Review Article | Published:

Moving tuberculosis vaccines from theory to practice


Tuberculosis (TB) vaccine research has reached a unique point in time. Breakthrough findings in both the basic immunology of Mycobacterium tuberculosis infection and the clinical development of TB vaccines suggest, for the first time since the discovery of the Mycobacterium bovis bacillus Calmette–Guérin (BCG) vaccine more than a century ago, that a novel, efficacious TB vaccine is imminent. Here, we review recent data in the light of our current understanding of the immunology of TB infection and discuss the identification of biomarkers for vaccine efficacy and the next steps in the quest for an efficacious vaccine that can control the global TB epidemic.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    World Health Organization. Global tuberculosis report 2018 (WHO, 2018).

  2. 2.

    Houben, R. M. & Dodd, P. J. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLOS Med. 13, e1002152 (2016).

  3. 3.

    Behr, M. A., Edelstein, P. H. & Ramakrishnan, L. Revisiting the timetable of tuberculosis. BMJ 362, k2738 (2018).

  4. 4.

    Barry, C. E. et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat. Rev. Microbiol. 7, 845–855 (2009).

  5. 5.

    Robertson, B. D. et al. Detection and treatment of subclinical tuberculosis. Tuberculosis (Edinb.) 92, 447–452 (2012).

  6. 6.

    Pai, M. et al. Tuberculosis. Nat. Rev. Dis. Primers 2, 16076 (2016).

  7. 7.

    Drain, P. K. et al. Incipient and subclinical tuberculosis: a clinical review of early stages and progression of infection. Clin. Microbiol. Rev. 31, e00021-18 (2018).

  8. 8.

    Scriba, T. J. et al. Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease. PLOS Pathog. 13, e1006687 (2017).

  9. 9.

    Hunter, R. L. The pathogenesis of tuberculosis: the early infiltrate of post-primary (adult pulmonary) tuberculosis: a distinct disease entity. Front. Immunol. 9, 2108 (2018).

  10. 10.

    Tameris, M. D. et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 381, 1021–1028 (2013). This paper reports the safety, immunogenicity and efficacy of the first viral vectored TB vaccine candidate, MVA85A, in infants who received BCG at birth. No protection against Mtb infection or TB disease was observed.

  11. 11.

    Nemes, E. et al. Prevention of M. tuberculosis infection with H4:IC31 vaccine or BCG revaccination. N. Engl. J. Med. 379, 138–149 (2018). This paper reports the results of a phase IIb prevention of Mtb infection trial and demonstrates that BCG revaccination affords significant protection against sustained IGRA conversion in South African adolescents who received BCG at birth.

  12. 12.

    Van Der Meeren, V. D. M. et al. Phase 2b controlled trial of M72/AS01E vaccine to prevent tuberculosis. N. Engl. J. Med. 379, 1621–1634 (2018). This phase IIb trial in IGRA-positive adults from three African countries demonstrates for the first time that a protein subunit TB vaccine candidate can protect against TB disease.

  13. 13.

    Cambier, C. J. et al. Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids. Nature 505, 218–222 (2014).

  14. 14.

    Shafiani, S., Tucker-Heard, G., Kariyone, A., Takatsu, K. & Urdahl, K. B. Pathogen-specific regulatory T cells delay the arrival of effector T cells in the lung during early tuberculosis. J. Exp. Med. 207, 1409–1420 (2010).

  15. 15.

    Ernst, J. D. Mechanisms of M. tuberculosis immune evasion as challenges to TB vaccine design. Cell Host Microbe 24, 34–42 (2018).

  16. 16.

    Reiley, W. W. et al. ESAT-6-specific CD4 T cell responses to aerosol Mycobacterium tuberculosis infection are initiated in the mediastinal lymph nodes. Proc. Natl Acad. Sci. USA 105, 10961–10966 (2008).

  17. 17.

    Poulsen, A. Some clinical features of tuberculosis. 1. Incubation period. Acta Tuberc. Scand. 24, 311–346 (1950).

  18. 18.

    Wallgren, A. The time-table of tuberculosis. Tubercle 29, 245–251 (1948).

  19. 19.

    Khader, S. A. et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat. Immunol. 8, 369–377 (2007).

  20. 20.

    Woodworth, J. S. et al. Subunit vaccine H56/CAF01 induces a population of circulating CD4 T cells that traffic into the Mycobacterium tuberculosis-infected lung. Mucosal Immunol. 10, 555–564 (2017).

  21. 21.

    Ahmed, M. et al. A novel nanoemulsion vaccine induces mucosal interleukin-17 responses and confers protection upon Mycobacterium tuberculosis challenge in mice. Vaccine 35, 4983–4989 (2017).

  22. 22.

    Dijkman, K. et al. Prevention of tuberculosis infection and disease by local BCG in repeatedly exposed rhesus macaques. Nat. Med. 25, 255–262 (2019). This paper demonstrates in an NHP model that mucosal BCG vaccination affords high-level protection against repeated, low-dose infection and identifies mucosal antigen-specific T H 1 cell and/or T H 17 cell and IgA responses as putative COP.

  23. 23.

    Nunes-Alves, C. et al. In search of a new paradigm for protective immunity to TB. Nat. Rev. Microbiol. 12, 289–299 (2014).

  24. 24.

    Sakai, S. et al. CD4 T cell-derived IFN-gamma plays a minimal role in control of pulmonary Mycobacterium tuberculosis infection and must be actively repressed by PD-1 to prevent lethal disease. PLOS Pathog. 12, e1005667 (2016).

  25. 25.

    Goldsack, L. & Kirman, J. R. Half-truths and selective memory: interferon gamma, CD4+ T cells and protective memory against tuberculosis. Tuberculosis (Edinb.) 87, 465–473 (2007).

  26. 26.

    Fletcher, H. A. et al. T cell activation is an immune correlate of risk in BCG vaccinated infants. Nat. Commun. 7, 11290 (2016). This paper investigates immunological correlates of risk of TB in infants who participated in the first phase IIb trial of the MVA85A vaccine candidate. BCG-specific IFNγ-expressing cells and Ag85A-specific IgG antibody titres correlate with low risk of progression to TB, while HLA-DR + CD4 + T cells correlate with high risk of progression to TB.

  27. 27.

    Tameris, M. et al. The candidate TB vaccine, MVA85A, induces highly durable Th1 responses. PLOS ONE 9, e87340 (2014).

  28. 28.

    Kagina, B. M. et al. Specific T cell frequency and cytokine expression profile do not correlate with protection against tuberculosis after bacillus Calmette-Guerin vaccination of newborns. Am. J. Respir. Crit. Care Med. 182, 1073–1079 (2010).

  29. 29.

    Sallin, M. A. et al. Host resistance to pulmonary Mycobacterium tuberculosis infection requires CD153 expression. Nat. Microbiol. 3, 1198–1205 (2018).

  30. 30.

    Billeskov, R., Vingsbo-Lundberg, C., Andersen, P. & Dietrich, J. Induction of CD8 T cells against a novel epitope in TB10.4: correlation with mycobacterial virulence and the presence of a functional region of difference-1. J. Immunol. 179, 3973–3981 (2007).

  31. 31.

    Lin, P. L. & Flynn, J. L. CD8 T cells and Mycobacterium tuberculosis infection. Semin. Immunopathol. 37, 239–249 (2015).

  32. 32.

    Chen, C. Y. et al. A critical role for CD8 T cells in a nonhuman primate model of tuberculosis. PLOS Pathog. 5, e1000392 (2009).

  33. 33.

    Lindenstrom, T., Aagaard, C., Christensen, D., Agger, E. M. & Andersen, P. High-frequency vaccine-induced CD8+ T cells specific for an epitope naturally processed during infection with Mycobacterium tuberculosis do not confer protection. Eur. J. Immunol. 44, 1699–1709 (2014).

  34. 34.

    Yang, J. D. et al. Mycobacterium tuberculosis-specific CD4+ and CD8+ T cells differ in their capacity to recognize infected macrophages. PLOS Pathog. 14, e1007060 (2018).

  35. 35.

    Nyendak, M. et al. Adenovirally-induced polyfunctional T cells do not necessarily recognize the infected target: lessons from a phase I trial of the AERAS-402 vaccine. Sci. Rep. 6, 36355 (2016).

  36. 36.

    Lu, L. L. et al. A functional role for antibodies in tuberculosis. Cell 167, 433–443 (2016).

  37. 37.

    Abebe, F. et al. IgA and IgG against Mycobacterium tuberculosis Rv2031 discriminate between pulmonary tuberculosis patients, Mycobacterium tuberculosis-infected and non-infected individuals. PLOS ONE 13, e0190989 (2018).

  38. 38.

    Portal-Celhay, C. et al. Mycobacterium tuberculosis EsxH inhibits ESCRT-dependent CD4+ T cell activation. Nat. Microbiol. 2, 16232 (2016).

  39. 39.

    Bold, T. D., Banaei, N., Wolf, A. J. & Ernst, J. D. Suboptimal activation of antigen-specific CD4+ effector cells enables persistence of M. tuberculosis in vivo. PLOS Pathog. 7, e1002063 (2011). This study demonstrates that Mtb is recognized in the first phase of infection in the mouse model by protective T cells recognizing the Ag85 antigen but that bacterial downregulation of this antigen allows bacterial persistence in the presence of antigen-specific T cells.

  40. 40.

    Srivastava, S., Grace, P. S. & Ernst, J. D. Antigen export reduces antigen presentation and limits T cell control of M. tuberculosis. Cell Host Microbe 19, 44–54 (2016).

  41. 41.

    Heimbeck, J. Incidence of tuberculosis in young adult women with special reference to employment. Br. J. Tuberculosis 32, 154–166 (1938).

  42. 42.

    Andrews, J. R. et al. Risk of progression to active tuberculosis following reinfection with Mycobacterium tuberculosis. Clin. Infect. Dis. 54, 784–791 (2012). This meta-analysis of 18 human studies from the pre-chemotherapeutic era suggests that prior Mtb infection provides high-level protection against risk of progression to TB disease when individuals in contact with patients with TB are exposed to Mtb again.

  43. 43.

    Cadena, A. M. et al. Concurrent infection with Mycobacterium tuberculosis confers robust protection against secondary infection in macaques. PLOS Pathog. 14, e1007305 (2018).

  44. 44.

    Kaushal, D. et al. Mucosal vaccination with attenuated Mycobacterium tuberculosis induces strong central memory responses and protects against tuberculosis. Nat. Commun. 6, 8533 (2015).

  45. 45.

    Mpande, C. A. M. et al. Functional, antigen-specific stem cell memory (TSCM) CD4+ T cells are induced by human Mycobacterium tuberculosis infection. Front. Immunol. 9, 324 (2018).

  46. 46.

    Boer, M. C. et al. KLRG1 and PD-1 expression are increased on T cells following tuberculosis-treatment and identify cells with different proliferative capacities in BCG-vaccinated adults. Tuberculosis (Edinb.) 97, 163–171 (2016).

  47. 47.

    Day, C. L. et al. Functional capacity of Mycobacterium tuberculosis-specific T cell responses in humans is associated with mycobacterial load. J. Immunol. 187, 2222–2232 (2011).

  48. 48.

    Rozot, V. et al. Combined use of Mycobacterium tuberculosis-specific CD4 and CD8 T cell responses is a powerful diagnostic tool of active tuberculosis. Clin. Infect. Dis. 60, 432–437 (2015).

  49. 49.

    Nikitina, I. Y. et al. Th1, Th17, and Th1Th17 lymphocytes during tuberculosis: Th1 lymphocytes predominate and appear as low-differentiated CXCR3+CCR6+ cells in the blood and highly differentiated CXCR3+/−CCR6- cells in the lungs. J. Immunol. 200, 2090–2103 (2018).

  50. 50.

    Jayaraman, P. et al. TIM3 mediates T cell exhaustion during Mycobacterium tuberculosis Infection. PLOS Pathog. 12, e1005490 (2016).

  51. 51.

    Reiley, W. W. et al. Distinct functions of antigen-specific CD4 T cells during murine Mycobacterium tuberculosis infection. Proc. Natl Acad. Sci. USA 107, 19408–19413 (2010).

  52. 52.

    Lindenstrom, T., Knudsen, N. P., Agger, E. M. & Andersen, P. Control of chronic Mycobacterium tuberculosis infection by CD4 KLRG1- IL-2-secreting central memory cells. J. Immunol. 190, 6311–6319 (2013). This study demonstrates the importance of vaccine-promoted T CM cells in the long-term maintenance of protection against chronic Mtb infection in the mouse model.

  53. 53.

    Orme, I. M. The Achilles heel of BCG. Tuberculosis (Edinb.) 90, 329–332 (2010).

  54. 54.

    Lindenstrom, T. et al. T cells primed by live mycobacteria versus a tuberculosis subunit vaccine exhibit distinct functional properties. EBioMedicine 27, 27–39 (2018). This study demonstrates that live mycobacteria (either Mtb or BCG) prime T cells in mice that are more differentiated than T cells induced in response to subunit vaccines and that this difference has profound influence on the migration of the Mtb-specific T cells to the lung parenchyma.

  55. 55.

    Sakai, S. et al. Cutting edge: control of Mycobacterium tuberculosis infection by a subset of lung parenchyma-homing CD4 T cells. J. Immunol. 192, 2965–2969 (2014). This paper is the first to demonstrate that, in the mouse model, less differentiated KLRG1 CXCR3 + T CM cell-like cells readily migrate into the Mtb-infected lung parenchyma, in contrast to KLRG1 + CXCR3 T EFF cells.

  56. 56.

    Torrado, E. et al. Interleukin 27R regulates CD4+ T cell phenotype and impacts protective immunity during Mycobacterium tuberculosis infection. J. Exp. Med. 212, 1449–1463 (2015).

  57. 57.

    Woodworth, J. S. et al. Protective CD4 T cells targeting cryptic epitopes of Mycobacterium tuberculosis resist infection-driven terminal differentiation. J. Immunol. 192, 3247–3258 (2014).

  58. 58.

    Sallin, M. A. et al. Th1 differentiation drives the accumulation of intravascular, non-protective CD4 T cells during tuberculosis. Cell Rep. 18, 3091–3104 (2017).

  59. 59.

    Behar, S. M., Carpenter, S. M., Booty, M. G., Barber, D. L. & Jayaraman, P. Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: immunity interruptus. Semin. Immunol. 26, 559–577 (2014).

  60. 60.

    Urdahl, K. B. Understanding and overcoming the barriers to T cell-mediated immunity against tuberculosis. Semin. Immunol. 26, 578–587 (2014).

  61. 61.

    Rogerson, B. J. et al. Expression levels of Mycobacterium tuberculosis antigen-encoding genes versus production levels of antigen-specific T cells during stationary level lung infection in mice. Immunology 118, 195–201 (2006).

  62. 62.

    Shi, L., North, R. & Gennaro, M. L. Effect of growth state on transcription levels of genes encoding major secreted antigens of Mycobacterium tuberculosis in the mouse lung. Infect. Immun. 72, 2420–2424 (2004).

  63. 63.

    Moguche, A. O. et al. Antigen availability shapes T cell differentiation and function during tuberculosis. Cell Host Microbe 21, 695–706 (2017). This paper demonstrates that the Mtb antigens Ag85B and ESAT6 are differentially expressed during infection in mice and humans. CD4 + T cells that recognize these antigens exhibit distinct patterns of differentiation, and their capacities to mediate protective immunity are restricted in different ways.

  64. 64.

    Coscolla, M. et al. M. tuberculosis T cell epitope analysis reveals paucity of antigenic variation and identifies rare variable TB antigens. Cell Host Microbe 18, 538–548 (2015).

  65. 65.

    Woodworth, J. S. & Andersen, P. Reprogramming the T cell response to tuberculosis. Trends Immunol. 37, 81–83 (2016).

  66. 66.

    Comas, I. et al. Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved. Nat. Genet. 42, 498–503 (2010).

  67. 67.

    Harari, A., Vallelian, F. & Pantaleo, G. Phenotypic heterogeneity of antigen-specific CD4 T cells under different conditions of antigen persistence and antigen load. Eur. J. Immunol. 34, 3525–3533 (2004).

  68. 68.

    Vordermeier, H. M. et al. Correlation of ESAT-6-specific gamma interferon production with pathology in cattle following Mycobacterium bovis BCG vaccination against experimental bovine tuberculosis. Infect. Immun. 70, 3026–3032 (2002).

  69. 69.

    Langermans, J. A. et al. Divergent effect of bacillus Calmette-Guerin (BCG) vaccination on Mycobacterium tuberculosis infection in highly related macaque species: implications for primate models in tuberculosis vaccine research. Proc. Natl Acad. Sci. USA 98, 11497–11502 (2001).

  70. 70.

    Barber, D. L., Mayer-Barber, K. D., Feng, C. G., Sharpe, A. H. & Sher, A. CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition. J. Immunol. 186, 1598–1607 (2011).

  71. 71.

    Cruz, A. et al. Pathological role of interleukin 17 in mice subjected to repeated BCG vaccination after infection with Mycobacterium tuberculosis. J. Exp. Med. 207, 1609–1616 (2010).

  72. 72.

    Billeskov, R. et al. High antigen dose is detrimental to post-exposure vaccine protection against tuberculosis. Front. Immunol. 8, 1973 (2018).

  73. 73.

    World Health Organization. WHO statement on BCG revaccination for the prevention of tuberculosis. Bull. World Health Organ. 73, 805–806 (1995).

  74. 74.

    Rodrigues, L. C. et al. Effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: the BCG-REVAC cluster-randomised trial. Lancet 366, 1290–1295 (2005).

  75. 75.

    Karonga Prevention Trial Group. Randomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevention of leprosy and tuberculosis in Malawi. Lancet 348, 17–24 (1996).

  76. 76.

    Barreto, M. L. et al. Causes of variation in BCG vaccine efficacy: examining evidence from the BCG REVAC cluster randomized trial to explore the masking and the blocking hypotheses. Vaccine 32, 3759–3764 (2014). This analysis of the BCG REVAC cluster-randomized trial in Brazil reports some protection against TB in Salvador and no protection in Manaus and shows that variability in BCG efficacy was high when BCG was administered to children of school age but absent when BCG was administered at birth. The study suggests that prior immunological sensitization blocks, rather than masks, the protective effects of BCG.

  77. 77.

    Nemes, E. et al. Optimization and interpretation of serial QuantiFERON testing to measure acquisition of Mycobacterium tuberculosis infection. Am. J. Respir. Crit. Care Med. 196, 638–648 (2017).

  78. 78.

    Dye, C. Making wider use of the world’s most widely used vaccine: bacille Calmette-Guerin revaccination reconsidered. J. R. Soc. Interface 10, 20130365 (2013). This paper discusses the considerations around strategies for utilizing BCG revaccination to achieve higher levels of protection against TB in different parts of the world.

  79. 79.

    Suliman, S. et al. Dose optimization of H56:IC31 vaccine for TB endemic populations: a double-blind, placebo-controlled, dose-selection trial. Am. J. Respir. Crit. Care Med. 199, 220–231 (2018).

  80. 80.

    Day, C. L. et al. Induction and regulation of T cell immunity by the novel tuberculosis vaccine M72/AS01 in South African adults. Am. J. Respir. Crit. Care Med. 188, 492–502 (2013).

  81. 81.

    Penn-Nicholson, A. et al. Safety and immunogenicity of candidate vaccine M72/AS01E in adolescents in a TB endemic setting. Vaccine 33, 4025–4034 (2015).

  82. 82.

    Rodo, M. J. et al. A comparison of antigen-specific T cell responses induced by six novel tuberculosis vaccine candidates. PLOS Pathog. 15, e1007643 (2019).

  83. 83.

    Macleod, M. Learning lessons from MVA85A, a failed booster vaccine for BCG. BMJ 360, k66 (2018).

  84. 84.

    Billeskov, R., Christensen, J. P., Aagaard, C., Andersen, P. & Dietrich, J. Comparing adjuvanted H28 and modified vaccinia virus ankara expressing H28 in a mouse and a non-human primate tuberculosis model. PLOS ONE 8, e72185 (2013).

  85. 85.

    Leung-Theung-Long, S. et al. A novel MVA-based multiphasic vaccine for prevention or treatment of tuberculosis induces broad and multifunctional cell-mediated immunity in mice and primates. PLOS ONE 10, e0143552 (2015).

  86. 86.

    Hansen, S. G. et al. Prevention of tuberculosis in rhesus macaques by a cytomegalovirus-based vaccine. Nat. Med. 24, 130–143 (2018). This study demonstrates in NHPs that a novel, cytomegalovirus-based TB vaccine candidate provides high-level protection against Mtb infection, disease progression and disease pathology.

  87. 87.

    Dietrich, J., Billeskov, R., Doherty, T. M. & Andersen, P. Synergistic effect of bacillus Calmette Guerin and a tuberculosis subunit vaccine in cationic liposomes: increased immunogenicity and protection. J. Immunol. 178, 3721–3730 (2007).

  88. 88.

    Brosch, R. et al. Genome plasticity of BCG and impact on vaccine efficacy. Proc. Natl Acad. Sci. USA 104, 5596–5601 (2007).

  89. 89.

    Behr, M. A. et al. Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science 284, 1520–1523 (1999).

  90. 90.

    Nieuwenhuizen, N. E. & Kaufmann, S. H. E. Next-generation vaccines based on bacille Calmette-Guerin. Front. Immunol. 9, 121 (2018).

  91. 91.

    Scriba, T. J. et al. Vaccination against tuberculosis with whole-cell mycobacterial vaccines. J. Infect. Dis. 214, 659–664 (2016).

  92. 92.

    Kaufmann, E. et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell 172, 176–190 (2018).

  93. 93.

    Fine, P. E. Variation in protection by BCG: implications of and for heterologous immunity. Lancet 346, 1339–1345 (1995).

  94. 94.

    Abubakar, I. et al. Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guerin vaccination against tuberculosis. Health Technol. Assess. 17, 1–372 (2013).

  95. 95.

    Aronson, N. E. et al. Long-term efficacy of BCG vaccine in American Indians and Alaska Natives: a 60-year follow-up study. JAMA 291, 2086–2091 (2004).

  96. 96.

    Nguipdop-Djomo, P., Heldal, E., Rodrigues, L. C., Abubakar, I. & Mangtani, P. Duration of BCG protection against tuberculosis and change in effectiveness with time since vaccination in Norway: a retrospective population-based cohort study. Lancet Infect. Dis. 16, 219–226 (2016).

  97. 97.

    Palmer, C. E. & Long, M. W. Effects of infection with atypical mycobacteria on BCG vaccination and tuberculosis. Am. Rev. Respir. Dis. 94, 553–568 (1966).

  98. 98.

    Mangtani, P. et al. Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials. Clin. Infect. Dis. 58, 470–480 (2014).

  99. 99.

    Andersen, P. & Doherty, T. M. The success and failure of BCG - implications for a novel tuberculosis vaccine. Nat. Rev. Microbiol. 3, 656–662 (2005).

  100. 100.

    Hoefsloot, W. et al. The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study. Eur. Respir. J. 42, 1604–1613 (2013).

  101. 101.

    von Reyn, C. F. BCG, latitude, and environmental mycobacteria. Clin. Infect. Dis. 59, 607–608 (2014).

  102. 102.

    Qin, L., Gilbert, P. B., Corey, L., McElrath, M. J. & Self, S. G. A framework for assessing immunological correlates of protection in vaccine trials. J. Infect. Dis. 196, 1304–1312 (2007).

  103. 103.

    Jasenosky, L. D., Scriba, T. J., Hanekom, W. A. & Goldfeld, A. E. T cells and adaptive immunity to Mycobacterium tuberculosis in humans. Immunol. Rev. 264, 74–87 (2015).

  104. 104.

    Voss, G. et al. Progress and challenges in TB vaccine development. F1000Res. 7, 199 (2018).

  105. 105.

    Nieuwenhuizen, N. E. et al. The recombinant bacille Calmette-Guerin vaccine VPM1002: ready for clinical efficacy testing. Front. Immunol. 8, 1147 (2017).

  106. 106.

    Loxton, A. G. et al. Safety and immunogenicity of the recombinant Mycobacterium bovis BCG vaccine VPM1002 in HIV-unexposed newborn infants in South Africa. Clin. Vaccine Immunol. 24, e00439-16 (2017).

  107. 107.

    Arbues, A. et al. Construction, characterization and preclinical evaluation of MTBVAC, the first live-attenuated M. tuberculosis-based vaccine to enter clinical trials. Vaccine 31, 4867–4873 (2013).

  108. 108.

    Aguilo, N. et al. Reactogenicity to major tuberculosis antigens absent in BCG is linked to improved protection against Mycobacterium tuberculosis. Nat. Commun. 8, 16085 (2017).

  109. 109.

    Spertini, F. et al. Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial. Lancet Respir. Med. 3, 953–962 (2015).

  110. 110.

    Cardona, P. J. RUTI: a new chance to shorten the treatment of latent tuberculosis infection. Tuberculosis (Edinb.) 86, 273–289 (2006).

  111. 111.

    Nell, A. S. et al. Safety, tolerability, and immunogenicity of the novel antituberculous vaccine RUTI: randomized, placebo-controlled phase II clinical trial in patients with latent tuberculosis infection. PLOS ONE 9, e89612 (2014).

  112. 112.

    Lahey, T. et al. Immunogenicity of a protective whole cell mycobacterial vaccine in HIV-infected adults: a phase III study in Tanzania. Vaccine 28, 7652–7658 (2010).

  113. 113.

    von Reyn, C. F. et al. Prevention of tuberculosis in bacille Calmette-Guerin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine. AIDS 24, 675–685 (2010).

  114. 114.

    Sharma, S. K. et al. Efficacy and safety of Mycobacterium indicus pranii as an adjunct therapy in category II pulmonary tuberculosis in a randomized trial. Sci. Rep. 7, 3354 (2017).

  115. 115.

    Mayosi, B. M. et al. Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis. N. Engl. J. Med. 371, 1121–1130 (2014).

  116. 116.

    Leroux-Roels, I. et al. Improved CD4+ T cell responses to Mycobacterium tuberculosis in PPD-negative adults by M72/AS01 as compared to the M72/AS02 and Mtb72F/AS02 tuberculosis candidate vaccine formulations: a randomized trial. Vaccine 31, 2196–2206 (2013).

  117. 117.

    Dietrich, J. et al. 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, 6332–6339 (2005).

  118. 118.

    Szabo, A. et al. The two-component adjuvant IC31® boosts type I interferon production of human monocyte-derived dendritic cells via ligation of endosomal TLRs. PLOS ONE 8, e55264 (2013).

  119. 119.

    Aagaard, C. et al. A multistage tuberculosis vaccine that confers efficient protection before and after exposure. Nat. Med. 17, 189–194 (2011).

  120. 120.

    Hoang, T. et al. ESAT-6 (EsxA) and TB10.4 (EsxH) based vaccines for pre- and post-exposure tuberculosis vaccination. PLOS ONE 8, e80579 (2013).

  121. 121.

    Lin, P. L. et al. The multistage vaccine H56 boosts the effects of BCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection. J. Clin. Invest. 122, 303–314 (2012).

  122. 122.

    Luabeya, A. K. et al. First-in-human trial of the post-exposure tuberculosis vaccine H56:IC31 in Mycobacterium tuberculosis infected and non-infected healthy adults. Vaccine 33, 4130–4140 (2015).

  123. 123.

    Coler, R. N. et al. The TLR-4 agonist adjuvant, GLA-SE, improves magnitude and quality of immune responses elicited by the ID93 tuberculosis vaccine: first-in-human trial. NPJ Vaccines 3, 34 (2018).

  124. 124.

    Penn-Nicholson, A. et al. Safety and immunogenicity of the novel tuberculosis vaccine ID93 + GLA-SE in BCG-vaccinated healthy adults in South Africa: a randomised, double-blind, placebo-controlled phase 1 trial. Lancet Respir. Med. 6, 287–298 (2018).

  125. 125.

    Satti, I. et al. Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trial. Lancet Infect. Dis. 14, 939–946 (2014).

  126. 126.

    Scriba, T. J. et al. Dose-finding study of the novel tuberculosis vaccine, MVA85A, in healthy BCG-vaccinated infants. J. Infect. Dis. 203, 1832–1843 (2011).

  127. 127.

    Jeyanathan, M. et al. Induction of an immune-protective T-cell repertoire with diverse genetic coverage by a novel viral-vectored tuberculosis vaccine in humans. J. Infect. Dis. 214, 1996–2005 (2016).

Download references


The authors thank P. Højlund for expert secretarial assistance, K. Korsholm for the graphical layout and R. Mortensen and J. Woodworth for valuable discussions and input on the content of the paper.

Reviewer information

Nature Reviews Immunology thanks P.-J. Cardona and other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

The authors contributed equally to all aspects of the article.

Competing interests

T.J.S. declares no competing interests. P.A. is a named co-inventor on patents covering the H56:IC31 tuberculosis vaccine. The patents are assigned to the Statens Serum Institute, a not for profit organization under the Danish Ministry of Health.

Correspondence to Peter Andersen or Thomas J. Scriba.


Incipient TB

A state of Mycobacterium tuberculosis infection in which the host is likely to progress to active tuberculosis (TB) disease but has not yet manifested clinical symptoms, radiographic abnormalities or microbiological evidence of active disease. Can be detected using transcriptomic or proteomic biomarkers of inflammation.

Subclinical TB

A state of Mycobacterium tuberculosis infection in which the host has radiographic abnormalities or microbiological evidence of active tuberculosis (TB) disease but has not yet manifested clinical symptoms of active disease.

Priming vaccines

Vaccines that mediate sensitization or stimulation of an immune response with antigen for the first time; that is, the vaccines prime the immune response.

Booster vaccines

Vaccines that are typically given after an earlier priming vaccine and further stimulate an immune response that already exists to an antigen to increase the response magnitude or modulate the function of the response; that is, the vaccines boost the pre-existing immune response.

Correlates of protection

(COP). A measurable feature, often a functional characteristic of an immune response, that associates with protection against becoming infected and/or developing disease.

ELISpot assay

(Enzyme-linked immunosorbent spot assay). A type of immune assay that quantifies the frequency of protein-secreting single cells on the basis of enzyme-linked detection of protein spots on immune-absorbent membranes.

Inducible bronchus-associated lymphoid tissue

A tertiary lymphoid structure that consists of lymphoid follicles in the lungs or bronchus and that is a site for priming immune responses.

Reactivation TB

Also known as post-primary tuberculosis (TB) or secondary TB; TB that typically occurs months to years after the initial infection and is associated with distinct disease manifestation compared to primary TB. Reactivation frequently occurs in the setting of weakened immunity and usually involves the lung apex.


The formation of a cavity in the centre of a tuberculosis (TB) nodule or area of consolidation, usually in the upper lung or apex. Cavities may be detected by chest radiography or computed tomography and are a characteristic feature of post-primary or adult type TB.

Chemotherapy for active TB

Drug-sensitive tuberculosis (TB) disease is typically treated with a 4-drug regimen of rifampicin, isoniazid, pyrazinamide and ethambutol for 2 months (the intensive phase of treatment), followed by isoniazid and rifampicin for 4 months (the continuation phase).

IFNγ release assay

(IGRA). A test for infection with Mycobacterium tuberculosis (Mtb) that measures IFNγ release by T cells after stimulation of blood or peripheral blood mononuclear cells with Mtb-specific peptides. IGRA conversion is an efficacy outcome in clinical trials that test prevention of Mtb infection, defined as conversion to a positive test without reversion to negative status in the next 2 consecutive IGRA tests, 3 months apart (that is, 3 consecutive positive IGRA results).

Rights and permissions

Reprints and Permissions

About this article

Fig. 1: The balance between Mtb-specific T cell differentiation into either T effector memory or T central memory cells.
Fig. 2: The effects of immunological sensitization to mycobacteria on vaccine efficacy.