Abstract:Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB), which severely endangers human health. Tuberculosis is one of the major infectious diseases causing harm and death to people globally. China has among the highest burden of TB worldwide. China’s TB prevention and control efforts are facing many problems and challenges. The current TB prevention and control service system and control capacity in China cannot meet the prevention and control needs. At present, the most common and effective vaccine to prevent tuberculosis is Bacillus Calmette-Guérin (BCG). However, because of the relatively low protective effect of BCG against pulmonary tuberculosis infection in adolescents and adults, as well as changes in external factors, BCG faces challenges in meeting the urgent needs of preventing and controlling tuberculosis in humans. Currently, research and development of a new TB vaccine is particularly urgent and important. This article introduces the live attenuated vaccine VPM1002 vaccine, protein/adjuvant vaccine H4/H56:IC31 vaccine, viral vector vaccine, adenovirus vector vaccine and other vaccines that have entered clinical trials. It additionally describes the current status of research on anti-TB immune mechanisms to provide a reference for future tuberculosis control, and it discusses ideas for the future development of new TB vaccines. This article should have important reference value for the development and innovation of TB vaccines in China.
[1] World Health Organization. Global tuberculosis report 2019[EB/OL].[2019-10-17](2020-02-06). https://www.who.int/tb/publications/global_report/en/ [2] Atmakuri K, Penn-Nicholson A, Tanner R, et al.Meeting report: 5th Global Forum on TB Vaccines, 20-23 February 2018, New Delhi India[J]. Tuberculosis (Edinb), 2018, 113: 55-64. DOI:10.1016/j.tube.2018.08.013 [3] Rakshit S, Ahmed A, Adiga V, et al.BCG revaccination boosts adaptive polyfunctional Th1/Th17 and innate effectors in IGRA+ and IGRA-Indian adults[J]. JCI insight, 2019, 4(24): e130540. DOI:10.1172/jci.insight.130540 [4] 王洪海. 全球结核病疫苗研究进展[J]. 微生物与感染, 2017, 12(4): 198-205. DOI:10.3969/j.issn.1673-6184.2017.04.003 [5] Méndezsamperio P.Global efforts in the development of vaccines for tuberculosis: Requirements for improved vaccines against Mycobacterium tuberculosis[J]. Scand J Immunol, 2016, 84(4): 204-210. DOI:10.1111/sji.12465 [6] Grode L, Seiler P, Baumann S, et al.Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guérin mutants that secrete listeriolysin[J]. J Clin Invest, 2005, 115(9): 2472-2479. DOI:10.1172/JCI24617 [7] Nieuwenhuizen NE, Kulkarni PS, Shaligram U, et al.The recombinant bacille calmette-guerin vaccine VPM1002: ready for clinical efficacy testing[J]. Front Immunol, 2017, 8: 1147. DOI:10.3389/fimmu.2017.01147 [8] Vogelzang A, Perdomo C, Zedler U, et al.Central memory $CD_4^+$ T cells are responsible for the recombinant bacillus calmette-guérin ΔureC::hly vaccine’s superior protection against tuberculosis[J]. J Infect Dis, 2014, 210(12): 1928-1937. DOI:10.1093/infdis/jiu347 [9] Desel C, Dorhoi A, Bandermann S, et al.Recombinant BCG DeltaureC hly+ induces superior protection over parental BCG by stimulating a balanced combination of type 1 and type 17 cytokine responses[J]. J Infect Dis, 2011, 204(10): 1573-1584. DOI:10.1093/infdis/jir592 [10] André G Loxton, Julia K. Knaul, Leander Grode, et al.Safety and Immunogenicity of the Recombinant Mycobacterium bovis BCG Vaccine VPM1002 in HIV-Unexposed Newborn Infants in South Africa[J].Clin Vaccine Immunol, 2017,24(2):e00439-16. DOI:10.1128/cvi.00439-16 [11] Saiga H, Nieuwenhuizen N, Gengenbacher M, et al.The recombinant BCG ΔureC::hly vaccine targets the AIM2 inflammasome to induce autophagy and inflammation[J]. J Infect Dis, 2015, 211(11): 1831-1841. DOI:10.1093/infdis/jiu675 [12] Counoupas C, Pinto R, Nagalingam G, et al.Protective efficacy of recombinant BCG over-expressing protective, stage-specific antigens of Mycobacterium tuberculosis[J]. Vaccine, 2018, 36(19): 2619-2629. DOI:10.1016/j.vaccine.2018.03.066 [13] Counoupas C, Pinto R, Nagalingam G, et al.Mycobacterium tuberculosis components expressed during chronic infection of the lung contribute to long-term control of pulmonary tuberculosis in mice[J]. NPJ Vaccines, 2016, 1:e16012. DOI:10.1038/npjvaccines.2016.12 [14] Counoupas C, Pinto RNagalingam G, et al.Delta inulin-based adjuvants promote the generation of polyfunctional $CD_4^+$ T cell responses and protection against Mycobacterium tuberculosis infection[J]. Sci Rep, 2017, 7(1): 8582. DOI:10.1038/s41598-017-09119-y [15] Broset E, Saubi N, Guitart N, et al.MTBVAC-Based TB-HIV vaccine is safe, elicits HIV-T cell responses, and protects against Mycobacterium tuberculosis in mice[J]. Mol Ther Methods Clin Dev, 2019, 13: 253-264. DOI:10.1016/j.omtm.2019.01.014 [16] Spertini F, Audran R, Chakour R, et al, Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: A randomised, double-blind, controlled phase I trial[J]. Lancet Respir Med,2015, 3(12): 953-962. DOI:10.1016/S2213-2600(15)00435-X [17] Aguilo N, Gonzalo-Asensio J, Alvarez-Arguedas S, et al.Reactogenicity to major tuberculosisantigens absent in BCG is linked to improved protection against Mycobacterium tuberculosis[J]. Nat Commun, 2017,8: e16085. DOI:10.1038/ncomms16085 [18] Jesus GA, Dessislava M, Carlos M, et al.MTBVAC: attenuating the human pathogen of tuberculosis (TB) toward a promising vaccine against the TB epidemic[J]. Front Immunol, 2017, 8: 1803. DOI:10.3389/fimmu.2017.01803 [19] Clark Simon, Lanni Faye, Marinova Dessislava, et al.Revaccination of guinea pigs with the live attenuated Mycobacterium tuberculosis vaccine MTBVAC improves BCG’s protection against tuberculosis[J]. J Infect Dis, 2017, 216(5):525-533. DOI:10.1093/infdis/jix030 [20] Ottenhoff TH, Doherty TM, van Dissel JT, et al. First in humans: a new molecularly defined vaccine shows excellent safety and strong induction of long-lived Mycobacterium tuberculosis-specific Th1-cell like responses[J]. Hum Vaccin, 2010, 6(12): 1007-1015. DOI:10.4161/hv.6.12.13143 [21] Rolf B, Elvang TT, Andersen PL, et al.The hyVac4 subunit vaccine efficiently boosts BCG-primed anti-Mycobacterial protective immunity[J]. PloS One, 2012, 7(6): e39909. DOI:10.1371/journal.pone.0039909 [22] Geldenhuys H, Mearns H, Miles DJ, et al.The tuberculosis vaccine H4:IC31 is safe and induces a persistent polyfunctional CD4 T cell response in South African adults: A randomized controlled trial[J]. Vaccine, 2015, 33(30): 3592-3599. DOI:10.1016/j.vaccine.2015.05.036 [23] Aboutorabian S, Hakimi J, Boudet F, et al.A high ratio of IC31 adjuvant to antigen is necessary for H4 TB vaccine immunomodulation[J]. Hum Vaccin Immunother, 2015, 11(6): 1449-1455. DOI:10.1080/21645515.2015.1023970 [24] Norrby M, Vesikari T, Lindqvist L, et al.Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: Two phase I dose escalation trials[J]. Vaccine, 2017, 35(12): 1652-1661. DOI:10.1016/j.vaccine.2017.01.055 [25] Nemes E, Geldenhuys H, Rozot V, et al.Prevention of M. tuberculosis infection with H4:IC31 Vaccine or BCG Revaccination[J]. N Engl J Med, 2018, 379(2): 138-149. DOI:10.3410/f.733620530.793549119 [26] Lin PL, Dietrich J, Tan E, 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]. J Clin Invest, 2012, 122(1): 303-314. DOI:10.1172/JCI46252 [27] Suliman S, Luabeya AKK, Geldenhuys H, et al.Dose optimization of H56:IC31 Vaccine for TB endemic populations: a double-blind, placebo-controlled, dose-selection trial[J]. Am J Respir Crit Care Med, 2019, 199(2): 220-231. DOI:10.1164/rccm.201802-0366OC [28] 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[J]. Vaccine, 2015, 33(33): 4130-4140. DOI:10.1016/j.vaccine.2015.06.051 [29] Bekker LG, Dintwe O, Fiore-Gartland A, et al.A phase 1b randomized study of the safety and immunological responses to vaccination with H4:IC31, H56:IC31, and BCG revaccination in Mycobacterium tuberculosis-uninfected adolescents in Cape Town, South Africa[J]. E Clin Med, 2020, 21:e100313. DOI:10.1016/j.eclinm.2020.100313 [30] Montoya J, Solon JA, Cunanan SRC, et al.A randomized, controlled dose-finding phase II study of the M72/AS01 candidate tuberculosis vaccine in healthy PPD-positive adults[J]. J Clin Immunol, 2013, 33(8):1360-1375. DOI:10.1007/s10875-013-9949-3 [31] Mushtaq ahmed, Shyamala thirunavukkarasu, Bruce ARosa, et al. Immune correlates of tuberculosis disease and risk translate across species [J]. Sci Transl Med, 2020, 12(528):eaay0233. DOI:10.1126/scitranslmed.aay0233 [32] Kumarasamy N, Poongulali S, Bollaerts A, et al.A randomized, controlled safety, and immunogenicity trial of the M72/AS01 candidate tuberculosis vaccine in HIV-positive indian adults[J]. Medicine (Baltimore), 2016, 95(3): 1-10. DOI:10.1097/MD.0000000000002459 [33] Cha SB, Kim WS, Kim JS, et al.Pulmonary immunity and durable protection induced by the ID93/GLA-SE vaccine candidate against the hyper-virulent Korean Beijing Mycobacterium tuberculosis strain K[J]. Vaccine, 2016, 34(19):2179-2187. DOI:10.1016/j.vaccine.2016.03.029 [34] Baldwin SL, Reese VA, Huang PW, et al.Protection and long-lived immunity induced by the ID93/GLA-SE vaccine candidate against a Clinical Mycobacterium tuberculosis Isolate[J]. Clin Vaccine Immunol, 2016, 23(2):137-147. DOI:10.1128/cvi.00458-15 [35] Coler RN, Day TA, Ellis R, 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[J]. NPJ Vaccines,2018, 3(1): 34. DOI:10.1038/s41541-018-0057-5 [36] Dubois Cauwelaert N, Desbien AL, Hudson TE, et al.The TLR4 agonist vaccine adjuvant, GLA-SE, requires canonical and atypical mechanisms of action for TH1 induction[J]. PloS One, 2016, 11:1-14. DOI:10.1371/journal.pone.0146372 [37] Zheng J, Chen L, Liu L, et al.Proteogenomic analysis and discovery of immune antigens in Mycobacterium vaccae[J]. Mol Cell Proteomics, 2017, 16(9): 1578-1590. DOI:10.1074/mcp.m116.065813 [38] Soundarya JSV, Ranganathan UD, Tripathy SP.Current trends in tuberculosis vaccine[J]. Med J Armed Forces India, 2019, 75(1): 18-24. DOI:10.1016/j.mjafi.2018.12.013 [39] Kaufmann SH.Tuberculosis vaccines: time to think about the next generation[J]. Semin Immunol, 2013, 25(2): 172-181. DOI:10.1016/j.smim.2013.04.006 [40] Xiao T, Li X, Yan Y, et al.Cross-reactive immune responses to Mycobacterium vaccae, Mycobacterium tuberculosis and Bacillus Calmette-Guerin[J]. Chin J Microbiol Immunol (China), 2019, 39(3):212-216. DOI:10.3760/cma.j.issn.0254-5101.2019.03.010 [41] 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[J]. Proc Natl Acad Sci U S A, 2016, 113(22):e3130-e3139. DOI:10.1073/pnas.1600324113 [42] Sharma A, Equbal MJ, Pandey S, et al.Immunodominant protein MIP_05962 from Mycobacterium indicus pranii displays chaperone activity[J]. FEBS J, 2017, 284(9):1338-1354. DOI:10.1111/febs.14057 [43] Rawat KD, Chahar M, Pvj R, et al.Immunoprophylaxis in Guinea pigs with Mycobacterium indicus pranii (Mw) in combination with standard chemotherapy of M. tuberculosis infection improves lung pathology[J]. Mycobact Dis, 2016, 6(5):e1000230. DOI:10.4172/2161-1068.1000230 [44] Alexander DC, Turenne CY."Mycobacterium indicus pranii" is a strain of Mycobacterium intracellulare[J]. mBio, 2015, 6(.2):e00013-e00015. DOI:10.1128/mBio.00013-15 [45] Scriba TJ, Kaufmann SH, Henri Lambert P, et al.Vaccination against tuberculosis with whole cell mycobacterial vaccines[J]. J Infect Dis, 2016, 214(5):659-664. DOI:10.3410/f.726392815.793537891 [46] Castejon M, Menéndez MC, Comas I, et al.Whole-genome sequence analysis of the Mycobacterium avium complex and proposal of the transfer of Mycobacterium yongonense to Mycobacterium intracellulare subsp. yongonense subsp. Nov[J]. Int J Syst Evol Microbiol, 2018, 68(6): 1998-2005. DOI:10.1099/ijsem.0.002767 [47] Saqib M, Khatri R, Singh B, et al.Cell wall fraction of Mycobacterium indicus pranii shows potential Th1 adjuvant activity[J]. Int Immunopharmacol. 2019, 70:408-416. DOI:10.1016/j.intimp.2019.02.049 [48] Gupta Ananya, Saqib Mohd, Saqib Mohd, et al.Mycobacterium indicus pranii Induced Memory T-Cells in lung airways are sentinels for improved protection against M.tb infection[J].Front Immunol, 2019,10: 2359. DOI:10.3389/fimmu.2019.02359 [49] Sharma A, Saqib M, Sheikh JA, et al.Mycobacterium indicus pranii protein MIP_05962 induces Th1 cell mediated immune response in mice[J]. Int J Med Microbiol, 2018, 308(8):1000-1008. DOI:10.1016/j.ijmm.2018.08.008 [50] Nagpal PS, Kesarwani A, Sahu P, et al.Aerosol immunization by alginate coated mycobacterium (BCG/MIP) particles provide enhanced immune response and protective efficacy than aerosol of plain mycobacterium against M.tb. H37Rv infection in mice[J]. BMC Infect Dis, 2019, 19(1):568. DOI:10.1186/s12879-019-4157-2 [51] Singh B, Saqib M, Chakraborty A, et al.Lipoarabinomannan from Mycobacterium indicus pranii shows immunostimulatory activity and induces autophagy in macrophages[J]. PloS One, 2019, 14(10):e0224239. DOI:10.1371/journal.pone.0224239 [52] Prabowo SA, Painter H, Zelmer A, et al.RUTI vaccination enhances inhibition of mycobacterial growth ex vivo and induces a shift of monocyte phenotype in mice[J]. Front Immunol,2019,10:894. DOI:10.3389/fimmu.2019.00894 [53] Lim JL, Koh VHQ, Cho SSL, et al.Harnessing the Immunomodulatory Properties of Bacterial Ghosts to Boost the Anti-mycobacterial Protective Immunity[J]. Front Immunol, 2019, 10:2737 DOI:10.3389/fimmu.2019.02737 [54] Pennisi M, Russo G, Sgroi G, et al.Predicting the artificial immunity induced by RUTI vaccine against tuberculosis using universal immune system simulator (UISS)[J]. BMC Bioinformatics, 2019, 20(6):504. DOI:10.1186/s12859-019-3045-5 [55] 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[J]. PLoS One, 2017, 12(5): e0175215. DOI:10.1371/journal.pone.0175215 [56] Masonou T, Hokey DA, Lahey T, et al.$CD_4^+$ T cell cytokine responses to the DAR-901 booster vaccine in BCG-primed adults: A randomized, placebo-controlled trial[J]. PLoS ONE, 2019, 14(5):e0217091. DOI:10.1371/journal.pone.0217091 [57] Lahey T, Laddy D, Hill K, et al.Immunogenicity and protective efficacy of the DAR-901 booster vaccine in a murine model of tuberculosis[J]. PLoS One, 2016, 11(12): e0168521. DOI:10.1371/journal.pone.0168521 [58] Santosuosso M, McCormick S, Roediger E, et al. Mucosal luminal manipulation of T cell geography switches on protective efficacy by otherwise ineffective parenteral genetic immunization[J]. J Immunol, 2007, 178(4):2387-2395. DOI:10.4049/jimmunol.178.4.2387 [59] Diaz-San Segundo F, Montiel NA, Sturza DF, et al. Combination of Adt-O1Manisa and Ad5-boIFNλ3 induces early protective immunity against foot-and-mouth disease in cattle[J]. Virology, 2016, 499: 340-349. DOI:10.1016/j.virol.2016.09.027 [60] Metcalfe HJ, Steinbach S, Jones GJ,et al.Protection associated with a TB vaccine is linked to increased frequency of Ag85A-specific $CD_4^+$ T cells but no increase in avidity for Ag85A[J]. Vaccine, 2016, 34(38): 4520-4525. DOI:10.1016/j.vaccine.2016.07.055 [61] Metcalfe HJ, Biffar L, Steinbach S, et al.Ag85A-specific $CD_4^+$ T cell lines derived after boosting BCG-vaccinated cattle with Ad5-85A possess both mycobacterial growth inhibition and anti-inflammatory properties[J]. Vaccine, 2018, 36(20): 2850-2854. DOI:10.1016/j.vaccine.2018.03.068 [62] 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[J]. Vaccine, 2015, 33(48): 6800-6808. DOI:10.1016/j.vaccine.2015.10.017 [63] Wilkie M, Satti I, Minhinnick A, et al.A phase I trial evaluating the safety and immunogenicity of a candidate tuberculosis vaccination regimen, ChAdOx1 85A prime - MVA85A boost in healthy UK adults[J]. Vaccine, 2020, 38(4):779-789. DOI:10.1016/j.vaccine.2019.10.102 [64] Hussain A, Singh S, Das S, et al.Nanomedicines as drug delivery carriers of anti-tubercular drugs: from pathogenesis to infection control[J]. Curr Drug Deliv, 2019, 16(5):400-429. DOI:10.2174/1567201816666190201144815 [65] Coppola M, van den Eeden SJF, Robbins N, et al. Vaccines for leprosy and tuberculosis: opportunities for shared research, development, and application[J]. Front Immunol, 2018, 9: 308. DOI:10.3389/fimmu.2018.00308 [66] Mendy J, Jarju S, Heslop R, et al.Changes in Mycobacterium tuberculosis-specific immunity with influenza co-infection at time of TB diagnosis[J]. Front Immunol, 2019, 10: 3093. DOI:10.3389/fimmu.2018.03093 [67] Taniguchi K, Takii T, Yamamoto S, et al.Reactivation of immune responses against Mycobacterium tuberculosis by boosting with the CpG oligomer in aged mice primarily vaccinated with Mycobacterium bovis BCG[J]. Immun Ageing, 2013,10(1): 25-25. DOI:10.1186/1742-4933-10-25 [68] Bekale RB, Du Plessis SM, Hsu NJ, et al.Mycobacterium tuberculosis and interactions with the host immune system: Opportunities for Nanoparticle Based Immunotherapeutics and Vaccines[J]. Pharm Res, 2019, 6(1):8. DOI:10.1007/s11095-018-2528-9 [69] Cooper AM, Khader SA.The role of cytokines in the initiation, expansion, and control of cellular immunity to tuberculosis[J]. Immunol Rev, 2010,.226(1): 191-204. DOI:10.1111/j.1600-065x.2008.00702.x [70] Redford PS, Murray PJ, O’Garra A. The role of IL-10 in immune regulation during M. tuberculosis infection[J]. Mucosal Immunol, 2011, 4(3): 261-270. DOI:10.1038/mi.2011.7 [71] Szpakowski P, Biet F, Locht C, et al.Dendritic cell activity driven by recombinant Mycobacterium bovis BCG producing human IL-18, in healthy BCG vaccinated adults[J]. Immunol Res, 2015, 2015(2): 359153. DOI:10.1155/2015/359153 [72] Lai R, Jeyanathan M, Afkhami S, et al.CD11b+ dendritic cell-mediated anti-Mycobacterium tuberculosis Th1 activation is counterregulated by CD103+ dendritic cells via IL-10[J]. J Immunol, 2018, 200(5): 1746-1760. DOI:10.4049/jimmunol.1701109 [73] Hatano R, Ohnuma K, Yamamoto J, et al.CD26-mediated co-stimulation in human $CD_8^+$ T cells provokes effector function via pro‐inflammatory cytokine production[J]. Immunology, 2013, 138(2): 165-172. DOI:10.1111/imm.12028 [74] Wallis RS, Hafner R.Advancing host-directed therapy for tuberculosis[J]. Nat Rev Immunol, 2015, 15(4): 255-263. DOI:10.15698/mic2017.03.565 [75] Rech G, Vilaplana C, Velasco J, et al.Draft genome sequences of Mycobacterium setense type strain DSM-45070 and the nonpathogenic strain manresensis, isolated from the bank of the cardener river in Manresa, Catalonia, Spain[J]. Genome Announc, 2015,3(1):e01485-14. DOI:10.1128/genomeA.01485-14 [76] Montané E, Barriocanal AM, Arellano AL, et al.Pilot, double-blind, randomized, placebocontrolled clinical trial of the supplement food Nyaditum resae in adults with or without latent TB infection: Safety and immunogenicity[J]. PLoS One, 2017, 12(2):e0171294. DOI:10.1371/journal.pone.0171294 [77] Cardona P, Marzo-Escartin E, Tapia G, et al.Oral Administration of heat-killed Mycobacterium manresensis delays progression toward active tuberculosis in C3HeB/FeJ Mice[J]. Front Microbiol, 2015, 6:1482. DOI:10.3389/fmicb.2015.01482 [78] EFSA Panel on Nutrition, Novel foods and food allergens (NDA), Turck D, et al. Safety of heat-killed Mycobacterium setense manresensis as a novel food pursuant to Regulation (EU) 2015/2283[J]. EFSA J, 2019, 17(11):e05824. DOI:10.2903/j.efsa.2019.5824 [79] Billeskov Rolf, Tan Esterlina V, Cang Marjorie, et al.Testing the H56 vaccine delivered in 4 different adjuvants as a BCG-booster in a non-human primate model of tuberculosis[J]. PLoS One, 2016, 11(8): e0161217. DOI:10.1371/journal.pone.0161217 [80] Van Rhijn I, Moody DB.Donor unrestricted T cells: a shared human T cell response[J]. J Immunol, 2015, 195(5): 1927-1932. DOI:10.4049/jimmunol.1500943 [81] Larrouy-Maumus G, Layre E, Clark S, et al.Protective efficacy of a lipid antigen vaccine in a guinea pig model of tuberculosis[J]. Vaccine, 2017, 35(10): 1395-1402. DOI:10.1016/j.vaccine.2017.01.079 [82] Suliman S, Murphy M, Musvosvi M, et al.MR1-independent activation of human mucosal-associated invariant T cells by Mycobacteria[J]. J Immunol, 2019, 203(11):2917-2927. DOI:10.4049/jimmunol.1900674 [83] Perdomo C, Zedler U, Kühl AA, et al.Mucosal BCG vaccination induces protective lung-resident memory T cell populations against tuberculosis(Article)[J]. mBio, 2016, 7(6):e01686-16. DOI: 10.1128/mBio.01686-16 [84] Bull NC, Stylianou E, Kaveh DA, et al.Enhanced protection conferred by mucosal BCG vaccination associates with presence of antigen-specific lung tissue-resident PD-1+ KLRG1- $CD_4^+$ T cells[J]. Mucosal Immunol, 2019, 12(2): 555-564. DOI:10.1038/s41385-018-0109-1 [85] Kaufmann E, Sanz J, Dunn JL, et al.BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis[J]. Cell, 2018, 172(1-2): 176-190. DOI:10.1016/j.cell.2017.12.031