抗原85复合物的致病机制及其在结核病疫苗研制中的应用进展

doi:10.3969/j.issn.1000-6621.2020.11.018

摘要/Abstract

摘要：

结核分枝杆菌(MTB)的传播亟需开发有效的疫苗来控制。目前已鉴定出多种MTB免疫原性分子,其中,抗原85(Ag85)复合物(Ag85A、Ag85B和Ag85C)是重要的毒力因子,介导MTB的黏附和侵袭及其细胞壁的合成。Ag85抗原已被用作多种新型疫苗的构建中,如重组减毒疫苗、蛋白佐剂疫苗和病毒载体疫苗。作者综述了Ag85复合物的致病机制及其在结核病疫苗研制中的应用进展,探讨了Ag85复合物作为抗原在不同类型疫苗研制中的作用。

关键词: 抗原,细菌, 抗原抗体复合物, 毒力因子类, 结核, 疫苗,合成, 综述文献(主题)

Abstract:

Effective vaccines are urgently needed to control the transmission of Mycobacterium tuberculosis (MTB). A variety of MTB immunogenic molecules have been identified by now. And of them, the antigen 85 (Ag85) complex (Ag85A, Ag85B and Ag85C) is an important virulence factor, it could mediate the adhesion and invasion of MTB and the synthesis of the cell wall. Ag85 complex has been used in the construction of many new vaccines, such as recombinant attenuated vaccines, protein adjuvant vaccines and virus vector vaccines. In this paper, pathogenic mechanism of Ag85 complex and its application progress in the development of tuberculosis vaccine are reviewed, and the effects of Ag85 complex as antigens in developing different types of tuberculosis vaccines are also investigated.

Key words: Antigens,bacterial, Antigen-antibody complex, Virulence factors, Tuberculosis, Vaccines,synthetic, Review literature as topic

梁正敏, 王元智, 刘一朵, 周向梅. 抗原85复合物的致病机制及其在结核病疫苗研制中的应用进展[J]. 中国防痨杂志, 2020, 42(11): 1243-1249. doi: 10.3969/j.issn.1000-6621.2020.11.018

LIANG Zheng-min, WANG Yuan-zhi, LIU Yi-duo, ZHOU Xiang-mei. Pathogenic mechanism of Ag85 complex and its application progress in the development of tuberculosis vaccine[J]. Chinese Journal of Antituberculosis, 2020, 42(11): 1243-1249. doi: 10.3969/j.issn.1000-6621.2020.11.018

图/表 1

参考文献 66

[1]	Dorhoi A, Reece ST, Kaufmann SH. For better or for worse: the immune response against Mycobacterium tuberculosis balances pathology and protection. Immunol Rev, 2011,240(1):235-251. doi: 10.1111/j.1600-065X.2010.00994.x. doi: 10.1111/j.1600-065X.2010.00994.x URL pmid: 21349097
[2]	Karbalaei Zadeh Babaki M, Soleimanpour S, Rezaee SA. Antigen 85 complex as a powerful Mycobacterium tuberculosis immunogene: Biology, immune-pathogenicity, applications in diagnosis, and vaccine design. Microb Pathog, 2017,112:20-29. doi: 10.1016/j.micpath.2017.08.040. doi: 10.1016/j.micpath.2017.08.040 URL pmid: 28942172
[3]	Lehmann J, Cheng TY, Aggarwal A, et al. An Antibacterial β-Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis. Angew Chem Int Ed Engl, 2018,57(1):348-353. doi: 10.1002/anie.201709365. doi: 10.1002/anie.201709365 URL pmid: 29067779
[4]	Li F, Kang H, Li J, et al. Subunit Vaccines Consisting of Antigens from Dormant and Replicating Bacteria Show Promising Therapeutic Effect against Mycobacterium Bovis BCG Latent Infection. Scand J Immunol, 2017,85(6):425-432. doi: 10.1111/sji.12556. doi: 10.1111/sji.12556 URL pmid: 28426145
[5]	Harth G, Lee BY, Wang J, et al. Novel insights into the genetics, biochemistry, and immunocytochemistry of the 30-kilodalton major extracellular protein of Mycobacterium tuberculosis. Infect Immun, 1996,64(8):3038-3047. doi: 10.1128/IAI.64.8.3038-3047.1996. doi: 10.1128/IAI.64.8.3038-3047.1996 URL pmid: 8757831
[6]	Abou-Zeid C, Ratliff TL, Wiker HG, et al. Characterization of fibronectin-binding antigens released by Mycobacterium tuberculosis and Mycobacterium bovis BCG. Infect Immun, 1988,56(12):3046-3051. doi: 10.1128/IAI.56.12.3046-3051.1988. doi: 10.1128/IAI.56.12.3046-3051.1988 URL pmid: 3141278
[7]	Viljoen A, Alsteens D, Dufrêne Y. Mechanical Forces between Mycobacterial Antigen 85 Complex and Fibronectin. Cells, 2020,9(3):716. doi: 10.3390/cells9030716. doi: 10.3390/cells9030716 URL
[8]	Kuo CJ, Ptak CP, Hsieh CL, et al. Elastin, a novel extracellular matrix protein adhering to mycobacterial antigen 85 complex. J Biol Chem, 2013,288(6):3886-3896. doi: 10.1074/jbc.M112.415679. doi: 10.1074/jbc.M112.415679 URL pmid: 23250738
[9]	Xolalpa W, Vallecillo AJ, Lara M, et al. Identification of novel bacterial plasminogen-binding proteins in the human pathogen Mycobacterium tuberculosis. Proteomics, 2007,7(18):3332-3341. doi: 10.1002/pmic.200600876. doi: 10.1002/pmic.200600876 URL pmid: 17849409
[10]	Belisle JT, Vissa VD, Sievert T, et al. Role of the major antigen of Mycobacterium tuberculosis in cell wall biogenesis. Science, 1997,276(5317):1420-1422. doi: 10.1126/science.276.5317.1420. doi: 10.1126/science.276.5317.1420 URL pmid: 9162010
[11]	Vasina DV, Kleymenov DA, Manuylov VA, et al. First-In-Human Trials of GamTBvac, a Recombinant Subunit Tuberculosis Vaccine Candidate: Safety and Immunogenicity Assessment. Vaccines (Basel), 2019,7(4):166. doi: 10.3390/vaccines7040166.
[12]	Moguche AO, Musvosvi M, Penn-Nicholson A, et al. Antigen Availability Shapes T Cell Differentiation and Function during Tuberculosis. Cell Host Microbe, 2017, 21(6):659-706.e5. doi: 10.1016/j.chom.2017.05.012. doi: 10.1016/j.chom.2017.06.003 URL pmid: 28618264
[13]	Jiang MJ, Liu SJ, Su L, et al. Intranasal vaccination with Listeria ivanovii as vector of Mycobacterium tuberculosis antigens promotes specific lung-localized cellular and humoral immune responses. Sci Rep, 2020,10(1):302. doi: 10.1038/s41598-019-57245-6. doi: 10.1038/s41598-019-57245-6 URL pmid: 31942003
[14]	Armitige LY, Jagannath C, Wanger AR, et al. Disruption of the genes encoding antigen 85A and antigen 85B of Mycobacterium tuberculosis H37Rv: effect on growth in culture and in macrophages. Infect Immun, 2000,68(2):767-778. doi: 10.1128/iai.68.2.767-778.2000. doi: 10.1128/iai.68.2.767-778.2000 URL pmid: 10639445
[15]	Jackson M, Raynaud C, Lanéelle MA, et al. Inactivation of the antigen 85C gene profoundly affects the mycolate content and alters the permeability of the Mycobacterium tuberculosis cell envelope. Mol Microbiol, 1999,31(5):1573-1587. doi: 10.1046/j.1365-2958.1999.01310.x. doi: 10.1046/j.1365-2958.1999.01310.x URL pmid: 10200974
[16]	Mangtani P, Abubakar I, Ariti C, et al. Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials. Clin Infect Dis, 2014,58(4):470-480. doi: 10.1093/cid/cit790. doi: 10.1093/cid/cit790 URL pmid: 24336911
[17]	Huygen K. The Immunodominant T-Cell Epitopes of the Mycolyl-Transferases of the Antigen 85 Complex of M.tuberculosis. Front Immunol, 2014,5:321. doi: 10.3389/fimmu.2014.00321. doi: 10.3389/fimmu.2014.00321 URL pmid: 25071781
[18]	D’Souza S, Rosseels V, Romano M, et al. Mapping of murine Th1 helper T-Cell epitopes of mycolyl transferases Ag85A, Ag85B, and Ag85C from Mycobacterium tuberculosis. Infect Immun, 2003,71(1):483-493. doi: 10.1128/iai.71.1.483-493.2003. doi: 10.1128/iai.71.1.483-493.2003 URL pmid: 12496199
[19]	Tameris MD, Hatherill M, Landry BS, 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, 2013,381(9871):1021-1028. doi: 10.1016/s0140-6736(13)60177-4. doi: 10.1016/S0140-6736(13)60177-4 URL pmid: 23391465
[20]	Hoft DF, Blazevic A, Abate G, et al. A new recombinant bacille Calmette-Guérin vaccine safely induces significantly enhanced tuberculosis-specific immunity in human volunteers. J Infect Dis, 2008,198(10):1491-1501. doi: 10.1086/592450. doi: 10.1086/592450 URL pmid: 18808333
[21]	Hoft DF, Blazevic A, Selimovic A, 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, 2016,7:278-286. doi: 10.1016/j.ebiom.2016.04.010. doi: 10.1016/j.ebiom.2016.04.010 URL pmid: 27322481
[22]	Xu ZZ, Chen X, Hu T, et al. Evaluation of Immunogenicity and Protective Efficacy Elicited by Mycobacterium bovis BCG Overexpressing Ag85A Protein against Mycobacterium tuberculosis Aerosol Infection. Front Cell Infect Microbiol, 2016,6:3. doi: 10.3389/fcimb.2016.00003. doi: 10.3389/fcimb.2016.00003 URL pmid: 26858942
[23]	da Costa AC, Costa-Júnior Ade O, de Oliveira FM, et al. A new recombinant BCG vaccine induces specific Th17 and Th1 effector cells with higher protective efficacy against tuberculosis. PLoS One, 2014,9(11):e112848. doi: 10.1371/journal.pone.0112848. doi: 10.1371/journal.pone.0112848 URL pmid: 25398087
[24]	Yuan X, Teng X, Jing Y, et al. A live attenuated BCG vaccine overexpressing multistage antigens Ag85B and HspX provides superior protection against Mycobacterium tuberculosis infection. Appl Microbiol Biotechnol, 2015,99(24):10587-10595. doi: 10.1007/s00253-015-6962-x. doi: 10.1007/s00253-015-6962-x URL pmid: 26363555
[25]	Tameris M, Hokey DA, Nduba V, et al. A double-blind, randomised, placebo-controlled, dose-finding trial of the novel tuberculosis vaccine AERAS-402, an adenovirus-vectored fusion protein, in healthy, BCG-vaccinated infants. Vaccine, 2015,33(25):2944-2954. doi: 10.1016/j.vaccine.2015.03.070. doi: 10.1016/j.vaccine.2015.03.070 URL pmid: 25936724
[26]	Smaill F, Xing Z. Human type 5 adenovirus-based tuberculosis vaccine: is the respiratory route of delivery the future?. Expert Rev Vaccines, 2014,13(8):927-930. doi: 10.1586/14760584.2014.929947. doi: 10.1586/14760584.2014.929947 URL pmid: 24935214
[27]	Wilkie M, Satti I, Minhinnick A, et al. A phase Ⅰ trial eva-luating the safety and immunogenicity of a candidate tuberculosis vaccination regimen, ChAdOx1 85A prime-MVA85A boost in healthy UK adults. Vaccine, 2020,38(4):779-789. doi: 10.1016/j.vaccine.2019.10.102. doi: 10.1016/j.vaccine.2019.10.102 URL pmid: 31735500
[28]	Zhang Y, Feng L, Li L, et al. Effects of the fusion design and immunization route on the immunogenicity of Ag85A-Mtb32 in adenoviral vectored tuberculosis vaccine. Hum Vaccin Immunother, 2015,11(7):1803-1813. doi: 10.1080/21645515.2015.1042193. doi: 10.1080/21645515.2015.1042193 URL pmid: 26076321
[29]	Hu Z, Gu L, Li CL, et al. The Profile of T Cell Responses in Bacille Calmette-Guérin-Primed Mice Boosted by a Novel Sendai Virus Vectored Anti-Tuberculosis Vaccine. Front Immunol, 2018,9:1796. doi: 10.3389/fimmu.2018.01796. doi: 10.3389/fimmu.2018.01796 URL pmid: 30123219
[30]	Mearns H, Geldenhuys HD, Kagina BM, et al. H1:IC31 vaccination is safe and induces long-lived TNF-α⁺IL-2⁺CD4 T cell responses in M.tuberculosis infected and uninfected adolescents: A randomized trial . Vaccine, 2017,35(1):132-141. doi: 10.1016/j.vaccine.2016.11.023. doi: 10.1016/j.vaccine.2016.11.023 URL pmid: 27866772
[31]	Nemes E, Geldenhuys H, Rozot V, et al. Prevention of M.tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination. N Engl J Med, 2018,379(2):138-149. doi: 10.1056/NEJMoa1714021. doi: 10.1056/NEJMoa1714021 URL pmid: 29996082
[32]	Suliman S, Luabeya A, Geldenhuys H, et al. Dose Optimization of H56:IC31 Vaccine for Tuberculosis-Endemic Populations. A Double-Blind, Placebo-controlled, Dose-Selection Trial. Am J Respir Crit Care Med, 2019,199(2):220-231. doi: 10.1164/rccm.201802-0366OC. doi: 10.1164/rccm.201802-0366OC URL pmid: 30092143
[33]	Chen H, Liu X, Ma X, et al. A New Rabbit-Skin Model to Evaluate Protective Efficacy of Tuberculosis Vaccines. Front Microbiol, 2017,8:842. doi: 10.3389/fmicb.2017.00842. doi: 10.3389/fmicb.2017.00842 URL pmid: 28567030
[34]	Huang Q, Yu W, Hu T. Potent Antigen-Adjuvant Delivery System by Conjugation of Mycobacterium tuberculosis Ag85B-HspX Fusion Protein with Arabinogalactan-Poly(I:C) Conjugate. Bioconjug Chem, 2016,27(4):1165-1174. doi: 10.1021/acs.bioconjchem.6b00116. doi: 10.1021/acs.bioconjchem.6b00116 URL pmid: 27002920
[35]	Karbalaei Zadeh Babaki M, Taghiabadi M, Soleimanpour S, et al. Mycobacterium tuberculosis Ag85b:hfcγ1 recombinant fusion protein as a selective receptor-dependent delivery system for antigen presentation. Microb Pathog, 2019,129:68-73. doi: 10.1016/j.micpath.2019.01.045. doi: 10.1016/j.micpath.2019.01.045 URL pmid: 30711546
[36]	Ji P, Hu ZD, Kang H, et al. Boosting BCG-primed mice with chimeric DNA vaccine HG856A induces potent multifunctional T cell responses and enhanced protection against Mycobacterium tuberculosis. Immunol Res, 2016,64(1):64-72. doi: 10.1007/s12026-015-8674-9. doi: 10.1007/s12026-015-8674-9 URL pmid: 26111521
[37]	Su H, Zhu S, Zhu L, et al. Mycobacterium tuberculosis Latent Antigen Rv2029c from the Multistage DNA Vaccine A39 Drives TH1 Responses via TLR-mediated Macrophage Activation. Front Microbiol, 2017,8:2266. doi: 10.3389/fmicb.2017.02266. doi: 10.3389/fmicb.2017.02266 URL pmid: 29204139
[38]	Yuan W, Dong N, Zhang L, et al. Immunogenicity and protective efficacy of a tuberculosis DNA vaccine expressing a fusion protein of Ag85B-Esat6-HspX in mice. Vaccine, 2012,30(14):2490-2497. doi: 10.1016/j.vaccine.2011.06.029. doi: 10.1016/j.vaccine.2011.06.029 URL pmid: 21704108
[39]	Komine-Aizawa S, Jiang J, Mizuno S, et al. MHC-restricted Ag85B-specific CD8⁺ T cells are enhanced by recombinant BCG prime and DNA boost immunization in mice . Eur J Immunol, 2019,49(9):1399-1414. doi: 10.1002/eji.201847988. doi: 10.1002/eji.201847988 URL pmid: 31135967
[40]	Dai FY, Wang JF, Gong XL, et al. Immunogenicity and protective efficacy of recombinant Bacille Calmette-Guerin strains expressing mycobacterium antigens Ag85A, CFP10, ESAT-6, GM-CSF and IL-12p70. Hum Vaccin Immunother, 2017,13(6):1-8. doi: 10.1080/21645515.2017.1279771. doi: 10.1080/21645515.2017.1285475 URL pmid: 28301266
[41]	Kaufmann SHE. Vaccination Against Tuberculosis: Revamping BCG by Molecular Genetics Guided by Immunology. Front Immunol, 2020,11:316. doi: 10.3389/fimmu.2020.00316. doi: 10.3389/fimmu.2020.00316 URL pmid: 32174919
[42]	Nieuwenhuizen NE, Kulkarni PS, Shaligram U, et al. The Recombinant Bacille Calmette-Guérin Vaccine VPM1002: Ready for Clinical Efficacy Testing. Front Immunol, 2017,8:1147. doi: 10.3389/fimmu.2017.01147. doi: 10.3389/fimmu.2017.01147 URL pmid: 28974949
[43]	Tkachuk AP, Gushchin VA, Potapov VD, et al. Multi-subunit BCG booster vaccine GamTBvac: Assessment of immunogenicity and protective efficacy in murine and guinea pig TB models. PLoS One, 2017,12(4):e0176784. doi: 10.1371/journal.pone.0176784. doi: 10.1371/journal.pone.0176784 URL pmid: 28453555
[44]	van Dissel JT, Soonawala D, Joosten SA, et al. Ag85B-ESAT-6 adjuvanted with IC31^® promotes strong and long-lived Mycobacterium tuberculosis specific T cell responses in volunteers with previous BCG vaccination or tuberculosis infection . Vaccine, 2011,29(11):2100-2109. doi: 10.1016/j.vaccine.2010.12.135. doi: 10.1016/j.vaccine.2010.12.135 URL pmid: 21256189
[45]	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. Vaccine, 2017,35(12):1652-1661. doi: 10.1016/j.vaccine.2017.01.055. doi: 10.1016/j.vaccine.2017.01.055 URL pmid: 28216183
[46]	Lin P, 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 Clin Invest, 2012,122(1):303-314. doi: 10.1172/jci46252. doi: 10.1172/JCI46252 URL pmid: 22133873
[47]	Woodworth JS, Christensen D, Cassidy JP, et al. Mucosal boosting of H56:CAF01 immunization promotes lung-localized T cells and an accelerated pulmonary response to Mycobacterium tuberculosis infection without enhancing vaccine protection. Mucosal Immunol, 2019,12(3):816-826. doi: 10.1038/s41385-019-0145-5. doi: 10.1038/s41385-019-0145-5 URL pmid: 30760832
[48]	Thakur A, Ingvarsson PT, Schmidt ST, et al. Immunological and physical evaluation of the multistage tuberculosis subunit vaccine candidate H56/CAF01 formulated as a spray-dried powder. Vaccine, 2018,36(23):3331-3339. doi: 10.1016/j.vaccine.2018.04.055. doi: 10.1016/j.vaccine.2018.04.055 URL pmid: 29699790
[49]	杨蕾, 王春花, 卢锦标, 等. 新型结核病疫苗AEH/Al/IC在小鼠中的免疫原性研究. 微生物学免疫学进展, 2019,47(6):28-33. doi: 10.13309/j.cnki.pmi.2019.06.005.
[50]	Mcshane H, Pathan AA, Sander CR, et al. Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans. Nat Med, 2004,10(11):1240-1244. doi: 10.1038/nm1128. doi: 10.1038/nm1128 URL pmid: 15502839
[51]	Nemes E, Hesseling AC, Tameris M, et al. Safety and Immunogenicity of Newborn MVA85A Vaccination and Selective, Delayed Bacille Calmette-Guerin for Infants of Human Immunodeficiency Virus-Infected Mothers: A Phase 2 Randomized, Controlled Trial. Clin Infect Dis, 2018,66(4):554-563. doi: 10.1093/cid/cix834. doi: 10.1093/cid/cix834 URL pmid: 29028973
[52]	Manjaly Thomas ZR, Satti I, Marshall JL, et al. Alternate aerosol and systemic immunisation with a recombinant viral vector for tuberculosis, MVA85A: A phase Ⅰ randomised controlled trial. PLoS Med, 2019,16(4):e1002790. doi: 10.1371/journal.pmed.1002790. doi: 10.1371/journal.pmed.1002790 URL pmid: 31039172
[53]	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(48):6800-6808. doi: 10.1016/j.vaccine.2015.10.017. doi: 10.1016/j.vaccine.2015.10.017 URL pmid: 26478198
[54]	Evans TG, Churchyard GJ, Penn-Nicholson A, et al. Epidemiologic studies and novel clinical research approaches that impact TB vaccine development. Tuberculosis (Edinb), 2016,99 Suppl 1: S21-25. doi: 10.1016/j.tube.2016.05.008. doi: 10.1016/j.tube.2016.05.008 URL
[55]	Brennan MJ, Stone MR, Evans T. A rational vaccine pipeline for tuberculosis. Int J Tuberc Lung Dis, 2012,16(12):1566-1573. doi: 10.5588/ijtld.12.0569. doi: 10.5588/ijtld.12.0569 URL pmid: 23131253
[56]	Hoft DF, Blazevic A, Stanley J, et al. A recombinant adenovirus expressing immunodominant TB antigens can significantly enhance BCG-induced human immunity. Vaccine, 2012,30(12):2098-2108. doi: 10.1016/j.vaccine.2012.01.048. doi: 10.1016/j.vaccine.2012.01.048 URL pmid: 22296955
[57]	Nyendak M, Swarbrick GM, Duncan A, 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, 2016,6:36355. doi: 10.1038/srep36355. doi: 10.1038/srep36355 URL pmid: 27805026
[58]	van Zyl-Smit RN, Esmail A, Bateman ME, et al. Safety and Immunogenicity of Adenovirus 35 Tuberculosis Vaccine Candidate in Adults with Active or Previous Tuberculosis. A Randomized Trial. Am J Respir Crit Care Med, 2017,195(9):1171-1180. doi: 10.1164/rccm.201603-0654OC. doi: 10.1164/rccm.201603-0654OC URL pmid: 28060545
[59]	Hu Z, Wong KW, Zhao HM, et al. Sendai Virus Mucosal Vaccination Establishes Lung-Resident Memory CD8 T Cell Immunity and Boosts BCG-Primed Protection against TB in Mice. Mol Ther, 2017,25(5):1222-1233. doi: 10.1016/j.ymthe.2017.02.018. doi: 10.1016/j.ymthe.2017.02.018 URL pmid: 28342639
[60]	史晓雨, 隋秀文, 苗伟, 等. 新型腺病毒载体肺结核疫苗的免疫原性研究. 中国免疫学杂志, 2020,36(6):719-722. doi: 10.3969/j.issn.1000-484X.2020.06.015.
[61]	Hu Z, Jiang W, Gu L, et al. Heterologous prime-boost vaccination against tuberculosis with recombinant Sendai virus and DNA vaccines. J Mol Med (Berl), 2019,97(12):1685-1694. doi: 10.1007/s00109-019-01844-3. doi: 10.1007/s00109-019-01844-3 URL
[62]	张真, 赵玲娜, 申梦, 等. 结核分枝杆菌Hsp65-Ag85B、Hsp65-ESAT6融合基因DNA疫苗株的构建及免疫原性研究. 免疫学杂志, 2020,36(2):109-115. doi: 10.13431/j.cnki.immunol.j.20200019.
[63]	Li H, Javid B. Antibodies and tuberculosis: finally coming of age?. Nat Rev Immunol, 2018,18(9):591-596. doi: 10.1038/s41577-018-0028-0.
[64]	Wang C, Lu J, Du W, et al. Ag85b/ESAT6-CFP10 adjuvanted with aluminum/poly-IC effectively protects guinea pigs from latent Mycobacterium tuberculosis infection. Vaccine, 2019,37(32):4477-4484. doi: 10.1016/j.vaccine.2019.06.078. doi: 10.1016/j.vaccine.2019.06.078 URL pmid: 31266673
[65]	Prados-Rosales R, Carreño L, Cheng T, et al. Enhanced control of Mycobacterium tuberculosis extrapulmonary dissemination in mice by an arabinomannan-protein conjugate vaccine. PLoS Pathog, 2017,13(3):e1006250. doi: 10.1371/journal.ppat.1006250. URL pmid: 28278283
[66]	Chen T, Blanc C, Liu Y, et al. Capsular glycan recognition provides antibody-mediated immunity against tuberculosis. J Clin Invest, 2020,130(4):1808-1822. doi: 10.1172/JCI128459. doi: 10.1172/JCI128459 URL pmid: 31935198

疫苗类型及名称	结核抗原	临床试验情况	参考文献
重组BCG疫苗
rBCG30	过表达Ag85B	免疫原性不佳,Ⅰ期结束	[20]
AERAS-422	过表达产气荚膜溶血素O、Ag85B、Ag85A、Rv3407	有不良反应,Ⅰ期结束	[21]
rBCG::Ag85A	过表达Ag85A	下一代	[22]
rBCG-CMX	过表达Ag85C、MPT51、HspX	下一代	[23]
rBCG::XB	过表达Ag85B和HspX	下一代	[24]
病毒载体疫苗
MVA85A	牛痘病毒表达Ag85A	Ⅱ期	[19]
Ad35-TBS/AERAS-402	35型腺病毒表达Ag85A、Ag85B和TB10.4	Ⅰ期	[25]
Ad5Ag85A	5型腺病毒表达Ag85A	Ⅰ期	[26]
ChAdOx1.85 A	猴腺病毒表达Ag85A	Ⅰ期	[27]
Ad5-gsgAM	5型腺病毒表达Ag85A和Mtb32 (Rv0125)	下一代	[28]
SeV85AB	仙台病毒表达Ag85A和Ag85B	下一代	[29]
蛋白佐剂疫苗
H1∶IC31	Ag85B-ESAT-6,佐剂:IC31	Ⅱ期	[30]
H4∶IC31	Ag85B-TB10.4,佐剂:IC31	Ⅱ期	[31]
H56∶IC31	Ag85B-ESAT-6 和Rv2660,佐剂:IC31	Ⅰ期	[32]
EAMM	ESAT-6-Ag85B-MPT6-Mtb8.4,佐剂:DDA,poly I∶C	下一代	[33]
Ag85B-HspX	Ag85B-HspX,佐剂:AG,poly I:C	下一代	[34]
GamTBvac	ESAT6-CFP10和Ag85A,佐剂:Dextrans,CpG ODN	Ⅰ期	[11]
Ag85B∶hfcγ1	融合蛋白Ag85B-hfcγ1	下一代	[35]
DNA疫苗
HG856A	表达Ag85A、ESAT-6	下一代	[36]
A39	表达Ag85A、Rv3425和Rv2029c	下一代	[37]
pAEH	表达Ag85B-ESAT-6-HspX的	下一代	[38]
DNA-Mkan85B	表达Ag85B	下一代	[39]