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. 1993 Feb;61(2):432–438. doi: 10.1128/iai.61.2.432-438.1993

Non-epitope-specific suppression of the antibody response to Haemophilus influenzae type b conjugate vaccines by preimmunization with vaccine components.

T Barington 1, M Skettrup 1, L Juul 1, C Heilmann 1
PMCID: PMC302747  PMID: 7678586

Abstract

Recently, conjugate vaccines containing Haemophilus influenzae type b capsular polysaccharide (HibCP) coupled to protein carriers were introduced for use in infants and certain adult risk groups. Similar conjugate vaccines against other capsulated bacteria are currently under development for both children and adults. Despite its potential importance, the possible influence of preexisting immunity to the components of such conjugates on the vaccination response in humans has been addressed by few studies. To study this issue, we randomized 82 healthy adult volunteers into six groups and vaccinated them twice, with a 4-week interval between immunizations. Four groups received tetanus toxoid (TT) or diphtheria toxoid (DT) and then HibCP coupled to TT (HibCP-TT) or DT (HibCP-DT). Two groups received HibCP-TT followed by HibCP-DT or vice versa. The total antibody levels to HibCP, TT, and DT and the anti-HibCP immunoglobulin G1 (IgG1) and IgG2 levels were measured before and 4 weeks after the immunizations. For some of the vaccinees, the number of circulating antibody-secreting cells was evaluated 7 days after immunization. Surprisingly, preimmunization with the relevant carrier protein reduced the subsequent increase in the total HibCP antibody levels (P < 0.05), affecting the IgG1 and the IgG2 subclasses equally. Also, the responses to the carrier portions of the conjugates were suppressed, as demonstrated by the lack of significant increases in the antibody levels (P > or = 0.29) and, for HibCP-TT, by reduced numbers of anticarrier antibody-secreting cells (P = 0.009). Similar non-epitope-specific suppression was seen in the groups receiving both conjugates. Thus, preimmunization with one conjugate reduced the subsequent response to the carrier portion of the other conjugate (HibCP-DT and then HibCP-TT, P = 0.00002; HibCP-TT and then HibCP-DT, P = 0.06) as well as to HibCP itself. Possible mechanisms behind this non-epitope-specific suppression and its relevance for vaccine development are discussed.

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Selected References

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  1. Anderson P. Antibody responses to Haemophilus influenzae type b and diphtheria toxin induced by conjugates of oligosaccharides of the type b capsule with the nontoxic protein CRM197. Infect Immun. 1983 Jan;39(1):233–238. doi: 10.1128/iai.39.1.233-238.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anderson P., Pichichero M., Edwards K., Porch C. R., Insel R. Priming and induction of Haemophilus influenzae type b capsular antibodies in early infancy by Dpo20, an oligosaccharide-protein conjugate vaccine. J Pediatr. 1987 Nov;111(5):644–650. doi: 10.1016/s0022-3476(87)80237-8. [DOI] [PubMed] [Google Scholar]
  3. Avery O. T., Goebel W. F. CHEMO-IMMUNOLOGICAL STUDIES ON CONJUGATED CARBOHYDRATE-PROTEINS : II. IMMUNOLOGICAL SPECIFICITY OF SYNTHETIC SUGAR-PROTEIN ANTIGENS. J Exp Med. 1929 Sep 30;50(4):533–550. doi: 10.1084/jem.50.4.533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barington T., Kristensen K., Henrichsen J., Heilmann C. Influence of prevaccination immunity on the human B-lymphocyte response to a Haemophilus influenzae type b conjugate vaccine. Infect Immun. 1991 Mar;59(3):1057–1064. doi: 10.1128/iai.59.3.1057-1064.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barington T., Sparholt S., Juul L., Heilmann C. A simplification of the enzyme-linked immunospot technique. Increased sensitivity for cells secreting IgG antibodies to Haemophilus influenzae type b capsular polysaccharide. J Immunol Methods. 1992 Dec 8;156(2):191–198. doi: 10.1016/0022-1759(92)90025-o. [DOI] [PubMed] [Google Scholar]
  6. Berkowitz C. D., Ward J. I., Meier K., Hendley J. O., Brunell P. A., Barkin R. A., Zahradnik J. M., Samuelson J., Gordon L. Safety and immunogenicity of Haemophilus influenzae type b polysaccharide and polysaccharide diphtheria toxoid conjugate vaccines in children 15 to 24 months of age. J Pediatr. 1987 Apr;110(4):509–514. doi: 10.1016/s0022-3476(87)80540-1. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Claesson B. A., Schneerson R., Robbins J. B., Johansson J., Lagergard T., Taranger J., Bryla D., Levi L., Cramton T., Trollfors B. Protective levels of serum antibodies stimulated in infants by two injections of Haemophilus influenzae type b capsular polysaccharide-tetanus toxoid conjugate. J Pediatr. 1989 Jan;114(1):97–100. doi: 10.1016/s0022-3476(89)80611-0. [DOI] [PubMed] [Google Scholar]
  9. Eardley D. D., Gershon R. K. Feedback induction of suppressor T-cell activity. J Exp Med. 1975 Aug 1;142(2):524–529. doi: 10.1084/jem.142.2.524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Etlinger H. M., Gillessen D., Lahm H. W., Matile H., Schönfeld H. J., Trzeciak A. Use of prior vaccinations for the development of new vaccines. Science. 1990 Jul 27;249(4967):423–425. doi: 10.1126/science.1696030. [DOI] [PubMed] [Google Scholar]
  11. Granoff D. M., Boies E. G., Munson R. S., Jr Immunogenicity of Haemophilus influenzae type b polysaccharide--diphtheria toxoid conjugate vaccine in adults. J Pediatr. 1984 Jul;105(1):22–27. doi: 10.1016/s0022-3476(84)80350-9. [DOI] [PubMed] [Google Scholar]
  12. Hamilton R. G. Application of engineered chimeric antibodies to the calibration of human antibody standards. Ann Biol Clin (Paris) 1991;49(4):242–248. [PubMed] [Google Scholar]
  13. Herrmann D. J., Hamilton R. G., Barington T., Frasch C. E., Arakere G., Mäkelä O., Mitchell L. A., Nagel J., Rijkers G. T., Zegers B. Quantitation of human IgG subclass antibodies to Haemophilus influenzae type b capsular polysaccharide. Results of an international collaborative study using enzyme immunoassay methodology. J Immunol Methods. 1992 Apr 8;148(1-2):101–114. doi: 10.1016/0022-1759(92)90163-n. [DOI] [PubMed] [Google Scholar]
  14. Herzenberg L. A., Tokuhisa T., Herzenberg L. A. Carrier-priming leads to hapten-specific suppression. Nature. 1980 Jun 26;285(5767):664–667. doi: 10.1038/285664a0. [DOI] [PubMed] [Google Scholar]
  15. Heyman B. The immune complex: possible ways of regulating the antibody response. Immunol Today. 1990 Sep;11(9):310–313. doi: 10.1016/0167-5699(90)90126-t. [DOI] [PubMed] [Google Scholar]
  16. Katz D. H., Paul W. E., Goidl E. A., Benacerraf B. Carrier function in anti-hapten immune responses. I. Enhancement of primary and secondary anti-hapten antibody responses by carrier preimmunization. J Exp Med. 1970 Aug 1;132(2):261–282. doi: 10.1084/jem.132.2.261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Klaus G. G., Bijsterbosch M. K., O'Garra A., Harnett M. M., Rigley K. P. Receptor signalling and crosstalk in B lymphocytes. Immunol Rev. 1987 Oct;99:19–38. doi: 10.1111/j.1600-065x.1987.tb01170.x. [DOI] [PubMed] [Google Scholar]
  18. Koskela M., Leinonen M., Häivä V. M., Timonen M., Mäkelä P. H. First and second dose antibody responses to pneumococcal polysaccharide vaccine in infants. Pediatr Infect Dis. 1986 Jan-Feb;5(1):45–50. doi: 10.1097/00006454-198601000-00009. [DOI] [PubMed] [Google Scholar]
  19. Manca F., Fenoglio D., Li Pira G., Kunkl A., Celada F. Effect of antigen/antibody ratio on macrophage uptake, processing, and presentation to T cells of antigen complexed with polyclonal antibodies. J Exp Med. 1991 Jan 1;173(1):37–48. doi: 10.1084/jem.173.1.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mitchison N. A. The carrier effect in the secondary response to hapten-protein conjugates. I. Measurement of the effect with transferred cells and objections to the local environment hypothesis. Eur J Immunol. 1971 Jan;1(1):10–17. doi: 10.1002/eji.1830010103. [DOI] [PubMed] [Google Scholar]
  21. Noelle R. J., Snow E. C. T helper cell-dependent B cell activation. FASEB J. 1991 Oct;5(13):2770–2776. doi: 10.1096/fasebj.5.13.1833257. [DOI] [PubMed] [Google Scholar]
  22. Paul W. E., Katz D. H., Benacerraf B. Augmented anti-S 3 antibody responses to an S 3 -protein conjugate. J Immunol. 1971 Sep;107(3):685–688. [PubMed] [Google Scholar]
  23. Paul W. E., Katz D. H., Goidl E. A., Benacerraf B. Carrier function in anti-hapten immune responses. II. Specific properties of carrier cells capable of enhancing anti-hapten antibody responses. J Exp Med. 1970 Aug 1;132(2):283–299. doi: 10.1084/jem.132.2.283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Peeters C. C., Tenbergen-Meekes A. M., Poolman J. T., Beurret M., Zegers B. J., Rijkers G. T. Effect of carrier priming on immunogenicity of saccharide-protein conjugate vaccines. Infect Immun. 1991 Oct;59(10):3504–3510. doi: 10.1128/iai.59.10.3504-3510.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Peltola H., Käyhty H., Sivonen A., Mäkelä H. 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. 1977 Nov;60(5):730–737. [PubMed] [Google Scholar]
  26. Rajewsky K., Schirrmacher V., Nase S., Jerne N. K. The requirement of more than one antigenic determinant for immunogenicity. J Exp Med. 1969 Jun 1;129(6):1131–1143. doi: 10.1084/jem.129.6.1131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Roosnek E., Lanzavecchia A. Efficient and selective presentation of antigen-antibody complexes by rheumatoid factor B cells. J Exp Med. 1991 Feb 1;173(2):487–489. doi: 10.1084/jem.173.2.487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sarvas H., Mäkelä O., Toivanen P., Toivanen A. Effect of carrier preimmunization on the anti-hapten response in the chicken. Scand J Immunol. 1974;3(4):455–460. doi: 10.1111/j.1365-3083.1974.tb01278.x. [DOI] [PubMed] [Google Scholar]
  29. Schneerson R., Barrera O., Sutton A., Robbins J. B. Preparation, characterization, and immunogenicity of Haemophilus influenzae type b polysaccharide-protein conjugates. J Exp Med. 1980 Aug 1;152(2):361–376. doi: 10.1084/jem.152.2.361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schneerson R., Robbins J. B., Chu C., Sutton A., Vann W., Vickers J. C., London W. T., Curfman B., Hardegree M. C., Shiloach J. Serum antibody responses of juvenile and infant rhesus monkeys injected with Haemophilus influenzae type b and pneumococcus type 6A capsular polysaccharide-protein conjugates. Infect Immun. 1984 Sep;45(3):582–591. doi: 10.1128/iai.45.3.582-591.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schutze M. P., Deriaud E., Przewlocki G., LeClerc C. Carrier-induced epitopic suppression is initiated through clonal dominance. J Immunol. 1989 Apr 15;142(8):2635–2640. [PubMed] [Google Scholar]
  32. Tada T., Takemori T. Selective roles of thymus-derived lymphocytes in the antibody response. I. Differential suppressive effect of carrier-primed T cells on hapten-specific IgM and IgG antibody responses. J Exp Med. 1974 Jul 1;140(1):239–252. doi: 10.1084/jem.140.1.239. [DOI] [PMC free article] [PubMed] [Google Scholar]

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