Antibodies and tuberculosis: finally coming of age?

Article metrics


Are antibodies important for protection against tuberculosis? The jury has been out for more than 100 years. B cell depletion in experimental Mycobacterium tuberculosis infection failed to identify a major role for these cells in immunity to tuberculosis. However, recent identification of naturally occurring antibodies in humans that are protective during M. tuberculosis infection has reignited the debate. Here, we discuss the evidence for a protective role for antibodies in tuberculosis and consider the feasibility of designing novel tuberculosis vaccines targeting humoral immunity.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Potential mechanisms of antibody-mediated protection against Mycobacterium tuberculosis.
Fig. 2: Potential CD4+ T cell-dependent mechanisms of antibody-mediated protection.


  1. 1.

    Kaufmann, S. H. et al. Progress in tuberculosis vaccine development and host-directed therapies—a state of the art review. Lancet Respir. Med. 2, 301–320 (2014).

  2. 2.

    Chen, T. et al. Association of human antibodies to arabinomannan with enhanced mycobacterial opsonophagocytosis and intracellular growth reduction. J. Infecti. Diseases 214, 300–310 (2016).

  3. 3.

    Li, H. et al. Latently and uninfected healthcare workers exposed to TB make protective antibodies against Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 114, 5023–5028 (2017).

  4. 4.

    Lu, L. L. et al. A functional role for antibodies in tuberculosis. Cell 167, 433–443.e414 (2016).

  5. 5.

    Zimmermann, N. et al. Human isotype-dependent inhibitory antibody responses against Mycobacterium tuberculosis. EMBO Mol. Med. 8, 1325–1339 (2016).

  6. 6.

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

  7. 7.

    World Health Organization. Global Tuberculosis Report 2017. WHO http://www.who.int/tb/publications/global_report/en/ (2017).

  8. 8.

    Casadevall, A. & Scharff, M. D. Return to the past: the case for antibody-based therapies in infectious diseases. Clin. Infect. Dis. 21, 150–161 (1995).

  9. 9.

    Glatman-Freedman, A. & Casadevall, A. Serum therapy for tuberculosis revisited: reappraisal of the role of antibody-mediated immunity against Mycobacterium tuberculosis. Clin. Microbiol. Rev. 11, 514–532 (1998).

  10. 10.

    Cooper, A. M. Mouse model of tuberculosis. Cold Spring Harb. Perspect. Med. 5, a018556 (2015).

  11. 11.

    Havlir, D. V. & Barnes, P. F. Tuberculosis in patients with human immunodeficiency virus infection. N. Engl. J. Med. 340, 367–373 (1999).

  12. 12.

    Maglione, P. J., Xu, J. & Chan, J. B cells moderate inflammatory progression and enhance bacterial containment upon pulmonary challenge with Mycobacterium tuberculosis. J. Immunol. 178, 7222–7234 (2007).

  13. 13.

    Vordermeier, H. M., Venkataprasad, N., Harris, D. P. & Ivanyi, J. Increase of tuberculous infection in the organs of B cell-deficient mice. Clin. Exp. Immunol. 106, 312–316 (1996).

  14. 14.

    Phuah, J. Y., Mattila, J. T., Lin, P. L. & Flynn, J. L. Activated B cells in the granulomas of nonhuman primates infected with Mycobacterium tuberculosis. Am. J. Pathol. 181, 508–514 (2012).

  15. 15.

    Phuah, J. et al. Effects of B cell depletion on early Mycobacterium tuberculosis infection in cynomolgus macaques. Infect. Immun. 84, 1301–1311 (2016).

  16. 16.

    Achkar, J. M. & Casadevall, A. Antibody-mediated immunity against tuberculosis: implications for vaccine development. Cell Host Microbe 13, 250–262 (2013).

  17. 17.

    Balu, S. et al. A novel human IgA monoclonal antibody protects against tuberculosis. J. Immunol. 186, 3113–3119 (2011).

  18. 18.

    Buccheri, S. et al. Prevention of the post-chemotherapy relapse of tuberculous infection by combined immunotherapy. Tuberculosis 89, 91–94 (2009).

  19. 19.

    Hamasur, B. et al. A mycobacterial lipoarabinomannan specific monoclonal antibody and its F(ab’) fragment prolong survival of mice infected with Mycobacterium tuberculosis. Clin. Exp. Immunol. 138, 30–38 (2004).

  20. 20.

    Pethe, K. et al. The heparin-binding haemagglutinin of M. tuberculosis is required for extrapulmonary dissemination. Nature 412, 190–194 (2001).

  21. 21.

    Teitelbaum, R. et al. A mAb recognizing a surface antigen of Mycobacterium tuberculosis enhances host survival. Proc. Natl Acad. Sci. USA 95, 15688–15693 (1998).

  22. 22.

    Guirado, E. et al. Passive serum therapy with polyclonal antibodies against Mycobacterium tuberculosis protects against post-chemotherapy relapse of tuberculosis infection in SCID mice. Microbes Infect. 8, 1252–1259 (2006).

  23. 23.

    Roy, E. et al. Therapeutic efficacy of high-dose intravenous immunoglobulin in Mycobacterium tuberculosis infection in mice. Infect. Immun. 73, 6101–6109 (2005).

  24. 24.

    Forget, A., Benoit, J. C., Turcotte, R. & Gusew-Chartrand, N. Enhancement activity of anti-mycobacterial sera in experimental Mycobacterium bovis (BCG) infection in mice. Infect. Immun. 13, 1301–1306 (1976).

  25. 25.

    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).

  26. 26.

    Beveridge, N. E. et al. Immunisation with BCG and recombinant MVA85A induces long-lasting, polyfunctional Mycobacterium tuberculosis-specific CD4+ memory T lymphocyte populations. Eur. J. Immunol. 37, 3089–3100 (2007).

  27. 27.

    Beverley, P. Selective presentation of MVA85A tuberculosis booster vaccine preclinical animal data. Int. J. Epidemiol. 45, 581–582 (2016).

  28. 28.

    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).

  29. 29.

    Burton, D. R. & Hangartner, L. Broadly neutralizing antibodies to HIV and Their role in vaccine design. Annu. Rev. Immunol. 34, 635–659 (2016).

  30. 30.

    Costello, A. M. et al. Does antibody to mycobacterial antigens, including lipoarabinomannan, limit dissemination in childhood tuberculosis? Trans. R. Soc. Trop. Med. Hyg. 86, 686–692 (1992).

  31. 31.

    Chu, H. et al. Risk of tuberculosis among healthcare workers in an intermediate-burden country: a nationwide population study. J. Infect. 69, 525–532 (2014).

  32. 32.

    Zhou, F. et al. Latent tuberculosis infection and occupational protection among health care workers in two types of public hospitals in China. PLOS One 9, e104673 (2014).

  33. 33.

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

  34. 34.

    Prados-Rosales, R. et al. The type of growth medium affects the presence of a mycobacterial capsule and is associated with differences in protective efficacy of BCG vaccination against Mycobacterium tuberculosis. J. Infecti. Diseases 214, 426–437 (2016).

  35. 35.

    Cole, S. T. et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537–544 (1998).

  36. 36.

    Sani, M. et al. Direct visualization by cryo-EM of the mycobacterial capsular layer: a labile structure containing ESX-1-secreted proteins. PLoS Pathog. 6, e1000794 (2010).

  37. 37.

    Deng, J. et al. Mycobacterium tuberculosis proteome microarray for global studies of protein function and immunogenicity. Cell Rep. 9, 2317–2329 (2014).

  38. 38.

    Prados-Rosales, R. et al. Enhanced control of Mycobacterium tuberculosis extrapulmonary dissemination in mice by an arabinomannan-protein conjugate vaccine. PLoS Pathog. 13, e1006250 (2017).

  39. 39.

    Shin, H. J., Franco, L. H., Nair, V. R., Collins, A. C. & Shiloh, M. U. A baculovirus-conjugated mimotope vaccine targeting Mycobacterium tuberculosis lipoarabinomannan. PLOS One 12, e0185945 (2017).

  40. 40.

    Bournazos, S. et al. Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell 158, 1243–1253 (2014).

  41. 41.

    Olivares, N. et al. The protective effect of immunoglobulin in murine tuberculosis is dependent on IgG glycosylation. Pathog. Dis. 69, 176–183 (2013).

  42. 42.

    Li, H., Wu, M., Shi, Y. & Javid, B. Over-expression of the mycobacterial trehalose-phosphate phosphatase OtsB2 results in a defect in macrophage phagocytosis associated with increased mycobacterial-macrophage adhesion. Front. Microbiol. 7, 1754 (2016).

  43. 43.

    Bogaert, D., Sluijter, M., De Groot, R. & Hermans, P. W. Multiplex opsonophagocytosis assay (MOPA): a useful tool for the monitoring of the 7-valent pneumococcal conjugate vaccine. Vaccine 22, 4014–4020 (2004).

  44. 44.

    Armstrong, J. A. & Hart, P. D. Phagosome-lysosome interactions in cultured macrophages infected with virulent tubercle bacilli. Reversal of the usual nonfusion pattern and observations on bacterial survival. J. Exp. Med. 142, 1–16 (1975).

  45. 45.

    Kumar, S. K., Singh, P. & Sinha, S. Naturally produced opsonizing antibodies restrict the survival of Mycobacterium tuberculosis in human macrophages by augmenting phagosome maturation. Open Biol. 5, 150171 (2015).

  46. 46.

    Wahid, R. et al. Live oral Salmonella enterica serovar Typhi vaccines Ty21a and CVD 909 induce opsonophagocytic functional antibodies in humans that cross-react with S. Paratyphi A and S. Paratyphi B. Clin. Vaccine Immunol. 21, 427–434 (2014).

  47. 47.

    McSorley, S. J. & Jenkins, M. K. Antibody is required for protection against virulent but not attenuated Salmonella enterica serovar typhimurium. Infect. Immun. 68, 3344–3348 (2000).

  48. 48.

    van Els, C. et al. Fast vaccine design and development based on correlates of protection (COPs). Hum. Vaccin Immunother. 10, 1935–1948 (2014).

  49. 49.

    Corey, L. et al. Immune correlates of vaccine protection against HIV-1 acquisition. Science Transl Med. 7, 310rv7 (2015).

  50. 50.

    Karp, C. L., Wilson, C. B. & Stuart, L. M. Tuberculosis vaccines: barriers and prospects on the quest for a transformative tool. Immunol. Rev. 264, 363–381 (2015).

  51. 51.

    Su, H. W. et al. The essential mycobacterial amidotransferase GatCAB is a modulator of specific translational fidelity. Nat. Microbiol. 1, 16147 (2016).

  52. 52.

    Riley, R. L. et al. Aerial dissemination of pulmonary tuberculosis. A two-year study of contagion in a tuberculosis ward. 1959. Am. J. Epidemiol. 142, 3–14 (1995).

  53. 53.

    Saini, D. et al. Ultra-low dose of Mycobacterium tuberculosis aerosol creates partial infection in mice. Tuberculosis 92, 160–165 (2012).

  54. 54.

    Gautam, R. et al. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 533, 105–109 (2016).

  55. 55.

    Calderon, V. E. et al. A humanized mouse model of tuberculosis. PLOS One 8, e63331 (2013).

  56. 56.

    Grover, A. et al. Humanized NOG mice as a model for tuberculosis vaccine-induced immunity: a comparative analysis with the mouse and guinea pig models of tuberculosis. Immunology 152, 150–162 (2017).

  57. 57.

    Gengenbacher, M., Nieuwenhuizen, N. E. & Kaufmann, S. BCG — old workhorse, new skills. Curr. Opin. Immunol. 47, 8–16 (2017).

  58. 58.

    Maiello, P. et al. Rhesus macaques are more susceptible to progressive tuberculosis than cynomolgus macaques: a quantitative comparison. Infect. Immun. 86, e00505-17 (2017).

  59. 59.

    Sauerwein, R. W., Roestenberg, M. & Moorthy, V. S. Experimental human challenge infections can accelerate clinical malaria vaccine development. Nat. Rev. Immunol. 11, 57–64 (2011).

  60. 60.

    Collins, A. M. et al. First human challenge testing of a pneumococcal vaccine. Double-blind randomized controlled trial. Am. J. Respiratory Crit. Care Med. 192, 853–858 (2015).

  61. 61.

    Dobinson, H. C. et al. Evaluation of the clinical and microbiological response to Salmonella Paratyphi A infection in the first paratyphoid human challenge model. Clin. Infect. Dis. 64, 1066–1073 (2017).

  62. 62.

    Kirkpatrick, B. D. et al. The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model. Sci. Transl Med. 8, 330ra336 (2016).

  63. 63.

    Garcon, N., Heppner, D. G. & Cohen, J. Development of RTS,S/AS02: a purified subunit-based malaria vaccine candidate formulated with a novel adjuvant. Expert Rev. Vaccines 2, 231–238 (2003).

  64. 64.

    Ackerman, M. E., Barouch, D. H. & Alter, G. Systems serology for evaluation of HIV vaccine trials. Immunol. Rev. 275, 262–270 (2017).

  65. 65.

    Vaccari, M. et al. Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition. Nature Med. 22, 762–770 (2016).

  66. 66.

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

  67. 67.

    Salazar, G., Zhang, N., Fu, T. M. & An, Z. Antibody therapies for the prevention and treatment of viral infections. NPJ Vaccines 2, 19 (2017).

  68. 68.

    Cardona, P. J. The progress of therapeutic vaccination with regard to tuberculosis. Front. Microbiol. 7, 1536 (2016).

Download references


This work was in part funded by a grant from the National Science Foundation of China (81661128044) to B.J. B.J. is a Wellcome Trust Investigator.

Reviewer information

Nature Reviews Immunology thanks S. Kaufmann and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Both authors contributed to researching data, discussion of content and the writing of the article. B.J. reviewed and edited the manuscript before submission.

Correspondence to Babak Javid.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading