Chapter 22 : Principles and Guidelines for Developing Better Tuberculosis Vaccines

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Tuberculosis vaccines have little or no effect on the establishment of a microscopic pulmonary lesion produced by the inhalation of a virulent tubercle bacillus. Such a lesion is established only when the pulmonary alveolar macrophages fail to destroy the inhaled bacillus. Alveolar macrophages do not expand their population in response to specific antigens. Therefore, the establishment of a microscopic pulmonary tubercle is not affected by vaccination. Effective tuberculosis vaccines may, however, stop the progression of a tiny established lesion, because the vaccination has expanded antigen-specific lymphocyte populations. These lymphocytes enter the early lesion, where they cause a rapid local delayed-type hypersensitivity (DTH) and cell-mediated immunity (CMI) response that often prevents progression of the disease. When comparing their relative efficacies, two or more live vaccines should be standardized for equal numbers of live and dead bacilli, equal numbers of log-phase and dormant bacilli, and equal numbers of clumps and isolated bacilli. If vaccines more effective than BCG are ever developed, they would probably produce in the host a higher CMI/DTH ratio, i.e., an expanded antigen-specific lymphocyte population capable of producing increased numbers of activated macrophages and decreased amounts of tissue necrosis. To do this, the improved vaccine would probably contain increased bacillary glycolipid-protein components and decreased tissue-damaging tuberculin-like protein components. The vaccine should also contain components that increase the Th1/Th2 ratio. Dendritic cell-vaccine carriers may find their best use as immunotherapy in immunocompetent patients with multidrugresistant tuberculosis.

Citation: Dannenberg, Jr. A. 2006. Principles and Guidelines for Developing Better Tuberculosis Vaccines, p 341-353. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch22
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1. Lurie, M. B. 1944. Experimental epidemiology of tuberculosis: hereditary resistance to attack by tuberculosis and to the ensuing disease and the effect of the concentration of tubercle bacilli upon these two phases of resistance. J. Exp. Med. 79: 573589.
2. Dannenberg, A. M., Jr. 1990. Controlling tuberculosis: the pathologist’s point of view. Res. Micro-biol. 141: 192196, 262263.
3. Lurie, M. B.,, P. Zappasodi, and, C. Tickner. 1955. On the nature of genetic resistance to tuberculosis in the light of the host-parasite relationships in natively resistant and susceptible rabbits. Am. Rev. Tuberc. 72: 297329.
4. Riley, R. L.,, C. C. Mills,, F. O’Grady,, L. U. Sultan,, F. Wittstadt, and, D. N. Shivpuri. 1962. Infectiousness of air from a tuberculosis ward. Ultra-violet irradiation of infected air: comparative infectiousness of different patients. Am. Rev. Respir. Dis. 85: 511525.
5. Schlesinger, L. S. 1996. Role of mononuclear phagocytes in M. tuberculosis pathogenesis. J. Investig. Med. 44: 312323.
6. Fenton, M. J.,, L. W. Riley, and, L. S. Schlesinger. 2005. Receptor-mediated recognition of Mycobacterium tuberculosis in host cells, p. 405426. In S. T. Cole,, K. D. Eisenach,, D. N. McMurray, and, W. R. Jacobs, Jr. (ed.), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, D.C.
7. Beharka, A.,, C. D. Gaynor,, B. K. Kang,, D. R. Voelker,, F. X. McCormack, and, L. S. Schlesinger. 2002. Pulmonary surfactant Protein A upregulates activity of the mannose receptor, a pattern recognition receptor expressed on human macrophages. J. Immunol. 169: 35653573.
8. Dannenberg, A. M., Jr. 1998. Lurie’s tubercle-count method to test TB vaccine efficacy in rabbits. Front. Biosci. 3: c2733. Available at http://www.bioscience.org/1998/v3/c/dannenbe/list.htm.
9. Lurie, M. B.,, P. Zappasodi,, E. Cardona-Lynch, and, A. M. Dannenberg, Jr. 1952. The response to the intracutaneous inoculation of BCG as an index of native resistance to tuberculosis. J. Immunol. 68: 369387.
10. Dannenberg, A. M., Jr. 1999. Pathophysiology: basic aspects. I. Pathogenesis of tuberculosis. II. Immunology of tuberculosis, p. 1747. In D. Schlossberg (ed.), Tuberculosis and Nontuberculous Mycobacterial Infections, 4th ed. The W. B. Saunders Co., Philadelphia, Pa.
11. Dannenberg, A. M., Jr.,, W. R. Bishai,, N. Parrish,, R. Ruiz,, W. Johnson,, B. C. Zook,, J. W. Boles, and, M. L. M. Pitt. 2000. Efficacies of BCG and vole bacillus ( Mycobacterium microti) vaccines in preventing clinically apparent pulmonary tuberculosis in rabbits: a preliminary report. Vaccine 19: 796800.
12. Lindgren, I. 1961. Anatomical and roentgeno-logic studies of tuberculosis infection in BCGvaccinated and non-vaccinated subjects, with biophysical investigations of calcified foci. Acta Radiol. Suppl. 209: 1101.
13. Lindgren, I. 1965. The pathology of tuberculous infection in BCG-vaccinated humans. Adv. Tuberc. Res. 14: 202234.
14. Sutherland, I., and, I. Lindgren. 1979. The protective effect of BCG vaccination as indicated by autopsy studies. Tubercle 60: 225231.
15. Nuermberger, E. L.,, T. Yoshimatsu,, S. Tyagi,, W. R. Bishai, and, J. H. Grosset. 2004. Paucibacillary tuberculosis in mice after prior aerosol immunization with Mycobacterium bovis BCG. Infect. Immun. 72: 10651071.
16. Morrison, N. E., and, F. M. Collins. 1975. Immunogenicity of an aerogenic BCG vaccine in T-cell-depleted and normal mice. Infect. Immun. 11: 11101121.
17. Cohn, M. L.,, C. L. Davis, and, G. Middle-brook. 1958. Airborne immunization against tuberculosis. Science 128: 12821283.
18. Middlebrook, G. 1961. Immunological aspects of airborne infection: reactions to inhaled antigens. Bacteriol. Rev. 25: 331346.
19. Strober, W.,, B. Kelsall, and, T. Marth. 1998. Oral tolerance. J. Clin. Immunol. 18: 130.
20. Aronson, J. D., and, A. M. Dannenberg. 1935. Effect of vaccination with BCG on tuberculosis in infancy and in childhood: correlation of reactions to tuberculin tests, roentgenologic diagnosis and mortality. Am. J. Dis. Child. 50: 11171130.
21. Ulrichs, T., and, S. H. E. Kaufmann. 2002. Mycobacterial persistence and immunity. Front. Biosci. 7: d458d469.
22. Troisier, J.,, J. Le Melletier, and, J. Sifferlen. 1944. La vaccination antituberculeuse par les voies respiratoires. Aérosols et brouillards de BCG. Ann. Inst. Pasteur 70: 3336.
23. Rosenthal, S. R.,, J. T. McEnery, and, N. Raisys. 1968. Aerogenic BCG vaccination against tuberculosis in animal and human subjects. J. Asthma Res. 5: 309323.
24. Andersen, P. 2001. TB vaccines: progress and problems. Trends Immunol. 22: 160168.
25. Allison, M. J.,, P. Zappasodi, and, M. B. Lurie. 1962. The correlation of a biphasic metabolic response with a biphasic response in resistance to tuberculosis in rabbits. J. Exp. Med. 115: 881890.
26. Comstock, G. W. 1994. Field trials of tuberculosis vaccines: how could we have done them better? Control. Clin. Trials 15: 247276.
27. Comstock, G. W. 1988. Identification of an effective vaccine against tuberculosis. Am. Rev. Respir. Dis. 138: 479480.
28. Crowle, A. J. 1988. Immunization against tuberculosis: what kind of vaccine? Infect. Immun. 56: 27692773.
29. Chan, J.,, X. Fan,, S. W. Hunter,, P. J. Brennan, and, B. R. Bloom. 1991. Lipoarabinomannan, a possible virulence factor involved in persistence of Mycobacterium tuberculosis within macrophages. Infect. Immun. 59: 17551761.
30. Barnes, P. F.,, V. Mehra,, G. R. Hirschfield,, S.-J. Fong,, C. Abou-Zeid,, G. A. W. Rook,, S. W. Hunter,, P. J. Brennan, and, R. L. Modlin. 1989. Characterization of T cell antigens associated with the cell wall protein peptidoglycan complex of Mycobacterium tuberculosis. J. Immunol. 143: 26562662.
31. Brennan, P. J. 1989. Structure of mycobacteria: recent developments in defining cell wall carbohydrates and proteins. Rev. Infect. Dis. 11( Suppl. 2) : S420S430.
32. Wiker, H. G.,, S. Nagai,, M. Harboe, and, L. Ljungqvist. 1992. A family of cross-reacting proteins secreted by Mycobacterium tuberculosis. Scand. J. Immunol. 36: 307319.
33. Young, D. B.,, S. H. E. Kaufmann,, P. W. M. Hermans, and, J. E. R. Thole. 1992. Mycobacterial protein antigens: a compilation. Mol. Microbiol. 6: 133145.
34. Crowle, A. J. 1972. Trypsin-extracted immunizing antigen of the tubercle bacillus: a practical vaccine? Adv. Tuberc. Res. 18: 31102.
35. Lurie, M. B. 1964. Resistance to Tuberculosis: Experimental Studies in Native and Acquired Defensive Mechanisms. Harvard University Press, Cambridge, Mass.
36. Reggiardo, A., and, G. Middlebrook. 1974. Delayed-type hypersensitivity and immunity against aerogenic tuberculosis in guinea pigs. Infect. Immun. 9: 815820.
37. Rich, A. R. 1951. The Pathogenesis of Tuberculosis, 2nd ed. Charles C Thomas Publisher, Springfield, Ill.
38. Harboe, M. 1992. The significance of proteins actively secreted by Mycobacterium tuberculosis in relation to immunity and complications of myco-bacterial diseases. Int. J. Leprosy 60: 470476.
39. Doherty, T. M., and, P. Andersen. 2002. Tuberculosis vaccine development. Curr. Opin. Pulm. Med. 8: 183187.
40. Sugisaki, K.,, A. M. Dannenberg, Jr.,, Y. Abe,, J. Tsuruta,, W.-J. Su,, W. Said,, L. Feng,, T. Yoshimura,, P. J. Converse, and, P. Mounts. 1998. Nonspecific and immune-specific upregulation of cytokines in rabbit dermal tuberculous (BCG) lesions. J. Leukoc. Biol. 63: 440450.
41. Abe, Y.,, K. Sugisaki, and, A. M. Dannenberg, Jr. 1996. Rabbit vascular endothelial adhesion molecules: ELAM-1 is most elevated in acute inflammation, whereas VCAM-1 and ICAM-1 predominate in chronic inflammation. J. Leukoc. Biol. 60: 692703.
42. Esser, M. T.,, R. D. Marchese,, L. S. Kierstead,, L. G. Tussey,, F. Wang,, N. Chirmule, and, M. W. Washabaugh. 2003. Memory T cells and vaccines. Vaccine 21: 419430.
43. Spickler, A. R., and, J. A. Roth. 2003. Adjuvants in veterinary medicine: modes of action and adverse effects. J. Vet. Intern. Med. 17: 273281.
44. Kaufmann, S. H. E. 2001. How can immunology contribute to the control of tuberculosis? Nat. Rev. Immunol. 1: 2030.
45. Young, D. B., and, G. R. Stewart. 2002. Tuberculosis vaccines. Br. Med. Bull. 62: 7386.
46. Murray, P. J.,, A. Aldovini, and, R. A. Young. 1996. Manipulation and potentiation of antibacterial immunity using recombinant Bacille Calmette-Guérin strains that secrete cytokines. Proc. Natl. Acad. Sci. USA 93: 934939.
47. Kaufmann, S. H. E. 1989. Leprosy and tuberculosis vaccine design. Trop. Med. Parasitol. 40: 251257.
48. Nossal, G. J. V. 1990. Immunogenicity. UCLA Symp. Mol. Cell Biol. 13: 309319.
49. Grange, J. M. 1988. Molecular biology: new hopes and challenges. Tubercle 69: 14.
50. Orme, I. M. 1988. Induction of nonspecific acquired resistance and delayed-type hypersensitivity, but not specific acquired resistance, in mice inoculated with killed mycobacterial vaccines. Infect. Immun. 56: 33103312.
51. Fine, P. E. M. 1989. The BCG story: lessons from the past and implications for the future. Rev. Infect. Dis. 11( Suppl. 2) : S353S359.
52. Orme, I. M. 2001. The search for new vaccines against tuberculosis. J. Leukoc. Biol. 70: 110.
53. Wang, J., and, Z. Xing. 2002. Tuberculosis vaccines: the past, present and future. Expert Rev. Vaccines 1: 341354.
54. Young, D. B., and, G. R. Stewart. 2002. Tuberculosis vaccines. Br. Med. Bull. 62: 7386.
55. Dannenberg, A. M., Jr. 2003. Macrophage turnover, division and activation within developing, peak and “healed” tuberculous lesions produced in rabbits by BCG. Tuberculosis 83: 251260.
56. Orme, I. M., and, F. M. Collins. 1984. Adoptive protection of the Mycobacterium tuberculosis-infected lung. Dissociation between cells that passively transfer protective immunity and those that transfer delayed-type hypersensitivity to tuberculin. Cell. Immunol. 84: 113120.
57. Barnes, P. F.,, R. L. Modlin, and, J. J. Ellner. 1994. T-cell responses and cytokines, p. 417435. In B. R. Bloom (ed.), Tuberculosis: Pathogenesis, Protection, and Control. ASM Press, Washington, D.C.
58. Rook, G. A. W.,, G. Seah, and, A. Ustianowski. 2001. M. tuberculosis: immunology and vaccination. Eur. Respir. J. 17: 537557.
59. Manabe, Y. C.,, A. M. Dannenberg, Jr.,, S. K. Tyagi,, C. L. Hatem,, M. Yoder,, S. C. Woolwine,, B. C. Zook,, M. L. M. Pitt, and, W. R. Bishai. 2003. Different strains of Mycobacterium tuberculosis cause various spectrums of disease in the rabbit model of tuberculosis. Infect. Immun. 71: 60046011.
60. Gheorghiu, M., and, P. H. Lagrange. 1983. Viability, heat stability, and immunogenicity of four BCG vaccines prepared from four different BCG strains. Ann. Immunol. (Paris) 134C: 125147.
61. Dietrich, G.,, H.-J. Mollenkopf,, H. Weber,, B. Knapp,, K.-D. Diehl,, J. Hess,, F. Blackkolb,, M. Bröker,, S. H. E. Kaufmann, and, E. Hundt. 2002. Cultivation of Mycobacterium bovis BCG in bioreactors. J. Biotechnol. 96: 259270.
62. Dietrich, G.,, J.-F. Viret, and, J. Hess. 2003. Mycobacterium bovis BCG-based vaccines against tuberculosis: novel developments. Vaccine 21: 667670.
63. Milstien, J. B., and, J. J. Gibson. 1990. Quality control of BCG vaccine by WHO: a review of factors that may influence vaccine effectiveness and safety. Bull. W. H. O. 68: 93108.
64. Behr, M. A. 2002. BCG—different strains, different vaccines? Lancet Infect. Dis. 2: 8692.
65. Wiegeshaus, E. H.,, G. E. Harding,, D. N. McMurray,, A. A. Grover, and, D. W. Smith. 1971. A cooperative evaluation of test systems used to assay tuberculosis vaccines. Bull. W. H. O. 45: 543550.
66. Fourie, P. B.,, J. J. Ellner, and, J. L. Johnson. 2002. Whither Mycobacterium vaccae—encore. Lancet 360: 10321033.
67. Stanford, J.,, C. Stanford, and, J. Grange. 2004. Immunotherapy with Mycobacterium vaccae in the treatment of tuberculosis. Front. Biosci. 9: 17011719.
68. Moll, H. 2003. Dendritic cells as a tool to combat infectious diseases. Immunol. Lett. 85: 153157.
69. Romeyn, J. A. 1970. Exogenous reinfection in tuberculosis. Am. Rev. Respir. Dis. 101: 923927.
70. van Rie, A.,, R. Warren,, M. Richardson,, T. C. Victor,, R. P. Gie,, D. A. Enarson,, N. Beyers, and, P. D. van Helden. 1999. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N. Engl. J. Med. 341: 11741179.
71. Nardell, E.,, B. McInnis,, B. Thomas, and, S. Weidhaas. 1986. Exogenous reinfection with tuberculosis in a shelter for the homeless. N. Engl. J. Med. 315: 15701575.
72. Small, P. M.,, R. W. Shafer,, P. C. Hopewell,, S. P. Singh,, M. J. Murphy,, E. Desmond,, M. F. Sierra, and, G. K. Schoolnik. 1993. Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection. N. Engl. J. Med. 328: 11371144.
73. Fine, P. E. M., and, P. M. Small. 1999. Exogenous reinfection in tuberculosis. N. Engl. J. Med. 341: 12261227.
74. Letters to the Editor. 2000. Recurrent tuberculosis due to exogenous infection. N. Engl. J. Med. 342: 10501051.
75. de Boer, A.,, M. W. Borgdorff,, P. E. W. de Haas,, N. J. D. Hagelkerke,, J. D. A. van Embden, and, D. van Soolingen. 1999. Analysis of rate of change of IS 6110 RFLP patterns of Mycobacterium tuberculosis based on serial patient isolates. J. Infect. Dis. 180: 12381244.
76. Warren, R. M.,, T. C. Victor,, E. M. Streicher,, M. Richardson,, N. Beyers,, N. C. Gey van Pittius, and, P. D. van Helden. 2004. Patients with active tuberculosis often have different strains in the same sputum specimen. Am. J. Respir. Crit. Care Med. 169: 610614.
77. Behr, M. A. 2004. Tuberculosis due to multiple strains: a concern for the patient? a concern for tuberculosis control? Am. J. Respir. Crit. Care Med. 169: 554555.
78. Rook, G. A. W.,, K. Dheda, and, A. Zumla. 2005. Do successful tuberculosis vaccines need to be immunoregulatory rather than Th1-boosting? Vaccine 23: 21152120.
79. Lurie, M. B. 1929. The fate of tubercle bacilli in the organs of reinfected rabbits. J. Exp. Med. 50: 747765.
80. Lurie, M. B. 1933. A correlation between the histological changes and the fate of living tubercle bacilli in the organs of reinfected rabbits. J. Exp. Med. 57: 181201.
81. Horowitz, M. A.,, G. Harth,, B. J. Dillon, and, S. Maslesa-Galic. 2000. Recombinant bacillus Calmette-Guérin (BCG) vaccines expressing the Mycobacterium tuberculosis 30-kDa major secretory protein induce greater protective immunity against tuberculosis than conventional BCG vaccines in a highly susceptible animal model. Proc. Natl. Acad. Sci. USA 97: 1385313858.
82. Ohara, N., and, T. Yamada. 2001. Recombinant BCG vaccines. Vaccine 19: 40894098.
83. Agger, E. M., and, P. Andersen. 2002. A novel TB vaccine; towards a strategy base on our understanding of BCG failure. Vaccine 21: 714.
84. O’Donnell, M. A. 1997. The genetic reconstitution of BCG as a new immunotherapeutic tool. Trends Biotechnol. 15: 512517.
85. Dhar, N.,, V. Rao, and, A. K. Tyagi. 2004. Immunogenicity of recombinant BCG strains over-expressing components of the antigen 85 complex of Mycobacterium tuberculosis. Med. Microbiol. Immunol. 193: 1925.
86. Behr, M. A.,, M. A. Wilson,, W. P. Gill,, H. Salamon,, G. K. Schoolnik,, S. Rane, and, P. M. Small. 1999. Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science 284: 15201523.
87. Mostowy, S.,, A. G. Tsolaki,, P. M. Small, and, M. A. Behr. 2003. The in vitro evolution of BCG vaccines. Vaccine 21: 42704274.
88. Orme, I. M.,, D. N. McMurray, and, J. T. Belisle. 2001. Tuberculosis vaccine development: recent progress. Trends Microbiol. 9: 115118.
89. McMurray, D. N. 2001. Determinants of vaccine-induced resistance in animal models of pulmonary tuberculosis. Scand. J. Infect. Dis. 33: 175178.
90. McMurray, D. N. 2003. Recent progress in the development and testing of vaccines against human tuberculosis. Int. J. Parasitol. 33: 547554.
91. Britton, W. J., and, U. Palendira. 2003. Improving vaccines against tuberculosis. Immunol. Cell Biol. 81: 3445.
92. Collins, H. L., and, S. H. E. Kaufmann. 2001. Prospects for better tuberculosis vaccines. Lancet Infect. Dis. 1: 2128.
93. Brooks, J. V.,, A. A. Frank,, M. A. Keen,, J. T. Belisle, and, I. M. Orme. 2001. Boosting vaccine for tuberculosis. Infect. Immun. 69: 27142717.
94. Lowrie, D. B. 2003. DNA vaccination: an update. Methods Mol. Med. 87: 377390.
95. Glickman, M. S., and, W. R. Jacobs, Jr. 2001. Microbial pathogenesis of Mycobacterium tuberculosis: dawn of a new discipline. Cell 104: 477485.
96. Braunstein, M.,, S. S. Bardarov, and, W. R. Jacobs, Jr. 2002. Genetic methods for deciphering virulence determinants of Mycobacterium tuberculosis. Methods Enzymol. 358: 6799.
97. Weiss, D. W. 1959. Vaccination against tuberculosis with nonliving vaccines. I. The problem and its historical background. Am. Rev. Respir. Dis. 80: 340358, 495509, 676688.


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Benefits of tuberculosis vaccines producing strong CMI and weak DTH, especially those producing little or no tuberculin sensitivity a

Citation: Dannenberg, Jr. A. 2006. Principles and Guidelines for Developing Better Tuberculosis Vaccines, p 341-353. In Pathogenesis of Human Pulmonary Tuberculosis. ASM Press, Washington, DC. doi: 10.1128/9781555815684.ch22

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