, Conjugation: Design, chemistry and analysis, in: Development and Clinical Uses of Haemophilus b Conjugate Vaccines (R. W. Ellis and D. M. Granoff, eds.), Dekker, New York, pp. 37–69.Google Scholar
  37. Kniskern, P. J., Hagopian, A., and Carlo, D. J., 1981, Meningitis Vaccines, U.S. Patent No. 4,307,080.Google Scholar
  38. Lifely, M. R., Moreno, C., and Lindon, J. C., 1987, An integrated molecular and immunological approach towards a meningococcal group B vaccine, Vaccine 5:11–26.PubMedCrossRefGoogle Scholar
  39. Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J., 1951, Protein measurement with the Folin phenol reagent, J. Biol. Chem. 193:265–275.PubMedGoogle Scholar
  40. Mangalo, R., Bizzini, B., Turpin, A., and Raynaud, M., 1968, The molecular weight of tetanus toxin, Biochim. Biophys. Acta 168:583–584.PubMedCrossRefGoogle Scholar
  41. Marburg, S., Jorn, D., Tolman, R. L., Arison, B., McCauley, J., Kniskern, P. J., Hagopian, A., and Vella, P. P., 1986, Bimolecular chemistry of macromolecules — Synthesis of bacterial Polysaccharide conjugates with Neisseria meningitidis membrane protein, J. Am. Chem. Soc. 108:5282–5297.CrossRefGoogle Scholar
  42. Marburg, S., Tolman, R. L., and Kniskern, P. J., 1987, Covalently-Modified Polyanionic Bacterial Polysaccharides, Stable Covalent Conjugates of Such Polysaccharides and Immunogenic Protein with Bigeneric Spacers, and Methods of Preparing Such Polysaccharides and Conjugates and of Confirming Covalency, U.S. Patent No. 4,695,624.Google Scholar
  43. Marburg, S., Tolman, R. L., and Kniskern, P. J., 1989, Covalently-Modified Polyanionic Bacterial Polysaccharides, Stable Covalent Conjugates of Such Polysaccharides and Immunogenic Protein with Bigen-eric Spacers, and Methods of Preparing Such Polysaccharides and Conjugates and of Confirming Covalency, U.S., Patent No. 4,882,317.Google Scholar
  44. MMWR, 1994, Progress toward elimination of Haemophilus influenza type b disease among infants and children, Morbid. Mortal. Weekly Rep. 2(8): 144–147.Google Scholar
  45. Musher, D., Gorlee, A., Murphy, T., Chapman, A., Zahradnik, J., Apicella, M., and Baughn, R., 1986, Immunity to Haemophilus influenzae type b in young adults: Correlation of bactericidal and opsonizing activity of serum with antibody to polyribosylribitol phosphate and lipooligosaccharide before and after vaccination, J. Infect. Dis. 154:935–943.PubMedCrossRefGoogle Scholar
  46. Pappenheimer, A. M., Jr., Uchida, T., and Harper, A. A., 1972, An immunological study of the diphtheria toxin molecule, Immunochemistry 9:891–906.PubMedCrossRefGoogle Scholar
  47. Parke, J. C., Schneerson, R., Reimer, C., Black, C., Welfare, S., Bryla, D., Levi, L., Pavliakova, D., Cramton, T., Schulz, D., Cadoz, M., and Robbins, J. B., 1991, Clinical and immunologie responses to Haemophilus influenzae type b-tetanus conjugate vaccine in infants injected at 3,5,7, and 18 months of age, J. Pediatr. 118:184–190.PubMedCrossRefGoogle Scholar
  48. Peeters, C. C. A. M., Tenbergen-Meekes, A.-M. J., Poolman, J. T. M., Zegers, B. J., and Rijkers, G. T., 1992, Immunogenicity of a Streptococcus pneumoniae type 4 polysaccharide-protein conjugate is decreased by admixture of high doses of free saccharide, Vaccine 10:833–840.PubMedCrossRefGoogle Scholar
  49. Peltola, H., Käyhty, H., Sivonen, A., and Mäkelä, P. H., 1977, Haemophilus influenzae type b capsular Polysaccharide vaccine in children: A double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland, Pediatrics 60:730–737.PubMedGoogle Scholar
  50. Peltola, H., Käyhty, H., Virtanen, M., and Mäkelä, P. H., 1984, Prevention of Haemophilus influenzae type b bacteremic infections with the capsular Polysaccharide vaccine, N. Engl. J. Med. 310:1561–1566.PubMedCrossRefGoogle Scholar
  51. Peltola, H., Kilpi, T., and Anttila, M., 1992, Rapid disappearance of Haemophilus influenzae type b meningitis after routine childhood immunization with conjugate vaccines, Lancet 340:592–594.PubMedCrossRefGoogle Scholar
  52. Robbins, J. B., Parke, J. C., Jr., Schneerson, R., and Whisnant, J. K., 1973, Quantitative measurement of “natural” and immunization induced Haemophilus influenzae type b capsular Polysaccharide antibodies, Pediatr. Res. 7:103–110.PubMedCrossRefGoogle Scholar
  53. Santosham, M., Wolff, M., Reid, R., Hohenboken, M., Bateman, M., Goepp, J., Cortese, M., Sack, D., Hill, J., Newcomer, W., Capriotti, L., Smith, J., Owen, M., Gahagan, S., Hu, D., Kling, R., Lukacs, L., Ellis, R. W, Vella, P. P., Calandra, G., Matthews, H., and Ahonkhai, V., 1991, The efficacy in Navajo infants of a conjugate vaccine consisting of Haemophilus influenzae type b Polysaccharide and Neisseria meningitidis outer-membrane protein complex, N. Engl. J. Med. 324:1767–1772.PubMedCrossRefGoogle Scholar
  54. Schneerson, R., Robbins, J. B., Parke, J. C., Bell, C., Schlesselman, J. J., Sutton, A., Wang, Z., Schiffman, G., Karpas, A., and Shiloach, J., 1986, Quantitative and qualitative analysis of serum antibodies elicited in adults by Haemophilus influenzae type b and pneumococcus type 6A capsular polysaccharidetetanus toxoid conjugates, Infect. Immun. 52:519–528.PubMedGoogle Scholar
  55. Seid, R. C., Jr., Boykins, R. A., Liu, D.-F., Kimbrough, K. W, Hsieh, C.-L., and Eby, R., 1989, Chemical evidence for covalent linkages of a semisynthetic glycoconjugate vaccine for Haemophilus influenzae type b disease, Glycoconjugate J. 6:489–498.CrossRefGoogle Scholar
  56. Smith, A. L., Smith, D. H., Averill, D. R., Marino, J., and Moxon, E. R., 1973, Production of Haemophilus influenzae b meningitis in infant rats by intraperitoneal inoculation, Infect. Immun. 8:278–290.PubMedGoogle Scholar
  57. Smith, D. H., Madore, D. V., Eby, R. J., Anderson, P. W, Insel, R. A., and Johnson, C. L., 1989, Haemophilus b oligosaccharide-CRM197 and other haemophilus b conjugate vaccines. A status report, in: Immunobiology of Proteins and Peptides V. Vaccines (M. Z. Atassi, ed.), Plenum Press, New York, pp. 65–82.Google Scholar
  58. Vadheim, C. M., and Ward, J. I., 1994, Epidemiology in developed countries, in: Development and Clinical Use of Haemophilus b Conjugate Vaccines (R. Ellis and D. M. Granoff, eds.), Dekker, New York, pp. 231–245.Google Scholar
  59. van Dam, J. E. G., Fleer, A., and Snippe, H., 1990, Immogenicity of Streptococcus pneumoniae capsular polysaccharides, Antoine van Leevwenhoek 58:1.CrossRefGoogle Scholar
  60. Vella, P. P., and Ellis, R. W., 1992, Haemophilus b conjugate vaccines, in: Vaccines: New Approaches to Immunological Problems (R. W. Ellis, ed.), Butterworth-Heinemann, London, pp. 1–21.Google Scholar
  61. Vella, P. P., Staub, J. M., Armstrong, J., Dolan, K. T., Rusk, C. M., Szymanski, S., Greer, W. E., Marburg, S., Kniskern, P. J., Schofield, T. L., Tolman, R. L., Hartner, F., Pan, S.-H., Gerety, R. J., and Ellis, R. W., 1990, Immunogenicity of a new Haemophilus influenzae type b conjugate vaccine (meningococcal protein conjugate) (PedvaxHIB®), Pediatrics 85(Apr. Suppl.):668–675.PubMedGoogle Scholar
  62. Ward, J., Brenneman, G., Letson, G. W., Heyward, W. L., and the Alaska H. influenzae Vaccine Study Group, 1990, Limited efficacy of a Haemophilus influenzae type b conjugate vaccine in Alaska native infants, N. Engl. J. Med. 323:1393–1401.PubMedCrossRefGoogle Scholar
  63. Wessels, R., and Kasper, D. L., 1989, Antibody recognition of the type 14 pneumococcal capsule. Evidence for a conformational epitope in a neutral Polysaccharide, J. Exp. Med. 169:2121–2131.PubMedCrossRefGoogle Scholar
  64. WHO Technical Report, 1991, Requirements for Haemophilus influenzae type b Conjugate Vaccines (Requirements for Biological Substances No. 46), No. 814, pp. 15-37.Google Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Peter J. Kniskern
    • 1
  • Stephen Marburg
    • 2
  • Ronald W. Ellis
    • 1
  1. 1.Virus and Cell BiologyMerck Research LaboratoriesWest PointUSA
  2. 2.Synthetic Chemical ResearchMerck Research LaboratoriesRahwayUSA

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