Chapter 45 : Immune Intervention Strategies against Tuberculosis

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Compared to most other infectious diseases, 10 million new cases of active tuberculosis (TB) annually is a horrifyingly high death rate. However, of the 2 billion individuals infected with , a mere 10% of infections transform into active TB disease. These comparisons also illustrate the effectiveness of naturally acquired immunity in containing , thus preventing TB disease outbreak. Immunity induced by chronic infection as well as immunity induced by vaccination, however, has to be long lived. Delayed type hypersensitivity (DTH) measures the encounter of the immune system with and hence cannot distinguish between latently infected individuals and patients with active TB disease. Novel vaccine strategies aim at either boosting bacille Calmette-Guérin (BCG) vaccine in children, boosting BCG later in adolescents, or replacing BCG with novel live vaccines such as genetically modified strains of BCG (rBCG), or attenuated strains of . DNA vaccines are easy to make and have the obvious advantage that they can be administered without the need for adjuvants. After injection, the DNA is introduced into host cells, which present the antigen in the context of MHC class I molecules, or they release the antigen, which is then engulfed, processed, and presented in the context of MHC class I by macrophages and DCs. Envisaging of highly speculative immune intervention strategies blocks PD ligand (PD-L)/programmed death 1 (PD-1) signaling, thus leading to T-cell exhaustion. This could prevent or at least delay outbreak of TB in latently infected individuals.

Citation: Andersen P, Kaufmann S. 2011. Immune Intervention Strategies against Tuberculosis, p 571-586. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch45
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Vaccination strategies. A preventive vaccine (cvrrently BCG) is given at birth to prevent infection and clinical disease. Novel vaccine strategies aim at either boosting BCG in children (early booster), boosting BCG later in adolescents (late booster), or replacing BCG with novel live vaccines such as genetically modified strains of BCG (rBCG), or attenuated strains of The ultimate vaccine strategy may also be based on a combination of both approaches (i.e., a prime-boost vaccination regime composed of priming with the best possible viable vaccine candidate and boosting with the best possible subunit vaccine candidate). A postexposure booster is designed to be effective against latent infection and to prevent reactivation of TB.

Citation: Andersen P, Kaufmann S. 2011. Immune Intervention Strategies against Tuberculosis, p 571-586. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch45
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Image of FIGURE 2

Different types of TB vaccination outcomes. The figure describes the course of disease in nonvaccinated individuals (solid line) and different forms of development that the disease may take. The dotted line depicts the outcome of vaccination, which delays TB outbreak. This is the lowest hurdle followed by consistent control of dormant to achieve lifelong latent infection, or, in other words, prevention of TB outbreak. A better option would be vaccines that achieve sterilizing immunity. An alternative would be vaccine-induced prevention of stable infection with (“vaccine prevents infection” line). The two latter options guarantee protection against TB even if an individual becomes infected with HIV, which causes disease outbreak in latently infected individuals.

Citation: Andersen P, Kaufmann S. 2011. Immune Intervention Strategies against Tuberculosis, p 571-586. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch45
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1. Aagaard,, C. S.,, T. T. Hoang,, C. Vingsbo-Lundberg,, J. Dietrich, and, P. Andersen. 2009. Quality and vaccine efficacy of CD4+ T cell responses directed to dominant and subdominant epitopes in ESAT-6 from Mycobacterium tuberculosis. J. Immunol. 183: 26592668.
2. Abebe, R, and, G. Bjune. 2009. The protective role of antibody responses during Mycobacterium tuberculosis infection. Clin. Exp. Immunol. 157: 235243.
3. Aeras Global TB Vaccine Foundation. 2010. Clinical trials. http://www.aeras.org/our-approach/vaccine-development.php?clinical-trials.
4. Agger,, E. M.,, I. Rosenkrands,, J. Hansen,, K. Brahimi,, B. S Vandahl,, C. Aagaard,, K. Werninghaus,, C. Kirschning,, R. Lang,, D. Christensen,, M. Theisen,, F. Follmann, and, P. Andersen. 2008. Cationic liposomes formulated with synthetic mycobacterial cordfactor (CAF01): a versatile adjuvant for vaccines with different immunological requirements. PLoS ONE 3: e3116.
5. Agger,, E. M.,, I. Rosenkrands,, A. W Olsen,, G. Hatch,, A. Williams,, C. Kritsch,, K. Lingnau,, A. von Gabain,, C. S. Andersen,, K. S. Korsholm, and, P. Andersen. 2006. Protective immunity to tuberculosis with Ag85B-ESAT-6 in a synthetic cationic adjuvant system IC31. Vaccine 24: 54525460.
6. Agranoff,, D., D. Fernandez-Reyes,, M. C. Papadopoulos,, S. A. Rojas,, M. Herbster,, A. Loosemore,, E. Tarelli,, J. Sheldon,, A. Schwenk,, R. Pollok,, C. F. Rayner, and, S. Krishna. 2006. Identification of diagnostic markers for tuberculosis by proteomic fingerprinting of serum. Lancet 368: 10121021.
7. Akira, S., S. Uematsu, and, O. Takeuchi. 2006. Pathogen recognition and innate immunity. Cell 124: 783801.
8. Andersen,, C. S.,, E. M. Agger,, I. Rosenkrands,, J. M Gomes,, V. Bhowruth,, K. J. Gibson,, R. V. Petersen,, D. E. Minnikin,, G. S. Besra, and, P. Andersen. 2009. A simple mycobacterial monomycolated glycerol lipid has potent immunostimulatory activity. J. Immunol. 182: 424432.
9. Andersen,, C. S.,, J. Dietrich,, E. M Agger,, N. Y. Lycke,, K. Lovgren, and, P. Andersen. 2007a. The combined CTA1-DD/ISCOMs vector is an effective intranasal adjuvant for boosting prior Mycobacterium bovis BCG immunity to Mycobacterium tuberculosis. Infect. Immun. 75: 408416.
10. Andersen, P. 1997. Host responses and antigens involved in protective immunity to Mycobacterium tuberculosis. Scand. J. Immunol. 45: 115131.
11. Andersen, P. 2007. Vaccine strategies against latent tuberculosis infection. Trends Microbiol. 15: 713.
12. Andersen, P., and, T. M. Doherty. 2005. The success and failure of BCG - implications for a novel tuberculosis vaccine. Nat. Rev. Microbiol. 3: 656662.
13. Andersen, P.,, T. M. Doherty,, M. Pai, and, K. Weldingh. 2007b. The prognosis of latent tuberculosis: can disease be predicted? Trends Mol. Med. 13: 175182.
14. Barber,, D. L.,, E. J. Wherry,, D. Masopust,, B. Zhu,, J. P Allison,, A. H Sharpe,, G. J. Freeman, and, R. Ahmed. 2006. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439: 682687.
15. 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.
16. Belkaid, Y., and, K. Tarbell. 2009. Regulatory T cells in the control of host-microorganism interactions (*). Annu. Rev. Immunol. 27: 551589.
17. Berry,, M. P.,, C. M. Graham,, F. W McNab,, Z. Xu,, S. A. Bloch,, T. Oni,, K. A. Wilkinson,, R. Banchereau,, J. Skinner,, R. J. Wilkinson,, C. Quinn,, D. Blankenship,, R. Dhawan,, J. J. Cush,, A. Mejias,, O. Ramilo,, O. M. Kon,, V. Pascual,, J. Banchereau,, D. Chaussabel, and, A. O’Garra. 2010. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 466: 973977.
18. Bertholet,, S.,, G. C. Ireton,, M. Kahn,, J. Guderian,, R. Mohamath,, N. Stride,, E. M Laughlin,, S. L Baldwin,, T. S. Vedvick,, R. N. Coler, and, S. G. Reed. 2008. Identification of human T cell antigens for the development of vaccines against Mycobacterium tuberculosis. J. Immunol. 181: 79487957.
19. Betts,, J. C,, P. T. Lukey,, L. C. Robb,, R. A. McAdam, and, K. Duncan. 2002. Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol. Microbiol. 43: 717731.
20. Beveridge,, N. E.,, D. A. Price,, J. P. Casazza,, A. A. Pathan,, C. R. Sander,, T. E. Asher,, D. R. Ambrozak,, M. L. Precopio,, P. Scheinberg,, N. C. Alder,, M. Roederer,, R. A. Koup,, D. C. Douek,, A. V. Hill, and, H. McShane. 2007. Immunisation with BCG and recombinant MVA85A induces longlasting, polyfunctional Mycobacterium tuberculosis-specific CD4+ memory T lymphocyte populations. Eur, J. Immunol. 37: 30893100.
21. Black,, G. R,, B. A. Thiel,, M. O. Ota,, S. K. Parida,, R. Adegbola,, W. H. Boom,, H. M. Dockrell,, K. L. Franken,, A. H. Friggen,, P. C. Hill,, M. R. Klein,, M. K. Lalor,, H. Mayanja,, G. Schoolnik,, K. Stanley,, K. Weldingh,, S. H. Kaufmann,, G. Walzl, and, T. H. Ottenhoff. 2009. Immunogenicity of novel DosR regulon-encoded candidate antigens of Mycobacterium tuberculosis in three high-burden populations in Africa. Clin, Vaccine Immunol. 16: 12031212.
22. Brennan,, M. J.,, U. Fruth,, J. Milstien,, R. Tiernan, S. de Andrade Nishioka, and, L. Chocarro. 2007. Development of new tuberculosis vaccines: a global perspective on regulatory issues. PLoS Med. 4: e252.
23. Brigl, M., and, M. B. Brenner. 2004. CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22: 817890.
24. Calmette, A., and, H. Plotz. 1929. Protective inoculation against tuberculosis with BCG. Am. Rev. Tuberc. 19: 567572.
25. Cardona, P. J. 2006. RUTI: anew chance to shorten the treatment of latent tuberculosis infection. Tuberculosis (Edinburgh) 86: 273289.
26. Cole, S. T.,, R. Brosch,, J. Parkhill,, T. Garnier,, C. Churcher,, D. Harris,, S. V. Gordon,, K. Eiglmeier,, S. Gas,, C. E. Barry, 3rd,, F. Tekaia,, K. Badcock,, D. Basham,, D. Brown,, T. Chillingworth,, R. Connor,, R. Davies,, K. Devlin,, T. Feltwell,, S. Gentles,, N. Hamlin,, S. Holroyd,, T. Hornsby,, K. Jagels,, A. Krogh,, J. McLean,, S. Moule,, L. Murphy,, K. Oliver,, J. Osborne,, M. A. Quail,, M. A. Rajandream,, J. Rogers,, S. Rutter,, K. Seeger,, J. Skelton,, R. Squares,, S. Squares,, J. E. Sulston,, K. Taylor,, S. Whitehead, and, B. G. Barrell. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393: 537544.
27. Cooper, A. M. 2009. Cell-mediated immune responses in tuberculosis. Annu. Rev. Immunol. 27: 393422.
28. Davidsen,, J., I. Rosenkrands,, D. Christensen,, A. Vangala,, D. Kirby,, Y. Perrie,, E. M Agger, and, P. Andersen. 2005. Characterization of cationic liposomes based on dimethyldioctadecylammonium and synthetic cord factor from M. tuberculosis (trehalose 6,6′-dibehenate)-a novel adjuvant inducing both strong CMI and antibody responses. Biochim. Biophys. Acta 1718: 2231.
29. Davis, J. M., and, L. Ramakrishnan. 2009. The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell 136: 3749.
30. Day,, C. L.,, D. E. Kaufmann,, P. Kiepiela,, J. A Brown,, E. S Moodley,, S. Reddy,, E. W. Mackey,, J. D. Miller,, A. J. Leslie,, C. DePierres,, Z. Mncube,, J. Duraiswamy,, B. Zhu,, Q. Eichbaum,, M. Altfeld,, E. J. Wherry,, H. M. Coovadia,, P. J. Goulder,, P. Klenerman,, R. Ahmed,, G. J. Freeman, and, B. D. Walker. 2006. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443: 350- 354.
31. Day, T. A.,, M. Koch,, G. Novailles,, M. Jacobsen,, G. A Kosmiadi,, D. Mickley,, S. Kuhlmann,, S. Jörg,, P. Gamradt,, H. J. Mollenkopf,, R. Hurwitz,, S. Reece,, S. H. E. Kaufmann, and, M. Kursar. 2010. Secondary lymphoid organs are dispensable for the development of T-cell-mediated immunity during tuberculosis. Eur. J. Immunol. 40: 16631673.
32. Delogu, G.,, A. Li,, C. Repique,, F. Collins, and, S. L. Morris. 2002. DNA vaccine combinations expressing either tissue plasminogen activator signal sequence fusion proteins or ubiquitin-conjugated antigens induce sustained protective immunity in a mouse model of pulmonary tuberculosis. Infect. Immun. 70: 292302.
33. Demissie,, A.,, E. M. Leyten,, M. Abebe,, L. Wassie,, A. Aseffa,, G. Abate,, H. Fletcher,, P. Owiafe,, P. C. Hill,, R. Brookes,, G. Rook,, A. Zumla,, S. M. Arend,, M. Klein,, T. H. Ottenhoff,, P. Andersen, and, T. M. Doherty. 2006. Recognition of stage-specific mycobacterial antigens differentiates between acute and latent infections with Mycobacterium tuberculosis. Clin. Vaccine Immunol. 13: 179186.
34. Denis-Mize,, K. S.,, M. Dupuis,, M. Singh,, C. Woo,, M. Ugozzoli,, D. T. O’Hagan,, J. J. Donnelly, 3rd,, G. Ott, and, D. M. McDonald. 2003. Mechanisms of increased immunogenicity for DNA-based vaccines adsorbed onto cationic microparticles. Cell Immunol. 225: 1220.
35. Derrick,, S. C,, L. P. Perera,, V. Dheenadhayalan,, A. Yang,, K. Kolibab, and, S. L. Morris. 2008. The safety of postexposure vaccination of mice infected with Mycobacterium tuberculosis. Vaccine 26: 60926098.
36. Dietrich,, J., C. Andersen,, R. Rappuoli,, T. M Doherty,, C. G. Jensen, and, P. Andersen. 2006. Mucosal administration of Ag85B-ESAT-6 protects against infection with Mycobacterium tuberculosis and boosts prior bacillus Calmette-Guerin immunity. J. Immunol. 177: 63536360.
37. Dietrich, J.,, R. Billeskov,, T. M. Doherty, and, P. Andersen. 2007. Synergistic effect of bacillus calmette guerin and a tuberculosis subunit vaccine in cationic liposomes: increased immunogenicity and protection. J. Immunol. 178: 37213730.
38. Dietrich,, J., C. Aagaard,, R. Leah,, A. W Olsen,, A. Stryhn,, T. M Doherty, and, P. Andersen. 2005. Exchanging ESAT6 with TB10.4 in an Ag85B fusion molecule-based tuberculosis subunit vaccine: efficient protection and ESAT6-based sensitive monitoring of vaccine efficacy. J. Immunol. 174: 63326339.
39. Dlugovitzky,, D., G. Fiorenza,, M. Farroni,, C. Bogue,, C. Stanford, and, J. Stanford. 2006. Immunological consequences of three doses of heat-killed Mycobacterium vaccae in the immunofherapy of tuberculosis. Respir. Med. 100: 10791087.
40. Dorhoi, A., and, S. H. Kaufmann. 2009. Fine-tuning of T cell responses during infection. Curr. Opin. Immunol. 21: 367377.
41. D’Souza,, S., V. Rosseels,, O. Denis,, A. Tanghe,, N. De Smet,, F. Jurion,, K. Palfliet,, N. Castiglioni,, A. Vanonckelen,, C. Wheeler, and, K. Huygen. 2002. Improved tuberculosis DNA vaccines by formulation in cationic lipids. Infect. Immun. 70: 36813688.
42. Elvang,, T.,, J. P. Christensen,, R. Billeskov, T. Thi Kim Thanh Hoang,, P. Holst,, A. R Thomsen,, P. Andersen, and, J. Dietrich. 2009. CD4 and CD8 T cell responses to the M. tuberculosis Ag85B-TB10.4 promoted by adjuvanted subunit, adenovector or heterologous prime boost vaccination. PLoS ONE 4: e5139.
43. Emergent BioSolutions. 2009. New TB vaccine candidate enters phase IIb proof-of-concept trial in South Africa. http://investors.emergentbiosolutions.com/phoenix.zhtml?c=202582&p=irol-newsArticle&ID=1279113&highlight=
44. Ferraz,, J. C,, E. Stavropoulos,, M. Yang,, S. Coade,, C. Espitia,, D. B. Lowrie,, M. J. Colston, and, R. E. Tascon. 2004. A heterologous DNA priming- Mycobacterium bovis BCG boosting immunization strategy using mycobacterial Hsp70, Hsp65, and Apa antigens improves protection against tuberculosis in mice. Infec. Immun. 72: 69456950.
45. Fine, P. E. 1995. Variation in protection by BCG: implications of and for heterologous immunity. Lancet 346: 13391345.
46. Flynn, J. L., and, J. Chan. 2001. Immunology of tuberculosis. Annu. Rev. Immunol. 19: 93129.
47. Foulds, K. E., C. Y. Wu, and, R. A. Seder. 2006. Th1 memory: implications for vaccine development. Immunol. Rev. 211: 5866.
48. Gao,, L. Y.,, S. Guo,, B. McLaughlin,, H. Morisaki,, J. N Engel, and, E. J. Brown. 2004. A mycobacterial virulence gene cluster extending RD1 is required for cytolysis, bacterial spreading and ESAT-6 secretion. Mol. Microbiol. 53: 16771693.
49. Garcon, N., P. Chomez, and, M. Van Mechelen. 2007. GlaxoS-mithKline Adjuvant Systems in vaccines: concepts, achievements and perspectives. Expert Rev. Vaccines 6: 723739.
50. Gilbert,, S. C,, V. S. Moorthy,, L. Andrews,, A. A Pathan,, S. J McConkey,, J. M. Vuola,, S. M. Keating,, T. Berthoud,, D. Webster,, H. McShane, and, A. V. Hill. 2006. Synergistic DNA-MVA prime-boost vaccination regimes for malaria and tuberculosis. Vaccine 24: 45544561.
51. Goriely, S., M. R Neurath, and, M. Goldman. 2008. How microorganisms tip the balance between interleukin-12 family members. Nat, Rev. Immunol. 8: 8186.
52. Greenwald, R. J., G. J. Freeman, and, A. H. Sharpe. 2005. The B7 family revisited. Annu. Rev. Immunol. 23: 515548.
53. Grode, L.,, P. Seller,, S. Baumann,, J. Hess,, V. Brinkmann,, A. Nasser Eddine,, P. Mann,, C. Goosmann,, S. Bandermann,, D. Smith,, G. J. Bancroft,, J. M. Reyrat,, D. van Soolingen,, B. Raupach, and, S. H. Kaufmann. 2005. Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guerin mutants that secrete listeriolysin. J. Clin. Invest. 115: 24722479.
54. Ha,, S. J.,, B. Y. Jeon,, J. I. Youn,, S. C. Kim,, S. N. Cho, and, Y. C. Sung. 2005. Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis. Gene Ther. 12: 634638.
55. Harty, J. T., A. R. Tvinnereim, and, D. W. White. 2000. CD8+ T cell effector mechanisms in resistance to infection. Annu. Rev. Immunol. 18: 275308.
56. Hayday, A. C. 2000. [gamma] [delta] cells: a right time and a right place for a conserved third way of protection. Annu. Rev. Immunol. 18: 9751026.
57. Henao-Tamayo,, M.,, G. S. Palaniswamy,, E. E. Smith,, C. A. Shanley,, B. Wang,, I. M. Orme,, R. J. Basaraba,, N. M. DuTeau, and, D. Ordway. 2009. Post-exposure vaccination against Mycobacterium tuberculosis. Tuberculosis (Edinburgh) 89: 142148.
58. Hesseling,, A. C.,, H. S. Schaaf,, T. Victor,, N. Beyers,, B. J Marais,, M. F Cotton,, I. Wild,, R. P. Gie,, P. van Helden, and, R. M. Warren. 2004. Resistant Mycobacterium bovis Bacillus Calmette-Guerin disease: implications for management of Bacillus Calmette-Guerin Disease in human immunodeficiency virus-infected children. Pediatr. Infect. Dis. J. 23: 476479.
59. Hoft,, D. F.,, A. Blazevic,, G. Abate,, W. A. Hanekom,, G. Kaplan,, J. H. Soler,, F. Weichold,, L. Geiter,, J. C. Sadoff, and, M. A. Horwitz. 2008. A new recombinant bacille Calmette-Guerin vaccine safely induces significantly enhanced tuberculosis-specific immunity in human volunteers. J. Inject. Dis. 198: 14911501.
60. Hogarth,, P. J.,, K. J. Jahans,, R. Hecker,, R. G Hewinson, and, M. A. Chambers. 2003. Evaluation of adjuvants for protein vaccines against tuberculosis in guinea pigs. Vaccine 21: 977982.
61. Horwitz, M. A.,, G. Harth,, B. J. Dillon, and, S. Maslesa-Galic. 2006. A novel live recombinant mycobacterial vaccine against bovine tuberculosis more potent than BCG. Vaccine 24: 15931600.
62. 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.
63. Idle, J. R., and, F. J. Gonzalez. 2007. Metabolomics. Cell. Metab. 6: 348351.
64. Ishii, K. J., and, S. Akira. 2007. Toll or toll-free adjuvant path toward the optimal vaccine development. J. Clin. Immunol. 27: 363371.
65. Jacobsen, M.,, J. Mattow,, D. Repsilber, and, S. H. Kaufmann. 2008. Novel strategies to identify biomarkers in tuberculosis. Biol. Chem. 389: 487495.
66. Jacobsen,, M., D. Repsilber,, A. Gutschmidt,, A. Neher,, K. Feldmann,, H. J Mollenkopf, A. Ziegler, and, S. H. Kaufmann. 2007. Candidate biomarkers for discrimination between infection and disease caused by Mycobacterium tuberculosis. J. Mol. Med. 85: 613621.
67. Jacobsen,, M., D. Repsilber,, K. Kleinsteuber,, A. Gutschmidt,, S. Schommer-Leitrier,, G. Black,, G. Walzl, and, S. H. E. Kaufmann. Suppressor of Cytokine Signaling (SOCS)-3 is affected in T cells from TB patients. Clin. Microbiol., in press.
68. Jurado, J. O.,, I. B. Alvarez,, V. Pasquinelli,, G. J. Martinez,, M. F. Quiroga,, E. Abbate,, R. M. Musella,, H. E. Chuluyan, and, V. E. Garcia. 2008. Programmed death (PD)-l:PD-ligand 1/PD-ligand 2 pathway inhibits T cell effector functions during human tuberculosis. J. Immunol. 181: 116125.
69. Kamath,, A. T.,, C. G. Feng,, M. Macdonald,, H. Briscoe, and, W. J. Britton. 1999. Differential protective efficacy of DNA vaccines expressing secreted proteins of Mycobacterium tuberculosis. Infect. Immun. 67: 17021707.
70. Kamath,, A. T.,, A. F. Rochat,, D. Christensen,, E. M Agger,, P. Andersen,, P. H. Lambert, and, C. A. Siegrist. 2009. A Liposome-based mycobacterial vaccine induces potent adult and neonatal multifunctional T cells through the exquisite targeting of dendritic cells. PLoS ONE 4: e5771.
71. Kamath, A. T.,, M. P. Valenti,, A. F. Rochat,, E. M. Agger,, K. Lingnau,, A. von Gabain,, P. Andersen,, P. H. Lambert, and, C. A. Siegrist. 2008. Protective antimycobacterial T cell responses through exquisite in vivo activation of vaccine-targeted dendritic cells. Eur. J. Immunol. 38: 12471256.
72. Kaufmann, S. H. 2006a. Envisioning future strategies for vaccination against tuberculosis. Nat. Rev. Immunol. 6: 699704.
73. Kaufmann, S. H. 2006b. Tuberculosis: back on the immunologists’ agenda. Immunity 24: 351357.
74. Kaufmann, S. H. 2007. The contribution of immunology to the rational design of novel antibacterial vaccines. Nat. Rev. Microbiol. 5: 491504.
75. Kaufmann, S. H., and, S. K. Parida. 2008. Tuberculosis in Africa: learning from pathogenesis for biomarker identification. Cell Host Microbe 4: 219228.
76. Kaufmann, S. H., and, U. E. Schaible. 2005. 100th anniversary of Robert Koch’s Nobel Prize for the discovery of the tubercle bacillus. Trends Microbiol. 13: 469475.
77. Kaufmann, S. H., and, F. Winau. 2005. From bacteriology to immunology: the dualism of specificity. Nature Immunol. 6: 10631066.
78. Kawai, T., and, S. Akira. 2009. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int. Immunol. 21: 317337.
79. Kirby,, D. J.,, I. Rosenkrands,, E. M Agger,, P. Andersen,, A. G. Coombes, and, Y. Perrie. 2008. PLGA microspheres for the delivery of a novel subunit TB vaccine. J. Drug Target 16: 282293.
80. Korn, T.,, E. Bettelli,, M. Oukka, and, V K. Kuchroo. 2009. IL-17 and Th17 Cells. Annu. Rev. Immunol. 27: 485517.
81. Korsholm,, K. S.,, E. M. Agger,, C. Foged,, D. Christensen, J. Dietrich,, C. S. Andersen,, C. Geisler, and, P. Andersen. 2007. The adjuvant mechanism of cationic dimethyldioctadecylammonium liposomes. Immunology 121: 216226.
82. Kremer,, L.,, W. N. Maughan,, R. A. Wilson,, L. G. Dover, and, G. S. Besra. 2002. The M. tuberculosis antigen 85 complex and mycolyltransferase activity. Lett. Appl. Microbiol. 34: 233237.
83. Kursar,, M., M. Koch,, H. W. Mittrucker,, G. Nouailles,, K. Bonhagen,, T. Kamradt, and, S. H. Kaufmann. 2007. Cutting edge: Regulatory T cells prevent efficient clearance of Mycobacterium tuberculosis. J. Immunol. 178: 26612665.
84. Langermans, J. A.,, T. M. Doherty,, R. A. Vervenne,, T. van der Laan,, K. Lyashchenko,, R. Greenwald,, E. M. Agger,, C. Aagaard,, H. Weiler,, D. van Soolingen,, W. Dalemans,, A. W. Thomas, and, P. Andersen. 2005. Protection of macaques against Mycobacterium tuberculosis infection by a subunit vaccine based on a fusion protein of antigen 85B and ESAT-6. Vaccine 23: 27402750.
85. Lee,, J. S.,, R. Krause,, J. Schreiber,, H. J. Mollenkopf,, J. Kowall,, R. Stein,, B. Y. Jeon,, J. Y. Kwak,, M. K. Song,, J. P. Patron,, S. Jorg,, K. Roh,, S. N. Cho, and, S. H. Kaufmann. 2008. Mutation in the transcriptional regulator PhoP contributes to avirulence of Mycobacterium tuberculosis H37Ra strain. Cell Host Microbe 3: 97103.
86. Li,, Z., H. Zhang,, X. Fan,, Y. Zhang,, J. Huang,, Q. Liu,, T. E Tjelle,, I. Mathiesen,, R. Kjeken, and, S. Xiong. 2006. DNA electroporation prime and protein boost strategy enhances humoral immunity of tuberculosis DNA vaccines in mice and non-human primates. Vaccine 24: 45654568.
87. Liang,, Y., X. Wu,, J. Zhang,, N. Li,, Q. Yu,, Y. Yang,, X. Bai,, C. Liu,, Y. Shi,, Q. Liu,, P. Zhang, and, Z. Li. 2008. The treatment of mice infected with multi-drug-resistant Mycobacterium tuberculosis using DNA vaccines or in combination with rifampin. Vaccine 26: 45364540.
88. Lin, M. Y., and, T. H. Ottenhoff. 2008. Not to wake a sleeping giant: new insights into host-pathogen interactions identify new targets for vaccination against latent Mycobacterium tuberculosis infection. Biol. Chem. 389: 497511.
89. Lindblad,, E. B.,, M. J. Elhay,, R. Silva,, R. Appelberg, and, P. Andersen. 1997. Adjuvant modulation of immune responses to tuberculosis subunit vaccines. Infect. Immun. 65: 623629.
90. Lindenstrom,, T.,, E. M. Agger,, K. S. Korsholm,, P. A. Darrah,, C. Aagaard,, R. A. Seder,, I. Rosenkrands, and, P. Andersen. 2009. Tuberculosis subunit vaccination provides longterm protective immunity characterized by multifunctional CD4 memory T cells. J. Immunol. 182: 80478055.
91. Lowrie, D. B. 2006. DNA vaccines for therapy of tuberculosis: where are we now? Vaccine 24: 19831989.
92. Lowrie, D. B.,, R. E. Tascon,, V. L. Bonato,, V. M. Lima,, L. H. Faccioli,, E. Stavropoulos,, M. J. Colston,, R. G. Hewinson,, K. Moelling, and, C. L. Silva. 1999. Therapy of tuberculosis in mice by DNA vaccination. Nature 400: 269271.
93. Maertzdorf,, J., D. Repsilber,, S. K. Parida,, K. Stanley,, T. Roberts,, G. Black,, G. Walzl, and, S. H. E. Kaufmann. Human gene expression profiles of susceptibility and resistance in tuberculosis. Genes & Immunity, in press.
94. Maglione, P. J., and, J. Chan. 2009. How B cells shape the immune response against Mycobacterium tuberculosis. Eur. J. Immunol. 39: 676686.
95. McShane,, H.,, A. A. Pathan,, C. R. Sander,, S. M. Keating,, S. C. Gilbert,, K. Huygen,, H. A. Fletcher, and, A. V. Hill. 2004. Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans. Nat. Med. 10: 12401244.
96. Mir, F. A., S. H. Kaufmann, and, A. N. Eddine. 2009. A multicistronic DNA vaccine induces significant protection against tuberculosis in mice and offers flexibility in the expressed antigen repertoire. Clin. Vaccine Immunol. 16: 14671475.
97. Mittrucker, H. W.,, U. Steinhoff,, A. Kohler,, M. Krause,, D. Lazar,, P. Mex,, D. Miekley, and, S. H. Kaufmann. 2007. Poor correlation between BCG vaccination-induced T cell responses and protection against tuberculosis. Proc. Natl. Acad. Sci. USA 104: 1243412439.
98. Morris, S.,, C. Kelley,, A. Howard,, Z. Li, and, F. Collins. 2000. The immunogenicity of single and combination DNA vaccines against tuberculosis. Vaccine 18: 21552163.
99. Mosmann, T. R., and, S. Sad. 1996. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol. Today 17: 138146.
100. Mu,, J., M. Jeyanathan,, C. L. Small,, X. Zhang,, E. Roediger,, X. Feng,, D. Chong,, J. Gauldie, and, Z. Xing. 2009. Immunization with a bivalent adenovirusvectored tuberculosis vaccine provides markedly improved protection over its monovalent counterpart against pulmonary tuberculosis. Mol. Ther. 17: 10931100.
101. Mueller,, H.,, A. K. Detjen,, S. D. Schuck,, A. Gutschmidt,, U. Wahn,, K. Magdorf,, S. H. Kaufmann, and, M. Jacobsen. 2008. Mycobacterium tuberculosis-specific CD4 +, IF-Ngamma+, and TNFalpha+ multifunctional memory T cells coexpress GM-CSF. Cytokine 43: 143148.
102. Olsen,, A. W.,, P. R. Hansen,, A. Holm, and, P. Andersen. 2000. Efficient protection against Mycobacterium tuberculosis by vaccination with a single subdominant epitope from the ESAT-6 antigen. Eur. J. Immunol. 30: 17241732.
103. Orme, I. M. 2006. Preclinical testing of new vaccines for tuberculosis: a comprehensive review. Vaccine 24: 219.
104. Oster,, C. G.,, N. Kim,, L. Grode,, L. Barbu-Tudoran,, A. K. Schaper,, S. H. Kaufmann, and, T. Kissel. 2005. Cationic microparticles consisting of poly(lactide-co-glycolide) and polyethylenimine as carriers systems for parental DNA vaccination. J. Control Release 104: 359377.
105. Parida, S. K., and, S. H. Kaufmann. 2009. The quest for biomarkers in tuberculosis. DrugDiscov. Today. 15: 148157.
106. Perera,, P. Y.,, S. C. Derrick,, K. Kolibab,, F. Momoi, M. Ya-mamoto,, S. L. Morris,, T. A. Waldmann, and, L. P. Perera. 2009. A multivalent vaccinia virus-based tuberculosis vaccine molecularly adjuvanted with interleukin-15 induces robust immune responses in mice. Vaccine 27: 21212127.
107. Phillips,, M.,, R. N. Cataneo,, R. Condos, G. A. Ring Erickson,, J. Greenberg, V. La Bombardi,, M. I. Munawar, and, O. Tietje. 2007. Volatile biomarkers of pulmonary tuberculosis in the breath. Tuberculosis (Edinburgh) 87: 4452.
108. Pulendran, B., and, R. Ahmed. 2006. Translating innate immunity into immunological memory: implications for vaccine development. Cell 124: 849863.
109. Radosevic,, K.,, C. W. Wieland,, A. Rodriguez, G. J. Wever-ling,, R. Mintardjo,, G. Gillissen,, R. Vogels,, Y. A. Skeiky,, D. M. Hone,, J. C. Sadoff,, T. van der Poll,, M. Havenga, and, J. Goudsmit. 2007. Protective immune responses to a recombinant adenovirus type 35 tuberculosis vaccine in two mouse strains: CD4 and CD8 T-cell epitope mapping and role of gamma interferon. Infect. Immun. 75: 41054115.
110. Reed,, S. G.,, R. N. Coler,, W. Dalemans,, E. V. Tan, E. C. DeLa Cruz,, R. J. Basaraba,, I. M. Orme,, Y. A. Skeiky,, M. R. Alderson,, K. D. Cowgill,, J. P. Prieels,, R. M. Abalos,, M. C. Dubois,, J. Cohen,, P. Mettens, and, Y. Lobet. 2009. Defined tuberculosis vaccine, Mtb72F/AS02A, evidence of protection in cynomolgus monkeys. Proc. Natl. Acad. Sci. USA 106: 23012306.
111. 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.
112. Romagnani, S. 2005. Cytokines, p. 273-299. In S. H. E. Kaufmann,, M. W. Steward (ed.). Immunology: Topley and Wilson’s Microbiology and Microbial Infections, 10th ed. Hodder Arnold, London, England.
113. Rook, G. A., and, J. L. Stanford. 1996. The Koch phenomenon and the immunopathology of tuberculosis. Curr. Top. Microbiol. Immunol. 215: 239262.
114. Rooney,, J. F.,, C. Wohlenberg,, K. J Cremer,, B. Moss, and, A. L. Notkins. 1988. Immunization with a vaccinia virus recombinant expressing herpes simplex virus type 1 glycoprotein D: long-term protection and effect of revaccination. J. Virol. 62: 15301534.
115. Russell, D. G. 2007. Who puts the tubercle in tuberculosis? Nat. Rev. Microbiol. 5 3947.
116. Rustad,, T. R.,, M. I. Harrell,, R. Liao, and, D. R. Sherman. 2008. The enduring hypoxic response of Mycobacterium tuberculosis. PLoS ONE 3: e1502.
117. Sadoff, J. C, and, J. Wittes. 2007. Correlates, surrogates, and vaccines. J. Infect. Dis. 196: 12791281.
118. Sallusto, F., J. Geginat, and, A. Lanzavecchia. 2004. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22: 745763.
119. Sambandamurthy, V. K.,, S. C. Derrick,, T. Hsu,, B. Chen,, M. H Larsen,, K. V. Jalapathy,, M. Chen,, J. Kim,, S. A. Porcelli,, J. Chan,, S. L. Morris, and, W. R. Jacobs, Jr. 2006. Mycobacterium tuberculosis DeltaRD1 DeltapanCD: a safe and limited replicating mutant strain that protects immunocompetent and immunocompromised mice against experimental tuberculosis. Vaccine 24: 63096320.
120. Santosuosso, M.,, S. McCormick,, X. Zhang,, A. Zganiacz, and, Z. Xing. 2006. Intranasal boosting with an adenovirusvectored vaccine markedly enhances protection by parenteral Mycobacterium bovis BCG immunization against pulmonary tuberculosis. Infect. Immun. 74: 46344643.
121. Sassetti, C. M., D. H. Boyd, and, E. J. Rubin. 2003. Genes required for mycobacterial growth defined by high density mutagenesis. Mol. Microbiol. 48: 7784.
122. 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.
123. Schaible, U. E.,, F. Winau,, P. A Sieling,, K. Fischer,, H. L Collins,, K. Hagens,, R. L. Modlin,, V. Brinkmann, and, S. H. Kaufmann. 2003. Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis. Nat. Med. 9: 10391046.
124. Schuck,, S. D.,, H. Mueller,, F. Kunitz,, A. Neher,, H. Hoffmann,, K. L Franken,, D. Repsilber,, T. H. Ottenhoff,, S. H. Kaufmann, and, M. Jacobsen. 2009. Identification of T-cell antigens specific for latent Mycobacterium tuberculosis infection. PLoS ONE 4: e5590.
125. Scott-Browne,, J. P.,, S. Shafiani, G. Tucker-Heard,, K. Ishida-Tsubota,, J. D. Fontenot,, A. Y. Rudensky,, M. J. Bevan, and, K. B. Urdahl. 2007. Expansion and function of Foxp3-expressing T regulatory cells during tuberculosis. J. Exp. Med. 204: 21592169.
126. Serbina, N. V.,, T. Jia,, T. M. Hohl, and, E. G. Pamer. 2008. Monocyte-mediated defense against microbial pathogens. Annu. Rev. Immunol. 26: 421452.
127. Sherman,, D. R.,, M. Voskuil,, D. Schnappinger,, R. Liao,, M. I Harrell, and, G. K. Schoolnik. 2001. Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding alpha-crystallin. Proc. Natl. Acad. Sci. USA 98: 75347539.
128. Shi, L.,, Y. J. Jung,, S. Tyagi,, M. L. Gennaro, and, R. J. North. 2003. Expression of Th1-mediated immunity in mouse lungs induces a Mycobacterium tuberculosis transcription pattern characteristic of nonreplicating persistence. Proc. Natl. Acad. Sci. USA 100: 241246.
129. Skeiky, Y. A.,, M. R. Alderson,, P. J. Ovendale,, J. A. Guderian,, L. Brandt,, D. C. Dillon,, A. Campos-Neto,, Y. Lobet,, W. Dalemans,, I. M. Orme, and, S. G. Reed. 2004. Differential immune responses and protective efficacy induced by components of a tuberculosis polyprotein vaccine, Mtb72F, delivered as naked DNA or recombinant protein. J. Immunol. 172: 76187628.
130. Skeiky,, Y. A.,, J. Dietrich,, T. Lasco,, K. Stagliano,, M. A Goetz,, L. Cantarero,, P. Bang,, I. Kromann,, J. C. Sadoff, and, P. Andersen. 2009. Non-clinical efficacy and safety of HyVac4:IC31 vaccine administered in a BCG prime-boost regimen. Vaccine 28: 10841093.
131. Soto,, C. Y.,, M. C. Menendez,, E. Perez,, S. Samper,, A. B Gomez,, M. J Garcia, and, C. Martin. 2004. IS6110 mediates increased transcription of the phoP virulence gene in a multidrug-resistant clinical isolate responsible for tuberculosis outbreaks. J. Clin. Microbiol. 42: 212219.
132. Stenger, S.,, D. A. Hanson,, R. Teitelbaum,, P. Dewan,, K. R. Niazi,, C. J. Froelich,, T. Ganz,, S. Thoma-Uszynski,, A. Melian,, C. Bogdan,, S. A. Porcelli,, B. R. Bloom,, A. M. Krensky, and, R. L. Modlin. 1998. An antimicrobial activity of cytolytic T cells mediated by granulysin. Science 282: 121125.
133. Sun,, R.,, Y. A. Skeiky,, A. Izzo,, V. Dheenadhayalan,, Z. Imam,, E. Penn,, K. Stagliano,, S. Haddock,, S. Mueller,, J. Fulkerson,, C. Scanga,, A. Grover,, S. C. Derrick,, S. Morris,, D. M. Hone,, M. A. Horwitz,, S. H. Kaufmann, and, J. C. Sadoff. 2009. Novel recombinant BCG expressing perfringolysin O and the over-expression of key immunodominant antigens; pre-clinical characterization, safety and protection against challenge with Mycobacterium tuberculosis. Vaccine 27: 44124423.
134. Syhre, M.,, L. Manning,, S. Phuanukoonnon,, P. Harino, and, S. T. Chambers. 2009. The scent of Mycobacterium tuberculosis—part II breath. Tuberculosis (Edinburgh) 89: 263266.
135. Tanghe,, A., P. Lefevre,, O. Denis, S. D’Souza,, M. Braibant,, E. Lozes,, M. Singh,, D. Montgomery,, J. Content, and, K. Huygen. 1999. Immunogenicity and protective efficacy of tuberculosis DNA vaccines encoding putative phosphate transport receptors. J. Immunol. 162: 11131119.
136. 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.
137. Trombetta, E. S., and, I. Mellman. 2005. Cell biology of antigen processing in vitro and in vivo. Annu. Rev. Immunol. 23: 9751028.
138. Turner, O. C,, A. D. Roberts,, A. A. Frank,, S. W. Phalen,, D. M. McMurray,, J. Content,, O. Denis,, S. D’Souza,, A. Tanghe,, K. Huygen, and, I. M. Orme. 2000. Lack of protection in mice and necrotizing bronchointerstitial pneumonia with bronchiolitis in guinea pigs immunized with vaccines directed against the hsp60 molecule of Mycobacterium tuberculosis. Infect. Immun. 68: 36743679.
139. Ulrichs, T, and, S. H. Kaufmann. 2006. New insights into the function of granulomas in human tuberculosis. J. Pathol. 208: 261269.
140. van der Wel,, N.,, D. Hava,, D. Houben,, D. Fluitsma,, M. van Zon,, J. Pierson,, M. Brenner, and, P. J. Peters. 2007. M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 129: 12871298.
141. van Kooyk, Y., and, T. B. Geijtenbeek. 2003. DC-SIGN: escape mechanism for pathogens. Nat. Rev. Immunol. 3: 697709.
142. Vilaplana,, C, E. Montane,, S. Pinto,, A. M Barriocanal,, G. Domenech,, F. Torres,, P. J Cardona, and, J. Costa. 2010. Double-blind, randomized, placebo-controlled phase I clinical trial of the therapeutical antituberculous vaccine RUTI®. Vaccine 28: 11061116.
143. Von Reyn, C. F.,, L. Mtei,, R. Arbeit,, R. Waddell,, B. Cole,, T. Mackenzie,, M. Matee,, M. Bakari,, S. Tvaroha,, J. M. Vuola,, L. V. Adams,, M. Carey,, W. Wieland-Alter,, H. Soini,, R. Horsburgh, and, K. Pallangyo. 2010. Prevention of tuberculosis in BCG-primed, HIV-infected adults boosted with an inactivated whole cell mycobacterial vaccine. AIDS 24: 675685.
144. Wang,, B., M. Henao-Tamayo,, M. Harton,, D. Ordway,, C. Shanley,, R. J Basaraba, and, I. M. Orme. 2007. A Toll-like receptor-2-directed fusion protein vaccine against tuberculosis. Clin. Vaccine Immunol. 14: 902906.
145. Weinrich Olsen, A.,, L. A. van Pinxteren,, L. Meng Okkels,, P. Birk Rasmussen, and, P. Andersen. 2001. Protection of mice with a tuberculosis subunit vaccine based on a fusion protein of antigen 85b and esat-6. Infect. Immun. 69: 27732778.
146. Winau, F.,, G. Hegasy,, S. H. Kaufmann, and, U. E. Schaible. 2005. No life without death—apoptosis as prerequisite for T cell activation. Apoptosis 10: 707715.
147. Winau,, F., S. Weber,, S. Sad, J. de Diego,, S. L. Hoops,, B. Breiden,, K. Sandhoff,, V. Brinkmann,, S. H. Kaufmann, and, U. E. Schaible. 2006. Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis. Immunity 24: 105117.
148. World Health Organization (WHO). 2007. Revised BCG vaccination guidelines for infants at risk for HIV infection. Wkly. Epidemiol. Rec. 82: 193196.
149. World Health Organization (WHO). 2009. Global turberculosis control: epidemiology, strategy, financing. WHO Report 2009. WHO, Geneva, Switzerland.
150. Zhu, D., S. Jiang, and, X. Luo. 2005. Therapeutic effects of Ag85B and MPT64 DNA vaccines in a murine model of Mycobacterium tuberculosis infection. Vaccine 23: 46194624.


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Mycobacterial antigens in leading vaccine candidates

Citation: Andersen P, Kaufmann S. 2011. Immune Intervention Strategies against Tuberculosis, p 571-586. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch45
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The leading TB vaccine candidates in clinical trials

Citation: Andersen P, Kaufmann S. 2011. Immune Intervention Strategies against Tuberculosis, p 571-586. In Kaufmann S, Rouse B, Sacks D (ed), The Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555816872.ch45

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