1887

Chapter 37 : Tuberculosis Vaccine Preclinical Screening and Development

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in
Zoomout

Tuberculosis Vaccine Preclinical Screening and Development, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817657/9781555812959_Chap37-1.gif /docserver/preview/fulltext/10.1128/9781555817657/9781555812959_Chap37-2.gif

Abstract:

Experimental-animal models of tuberculosis began to emerge shortly after the discovery of the bacterium itself. If one is an optimist, one can argue that the animal models are fully validated because they predict that the only vaccine fully tested in humans, BCG, will have a positive effect and that this will be mediated via CD4 Th1 T-cell responses. The primary models that are currently used in the preclinical screening program for vaccine candidates are (i) the low-dose aerosol mouse model and (ii) the low-dose aerosol guinea pig model. The National Institutes of Health preclinical tuberculosis vaccine screening program was established to identify novel vaccines that will eventually be used throughout the world to combat tuberculosis. The presence of the infection in the lung tissues sets up a local inflammation, creating chemokine gradients and blood vessel adhesion molecule expression, which facilitate the influx of granulocytes (which are short-lived and therefore not sustained) and monocytes from the bloodstream. The purpose of vaccination is to establish a long-lived state of heightened resistance to challenge infection, which in practical terms means many recirculating memory T cells capable of rapidly entering sites of inflammation in the lungs. With the current enthusiasm for attenuated live vaccines based on BCG or itself, this is a serious issue that needs to be resolved. Fortunately, such environmental mycobacteria (EM) effects may be less important in interfering with other classes of vaccines including DNAs and subunit nonliving vaccines.

Citation: Orme I, Izzo A. 2005. Tuberculosis Vaccine Preclinical Screening and Development, p 561-571. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch37
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of Figure 1.
Figure 1.

The BHRB building at Colorado State University (top left) is a biosafety level 3 facility in which much of our vaccine testing is performed. Mouse aerosol exposures are performed using a Middlebrook apparatus (top right), whereas guinea pigs are infected using an instrument manufactured by the University of Wisconsin at Madison (bottom).

Citation: Orme I, Izzo A. 2005. Tuberculosis Vaccine Preclinical Screening and Development, p 561-571. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch37
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2.
Figure 2.

Survival of guinea pigs following low-dose (ca. 20 bacilli) aerosol exposure. Animals injected with saline live about 25 weeks (♦), whereas those vaccinated with BCG live about a year on average (▄).

Citation: Orme I, Izzo A. 2005. Tuberculosis Vaccine Preclinical Screening and Development, p 561-571. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch37
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3.
Figure 3.

Some explanations of why certain mouse strains, such as CBA/J, are prone to reactivation or regrowth of pulmonary infection about 150 days after aerosol exposure. These include bronchial epithelial degeneration (top left), failure to upregulate the expression of adhesion molecules such as ICAM-1 on responding T cells (top right; open trace, CBA/J; filled trace, C57BL/6), and accumulation of large amounts of interleukin-10 (IL-10) in macrophages in lung lesions. C57BL/6 mice rendered transgenic (Tg) overexpressors of IL-10 behave like reactivation-prone strains in terms of the course of the infection (bottom).

Citation: Orme I, Izzo A. 2005. Tuberculosis Vaccine Preclinical Screening and Development, p 561-571. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch37
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 4.
Figure 4.

CD4 cells in the lungs express an activated/effector phenotype even well into the chronic stage of the disease process.

Citation: Orme I, Izzo A. 2005. Tuberculosis Vaccine Preclinical Screening and Development, p 561-571. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch37
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 5.
Figure 5.

The possible fates of antigen-specific T cells may be different for chronic infectious diseases such as tuberculosis in comparison to T cells induced into individual protein antigens.

Citation: Orme I, Izzo A. 2005. Tuberculosis Vaccine Preclinical Screening and Development, p 561-571. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch37
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 6.
Figure 6.

Low-power (A, C, E, and G) and high-power (B, D, F, and H) photomicrographs of lung lesions in guinea pigs 10 (A and B), 20 (C and D), 30 (E and F), and 90 (G and H) days after aerosol exposure to . As described in the text, a “classical” granuloma develops over the first 30 days and then degenerates into a highly mineralized mass that erodes out through adjacent vessels. Reprinted from reference 72a.

Citation: Orme I, Izzo A. 2005. Tuberculosis Vaccine Preclinical Screening and Development, p 561-571. In Cole S, Eisenach K, McMurray D, Jacobs, Jr. W (ed), Tuberculosis and the Tubercle Bacillus. ASM Press, Washington, DC. doi: 10.1128/9781555817657.ch37
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555817657.chap37
1. Baldwin, S. L.,, C. D’Souza,, A. D. Roberts,, B. P. Kelly,, A. A. Frank,, M. A. Lui,, J. B. Ulmer,, K. Huygen,, D. M. McMurray,, and I. M. Orme. 1998. Evaluation of new vaccines in the mouse and guinea pig model of tuberculosis. Infect. Immun. 66:29512959.
2. Bevan, M. J. 2002. Immunology: remembrance of things past. Nature 420:748749.
3. Bishai, W. R.,, A. M. Dannenberg, Jr.,, N. Parrish,, R. Ruiz,, P. Chen,, B. C. Zook,, W. Johnson,, J. W. Boles,, and M. L. Pitt. 1999. Virulence of Mycobacterium tuberculosis CDC1551 and H37Rv in rabbits evaluated by Lurie’s pulmonary Tubercle count method. Infect. Immun. 67:49314934.
4. Bodnar, K. A.,, N. V. Serbina,, and J. L. Flynn. 2001. Fate of Mycobacterium tuberculosis within murine dendritic cells. Infect. Immun. 69:800809.
5. Brandt, L.,, J. Feino Cunha,, A. Weinreich Olsen,, B. Chilima,, P. Hirsch,, R. Appelberg,, and P. Andersen. 2002. Failure of the Mycobacterium bovis BCG vaccine: some species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to tuberculosis. Infect. Immun. 70:672678.
6. Brandt, L.,, and I. Orme. 2002. Prospects for new vaccines against tuberculosis. BioTechniques 33:1098, 1100, 1102.
7. Brooks, J. V.,, A. A. Frank,, M. A. Keen,, J. T. Bellisle,, and I. M. Orme. 2001. Boosting vaccine for tuberculosis. Infect. Immun. 69:27142717.
8. Caruso, A. M.,, N. Serbina,, E. Klein,, K. Triebold,, B. R. Bloom,, and J. L. Flynn. 1999. Mice deficient in CD4 T cells have only transiently diminished levels of IFN-gamma, yet succumb to tuberculosis. J. Immunol. 162:54075416.
9. Converse, P. J.,, A. M. Dannenberg, Jr.,, J. E. Estep,, K. Sugisaki,, Y. Abe,, B. H. Schofield,, and M. L. Pitt. 1996. Cavitary tuberculosis produced in rabbits by aerosolized virulent Tubercle bacilli. Infect. Immun. 64:47764787.
10. Converse, P. J.,, A. M. Dannenberg, Jr.,, T. Shigenaga,, D. N. Mc-Murray,, S. W. Phalen,, J. L. Stanford,, G. A. Rook,, T. Koru-Sengul,, H. Abbey,, J. E. Estep,, and M. L. Pitt. 1998. Pulmonary bovine-type tuberculosis in rabbits: bacillary virulence, inhaled dose effects, tuberculin sensitivity, and Mycobacterium vaccae immunotherapy. Clin. Diagn. Lab. Immunol. 5:871881.
11. Cooper, A. M.,, J. E. Callahan,, M. Keen,, J. T. Belisle,, and I. M. Orme. 1997. Expression of memory immunity in the lung following re-exposure to Mycobacterium tuberculosis. Tubercle Lung Dis. 78:6773.
12. Cooper, A. M.,, D. K. Dalton,, T. A. Stewart,, J. P. Griffin,, D. G. Russell,, and I. M. Orme. 1993. Disseminated tuberculosis in interferon gamma gene-disrupted mice. J. Exp. Med. 178:22432247.
13. Cooper, A. M.,, A. Kipnis,, J. Turner,, J. Magram,, J. Ferrante,, and I. M. Orme. 2002. Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present. J. Immunol. 168:13221327.
14. Cooper, A. M.,, J. Magram,, J. Ferrante,, and I. M. Orme. 1997. Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with Mycobacterium tuberculosis. J. Exp. Med. 186:3945.
15. Cooper, A. M.,, A. D. Roberts,, E. R. Rhoades,, J. E. Callahan,, D. M. Getzy,, and I. M. Orme. 1995. The role of interleukin-12 in acquired immunity to Mycobacterium tuberculosis infection. Immunology 84:423432.
16. Corbett, E. L. 2003. HIV and tuberculosis: surveillance revisited. Int. J. Tuberc. Lung Dis. 7:709.
17. Dannenberg, A. M.,, W. R. Bishai,, N. Parrish,, R. Ruiz,, W. Johnson,, B. C. Zook,, J. W. Boles,, and 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.
18. Dannenberg, A. M., Jr. 1994. Roles of cytotoxic delayed-type hypersensitivity and macrophage-activating cell-mediated immunity in the pathogenesis of tuberculosis. Immunobiology 191:461473.
19. Davies, P. D. 2003. The world-wide increase in tuberculosis: how demographic changes, HIV infection and increasing numbers in poverty are increasing tuberculosis. Ann. Med. 35:235243.
20. Flynn, J. L.,, and B. R. Bloom. 1996. Role of T1 and T2 cytokines in the response to Mycobacterium tuberculosis. Ann. N.Y. Acad. Sci. 795:137146.
21. Flynn, J. L.,, and J. Chan. 2003. Immune evasion by Mycobacterium tuberculosis: living with the enemy. Curr. Opin. Immunol. 15:450455.
22. Flynn, J. L.,, and J. Chan. 2001. Immunology of tuberculosis. Annu. Rev. Immunol. 19:93129.
23. Flynn, J. L.,, and J. Chan. 2001. Tuberculosis: latency and reactivation. Infect. Immun. 69:41954201.
24. Flynn, J. L.,, J. Chan,, K. J. Triebold,, D. K. Dalton,, T. A. Stewart,, and B. R. Bloom. 1993. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J. Exp. Med. 178:22492254.
25. Flynn, J. L.,, M. M. Goldstein,, K. J. Triebold,, J. Sypek,, S. Wolf,, and B. R. Bloom. 1995. IL-12 increases resistance of BALB/c mice to Mycobacterium tuberculosis infection. J. Immunol. 155:25152524.
26. Frucht, D. M.,, and S. M. Holland. 1996. Defective monocyte costimulation for IFN-gamma production in familial disseminated Mycobacterium avium complex infection: abnormal IL-12 regulation. J. Immunol. 157:411416.
27. Frucht, D. M.,, D. I. Sandberg,, M. R. Brown,, S. M. Gerstberger,, and S. M. Holland. 1999. IL-12-independent costimulation pathways for interferon-gamma production in familial disseminated Mycobacterium avium complex infection. Clin. Immunol. 91:234241.
28. Gonzalez-Juarrero, M.,, and I. M. Orme. 2001. Characterization of murine lung dendritic cells infected with Mycobacterium tuberculosis. Infect. Immun. 69:11271133.
29. Gonzalez-Juarrero, M.,, T. S. Shim,, A. Kipnis,, A. P. Junqueira- Kipnis,, and I. M. Orme. 2003. Dynamics of macrophage cell populations during murine pulmonary tuberculosis. J. Immunol. 171:31283135.
30. Gonzalez-Juarrero, M.,, O. C. Turner,, J. Turner,, P. Marietta,, J. V. Brooks,, and I. M. Orme. 2001. Temporal and spatial arrangement of lymphocytes within lung granulomas induced by aerosol infection with Mycobacterium tuberculosis. Infect. Immun. 69:17221728.
31. Gruppo, V.,, O. C. Turner,, I. M. Orme,, and J. Turner. 2002. Reduced up-regulation of memory and adhesion/integrin molecules in susceptible mice and poor expression of immunity to pulmonary tuberculosis. Microbiology 148:29592966.
32. Gumperz, J. E.,, and M. B. Brenner. 2001. CD1-specific T cells in microbial immunity. Curr. Opin. Immunol. 13:471478.
33. Heldwein, K. A.,, and M. J. Fenton. 2002. The role of Tolllike receptors in immunity against mycobacterial infection. Microbes Infect. 4:937944.
34. Henderson, R. A.,, S. C. Watkins,, and J. L. Flynn. 1997. Activation of human dendritic cells following infection with Mycobacterium tuberculosis. J. Immunol. 159:635643.
35. Hernandez-Pando, R.,, L. Pavon,, K. Arriaga,, H. Orozco,, V. Madrid-Marina,, and G. Rook. 1997. Pathogenesis of tuberculosis in mice exposed to low and high doses of an environmental mycobacterial saprophyte before infection. Infect. Immun. 65:33173327.
36. Huygen, K.,, J. Content,, O. Denis,, D. L. Montgomery,, A. M. Yawman,, R. R. Deck,, C. M. DeWitt,, I. M. Orme,, S. Baldwin,, C. D’Souza,, A. Drowart,, E. Lozes,, P. Vandenbussche,, J. P. Van Vooren,, M. A. Liu,, and J. B. Ulmer. 1996. Immunogenicity and protective efficacy of a tuberculosis DNA vaccine. Nat. Med. 2:893898.
37. Jungueira-Kipnis, A.,, P. J., Turner,, M. Gonzalez-Juarrero,, O. C. Turner,, and I. M. Orme. 2004. Stable T-cell population expressing an effector cell surface phenotype in the lungs of mice chronically infected with Mycobacterium tuberculosis. Infect. Immun. 72:570575.
38. Manabe, Y. C.,, A. M. Dannenberg, Jr.,, S. K. Tyagi,, C. L. Hatem,, M. Yoder,, S. C. Woolwine,, B. C. Zook,, M. L. 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.
39. McMurray, D. N. 2000. A nonhuman primate model for preclinical testing of new tuberculosis vaccines. Clin. Infect. Dis. 30(Suppl 3):S210S212.
40. McMurray, D. N.,, F. M. Collins,, A. M. Dannenberg, Jr.,, and D. W. Smith. 1996. Pathogenesis of experimental tuberculosis in animal models. Curr. Top. Microbiol. Immunol. 215:157179.
41. McMurray, D. N.,, G. Dai,, and S. Phalen. 1999. Mechanisms of vaccine-induced resistance in a guinea pig model of pulmonary tuberculosis. Tubercle Lung Dis. 79:261266.
42. Medina, E.,, and R. J. North. 1996. Evidence inconsistent with a role for the Bcg gene (Nramp1) in resistance of mice to infection with virulent Mycobacterium tuberculosis. J. Exp. Med. 183:10451051.
43. Medina, E.,, and R. J. North. 1998. Resistance ranking of some common inbred mouse strains to Mycobacterium tuberculosis and relationship to major histocompatibility complex haplotype and Nramp1 genotype. Immunology 93:270274.
44. Moody, D. B.,, M. Sugita,, P. J. Peters,, M. B. Brenner,, and S. A. Porcelli. 1996. The CD1-restricted T-cell response to mycobacteria. Res. Immunol. 147:550559.
45. Orme, I. M. 1999. Beyond BCG: the potential for a more effective TB vaccine. Mol. Med. Today 5:487492.
46. Orme, I. M. 1998. The immunopathogenesis of tuberculosis: a new working hypothesis. Trends Microbiol. 6:9497.
47. Orme, I. M. 1987. The kinetics of emergence and loss of mediator T lymphocytes acquired in response to infection with Mycobacterium tuberculosis. J. Immunol. 138:293298.
48. Orme, I. M. 2003. The mouse as a useful model of tuberculosis. Tuberculosis 83:112115.
49. Orme, I. M. 1999. New vaccines against tuberculosis. The status of current research. Infect. Dis. Clin. North Am. 13:169185, vii-viii.
50. Orme, I. M. 1997. Progress in the development of new vaccines against tuberculosis. Int. J. Tuberc. Lung Dis. 1:95100.
51. Orme, I. M. 1995. Prospects for new vaccines against tuberculosis. Trends Microbiol. 3:401404.
52. Orme, I. M. 2001. The search for new vaccines against tuberculosis. J. Leukoc. Biol. 70:110.
53. Orme, I. M. 2000. Tuberculosis: recent progress in basic immunity and vaccine development. Kekkaku 75:97101.
54. Orme, I. M. 1999. Vaccination against tuberculosis: recent progress. Adv. Vet. Med. 41:135143.
55. Orme, I. M.,, P. Andersen,, and W. H. Boom. 1993. T cell response to Mycobacterium tuberculosis. J. Infect. Dis. 167:14811497.
56. Orme, I. M.,, and J. T. Belisle. 1999. TB vaccine development: after the flood. Trends Microbiol. 7:394395.
57. Orme, I. M.,, and F. M. Collins. 1986. Crossprotection against nontuberculous mycobacterial infections by Mycobacterium tuberculosis memory immune T lymphocytes. J. Exp. Med. 163:203208.
58. Orme, I. M.,, and F. M. Collins. 1984. Efficacy of Mycobacterium bovis BCG vaccination in mice undergoing prior pulmonary infection with atypical mycobacteria. Infect. Immun. 44:2832.
59. Orme, I. M.,, and F. M. Collins. 1983. Infection with Mycobacterium kansasii and efficacy of vaccination against tuberculosis. Immunology 50:581586.
60. Orme, I. M.,, and A. M. Cooper. 1999. Cytokine/chemokine cascades in immunity to tuberculosis. Immunol. Today 20:307312.
61. Orme, I. M.,, D. N. McMurray,, and J. T. Belisle. 2001. Tuberculosis vaccine development: recent progress. Trends Microbiol. 9:115118.
62. Porcelli, S. A.,, and R. L. Modlin. 1999. The CD1 system: antigen-presenting molecules for T cell recognition of lipids and glycolipids. Annu. Rev. Immunol. 17:297329.
63. Repique, C. J.,, A. Li,, F. M. Collins,, and S. L. Morris. 2002. DNA immunization in a mouse model of latent tuberculosis: effect of DNA vaccination on reactivation of disease and on reinfection with a secondary challenge. Infect. Immun. 70:33183323.
64. Rhoades, E. R.,, A. A. Frank,, and I. M. Orme. 1997. Progression of chronic pulmonary tuberculosis in mice aerogenically infected with virulent Mycobacterium tuberculosis. Tubercle Lung Dis. 78:5766.
65. Scanga, C. A.,, V. P. Mohan,, H. Joseph,, K. Yu,, J. Chan,, and J. L. Flynn. 1999. Reactivation of latent tuberculosis: variations on the Cornell murine model. Infect. Immun. 67:45314538.
66. Sieling, P. A.,, D. Chatterjee,, S. A. Porcelli,, T. I. Prigozy,, R. J. Mazzaccaro,, T. Soriano,, B. R. Bloom,, M. B. Brenner,, M. Kronenberg,, P. J. Brennan,, and R. L. Modlin. 1995. CD1-restricted T cell recognition of microbial lipoglycan antigens. Science 269:227230.
67. Smith, D. W.,, V. Balasubramanian,, and E. Wiegeshaus. 1991. A guinea pig model of experimental airborne tuberculosis for evaluation of the response to chemotherapy: the effect on bacilli in the initial phase of treatment. Tubercle 72:223231.
68. Smith, D. W.,, and G. E. Harding. 1977. Animal model of human disease. Pulmonary tuberculosis. Animal model: experimental airborne tuberculosis in the guinea pig. Am. J. Pathol. 89:273276.
69. Stanford, J. L.,, M. J. Shield,, and G. A. Rook. 1981. How environmental mycobacteria may predetermine the protective efficacy of BCG. Tubercle 62:5562.
70. Stenger, S.,, and R. L. Modlin. 2002. Control of Mycobacterium tuberculosis through mammalian Toll-like receptors. Curr. Opin. Immunol. 14:452457.
71. Taylor, J. L.,, O. C. Turner,, R. J. Basaraba,, J. T. Belisle,, K. Huygen,, and I. M. Orme. 2003. Pulmonary necrosis resulting from DNA vaccination against tuberculosis. Infect. Immun. 71:21922198.
72. Tsenova, L.,, A. Bergtold,, V. H. Freedman,, R. A. Young,, and G. Kaplan. 1999. Tumor necrosis factor alpha is a determinant of pathogenesis and disease progression in mycobacterial infection in the central nervous system. Proc. Natl. Acad. Sci. USA 96:56575662.
72.a. Turner, O. C.,, R. J. Basaraba,, A. A. Frank,, I. M. Orme,. 2003. Granuloma formation in mouse and guinea pig models of experimental tuberculosis, p. 6584. In D. L. Boros (ed.), Granulomatous Infections and Inflammations. ASM Press, Washington, D.C.
73. Turner, J.,, M. Gonzalez-Juarrero,, B. M. Saunders,, J. V. Brooks,, P. Marietta,, D. L. Ellis,, A. A. Frank,, A. M. Cooper,, and I. M. Orme. 2001. Immunological basis for reactivation of tuberculosis in mice. Infect. Immun. 69:32643270.
74. Turner, J.,, E. R. Rhoades,, M. Keen,, J. T. Belisle,, A. A. Frank,, and I. M. Orme. 2000. Effective preexposure tuberculosis vaccines fail to protect when they are given in an immunotherapeutic mode. Infect. Immun. 68:17061709.
75. Turner, O. C.,, R. J. Basaraba,, and I. M. Orme. 2003. Immunopathogenesis of pulmonary granulomas in the guinea pig after infection with Mycobacterium tuberculosis. Infect. Immun. 71:864871.
76. Ulmer, J. B.,, D. L. Montgomery,, A. Tang,, L. Zhu,, R. R. Deck,, C. DeWitt,, O. Denis,, I. Orme,, J. Content,, and K. Huygen. 1998. DNA vaccines against tuberculosis. Novartis Found. Symp. 217:239253.
77. Wolday, D.,, B. Hailu,, M. Girma,, E. Hailu,, E. Sanders,, and A. L. Fontanet. 2003. Low CD4+ T-cell count and high HIV viral load precede the development of tuberculosis disease in a cohort of HIV-positive ethiopians. Int. J. Tuberc. Lung Dis. 7:110116.
78. Wu, C. Y.,, J. R. Kirman,, M. J. Rotte,, D. F. Davey,, S. P. Perfetto,, E. G. Rhee,, B. L. Freidag,, B. J. Hill,, D. C. Douek,, and R. A. Seder. 2002. Distinct lineages of T(H)1 cells have differential capacities for memory cell generation in vivo. Nat. Immunol. 3:852858.
79. Yun, H. J.,, C. C. Whalen,, A. Okwera,, R. D. Mugerwa,, and J. J. Ellner. 2003. HIV disease progression and effects of tuberculosis preventive therapy in HIV-infected adults. Ann. Epidemiol. 13:577578.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error