The Historical Role of Animal Experiments in the Development of Diphtheria Prophylaxis

  • Coenraad F. M. Hendriksen
Part of the Developements in Hematology and Immunology book series (DIHI, volume 20)


In several respects the experimental work carried out over the decades to find a specific and reliable way of treating and preventing diphtheria determined the use of laboratory animals in the quality control of biological products in general. On the one hand, diphtheria was one of the first diseases where experimental animal research laid the foundation for combatting this disease (1, 2). On the other hand, many common routine procedures such as the determination of the efficacy of a vaccine and the use of a standard vaccine arose from diphtheria research. Before discussing the current method of vaccine production and control, attention will therefore be paid to the history of diphtheria prophylaxis and in particular to the significance of the animal experiment in this.


Diphtheria Toxin Diphtheria Toxoid Potency Testing Corynebacterium Diphtheriae Potency Assay 
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  1. 1.
    Turner, J.: Reckoning with the beast. The Johns Hopkins University Press, Baltimore (1980), p. 115, ISBN 0-8018-2399-4.Google Scholar
  2. 2.
    Prigge, R.: Diphtherie-Schutzimpfungen mit hochactiven Impfstof. (Diphtheria vaccination with highly active vaccines.) Ergebnisse der Hygiene, (1939), 22, 1–63.Google Scholar
  3. 3.
    Ramshorst, J.D. van and Ehrengut, E.: Diphtherieschutzimpfung (Diphtheria vaccination, in the book entitled Handbuch der Schutzimpfungen (Vaccination Manual) by Herrlich, A., (1965), p. 394, Springer Verlag, Berlin.Google Scholar
  4. 4.
    Parish, H.J.: A history of immunization. E and S Livingstone Ltd., Edinburgh/London, 1965.Google Scholar
  5. 5.
    Guye.: Ned. Tijdschrift v. Geneeskunde (1889), II, 13, p.435.Google Scholar
  6. 6.
    Hoogendoorn, D.: Statistisch onderzoek naar de uitkomsten der inentingen tegen difterie. (Statistical examination of the results of diphtheria vaccination.) Ned. Tijdschr. Geneeskd. (1949), 93, III, 37, 3153–3162.PubMedGoogle Scholar
  7. 7.
    Kwantes, W.: Diphtheria in Europe, J. Hyg. Camb. (1984), 93, 433–437.PubMedCrossRefGoogle Scholar
  8. 8.
    Loeffler, M.: Untersuchung über die Bedeutung der Microorganismen für die Entstehung der Diphtherie beim Menschen, bei der Taube and beim Kalbe. (The role of microorganisms in the causation of diphtheria in man, pigeons and calves.) Mitteilungen aus den Kaiserl. Gesundheitsamte, Vol. II, (1884), p. 421.Google Scholar
  9. 9.
    Roux, E. and Yersin, A.: Contribution à l’etude de la diphtherie. (Contribution to the study of diphtheria). Annales de l’Institut Pasteur, (1888), 2, 12, 629–661.Google Scholar
  10. 10.
    Behring, E. von and Wernicke: Uber Immunisierung und Heilung von Versuchstieren bei der Diphtherie. (Immunisation and cure of experimental animals with respect to diphtheria.) Zeitschrift für Hygiene, (1892), 12, 10–44.CrossRefGoogle Scholar
  11. 11.
    Behring, E. von and Kitasato: Uber das Zustandekommen der Diphtherie-Immunität und der Tetanus-Immunität bei Tieren. (Production of diphtheria immunity and tetanus immunity in animals.) Deutsche Medizinische Wochenschrift, (1890), 49, 113.Google Scholar
  12. 12.
    Wernicke: Ein experimenteller beitrag zur kenntnis des Löffler-schen Diphtheriebacillus und zur “Blutserumtherapie”. (Experimental work on Loeffler’s dipththeria bacillus and blood serum therapy.) Archiv. für Hygiene, (1893), XVIII, 193–250.Google Scholar
  13. 13.
    Fokker: Ned. Tijdschr. Geneesk., (1891), I, 1, p. 19.Google Scholar
  14. 14.
    Ehrlich, P. and Wassermann, A.: Uber die Gewinnung der Diphtherie-Antitoxine aus Blutserum und Milch immunisierter Tiere. (Preparation of diphtheria from the serum and milk of immunized animals.) Zeitschr. für Hygiene, (1894), 18, 239–251.CrossRefGoogle Scholar
  15. 15.
    Roux, M.E. and Martin, M.L.: Contribution á l’etude de la Diphtherie. (Contribution to the study of diphtheria.) Annales de l’Institut Pasteur, (1894), 8, 9, 609.Google Scholar
  16. 16.
    Strauss, M.: De serum-therapie der Diphtherie. (Serum therapy of diphtheria.) Ned. Tijdschr. Geneesk. (1899), I, 6, 197–209.Google Scholar
  17. 17.
    Bierens de Haan, J.C.: De uitkomsten der serumbehandeling van diptherie aan het Leidsche ziekenhuis van 1894–1899. (Results of diphtheria serum treatment in the Leiden Hospital, 1894-99.) Ned. Tijdschr. Geneeskd. (1899), II, 289–297.Google Scholar
  18. 18.
    Virchow, R.: An address on the value of pathological experiments, The British Medical Journal, (1881), 198–204.Google Scholar
  19. 19.
    Anonymus: Klinische und therapeutische Mitteilungen. (Clinical and therapeutic communications.) Wiener Klinische Wochenschrift, (1895), 10, 190.Google Scholar
  20. 20.
    Babes, V.: Bull, Acad. Med. (Paris), (1895), 34, 216.Google Scholar
  21. 21.
    Smith, T.: Active immunity produced by so-called balanced or neutral mixtures of diphtheria toxin and antitoxin. J. Exp. Med. (1909), 102, 1288–1289.Google Scholar
  22. 22.
    Behring, E. von: Uber ein neues Diphtherieschutzmittel. (A new anti-diphtheria agent.) Deutsche Medizinische Wochenschrift, (1913), 39, 19, 873–876.CrossRefGoogle Scholar
  23. 23.
    Otto, R. and Blumenthal, G.: Weitere tierexperimentelle Beitrage zur aktiven Immunisierung gegen Diphtherie. (Further animal experiments concerning active immunization against diphtheria.) Zeitsch. für Hygiene, (1930), 111, 380.CrossRefGoogle Scholar
  24. 24.
    Wilson, G.S.: The Hazards of Immunization, The Athlone Press (1969).Google Scholar
  25. 25.
    Ramon, G.: Sur le pouvoir floculant et sur les propriétés immunisantes d’une diphtherique rendue anatoxique (anatoxine). (Flocculating activity and immunizing properties of a diphtheria anatoxin.) C.R. Acad. Sci. (1923), 177, 1338–1342.Google Scholar
  26. 26.
    Ehrlich, P.: Klin. Jahrbuch (1898), 6, 299.Google Scholar
  27. 27.
    Salkowski, E.: Uber die Wirkung der Antiseptica auf Toxine. (Effect of antiseptics on toxins.) Berl. Klin. Wschr. (1898), 35, 545–549.Google Scholar
  28. 28.
    Löwenstein, E. and Eisler, R. von: über den Einfluss des Formaldehyd auf Blutserum. (Effect of formaldehyde on blood serum.) Zentralb. für Bakt. Origin. (1912), 261–281.Google Scholar
  29. 29.
    Glenny, A.T. and Hopkins, B.E.: Diphtheria toxoid as an immunizing agent. Brit. J. Exp. Pathol. (1923), 4, 283–288.Google Scholar
  30. 30.
    Glenny, A.T. and Südmersen: Notes on the production of immunity to diphtheria toxin. J. of Hyg. (1921), 20, 184.Google Scholar
  31. 31.
    Lévy, F.M.: The fiftieth anniversary of diphtheria and tetanus immunization. Preventive Medicine,, (1975), 4, 226–237.PubMedCrossRefGoogle Scholar
  32. 32.
    Ramon, G.: Sur la production de l’antitoxine diphterique. (Production of diphtheria antitoxin.) C.R., Acad. Sci. (Paris). (1925), 93, 506.Google Scholar
  33. 33.
    Günther, O.: Antagonism and synergy of antigens. Bull. Wld. Hlth. Org. (1955), 13, 479–489.Google Scholar
  34. 34.
    Glenny, A.T.: J. Path. Bact. (1926), 29, 38.Google Scholar
  35. 35.
    Holt, L.B. and Bousfeld, G.: Brit. Med. J. (1949), 1, 695.PubMedCrossRefGoogle Scholar
  36. 36.
    Schmidt, S. and Hansen: Uber die Reinigung und konzentrierung von Diphtherie-toxin und Diphtherie-anatoxin mit besonderem Hinblick auf die aktive Immunisierung von Menschen. (Purification and concentration of diphtheria toxin and anatoxin with special reference to active immunization in man.) Biochem. Z. (1930), 228, 263.Google Scholar
  37. 37.
    Farago, F.: Uber das Schicksal und die Wirksamkeit des Anatoxin Präzipitatdepots im Organismus. (Fate and activity of the anatoxin precipitate depot in the body.) Zeitschr. Immun. Forsch. (1935), 86, 191–204.Google Scholar
  38. 38.
    Roux, M.E., Martin, M.L. and Chaillou, P.: Trois cents cas de diphterie par le serum antidiphthérique. (300 Cases of diphtheria caused by anti-diphtheria serum.) Annales de l’Institut Pasteur, (1894), VIII, 9, 640–667.Google Scholar
  39. 39.
    Ehrlich, P.: Die Wehrtbemessung des Diphtherieheilserums und deren theoretische Grundlage. (Assessing the potency of the diphtheria serum and its theoretical foundations) Klin. Jahrbuch, (1897), Vol. VI, 299.Google Scholar
  40. 40.
    Marx: Experimentelle Untersuchungen über die Beziehung zwischen den Gehalt an Immunitätseinheiten und dem schützenden und heilenden Werth der Diphtherieheilsera. (Experimental investigation of the connection between the level of immunity units and the protective and therapeutic activity of diphtheria sera.) Zeitschr. für Hygiene, (1901), 38, 372–285.CrossRefGoogle Scholar
  41. 41.
    Madsen, Th.: Uber Messung der Stärke des antidiphtherischen Serums. (Determination of the activity of anti-diphtheria serum.) Zeitschr. für Hygiene, (1897), 24, 425–443.CrossRefGoogle Scholar
  42. 42.
    Dreyer, G. and Madsen, Th.: Uber Immunisierung mit den Toxonen des Diphtheriegiftes. (Immunization with the toxoids of the diphtheria toxin.) Zeitschr. für Hygiene, (1901), 37, 250–267.CrossRefGoogle Scholar
  43. 43.
    Prausnitz, C.: III Die Standardisierung von Heilseren, serologischen Reaktionen und Impfstoffen. (Standardizing antitoxins, serological reactions and vaccines. Part III.) Ergebnisse der Immunitätsforschung, (1929), 10, 271–332.Google Scholar
  44. 44.
    Krause, R. and Backer, S.: Zbl. Bakt., I Abt. Ref. Suppl. (1913), 57, 106.Google Scholar
  45. 45.
    Ramon, G.: La floculation dans les mélanges de toxine et de serum antidiphtérique. (Flocculation in mixtures of antidiphtheria serum and toxin.) Annales de 1’Institut Pasteur, (1923), 37, 12, 1001–1011.Google Scholar
  46. 46.
    Glenny, A.T. and Barr, M.: Alum-toxoid precipitates as antigens. Journ. of Path., (1931), 34, 118–119.Google Scholar
  47. 47.
    Prigge, R.: Experimentelle Untersuchungen über die Wirksamkeit von Diphtherie Impfstoffen. (Experimental investigations of the activity of diphtheria vaccines.) Deutsch. Med. Wochenschr., (1937), 39, 1478–1482.CrossRefGoogle Scholar
  48. 48.
    Madsen, Th. and Schmidt, S.: Seasonal variation in the susceptibility of laboratory animals to diphtheria toxin. Acta Soc. Medic Fenn. Duodecim, Ser. A. 15, (1932); 15.Google Scholar
  49. 49.
    Prigge, R.: Theorie und Methodik der Antigenmessung. (Theory and method of antigen determination.) Zeitschr. für Hygiene, (1937), 119, 186–192.CrossRefGoogle Scholar
  50. 50.
    Greenberg, L.: International standardization of diphtheria toxoids. Bull. Wld. Hlth. Org., (1953), 9, 829–836.Google Scholar
  51. 51.
    World Health Organization, Expert Committee on Biological Standardization. (1952), Wld. Hlth. Org. Tech. Rep. Ser., 56, 4, 5.Google Scholar
  52. 52.
    Bonin, O.: Einige Grundlagen der Prüfung von Biologische Produkten. (Basis of testing biological products.) In the book entitled Handbuch der Schutzimpfungen (Vaccination Manual). Herrlich, A., (1965), p. 53, Springer Verlag, Berlin.Google Scholar
  53. 53.
    Trevan, J.W.: The error of determination of toxicity. Proc. Roy. Soc. (London), (1927), 101B, 483–514.Google Scholar
  54. 54.
    Trevan, J.W.: A statistical note on the testing of antidysentry sera. Journ. of Path., (1929), Vol. 32, 127–135.CrossRefGoogle Scholar
  55. 55.
    Vorschriften für die Staatl, Prüfung der Impfstoffe zur aktiven Schutzimpfung gegen Diphtherie. (Instructions for the official testing of vaccines intended for active immunization against diphtheria.) Issued by the German Ministry of Internal Affairs, Ministerialbl. f.d. Innere Verwaltung (1935), 52, p. 1525.Google Scholar
  56. 56.
    Noordam, A.L. et al.: De nieuwe diphtherie-entstof, PT. (The new diphtheria vaccine called PT.) Ned. Tijdschr. Geneesk. (1949), 93, 48, 4014–1419.Google Scholar
  57. 57.
    Bonebakker, A. et al.: Vaccinatie tegen infectieziekten. (Vaccination against infectious diseases.) Stafleu’s Wetenschappelijke Uitgeversmaatschappij N.V., Leiden (1965).Google Scholar
  58. 58.
    W.H.O.-Technical Report Series 638 (1979).Google Scholar
  59. 59.
    Hardegree, M.C.: WHO Ad Hoc Meeting: Potency testing of toxoids, Geneva, Dec. 12–14, 1983.Google Scholar
  60. 60.
    Knight, P.A.: A consideration of some methods by which the cost of potency assays for diphtheria and tetanus vaccines might be reduced. Develop. Biol. Standard. (1978), 41, 67–72.Google Scholar
  61. 61.
    European Pharmacopoeia, (Suppl. Vol. III (1977)).Google Scholar
  62. 62.
    Kreeftenberg, J.G. et al.: A mouse model to estimate the potency of the diphtheria component in combined vaccines, Symposium IABS, April 1985, London. Develop. Biol. Standard (1986), 64, 21–24.Google Scholar
  63. 63.
    Kreeftenberg, J.G. et al.: An investigation of a mouse model to estimate the potency of the diphtheria component in vaccines. Journ. Biol. Standard. (1985), 13, 229–234.CrossRefGoogle Scholar
  64. 64.
    W.H.O.-Technical Report Series 760 (1987).Google Scholar
  65. 65.
    Kreeftenberg, J.G.: Report of an informal meeting about alternative methods for the potency control of the diphtheria and tetanus components in vaccines, Bilthoven, December 1985. Develop. Biol. Standard. (1986), 65, 261–266.Google Scholar
  66. 66.
    Abreo, C.B. and Stainer, D.W.: A tissue culture assay for diphtheria toxicity testing. Symposium IABS, April 1985, London. Develop. Biol. Standard. (1986), 64, 33–37.Google Scholar

Copyright information

© Kluwer Academic Publishers 1988

Authors and Affiliations

  • Coenraad F. M. Hendriksen
    • 1
  1. 1.National Institute of Public Health and Environmental ProtectionThe Netherlands

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