BCG-Induced Cross-Protection and Development of Trained Immunity: Implication for Vaccine Design

Camila Covián, Ayleen Fernández-Fierro, Angello Retamal-Díaz, Fabián E Díaz, Abel E Vasquez, Margarita K Lay, Claudia A Riedel, Pablo A González, Susan M Bueno, Alexis M Kalergis, Camila Covián, Ayleen Fernández-Fierro, Angello Retamal-Díaz, Fabián E Díaz, Abel E Vasquez, Margarita K Lay, Claudia A Riedel, Pablo A González, Susan M Bueno, Alexis M Kalergis

Abstract

The Bacillus Calmette-Guérin (BCG) is a live attenuated tuberculosis vaccine that has the ability to induce non-specific cross-protection against pathogens that might be unrelated to the target disease. Vaccination with BCG reduces mortality in newborns and induces an improved innate immune response against microorganisms other than Mycobacterium tuberculosis, such as Candida albicans and Staphylococcus aureus. Innate immune cells, including monocytes and natural killer (NK) cells, contribute to this non-specific immune protection in a way that is independent of memory T or B cells. This phenomenon associated with a memory-like response in innate immune cells is known as "trained immunity." Epigenetic reprogramming through histone modification in the regulatory elements of particular genes has been reported as one of the mechanisms associated with the induction of trained immunity in both, humans and mice. Indeed, it has been shown that BCG vaccination induces changes in the methylation pattern of histones associated with specific genes in circulating monocytes leading to a "trained" state. Importantly, these modifications can lead to the expression and/or repression of genes that are related to increased protection against secondary infections after vaccination, with improved pathogen recognition and faster inflammatory responses. In this review, we discuss BCG-induced cross-protection and acquisition of trained immunity and potential heterologous effects of recombinant BCG vaccines.

Keywords: BCG; heterologous protection; innate immunity; trained immunity; vaccine.

Copyright © 2019 Covián, Fernández-Fierro, Retamal-Díaz, Díaz, Vasquez, Lay, Riedel, González, Bueno and Kalergis.

Figures

Figure 1
Figure 1
The immune response elicited after BCG vaccination in the newborn. (A) Recognition of the BCG at the inoculation site by neutrophils, macrophages, and DCs. (B) Activated skin DCs migrate to the draining lymph nodes to activate adaptive immune cells (C) Activation of Mycobacteria-specific CD4+ and CD8+ T cells with a TH1 profile, secreting elevated amounts of IFN-γ and granzymes (D) Activation of B cells leads to the generation of memory and plasma cells and the production of antigen-specific antibodies in response to the presence of antigens of BCG. After their activation, memory T and B cells reside in lymph nodes.
Figure 2
Figure 2
BCG applications in immunotherapy. Clinical applications of BCG in autoimmunity (left boxes) and cancer (right boxes). HbA1c, glycosylated hemoglobin; CNS, central nervous system; NK, natural killer cells; Mϕ, macrophages; NMI, non-muscle invasive.
Figure 3
Figure 3
BCG vaccination induces an innate immune training. BCG vaccination activates the innate immune system and induces changes in the pattern of histone modifications of specific genes in innate immune cells. This chromatin rearrangement induces a “trained” state in the cell, enhancing the effectiveness of the innate immune response when exposed to a non-specific pathogen, inducing the secretion of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6. The pink line represents a trained immune response, the purple line represents a naïve innate immune response.

References

    1. WHO Global World Health Organization. (2018). Available online at:
    1. Herr HW, Morales A. History of bacillus calmette-guerin and bladder cancer: an immunotherapy success story. J Urol. (2008) 179:53–6. 10.1016/j.juro.2007.08.122
    1. Brosch R, Gordon SV, Pym A, Eiglmeier K, Garnier T, Cole ST. Comparative genomics of the mycobacteria. Int J Med Microbiol. (2000) 290:143–52. 10.1016/S1438-4221(00)80083-1
    1. Colditz GA, Berkey CS, Mosteller F, Brewer TF, Wilson ME, Burdick E, et al. . The efficacy of Bacillus Calmette-Guérin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature. Pediatrics. (1995) 96:29–35.
    1. Miceli I, de Kantor IN, Colaiácovo D, Peluffo G, Cutillo I, Gorra R, et al. . Evaluation of the effectiveness of BCG vaccination using the case-control method in Buenos Aires, Argentina. Int J Epidemiol. (1988) 17:629–34. 10.1093/ije/17.3.629
    1. Trunz BB, Fine PEM, Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet. (2006) 367:1173–80. 10.1016/S0140-6736(06)68507-3
    1. Bonifachich E, Chort M, Astigarraga A, Diaz N, Brunet B, Pezzotto SM, et al. Protective effect of Bacillus Calmette-Guerin (BCG) vaccination in children with extra-pulmonary tuberculosis, but not the pulmonary disease: a case-control study in Rosario, Argentina. Vaccine. (2006) 24:2894–9. 10.1016/j.vaccine.2005.12.044
    1. Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV, et al. . Efficacy of BCG Vaccine in the Prevention of Tuberculosis: Meta-analysis of the Published Literature. J Am Med Assoc. (1994) 271:698–702. 10.1001/jama.271.9.698
    1. Fine PEM. Variation in protection by BCG: implications of and for heterologous immunity. Lancet. (1995) 346:1339–45. 10.1016/S0140-6736(95)92348-9
    1. Brewer TF. Preventing tuberculosis with Bacillus Calmette-Guérin vaccine: a meta-analysis of the literature. Clin Infect Dis. (2000) 31:S64–7. 10.1086/314072
    1. Rey-Jurado E, Tapia F, Muñoz-Durango N, Lay MK, Carreño LJ, Riedel CA, et al. . Assessing the importance of domestic vaccine manufacturing centers: an overview of immunization programs, vaccine manufacture, and distribution. Front Immunol. (2018) 9:26. 10.3389/fimmu.2018.00026
    1. De Bree LCJ, Koeken VACM, Joosten LAB, Aaby P, Benn CS, van Crevel R, et al. . Non-specific effects of vaccines: Current evidence and potential implications. Semin Immunol. (2018) 39:35–43. 10.1016/j.smim.2018.06.002
    1. De Castro MJ, Pardo-Seco J, Martinón-Torres F. Nonspecific (heterologous) protection of neonatal BCG vaccination against hospitalization due to respiratory infection and sepsis. Clin Infect Dis. (2015) 60:1611–9. 10.1093/cid/civ144
    1. Aaby P, Benn CS. Saving lives by training innate immunity with Bacille Calmette-Guérin vaccine. Proc Natl Acad Sci USA. (2012) 109:17317–8. 10.1073/pnas.1215761109
    1. Calmette A. Preventive Vaccination against tuberculosis with BCG. J R Soc Med. (1931) 24:1481–90. 10.1177/003591573102401109
    1. Roth A, Gustafson P, Nhaga A, Djana Q, Poulsen A, Garly M, et al. . BCG vaccination scar associated with better childhood survival in Guinea-Bissau. Int J Epidemiol. (2005) 34:540–7. 10.1093/ije/dyh392
    1. Stensballe LG, Nante E, Jensen IP, Kofoed PE, Poulsen A, Jensen H, et al. . Acute lower respiratory tract infections and respiratory syncytial virus in infants in Guinea-Bissau: a beneficial effect of BCG vaccination for girls: Community based case-control study. Vaccine. (2005) 23:1251–7. 10.1016/j.vaccine.2004.09.006
    1. Biering-Sørensen S, Aaby P, Napirna BM, Roth A, Ravn H, Rodrigues A, et al. . Small randomized trial among low-birth-weight children receiving Bacillus Calmette-Guérin vaccination at first health center contact. Pediatr Infect Dis J. (2012) 31:306–8. 10.1097/INF.0b013e3182458289
    1. Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM, et al. . Randomized trial of BCG vaccination at birth to low-birth-weight children : beneficial nonspecific effects in the neonatal period? J Infect Dis. (2011) 204:245–52. 10.1093/infdis/jir240
    1. Ponnighaus JM, Msosa E, Gruer PJK, Liomba NG, Fine PEM, Sterne JAC, et al. . Efficacy of BCG vaccine against leprosy and tuberculosis in northern Malawi. Lancet. (1992) 339:636–9. 10.1016/0140-6736(92)90794-4
    1. Garly M-L, Martins CL, Balé C, Baldé MA, Hedegaard KL, Gustafson P, et al. BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG? Vaccine. (2003) 21:2782–90. 10.1016/S0264-410X(03)00181-6
    1. Shann F. The non-specific effects of vaccines. Arch Dis Child. (2010) 95:662–7. 10.1136/adc.2009.157537
    1. Shann F. Nonspecific effects of vaccines and the reduction of mortality in children. Clin Ther. (2013) 35:109–14. 10.1016/j.clinthera.2013.01.007
    1. Higgins JPT, Soares-Weiser K, López-López JA, Kakourou A, Chaplin K, Christensen H, et al. . Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ. (2016) 355:i5170. 10.1136/bmj.i5170
    1. Stover CK, de la Cruz VF, Fuerst TR, Burlein JE, Benson LA, Bennett LT, et al. . New use of BCG for recombinant vaccines. Nature. (1991) 351:456–60. 10.1038/351456a0
    1. Fennelly GJ, Flynn JL, Meulen V, Liebert UG, Bloom BR. Recombinant bacille calmette-guréin priming against measles. J Infect Dis. (1995) 172:698–705. 10.1093/infdis/172.3.698
    1. Wang H, Liu Q, Liu K, Zhong W, Gao S, Jiang L, et al. . Immune response induced by recombinant Mycobacterium bovis BCG expressing ROP2 gene of Toxoplasma gondii. Parasitol Int. (2007) 56:263–8. 10.1016/j.parint.2007.04.003
    1. Yu JS, Peacock JW, Jacobs WR, Frothingham R, Letvin NL, Liao HX, et al. . Recombinant Mycobacterium bovis Bacillus Calmette-Guérin elicits human immunodeficiency virus type 1 envelope-specific T lymphocytes at mucosal sites. Clin Vaccine Immunol. (2007) 14:886–93. 10.1128/CVI.00407-06
    1. Chapman R, Stutz H, Jacobs W, Shephard E, Williamson AL. Priming with recombinant auxotrophic BCG expressing HIV-1 Gag, RT and Gp120 and boosting with recombinant MVA induces a robust T cell response in mice. PLoS ONE. (2013) 8:e71601 10.1371/annotation/4f08219c-2d7b-4309-8351-d3fe2378993f
    1. Hopkins R, Bridgeman A, Bourne C, Mbewe-Mvula A, Sadoff JC, Both GW, et al. . Optimizing HIV-1-specific CD8 + T-cell induction by recombinant BCG in prime-boost regimens with heterologous viral vectors. Eur J Immunol. (2011) 41:3542–52. 10.1002/eji.201141962
    1. Hopkins R, Bridgeman A, Joseph J, Gilbert SC, McShane H, Hanke T. Dual neonate vaccine platform against HIV-1 and M. tuberculosis. PLoS ONE. (2011) 6:e20067. 10.1371/journal.pone.0020067
    1. Soto JA, Gálvez NMS, Rivera CA, Palavecino CE, Céspedes PF, Rey-Jurado E, et al. . Recombinant BCG vaccines reduce pneumovirus-caused airway pathology by inducing protective humoral immunity. Front Immunol. (2018) 9:2875. 10.3389/fimmu.2018.02875
    1. Céspedes PF, Gonzalez PA, Kalergis AM. Human metapneumovirus keeps dendritic cells from priming antigen-specific naive T cells. Immunology. (2013) 139:366–76. 10.1111/imm.12083
    1. Palavecino CE, Cespedes PF, Gomez RS, Kalergis AM, Bueno SM. Immunization with a recombinant bacillus calmette-guerin strain confers protective Th1 immunity against the human metapneumovirus. J Immunol. (2014) 192:214–23. 10.4049/jimmunol.1300118
    1. Pfahlberg A, Kölmel KF, Grange JM, Mastrangelo G, Krone B, Botev IN, et al. . Inverse association between melanoma and previous vaccinations against tuberculosis and smallpox: results of the FEBIM study. J Invest Dermatol. (2002) 119:570–5. 10.1046/j.1523-1747.2002.00643.x
    1. Morra ME, Kien ND, Elmaraezy A, Abdelaziz OAM, Elsayed AL, Halhouli O, et al. . Early vaccination protects against childhood leukemia: a systematic review and meta-analysis. Sci Rep. (2017) 7:1–9. 10.1038/s41598-017-16067-0
    1. Morton DL, Eilber FR, Holmes EC, Hunt JS, Ketcham AS, Silverstein MJ, et al. . BCG immunotherapy of malignant melanoma: Summary of a seven year experience. Ann Surg. (1974) 180:635–43. 10.1097/00000658-197410000-00029
    1. Herr HW, Laudone VP, Badalament RA, Oettgen HF, Sogani PC, Freedman BD, et al. . Bacillus Calmette-Guerin therapy alters the progression of superficial bladder cancer. J Clin Oncol. (1988) 6:1450–5. 10.1200/JCO.1988.6.9.1450
    1. Böhle A, Brandau S. Immune mechanisms in bacillus calmette-guerin immunotherapy for superficial bladder cancer. J Urol. (2003) 170:964–9. 10.1097/01.ju.0000073852.24341.4a
    1. Prescott S, James K, Hargreave TB, Chisholm GD, Smyth JF. Intravesical evans strain BCG therapy: quantitative immunohistochemical analysis of the immune response within the bladder wall. J Urol. (1992) 147:163642 10.1016/S0022-5347(17)37668-1
    1. de Boer EC, de Jong WH, van der Meijden APM, Steerenberg PA, Witjes F, Vegt PDJ, et al. . Leukocytes in the urine after intravesical BCG treatment for superficial bladder cancer. Urol Res. (1991) 19:45–50. 10.1007/BF00294021
    1. Ikeda N, Toida I, Iwasaki A, Kawai K, Akaza H. Surface antigen expression on bladder tumor cells induced by Bacillus Calmette-Guérin (BCG): a role of BCG internalization into tumor cells. Int J Urol. (2002) 9:29–35. 10.1046/j.1442-2042.2002.00415.x
    1. Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, Coussens LM, et al. . Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. (2018) 24:541–50. 10.1038/s41591-018-0014-x
    1. Dockrell HM, Smith SG. What have we learnt about BCG vaccination in the last 20 years? Front Immunol. (2017) 8:1134. 10.3389/fimmu.2017.01134
    1. Kilpeläinen A, Maya-Hoyos M, Saubí N, Soto CY, Joseph Munne J. Advances and challenges in recombinant Mycobacterium bovis BCG-based HIV vaccine development: lessons learned. Expert Rev Vaccines. (2018) 17:1005–20. 10.1080/14760584.2018.1534588
    1. Moliva JI, Turner J, Torrelles JB. Immune responses to bacillus calmette–guérin vaccination: why do they fail to protect against Mycobacterium tuberculosis?. Front Immunol. (2017) 8:407. 10.3389/fimmu.2017.00407
    1. Kumar S, Sunagar R, Gosselin E. Bacterial protein toll-like-receptor agonists: a novel perspective on vaccine adjuvants. Front Immunol. (2019) 10:1144. 10.3389/fimmu.2019.01144
    1. Gagliardi MC, Teloni R, Giannoni F, Pardini M, Sargentini V, Brunori L, et al. . Mycobacterium bovis bacillus calmette-guerin infects DC-SIGN- dendritic cell and causes the inhibition of IL-12 and the enhancement of IL-10 production. J Leukoc Biol. (2005) 78:106–13. 10.1189/jlb.0105037
    1. Jiao X, Lo-Man R, Guermonprez P, Fiette L, Dériaud E, Burgaud S, et al. . Dendritic cells are host cells for mycobacteria in vivo that trigger innate and acquired immunity. J Immunol. (2002) 168:1294–301. 10.4049/jimmunol.168.3.1294
    1. Tsuji S, Matsumoto M, Takeuchi O, Akira S, Azuma I, Hayashi A, et al. . Maturation of human dendritic cells by cell wall skeleton of Mycobacterium bovis bacillus calmette-guérin : involvement of toll-like receptors. Infect Immun. (2000) 68:6883–90. 10.1128/IAI.68.12.6883-6890.2000
    1. Joosten SA, van Meijgaarden KE, Arend SM, Prins C, Oftung F, Korsvold GE, et al. . Mycobacterial growth inhibition is associated with trained innate immunity. J Clin Invest. (2018) 128:1837–51. 10.1172/JCI97508
    1. Bertholet S, Ireton GC, Kahn M, Guderian J, Mohamath R, Stride N, et al. . Identification of human T cell antigens for the development of vaccines against Mycobacterium tuberculosis. J Immunol. (2008) 181:7948–57. 10.4049/jimmunol.181.11.7948
    1. Kaufmann SHE. Tuberculosis vaccines: time to think about the next generation. Semin Immunol. (2013) 25:172–81. 10.1016/j.smim.2013.04.006
    1. Bollampalli VP, Yamashiro LH, Feng X, Bierschenk D, Gao Y, Blom H, et al. BCG skin infection triggers IL-1R-MyD88- dependent migration of EpCAM low CD11b high skin dendritic cells to draining lymph node during CD4 + T-cell priming. PLoS Pathog. (2015) 11:e1005206 10.1371/journal.ppat.1005206
    1. Su H, Peng B, Zhang Z, Liu Z, Zhang Z. The Mycobacterium tuberculosis glycoprotein Rv1016c protein inhibits dendritic cell maturation, and impairs Th1 /Th17 responses during mycobacteria infection. Mol Immunol. (2019) 109:58–70. 10.1016/j.molimm.2019.02.021
    1. Bizzell E, Sia JK, Quezada M, Enriquez A, Georgieva M, Rengarajan J. Deletion of BCG Hip1 protease enhances dendritic cell and CD4 T cell responses. J Leukoc Biol. (2018) 103:739–48. 10.1002/JLB.4A0917-363RR
    1. Humphreys IR, Stewart GR, Turner DJ, Patel J, Karamanou D, Snelgrove RJ, et al. . A role for dendritic cells in the dissemination of mycobacterial infection. Microbes Infect. (2006) 8:1339–46. 10.1016/j.micinf.2005.12.023
    1. Morel C, Badell E, Abadie V, Robledo M, Setterblad N, Gluckman JC, et al. . Mycobacterium bovis BCG-infected neutrophils and dendritic cells cooperate to induce specific T cell responses in humans and mice. Eur J Immunol. (2008) 38:437–47. 10.1002/eji.200737905
    1. Andersen P, Kaufmann SHE. Novel vaccination strategies against tuberculosis. Cold Spring Harb Perspect Med. (2014) 4:a018523. 10.1101/cshperspect.a018523
    1. Hanekom WA. The immune response to BCG vaccination of newborns. Ann New York Acad Sci. (2005) 1062:69–78. 10.1196/annals.1358.010
    1. Murray RA, Mansoor N, Harbacheuski R, Soler J, Davids V, Soares A, et al. . Bacillus calmette guerin vaccination of human newborns induces a specific, functional CD8+ T cell response. J Immunol. (2014) 177:5647–51. 10.4049/jimmunol.177.8.5647
    1. Soares AP, Scriba TJ, Joseph S, Harbacheuski R, Ann R, Gelderbloem SJ, et al. Bacille calmette guerin vaccination of human newborns induces T cells with complex cytokine and phenotypic profiles. J Immunol. (2010) 180:3569–77. 10.4049/jimmunol.180.5.3569
    1. Ravn P, Boesen H, Pedersen BK, Andersen P. Human T cell responses induced by vaccination with Mycobacterium bovis bacillus calmette-Guérin. J Immunol. (1997) 158:1949–55.
    1. Soares AP, Kwong Chung CKC, Choice T, Hughes EJ, Jacobs G, Van Rensburg EJ, et al. . Longitudinal changes in CD4+ T-cell memory responses induced by BCG vaccination of newborns. J Infect Dis. (2013) 207:1084–94. 10.1093/infdis/jis941
    1. Feng CG, Britton WJ. CD4 + and CD8 + T cells mediate adoptive immunity to aerosol infection of Mycobacterium bovis bacillus calmette-Guérin. J Infect Dis. (2000) 181:1846–9. 10.1086/315466
    1. Silva CL, Bonato VLD, Lima VMF, Faccioli LH, Leão SC. Characterization of the memory/activated T cells that mediate the long- lived host response against tuberculosis after bacillus Calmette-Guerin or DNA vaccination. Immunology. (1999) 97:573–81. 10.1046/j.1365-2567.1999.00840.x
    1. Chen T, Blanc C, Eder AZ, Prados-Rosales R, Oliveira Souza AC, Kim RS, et al. . Association of human antibodies to arabinomannan with enhanced mycobacterial opsonophagocytosis and intracellular growth reduction. J Infect Dis. (2016) 214:300–10. 10.1093/infdis/jiw141
    1. Sebina I, Cliff JM, Smith SG, Nogaro S, Webb EL, Riley EM, et al. . Long-lived memory B-cell responses following BCG vaccination. PLoS ONE. (2012) 7:e51381. 10.1371/journal.pone.0051381
    1. Perdomo C, Zedler U, Kühl AA, Lozza L, Saikali P, Sander LE, et al. . Mucosal BCG Vaccination induces protective lung-resident memory T cell populations against tuberculosis. MBio. (2016) 7:1–11. 10.1128/mBio.01686-16
    1. Uranga S, Marinova D, Martin C, Aguilo N. Protective efficacy and pulmonary immune response following subcutaneous and intranasal BCG administration in mice. J Vis Exp. (2016) 115:e54440 10.3791/54440
    1. Hansen IS, Baeten DLP, den Dunnen J. The inflammatory function of human IgA. Cell Mol Life Sci. (2019) 76:1041–55. 10.1007/s00018-018-2976-8
    1. Martinov T, Fife BT. Type 1 diabetes pathogenesis and the role of inhibitory receptors in islet tolerance. Ann New York Acad Sci. (2019). 10.1111/nyas.14106. [Epub ahead of print].
    1. Kowalewicz-Kulbat M, Locht C. BCG and protection against inflammatory and auto-immune diseases. Expert Rev Vaccines. (2017) 16:699–708. 10.1080/14760584.2017.1333906
    1. Shehadeh N, Bruchlim I, Vardi P, Calcinaro F, Lafferty K. Effect of adjuvant therapy on development of diabetes in mouse and man. Lancet. (1994) 343:706–7. 10.1016/S0140-6736(94)91583-0
    1. Allen HF, Simoes EAF, Klingensmith GJ, Hayward A, Jensen P, Chase HP. Effect of Bacillus Calmette-Guerin Vaccination on New-Onset Type 1 Diabetes. Diabetes Care. (1999) 22:1703–7. 10.2337/diacare.22.10.1703
    1. Faustman DL, Wang L, Okubo Y, Burger D, Ban L, Man G, et al. . Proof-of-concept, randomized, controlled clinical trial of bacillus-calmette-guerin for treatment of long-term type 1 diabetes. PLoS ONE. (2012) 7:e41756. 10.1371/journal.pone.0041756
    1. Kuhtreiber W, Tran L, Nguyen B, Janes Se, Defusco AA, Faustman DL. Long-term reduction in hyperglycemia in advanced type 1 diabetes—the value of induced aerobic glycolysis by BCG vaccinations. Diabetes. (2018) 67:2339 10.2337/db18-2339-PUB
    1. Sadelain MWJ, Qin HY, Lauzon J, Singh B. Prevention of type I diabetes in NOD mice by adjuvant immunotherapy. Diabetes. (1990) 39:583–9. 10.2337/diabetes.39.5.583
    1. Kodama S, Kühtreiber W, Fujimura S, Dale EA, Faustman DL. Islet regeneration during the reversal of autoimmune diabetes in NOD Mice. Science. (2003) 302:1223–7. 10.1126/science.1088949
    1. Vaughn CB, Benedict RHB, Zivadinov R, Weinstock- B. Epidemiology and treatment of multiple sclerosis in elderly populations. Nat Rev Neurol. (2004) 15:329–42. 10.1038/s41582-019-0183-3
    1. Ristori G, Buzzi MG, Sabatini U, Giugni E, Bastianello S, Viselli F, et al. . Use of Bacille Calmette-Guérin (BCG) in multiple sclerosis. Neurology. (1999) 53:1588–1589. 10.1212/WNL.53.7.1588
    1. Ristori G, Romano S, Cannoni S, Visconti A, Tinelli E, Mendozzi L, et al. Effects of Bacille Calmette-Guérin after the first demyelinating event in the CNS. Neurology. (2014) 82:41–8. 10.1212/01.wnl.0000438216.93319.ab
    1. Lippens C, Garnier L, Guyonvarc'h PM, Santiago-Raber ML, Hugues S. Extended freeze-dried BCG instructed pDCs induce suppressive tregs and dampen EAE. Front Immunol. (2018) 9:2777. 10.3389/fimmu.2018.02777
    1. Kleinnijenhuis J, Quintin J, Preijers F, Benn CS, Joosten LAB, Jacobs C, et al. . Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J Innate Immun. (2015) 6:152–8. 10.1159/000355628
    1. Kagina BMN, Abel B, Scriba TJ, Hughes EJ, Keyser A, Soares A, et al. Specific T cell frequency and cytokine expression profile do not correlate with protection against tuberculosis after Bacillus Calmette-Guérin vaccination of newborns. Am J Respir Crit Care Med. (2010) 182:1073–9. 10.1164/rccm.201003-0334OC
    1. Arts RJW, Carvalho A, La Rocca C, Palma C, Rodrigues F, Silvestre R, et al. . Immunometabolic pathways in BCG-induced trained immunity. Cell Rep. (2016) 17:2562–71. 10.1016/j.celrep.2016.11.011
    1. Procaccini C, Carbone F, Di Silvestre D, Brambilla F, De Rosa V, Galgani M, et al. The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements. Immunity. (2016) 44:406–21. 10.1016/j.immuni.2016.01.028
    1. Ristori G, Faustman D, Matarese G, Romano S, Salvetti M. Bridging the gap between vaccination with Bacille Calmette-Guérin (BCG) and immunological tolerance: the cases of type 1 diabetes and multiple sclerosis. Curr Opin Immunol. (2018) 55:89–96. 10.1016/j.coi.2018.09.016
    1. Dalton DK, Haynes L, Chu CQ, Swain SL, Wittmer S. Interferon γ eliminates responding CD4 T cells during mycobacterial infection by inducing apoptosis of activated CD4 T cells. J Exp Med. (2000) 192:117–22. 10.1084/jem.192.1.117
    1. Lampropoulou V, Hoehlig K, Roch T, Neves P, Gómez EC, Sweenie CH, et al. . TLR-activated B cells suppress T cell-mediated autoimmunity. J Immunol. (2008) 180:4763–73. 10.4049/jimmunol.180.7.4763
    1. Lardone RD, Chan AA, Lee AF, Foshag LJ, Faries MB, Sieling PA, et al. . Mycobacterium bovis bacillus calmette–guérin alters melanoma microenvironment favoring antitumor T cell responses and improving M2 macrophage function. Front Immunol. (2017) 8:965. 10.3389/fimmu.2017.00965
    1. Herr HW, Schwalb DM, Zhang ZF, Sogani PC, Whitmore WF, Oettgen HF. Intravesical BCG therapy delays tumor progression and death from superficial bladder cancer: ten-year followup of a prospective randomized trial: author update. Class Pap Curr Comments Highlights Genitourin Cancer Res. (1998) 13:1404–8. 10.1200/JCO.1995.13.6.1404
    1. Bohle A, Gerdes J, Ulmer AJ, Hofstetter AG, Flad HD. Effects of local bacillus Calmette-Guerin therapy in patients with bladder carcinoma on immunocompetent cells of the bladder wall. J Urol. (1990) 144:53–8. 10.1016/S0022-5347(17)39365-5
    1. Netea MG, Quintin J, Van Der Meer JWM. Trained immunity: a memory for innate host defense. Cell Host Microbe. (2011) 9:355–61. 10.1016/j.chom.2011.04.006
    1. Kleinnijenhuis J, Van Crevel R, Netea MG. Trained immunity: consequences for the heterologous effects of BCG vaccination. Trans R Soc Trop Med Hyg. (2014) 109:29–35. 10.1093/trstmh/tru168
    1. Kleinnijenhuis J, Quintin J, Preijers F, Joosten LAB, Ifrim DC, Saeed S, et al. . Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci USA. (2012) 109:17537–42. 10.1073/pnas.1202870109
    1. Wout JW, Poell R, Furth R. The Role of BCG/PPD-activated macrophages in resistance against systemic candidiasis in mice. Scand J Immunol. (1992) 36:713–20. 10.1111/j.1365-3083.1992.tb03132.x
    1. Kleinnijenhuis J, Quintin J, Preijers F, Joosten LAB, Jacobs C, Xavier RJ, et al. . BCG-induced trained immunity in NK cells: role for non-specific protection to infection. Clin Immunol. (2014) 155:213–9. 10.1016/j.clim.2014.10.005
    1. Guerra-Maupome M, Vang DX, McGill JL. Aerosol vaccination with Bacille Calmette-Guerin induces a trained innate immune phenotype in calves. PLoS ONE. (2019) 14:1–16. 10.1371/journal.pone.0212751
    1. Zhang Q, Cao X. Epigenetic regulation of the innate immune response to infection. Nat Rev Immunol. (2019) 19:417–32. 10.1038/s41577-019-0151-6
    1. Wen H, Dou Y, Hogaboam CM, Kunkel SL, DC W. Epigenetic regulation of dendritic cell – derived interleukin-12 facilitates immunosuppression after a severe innate immune response. Public Health. (2008) 111:1797–804. 10.1182/blood-2007-08-106443
    1. Foster SL, Medzhitov R. Gene-specific control of the TLR-induced inflammatory response. Clin Immunol. (2008) 130:7–15. 10.1016/j.clim.2008.08.015
    1. Doñas C, Fritz M, Manríquez V, Tejón G, Bono MR, Loyola A, et al. . Trichostatin A promotes the generation and suppressive functions of regulatory T cells. Clin Dev Immunol. (2013) 2013:1–8. 10.1155/2013/679804
    1. Kouzarides T. Chromatin modifications and their function. Cell. (2007) 128:693–705. 10.1016/j.cell.2007.02.005
    1. Liu H, Li P, Wei Z, Zhang C, Xia M, Du Q, et al. . Regulation of T cell differentiation and function by epigenetic modification enzymes. Semin Immunopathol. (2019) 41:315–26. 10.1007/s00281-019-00731-w
    1. Arts RJW, Blok BA, Aaby P, Joosten LAB, de Jong D, van der Meer JWM, et al. . Long-term in vitro and in vivo effects of γ-irradiated BCG on innate and adaptive immunity. J Leukoc Biol. (2015) 98:995–1001. 10.1189/jlb.4MA0215-059R
    1. Arts RJW, Novakovic B, ter Horst R, Carvalho A, Bekkering S, Lachmandas E, et al. . Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. (2016) 24:807–19. 10.1016/j.cmet.2016.10.008
    1. Cheng S-C, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, et al. mTOR/HIF1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. (2014) 345:1–18. 10.1126/science.1250684
    1. Bekkering S, Arts RJW, Novakovic B, Kourtzelis I, van der Heijden CDCC, Li Y, et al. . Metabolic induction of trained immunity through the mevalonate pathway. Cell. (2018) 172:135–46.e9. 10.1016/j.cell.2017.11.025
    1. Czarnewski P, Das S, Parigi SM, Villablanca EJ. Retinoic acid and its role in modulating intestinal innate immunity. Nutrients. (2017) 9:68. 10.3390/nu9010068
    1. Arts RJW, Blok BA, van Crevel R, Joosten LAB, Aaby P, Benn CS, et al. . Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes. J Leukoc Biol. (2015) 98:129–36. 10.1189/jlb.6AB0914-416R
    1. Arts RJW, Moorlag SJCFM, Novakovic B, Li Y, Wang SY, Oosting M, et al. . BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe. (2018) 23:89–100.e5. 10.1016/j.chom.2017.12.010
    1. Mitroulis I, Ruppova K, Wang B, Chen LS, Grzybek M, Grinenko T, et al. . Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell. (2018) 172:147–61.e12. 10.1016/j.cell.2017.11.034
    1. Kaufmann E, Sanz J, Dunn JL, Khan N, Mendonça LE, Pacis A, et al. . BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell. (2018) 172:176–90.e19. 10.1016/j.cell.2017.12.031
    1. Khader SA, Divangahi M, Hanekom W, Hill PC, Maeurer M, Makar KW, Mayer-Barber KD, et al. . Targeting innate immunity for tuberculosis vaccination. J Clin Invest. (2019) 129:3482–91. 10.1172/JCI128877
    1. Zhu Y, Fennelly G, Miller C, Tarara R, Saxe I, Bloom B, et al. . Recombinant Bacille Calmette-Guérin expressing the measles virus nucleoprotein protects infant rhesus macaques from measles virus pneumonia. Oxford Univ Press. (1997) 176:1445–53. 10.1086/514140
    1. Saadatnia G, Golkar M. A review on human toxoplasmosis. Scand J Infect Dis. (2012) 44:805–14. 10.3109/00365548.2012.693197
    1. Daniels HL, Sabella C. Bordetella pertussis (Pertussis). Pediatr Rev. (2018) 39:247–57. 10.1542/pir.2017-0229
    1. Nascimento IP, Dias WO, Mazzantini RP, Miyaji EN, Gamberini M, Quintilio W, et al. . Recombinant Mycobacterium bovis BCG expressing pertussis toxin subunit S1 induces protection against an intracerebral challenge with live Bordetella pertussis in mice. Infect Immun. (2000) 68:4877–83. 10.1128/IAI.68.9.4877-4883.2000
    1. Medeiros MA, Armôa GR, Dellagostin OA, McIntosh D. Induction of humoral immunity in response to immunization with recombinant Mycobacterium bovis BCG expressing the S1 subunit of Bordetella pertussis toxin. Can J Microbiol. (2006) 51:1015–20. 10.1139/w05-095
    1. Nascimento IP, Dias WO, Quintilio W, Christ AP, Moraes JF, Vancetto MDC, et al. . Neonatal immunization with a single dose of recombinant BCG expressing subunit S1 from pertussis toxin induces complete protection against Bordetella pertussis intracerebral challenge. Microbes Infect. (2008) 10:198–202. 10.1016/j.micinf.2007.10.010
    1. WHO WHO|HIV/AIDS. WHO; (2016).
    1. Loxton AG, Knaul JK, Grode L, Gutschmidt A, Meller C, Eisele B, et al. . Safety and immunogenicity of the vaccine VPM1002 in HIV-unexposed newborn infants in South Africa. Clin Vaccine Immunol. (2017) 24: e00439–16. 10.1128/CVI.00439-16
    1. Kim BJ, Kim BR, Kook YH, Kim BJ. Development of a live recombinant BCG expressing human immunodeficiency virus type 1 (HIV-1) gag using a pMyong2 vector system: Potential use as a novel HIV-1 vaccine. Front Immunol. (2018) 9:643. 10.3389/fimmu.2018.00643
    1. Mahant A, Saubi N, Eto Y, Guitart N, Gatell JM, Hanke T, et al. . Preclinical development of , harboring an integrative expression vector, for a HIV-TB pediatric vaccine. Enhancement of stability and specific HIV-1 T-cell immunity. Hum Vaccines Immunother. (2017) 13:1798–810. 10.1080/21645515.2017.1316911
    1. Hoft DF, Blazevic A, Selimovic A, Turan A, Tennant J, Abate G, et al. . Safety and Immunogenicity of the recombinant BCG vaccine AERAS-422 in healthy BCG-Naïve adults: a randomized, active-controlled, first-in-human phase 1 trial. EBioMedicine. (2016) 7:278–86. 10.1016/j.ebiom.2016.04.010
    1. Nieuwenhuizen NE, Kulkarni PS, Shaligram U, Cotton MF, Rentsch CA, Eisele B, et al. . The recombinant Bacille Calmette-Guérin vaccine VPM1002: Ready for clinical efficacy testing. Front Immunol. (2017) 8:1147. 10.3389/fimmu.2017.01147
    1. Lay MK, Céspedes PF, Palavecino CE, León MA, Díaz RA, Salazar FJ, et al. . Human metapneumovirus infection activates the TSLP pathway that drives excessive pulmonary inflammation and viral replication in mice. Eur J Immunol. (2015) 45:1680–95. 10.1002/eji.201445021
    1. Céspedes PF, Rey-Jurado E, Espinoza JA, Rivera CA, Canedo-Marroquín G, Bueno SM, et al. . A single, low dose of a cGMP recombinant BCG vaccine elicits protective T cell immunity against the human respiratory syncytial virus infection and prevents lung pathology in mice. Vaccine. (2017) 35:757–66. 10.1016/j.vaccine.2016.12.048
    1. Shi T, McAllister DA, O'Brien KL, Simoes EAF, Madhi SA, Gessner BD, et al. . Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet. (2017) 390:946–58. 10.1016/S0140-6736(17)30938-8
    1. Mazur NI, Higgins D, Nunes MC, Melero JA, Langedijk AC, Horsley N, et al. . The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates. Lancet Infect Dis. (2018) 18:e295–311. 10.1016/S1473-3099(18)30292-5
    1. Saeed S, Quintin J, Kerstens HHD, Rao NA, Aghajanirefah A, Matarese F, et al. . Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science. (2014) 345:1251086. 10.1126/science.1251086
    1. Xue KS, Moncla LH, Bedford T, Bloom JD. Within-host evolution of human influenza virus. Trends Microbiol. (2018) 26:781–93. 10.1016/j.tim.2018.02.007
    1. Harding AT, Heaton NS. Efforts to improve the seasonal influenza vaccine. Vaccines. (2018) 6:E19. 10.3390/vaccines6020019
    1. Nam HH, Ison MG. Respiratory syncytial virus infection in adults. BMJ. (2019) 366:l5021. 10.1136/bmj.l5021
    1. Witt DJ, Craven DE, McCabe WR. Bacterial infections in adult patients with the acquired immune deficiency syndrome (AIDS) and AIDS-related complex. Am J Med. (1987) 82:900–6. 10.1016/0002-9343(87)90150-1
    1. Shannon KM, Ammann AJ. Acquired immune deficiency syndrome in childhood. J Pediatr. (1985) 106:332–42. 10.1016/S0022-3476(85)80320-6
    1. Abzug MJ. Acute sinusitis in children: Do antibiotics have any role? J Infect. (2014) 68:S33–7. 10.1016/j.jinf.2013.09.012
    1. Wilson R, Sethi S, Anzueto A, Miravitlles M. Antibiotics for treatment and prevention of exacerbations of chronic obstructive pulmonary disease. J Infect. (2013) 67:497–515. 10.1016/j.jinf.2013.08.010
    1. Esposito S, Soto-Martinez ME, Feleszko W, Jones MH, Shen KL, Schaad UB. Nonspecific immunomodulators for recurrent respiratory tract infections, wheezing and asthma in children: a systematic review of mechanistic and clinical evidence. Curr Opin Allergy Clin Immunol. (2018) 18:198–209. 10.1097/ACI.0000000000000433
    1. Kline KA, Bowdish DME. Infection in an aging population. Curr Opin Microbiol. (2016) 29:63–7. 10.1016/j.mib.2015.11.003
    1. Honda M, Matsuo K, Nakasone T, Okamoto Y, Yoshizaki H, Kitamura K, et al. . Protective immune responses induced by secretion of a chimeric soluble protein from a recombinant Mycobacterium bovis Bacillus Calmette-Guérin vector candidate vaccine for human immunodeficiency virus type 1 in small animals. Proc Natl Acad Sci USA. (1995) 92:10693–7. 10.1073/pnas.92.23.10693
    1. Me I, Bourguin I, Ensergueix D, Badell E, Gicquel B, Winter N. Plasmidic versus insertional cloning of heterologous genes in Mycobacterium bovis BCG: impact on in vivo antigen persistence and immune responses. Infect Immun. (2002) 70:303–14. 10.1128/IAI.70.1.303-314.2002
    1. Oliveira TL, Rizzi C, Dellagostin OA. Recombinant BCG vaccines: molecular features and their influence in the expression of foreign genes. Appl Microbiol Biotechnol. (2017) 101:6865–77. 10.1007/s00253-017-8439-6
    1. Knipe DM, Howley PM, Cohen JI, Griffin DE, Lamb RA, Martin MA, et al. Fields in Virology. Philadelphia, PA: Lippincott Williams & Wilkins; (2013).

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