Clinical and Experimental Vaccine Research

The Korean Vaccine Society (대한백신학회)
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The BCG vaccine, advantages, and disadvantages of introducing new generation vaccines against Mycobacterium tuberculosis

  • Marzie Mahdizade Ari (Department of Microbiology, School of Medicine, Iran University of Medical Sciences) ;
  • Masoumeh Beig (Department of Bacteriology, Pasteur Institute of Iran) ;
  • Mohammad Sholeh (Department of Bacteriology, Pasteur Institute of Iran) ;
  • Majid Khoshmirsafa (Department of Microbiology, School of Medicine, Iran University of Medical Sciences)
  • Received : 2023.10.29
  • Accepted : 2024.03.29
  • Published : 2024.07.31
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Abstract

Tuberculosis (TB) is consistently ranked among the deadliest diseases worldwide, causing millions of deaths annually. Mycobacterium tuberculosis is the causative agent for this infection. Different antibiotics and vaccines have been discussed as potential treatments and prevention. Currently, there is only one licensed vaccine against TB, Bacillus Calmette-Guérin (BCG). Despite its protective efficacy against TB in children, BCG has failed to protect adults against pulmonary TB, lacks therapeutic value, and can cause complications in immunocompromised individuals. In this review, BCG, the most widely administered vaccine, is discussed, and the newest vaccines available in medicine are discussed. Based on the restrictions that prevent optimal BCG efficacy and the vaccines that are now being tested in various clinical studies, some criteria need to be considered in designing future vaccines.

Keywords

Acknowledgement

We want to thank the personnel of the Department of Microbiology of Iran University of Medical Sciences and the Bacteriology Department of the Pasteur Institute of Iran for their assistance.

References

  1. Kaufmann SH. Envisioning future strategies for vaccination against tuberculosis. Nat Rev Immunol 2006;6:699-704. https://doi.org/10.1038/nri1920
  2. Torrado E, Robinson RT, Cooper AM. Cellular response to mycobacteria: balancing protection and pathology. Trends Immunol 2011;32:66-72.
  3. Rohde K, Yates RM, Purdy GE, Russell DG. Mycobacterium tuberculosis and the environment within the phagosome. Immunol Rev 2007;219:37-54. https://doi.org/10.1111/j.1600-065X.2007.00547.x
  4. Jouanguy E, Lamhamedi-Cherradi S, Altare F, et al. Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guerin infection and a sibling with clinical tuberculosis. J Clin Invest 1997;100:2658-64. https://doi.org/10.1172/JCI119810
  5. Gengenbacher M, Kaufmann SH. Mycobacterium tuberculosis: success through dormancy. FEMS Microbiol Rev 2012;36:514-32. https://doi.org/10.1111/j.1574-6976.2012.00331.x
  6. Mills KH. Regulatory T cells: friend or foe in immunity to infection? Nat Rev Immunol 2004;4:841-55. https://doi.org/10.1038/nri1485
  7. StockP,AkbariO,BerryG, FreemanGJ,DekruyffRH,Umetsu DT. Induction of T helper type 1-like regulatory cells that express Foxp3 and protect against airway hyper-reactivity. Nat Immunol 2004;5:1149-56. https://doi.org/10.1038/ni1122
  8. Wilkinson KA, Wilkinson RJ, Pathan A, et al. Ex vivo characterization of early secretory antigenic target 6-specific T cells at sites of active disease in pleural tuberculosis. Clin Infect Dis 2005;40:184-7.
  9. Hisaeda H, Maekawa Y, Iwakawa D, et al. Escape of malaria parasites from host immunity requires CD4+ CD25+ regulatory T cells. Nat Med 2004;10:29-30. https://doi.org/10.1038/nm975
  10. Richeldi L, Ewer K, Losi M, et al. T cell-based tracking of multidrug resistant tuberculosis infection after brief exposure. Am J Respir Crit Care Med 2004;170:288-95. https://doi.org/10.1164/rccm.200403-307OC
  11. Kaufmann SH. Tuberculosis vaccine development: strength lies in tenacity. Trends Immunol 2012;33:373-9. https://doi.org/10.1016/j.it.2012.03.004
  12. Wangoo A, Sparer T, Brown IN, et al. Contribution of Th1 and Th2 cells to protection and pathology in experimental models of granulomatous lung disease. J Immunol 2001;166:3432-9. https://doi.org/10.4049/jimmunol.166.5.3432
  13. Tramontana JM, Utaipat U, Molloy A, et al. Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis. Mol Med 1995;1:384-97. https://doi.org/10.1007/BF03401576
  14. Hernandez-Pando R, Aguilar D, Hernandez ML, Orozco H, Rook G. Pulmonary tuberculosis in BALB/c mice with non-functional IL-4 genes: changes in the inflammatory effects of TNF-alpha and in the regulation of fibrosis. Eur J Immunol 2004;34:174-83.
  15. Pina A, Valente-Ferreira RC, Molinari-Madlum EE, Vaz CA, Keller AC, Calich VL. Absence of interleukin-4 determines less severe pulmonary paracoccidioidomycosis associated with impaired Th2 response. Infect Immun 2004;72:2369-78. https://doi.org/10.1128/IAI.72.4.2369-2378.2004
  16. Voskuil MI, Schnappinger D, Visconti KC, et al. Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. J Exp Med 2003;198:705-13. https://doi.org/10.1084/jem.20030205
  17. Zuany-Amorim C, Sawicka E, Manlius C, et al. Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med 2002;8:625-9.
  18. Koch R. Fortsetzung der Mittheilungen uber ein Heilmittel gegen Tuberculose [Continuation of the reports on a remedy for tuberculosis]. Dtsch Med Wochenschr 1891;17:101-2. https://doi.org/10.1055/s-0029-1206198
  19. Anderson M. On Koch's treatment. Lancet 1891;137:P651-2. https://doi.org/10.1016/S0140-6736(02)18484-4
  20. World Health Organization. Global tuberculosis report 2013. Geneva: World Health Organization; 2013.
  21. Kaufmann SH. Recent findings in immunology give tuberculosis vaccines a new boost. Trends Immunol 2005;26:660-7. https://doi.org/10.1016/j.it.2005.09.012
  22. Ulrichs T, Kaufmann SH. New insights into the function of granulomas in human tuberculosis. J Pathol 2006;208:261-9. https://doi.org/10.1002/path.1906
  23. Mahmoudi S, Khaheshi S, Pourakbari B, et al. Adverse reactions to Mycobacterium bovis bacille Calmette-Guerin vaccination against tuberculosis in Iranian children. Clin Exp Vaccine Res 2015;4:195-9. https://doi.org/10.7774/cevr.2015.4.2.195
  24. Fine PE. Variation in protection by BCG: implications of and for heterologous immunity. Lancet 1995;346:1339-45. https://doi.org/10.1016/S0140-6736(95)92348-9
  25. Fine PE, Floyd S, Stanford JL, et al. Environmental mycobacteria in northern Malawi: implications for the epidemiology of tuberculosis and leprosy. Epidemiol Infect 2001;126:379-87. https://doi.org/10.1017/S0950268801005532
  26. Dheda K, Chang JS, Breen RA, et al. In vivo and in vitro studies of a novel cytokine, interleukin 4delta2, in pulmonary tuberculosis. Am J Respir Crit Care Med 2005;172:501-8. https://doi.org/10.1164/rccm.200502-278OC
  27. Rook GA, Dheda K, Zumla A. Do successful tuberculosis vaccines need to be immunoregulatory rather than merely Th1-boosting? Vaccine 2005;23:2115-20. https://doi.org/10.1016/j.vaccine.2005.01.069
  28. Rook GA, Dheda K, Zumla A. Immune responses to tuberculosis in developing countries: implications for new vaccines. Nat Rev Immunol 2005;5:661-7. https://doi.org/10.1038/nri1666
  29. Vasiliev AM, Vasilenko RN, Kulikova NL, et al. Structural and functional properties of IL-4delta2, an alternative splice variant of human IL-4. J Proteome Res 2003;2:273-81. https://doi.org/10.1021/pr025586y
  30. Schoenen H, Bodendorfer B, Hitchens K, et al. Cutting edge: Mincle is essential for recognition and adjuvanticity of the mycobacterial cord factor and its synthetic analog trehalose-dibehenate. J Immunol 2010;184:2756-60. https://doi.org/10.4049/jimmunol.0904013
  31. Kim SH, Jang YS. Antigen targeting to M cells for enhancing the efficacy of mucosal vaccines. Exp Mol Med 2014;46:e85.
  32. Stewart E, Triccas JA, Petrovsky N. Adjuvant strategies for more effective tuberculosis vaccine immunity. Microorganisms 2019;7:255.
  33. Khoshnood S, Heidary M, Haeili M, et al. Novel vaccine candidates against Mycobacterium tuberculosis. Int J Biol Macromol 2018;120:180-8. https://doi.org/10.1016/j.ijbiomac.2018.08.037
  34. Walburger A, Koul A, Ferrari G, et al. Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science 2004;304:1800-4. https://doi.org/10.1126/science.1099384
  35. Caccamo N, Guggino G, Joosten SA, et al. Multifunctional CD4(+) T cells correlate with active Mycobacterium tuberculosis infection. Eur J Immunol 2010;40:2211-20. https://doi.org/10.1002/eji.201040455
  36. Aagaard C, Hoang TT, Izzo A, et al. Protection and poly-functional T cells induced by Ag85B-TB10.4/IC31 against Mycobacterium tuberculosis is highly dependent on the antigen dose. PLoS One 2009;4:e5930.
  37. Wang C, Chen Z, Fu R, et al. A DNA vaccine expressing CFP21 and MPT64 fusion protein enhances BCG-induced protective immunity against Mycobacterium tuberculosis infection in mice. Med Microbiol Immunol 2011;200:165-75. https://doi.org/10.1007/s00430-011-0188-z
  38. Kaufmann SH, Dockrell HM, Drager N, et al. TBVAC2020: advancing tuberculosis vaccines from discovery to clinical development. Front Immunol 2017;8:1203.
  39. Penn-Nicholson A, Tameris M, Smit E, 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 2018;6:287-98. https://doi.org/10.1016/S2213-2600(18)30077-8
  40. Penn-Nicholson A, Geldenhuys H, Burny W, et al. Safety and immunogenicity of candidate vaccine M72/AS01E in adolescents in aTBendemic setting.Vaccine 2015;33:4025-34. https://doi.org/10.1016/j.vaccine.2015.05.088
  41. Davidsen J, Rosenkrands I, Christensen D, et al. 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 2005;1718:22-31. https://doi.org/10.1016/j.bbamem.2005.10.011
  42. Kamath AT, Valenti MP, Rochat AF, et al. Protective anti-mycobacterial T cell responses through exquisite in vivo activation of vaccine-targeted dendritic cells. Eur J Immunol 2008;38:1247-56. https://doi.org/10.1002/eji.200737889
  43. van Dissel JT, Arend SM, Prins C, et al. Ag85B-ESAT-6 adjuvanted with IC31 promotes strong and long-lived Mycobacterium tuberculosis specific T cell responses in naive human volunteers. Vaccine 2010;28:3571-81. https://doi.org/10.1016/j.vaccine.2010.02.094
  44. Homolka S, Ubben T, Niemann S. High sequence variability of the ppE18 gene of clinical Mycobacterium tuberculosis complex strains potentially impacts effectivity of vaccine candidate M72/AS01E. PLoS One 2016;11:e0152200.
  45. Luabeya AK, Kagina BM, Tameris MD, et al. First-in-human trial of the post-exposure tuberculosis vaccine H56:IC31 in Mycobacterium tuberculosis infected and non-infected healthy adults. Vaccine 2015;33:4130-40. https://doi.org/10.1016/j.vaccine.2015.06.051
  46. Lin PL, Dietrich J, Tan E, et al. The multistage vaccine H56 boosts the effects ofBCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection. J Clin Invest 2012;122:303-14. https://doi.org/10.1172/JCI46252
  47. Santosuosso M, McCormick S, Zhang X, Zganiacz A, Xing Z. Intranasal boosting with an adenovirus-vectored vaccine markedly enhances protection by parenteral Mycobacterium bovis BCG immunization against pulmonary tuberculosis. Infect Immun 2006;74:4634-43. https://doi.org/10.1128/IAI.00517-06
  48. Usman MM, Ismail S, Teoh TC. Vaccine research and development: tuberculosis as a global health threat. Cent Eur J Immunol 2017;42:196-204. https://doi.org/10.5114/ceji.2017.69362
  49. Stylianou E, Griffiths KL, Poyntz HC, et al. Improvement of BCG protective efficacy with a novel chimpanzee adenovirus and a modified vaccinia Ankara virus both expressing Ag85A. Vaccine 2015;33:6800-8. https://doi.org/10.1016/j.vaccine.2015.10.017
  50. Wang J, Thorson L, Stokes RW, et al. Single mucosal, but not parenteral, immunization with recombinant adenoviral-based vaccine provides potent protection from pulmonary tuberculosis. J Immunol 2004;173:6357-65. https://doi.org/10.4049/jimmunol.173.10.6357
  51. Reither K, Katsoulis L, Beattie T, et al. Safety and immunogenicity of H1/IC31(R), an adjuvanted TB subunit vaccine, in HIV-infected adults with CD4+ lymphocyte counts greater than 350 cells/mm3: a phase II, multi-centre, double-blind, randomized, placebo-controlled trial. PLoS One 2014;9:e114602.
  52. Pu F, Feng J, Xia P. Association between heparin-binding hemagglutinin and tuberculosis. Adv Clin Exp Med 2020;29:893-7. https://doi.org/10.17219/acem/121011
  53. Bertholet S, Ireton GC, Ordway DJ, et al. A defined tuberculosis vaccine candidate boosts BCG and protects against multidrug-resistant Mycobacterium tuberculosis. Sci Transl Med 2010;2:53ra74.
  54. Parra M, Pickett T, Delogu G, et al. The mycobacterial heparin-binding hemagglutinin is a protective antigen in the mouse aerosol challenge model of tuberculosis. Infect Immun 2004;72:6799-805.
  55. Comas I, Chakravartti J, Small PM, et al. Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved. Nat Genet 2010;42:498-503. https://doi.org/10.1038/ng.590
  56. Aagaard CS, Hoang TT, Vingsbo-Lundberg C, Dietrich J, Andersen P. Quality and vaccine efficacy of CD4+ T cell responses directed to dominant and subdominant epitopes in ESAT-6 from Mycobacterium tuberculosis. J Immunol 2009;183:2659-68.
  57. Sweeney KA, Dao DN, Goldberg MF, et al. A recombinant Mycobacterium smegmatis induces potent bactericidal immunity against Mycobacterium tuberculosis. Nat Med 2011;17:1261-8.
  58. Commandeur S, van Meijgaarden KE, Prins C, et al. An unbiased genome-wide Mycobacterium tuberculosis gene expression approach to discover antigens targeted by human T cells expressed during pulmonary infection. J Immunol 2013;190:1659-71. https://doi.org/10.4049/jimmunol.1201593
  59. Boisson-Dupuis S, Bustamante J, El-Baghdadi J, et al. Inherited and acquired immunodeficiencies underlying tuberculosis in childhood. Immunol Rev 2015;264:103-20. https://doi.org/10.1111/imr.12272
  60. Schrager LK, Vekemens J, Drager N, Lewinsohn DM, Olesen OF. The status of tuberculosis vaccine development. Lancet Infect Dis 2020;20:e28-37. https://doi.org/10.1016/S1473-3099(19)30625-5
  61. Reed SG, Orr MT, Fox CB. Key roles of adjuvants in modern vaccines. Nat Med 2013;19:1597-608. https://doi.org/10.1038/nm.3409
  62. Hutchison S, Benson RA, Gibson VB, Pollock AH, Garside P, Brewer JM. Antigen depot is not required for alum adjuvanticity. FASEB J 2012;26:1272-9. https://doi.org/10.1096/fj.11-184556
  63. Mustafa AS. Biotechnology in the development of new vaccines and diagnostic reagents against tuberculosis. Curr Pharm Biotechnol 2001;2:157-73. https://doi.org/10.2174/1389201013378707
  64. Dong Y, Gong JY, Liu X, Li JW. Enhanced immune response of a bicistronic DNA vaccine expressing fusion antigen Hsp65-Esat-6 of Mycobacterium tuberculosis with GM-CSF as a molecular adjuvant. Braz Arch Biol Technol 2013;56:757-65. https://doi.org/10.1590/S1516-89132013000500006
  65. Moradi B, Sankian M,Amini Y, Meshkat Z.Construction of a novel DNA vaccine candidate encoding an HspX-PPE44-EsxV fusion antigen of Mycobacterium tuberculosis. Rep Biochem Mol Biol 2016;4:89-97.
  66. Decatur AL, Portnoy DA. A PEST-like sequence in listeriolysin O essential for Listeria monocytogenes pathogenicity. Science 2000;290:992-5. https://doi.org/10.1126/science.290.5493.992
  67. Nieuwenhuizen NE, Kulkarni PS, Shaligram U, et al. The recombinant bacille Calmette-Guerin vaccine VPM1002: ready for clinical efficacy testing. Front Immunol 2017;8:1147.
  68. Hoft DF,BlazevicA,Abate G, et al.Anew recombinant bacille Calmette-Guerin vaccine safely induces significantly enhanced tuberculosis-specific immunity in human volunteers. J Infect Dis 2008;198:1491-501. https://doi.org/10.1086/592450
  69. Gonzalo-Asensio J, Marinova D, Martin C, Aguilo N. MTBVAC: attenuating the human pathogen of tuberculosis (TB)toward a promising vaccine against the TB epidemic. Front Immunol 2017;8:1803.
  70. Lee JS, Krause R, Schreiber J, et al. Mutation in the transcriptional regulator PhoP contributes to avirulence of Mycobacterium tuberculosis H37Ra strain. Cell Host Microbe 2008;3:97-103. https://doi.org/10.1016/j.chom.2008.01.002
  71. Haile M, Kallenius G. Recent developments in tuberculosis vaccines. Curr Opin Infect Dis 2005;18:211-5. https://doi.org/10.1097/01.qco.0000168380.08895.9a
  72. Grode L, Seiler P, Baumann S, et al. Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guerin mutants that secrete listeriolysin. J Clin Invest 2005;115:2472-9. https://doi.org/10.1172/JCI24617
  73. Kupferschmidt K. Infectious disease: taking a new shot at a TB vaccine. Science 2011;334:1488-90. https://doi.org/10.1126/science.334.6062.1488
  74. Zhu B, Dockrell HM, Ottenhoff TH, Evans TG, Zhang Y. Tuberculosis vaccines: opportunities and challenges. Respirology 2018;23:359-68. https://doi.org/10.1111/resp.13245
  75. von Reyn CF, Lahey T, Arbeit RD, et al. Safety and immunogenicity of an inactivated whole cell tuberculosis vaccine booster in adults primed with BCG: a randomized, controlled trial of DAR-901. PLoS One 2017;12:e0175215.
  76. Master SS, Rampini SK, Davis AS, et al. Mycobacterium tuberculosis prevents inflammasome activation. Cell Host Microbe 2008;3:224-32.
  77. Reber SO, Siebler PH, Donner NC, et al. Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice. Proc Natl Acad Sci U S A 2016;113:E3130-9.
  78. Hernandez-Pando R, Pavon L, Arriaga K, Orozco H, Madrid-Marina V, Rook G. Pathogenesis of tuberculosis in mice exposed to low and high doses of an environmental mycobacterial saprophyte before infection. Infect Immun 1997;65:3317-27.
  79. Diaz C, Perez Del Palacio J, Valero-Guillen PL, et al. Comparative Metabolomics between Mycobacterium tuberculosis and the MTBVAC vaccine candidate. ACS Infect Dis 2019;5:1317-26. https://doi.org/10.1021/acsinfecdis.9b00008
  80. Moreno-Mendieta SA, Rocha-Zavaleta L, Rodriguez-Sanoja R. Adjuvants in tuberculosis vaccine development. FEMS Immunol Med Microbiol 2010;58:75-84. https://doi.org/10.1111/j.1574-695X.2009.00629.x
  81. Lyadova IV, Panteleev AV. Th1 and Th17 cells in tuberculosis: protection, pathology, and biomarkers. Mediators Inflamm 2015;2015:854507.
  82. Zygmunt BM, Rharbaoui F, Groebe L, Guzman CA. Intranasal immunization promotes th17 immune responses. J Immunol 2009;183:6933-8. https://doi.org/10.4049/jimmunol.0901144
  83. Bhatt K, Verma S, EllnerJJ, Salgame P. Quest for correlates of protection against tuberculosis. Clin Vaccine Immunol 2015;22:258-66. https://doi.org/10.1128/CVI.00721-14