Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1982 Aug;79(16):5042–5046. doi: 10.1073/pnas.79.16.5042

Successful immunization with a totally synthetic diphtheria vaccine.

F Audibert, M Jolivet, L Chedid, R Arnon, M Sela
PMCID: PMC346823  PMID: 6956913

Abstract

Three peptides corresponding to fragments of diphtheria toxin have been synthesized. They include the previously described tetradecapeptide and two structural analogs, the hexadecapeptide and the octadecapeptide. Conjugates of these peptides to proteins or a synthetic carrier have induced in guinea pig protection against the dermonecrotic activity of diphtheria toxin. All of the conjugates were immunogenic when administered either in complete Freund's adjuvant or with N-acetylmuramyl-L-alanyl-D-isoglutamine in aqueous medium. Positive immune response toward the octadecapeptide was obtained in mice as well. In this case, the immunogenic combinations were conjugates with bovine serum albumin administered either in Freund's adjuvant or with the muramyl dipeptide and a complete synthetic conjugate comprising both the octadecapeptide and the muramyl dipeptide covalently attached to a synthetic carrier, multichain poly(DLAla). This last immunogen, which induced the most effective immune response, is a completely synthetic immunogen with built-in adjuvanticity and induces protective antitoxic immunity when administered in a physiological medium.

Full text

PDF
5042

Selected References

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

  1. Arnon R. Chemically defined antiviral vaccines. Annu Rev Microbiol. 1980;34:593–618. doi: 10.1146/annurev.mi.34.100180.003113. [DOI] [PubMed] [Google Scholar]
  2. Arnon R., Maron E., Sela M., Anfinsen C. B. Antibodies reactive with native lysozyme elicited by a completely synthetic antigen. Proc Natl Acad Sci U S A. 1971 Jul;68(7):1450–1455. doi: 10.1073/pnas.68.7.1450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arnon R., Sela M., Parant M., Chedid L. Antiviral response elicited by a completely synthetic antigen with built-in adjuvanticity. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6769–6772. doi: 10.1073/pnas.77.11.6769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Audibert F., Chedid L., Hannoun C. Augmentation de la réponse immunitaire au vaccin grippal par un glycopeptide synthétique adjuvant (N-acétyl muramyl-L-alanyl-D-isoglutamine). C R Acad Sci Hebd Seances Acad Sci D. 1977 Sep 12;285(4):467–470. [PubMed] [Google Scholar]
  5. Audibert F., Chédid L., Lefrancier P., Choay J. Distinctive adjuvanticity of synthetic analogs of mycobacterial water-soluble components. Cell Immunol. 1976 Feb;21(2):243–249. doi: 10.1016/0008-8749(76)90053-8. [DOI] [PubMed] [Google Scholar]
  6. Audibert F., Jolivet M., Chedid L., Alouf J. E., Boquet P., Rivaille P., Siffert O. Active antitoxic immunization by a diphtheria toxin synthetic oligopeptide. Nature. 1981 Feb 12;289(5798):593–594. doi: 10.1038/289593a0. [DOI] [PubMed] [Google Scholar]
  7. Beachey E. H., Seyer J. M., Dale J. B., Simpson W. A., Kang A. H. Type-specific protective immunity evoked by synthetic peptide of Streptococcus pyogenes M protein. Nature. 1981 Jul 30;292(5822):457–459. doi: 10.1038/292457a0. [DOI] [PubMed] [Google Scholar]
  8. Chedid L. A., Parant M. A., Audibert F. M., Riveau G. J., Parant F. J., Lederer E., Choay J. P., Lefrancier P. L. Biological activity of a new synthetic muramyl peptide adjuvant devoid of pyrogenicity. Infect Immun. 1982 Feb;35(2):417–424. doi: 10.1128/iai.35.2.417-424.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chedid L., Audibert F., Johnson A. G. Biological activities of muramyl dipeptide, a synthetic glycopeptide analogous to bacterial immunoregulating agents. Prog Allergy. 1978;25:63–105. [PubMed] [Google Scholar]
  10. Chedid L., Parant M., Parant F., Audibert F., Lefrancier F., Choay J., Sela M. Enhancement of certain biological activities of muramyl dipeptide derivatives after conjugation to a multi-poly(DL-alanine)--poly(L-lysine) carrier. Proc Natl Acad Sci U S A. 1979 Dec;76(12):6557–6561. doi: 10.1073/pnas.76.12.6557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Collier R. J. Diphtheria toxin: mode of action and structure. Bacteriol Rev. 1975 Mar;39(1):54–85. doi: 10.1128/br.39.1.54-85.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cryz S. J., Jr, Friedman R. L., Pavlovskis O. R., Iglewski B. H. Effect of formalin toxoiding on Pseudomonas aeruginosa toxin A: biological, chemical, and immunochemical studies. Infect Immun. 1981 May;32(2):759–768. doi: 10.1128/iai.32.2.759-768.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dreesman G. R., Sanchez Y., Ionescu-Matiu I., Sparrow J. T., Six H. R., Peterson D. L., Hollinger F. B., Melnick J. L. Antibody to hepatitis B surface antigen after a single inoculation of uncoupled synthetic HBsAg peptides. Nature. 1982 Jan 14;295(5845):158–160. doi: 10.1038/295158a0. [DOI] [PubMed] [Google Scholar]
  14. Ellouz F., Adam A., Ciorbaru R., Lederer E. Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives. Biochem Biophys Res Commun. 1974 Aug 19;59(4):1317–1325. doi: 10.1016/0006-291x(74)90458-6. [DOI] [PubMed] [Google Scholar]
  15. GOODFRIEND T. L., LEVINE L., FASMAN G. D. ANTIBODIES TO BRADYKININ AND ANGIOTENSIN: A USE OF CARBODIIMIDES IN IMMUNOLOGY. Science. 1964 Jun 12;144(3624):1344–1346. doi: 10.1126/science.144.3624.1344. [DOI] [PubMed] [Google Scholar]
  16. Hopp T. P. A synthetic peptide with hepatitis B surface antigen reactivity. Mol Immunol. 1981 Sep;18(9):869–872. doi: 10.1016/0161-5890(81)90009-2. [DOI] [PubMed] [Google Scholar]
  17. Hopp T. P., Woods K. R. Prediction of protein antigenic determinants from amino acid sequences. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3824–3828. doi: 10.1073/pnas.78.6.3824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kotani S., Watanabe Y., Shimono T., Narita T., Kato K. Immunoadjuvant activities of cell walls, their water-soluble fractions and peptidoglycan subunits, prepared from various gram-positive bacteria, and of synthetic n-acetylmuramyl peptides. Z Immunitatsforsch Exp Klin Immunol. 1975 Jul;149(2-4):302–319. [PubMed] [Google Scholar]
  19. Langbeheim H., Arnon R., Sela M. Adjuvant effect of a peptidoglycan attached covalently to a synthetic antigen provoking anti-phage antibodies. Immunology. 1978 Oct;35(4):573–579. [PMC free article] [PubMed] [Google Scholar]
  20. Langbeheim H., Arnon R., Sela M. Antiviral effect on MS-2 coliphage obtained with a synthetic antigen. Proc Natl Acad Sci U S A. 1976 Dec;73(12):4636–4640. doi: 10.1073/pnas.73.12.4636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lerner R. A., Green N., Alexander H., Liu F. T., Sutcliffe J. G., Shinnick T. M. Chemically synthesized peptides predicted from the nucleotide sequence of the hepatitis B virus genome elicit antibodies reactive with the native envelope protein of Dane particles. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3403–3407. doi: 10.1073/pnas.78.6.3403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Merser C., Sinay P., Adam A. Total synthesis and adjuvant activity of bacterial peptidoglycan derivatives. Biochem Biophys Res Commun. 1975 Oct 27;66(4):1316–1322. doi: 10.1016/0006-291x(75)90503-3. [DOI] [PubMed] [Google Scholar]
  23. Mozes E., Sela M., Chedid L. Efficient genetically controlled formation of antibody to a synthetic antigen [poly(LTyr, LGlu)-poly(DLAla)- -poly(LLys)] covalently bound to a synthetic adjuvant (N-acetylmuramyl-L-alanyl-D-isoglutamine). Proc Natl Acad Sci U S A. 1980 Aug;77(8):4933–4937. doi: 10.1073/pnas.77.8.4933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Müller G. M., Shapira M., Arnon R. Anti-influenza response achieved by immunization with a synthetic conjugate. Proc Natl Acad Sci U S A. 1982 Jan;79(2):569–573. doi: 10.1073/pnas.79.2.569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pappenheimer A. M., Jr Diphtheria toxin. Annu Rev Biochem. 1977;46:69–94. doi: 10.1146/annurev.bi.46.070177.000441. [DOI] [PubMed] [Google Scholar]
  26. Prince A. M., Ikram H., Hopp T. P. Hepatitis B virus vaccine: identification of HBsAg/a and HBsAg/d but not HBsAg/y subtype antigenic determinants on a synthetic immunogenic peptide. Proc Natl Acad Sci U S A. 1982 Jan;79(2):579–582. doi: 10.1073/pnas.79.2.579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Reese R. T., Trager W., Jensen J. B., Miller D. A., Tantravahi R. Immunization against malaria with antigen from Plasmodium falciparum cultivated in vitro. Proc Natl Acad Sci U S A. 1978 Nov;75(11):5665–5668. doi: 10.1073/pnas.75.11.5665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sela M. Antigenicity: some molecular aspects. Science. 1969 Dec 12;166(3911):1365–1374. doi: 10.1126/science.166.3911.1365. [DOI] [PubMed] [Google Scholar]
  29. Siddiqui W. A., Taylor D. W., Kan S. C., Kramer K., Richmond-Crum S. M., Kotani S., Shiba T., Kusumoto S. Vaccination of experimental monkeys against Plasmodium falciparum: a possible safe adjuvant. Science. 1978 Sep 29;201(4362):1237–1239. doi: 10.1126/science.99814. [DOI] [PubMed] [Google Scholar]
  30. Webster R. G., Glezen W. P., Hannoun C., Laver W. G. Potentiation of the immune response to influenza virus subunit vaccines. J Immunol. 1977 Dec;119(6):2073–2077. [PubMed] [Google Scholar]
  31. Woodard L. F., Toone N. M., McLaughlin C. A. Immunogenic properties of soluble antigens or whole cells of Brucella abortus strain 45/20 associated with immunoadjuvants. I. Soluble antigens. Can J Comp Med. 1980 Oct;44(4):453–455. [PMC free article] [PubMed] [Google Scholar]
  32. Woodard L. F., Toone N. M., McLaughlin C. A. Immunogenic properties of soluble antigens or whole cells of Brucella abortus strain 45/20 associated with immunoadjuvants. II. Whole cells. Can J Comp Med. 1980 Oct;44(4):456–458. [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES