{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:43:05Z","timestamp":1787510585038,"version":"build-2736575974"},"reference-count":83,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,16]],"date-time":"2020-09-16T00:00:00Z","timestamp":1600214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["RTI2018-096494-B-100"],"award-info":[{"award-number":["RTI2018-096494-B-100"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["SEV-2016-0644"],"award-info":[{"award-number":["SEV-2016-0644"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["860325"],"award-info":[{"award-number":["860325"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Vaccine design traditionally focuses on inducing adaptive immune responses against a sole target pathogen. Considering that many microbes evade innate immune mechanisms to initiate infection, and in light of the discovery of epigenetically mediated innate immune training, the paradigm of vaccine design has the potential to change. The Bacillus Calmette-Gu\u00e9rin (BCG) vaccine induces some level of protection against Mycobacterium tuberculosis (Mtb) while stimulating trained immunity that correlates with lower mortality and increased protection against unrelated pathogens. This review will explore BCG-induced trained immunity, including the required pathways to establish this phenotype. Additionally, potential methods to improve or expand BCG trained immunity effects through alternative vaccine delivery and formulation methods will be discussed. Finally, advances in new anti-Mtb vaccines, other antimicrobial uses for BCG, and \u201cinnate memory-based vaccines\u201d will be examined.<\/jats:p>","DOI":"10.3390\/cells9092109","type":"journal-article","created":{"date-parts":[[2020,9,16]],"date-time":"2020-09-16T20:44:13Z","timestamp":1600289053000},"page":"2109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Lessons from Bacillus Calmette-Gu\u00e9rin: Harnessing Trained Immunity for Vaccine Development"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4276-4098","authenticated-orcid":false,"given":"Samuel T.","family":"Pasco","sequence":"first","affiliation":[{"name":"Inflammation and Macrophage Plasticity Laboratory, CIC bioGUNE-Basque Research and Technology Alliance (BRTA), Parque Tecnol\u00f3gico de Bizkaia, 48160 Derio, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2061-7182","authenticated-orcid":false,"given":"Juan","family":"Anguita","sequence":"additional","affiliation":[{"name":"Inflammation and Macrophage Plasticity Laboratory, CIC bioGUNE-Basque Research and Technology Alliance (BRTA), Parque Tecnol\u00f3gico de Bizkaia, 48160 Derio, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.smim.2018.06.002","article-title":"Non-specific effects of vaccines: Current evidence and potential implications","volume":"39","author":"Koeken","year":"2018","journal-title":"Semin. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2869","DOI":"10.3389\/fimmu.2018.02869","article-title":"Non-specific Effects of Vaccines Illustrated Through the BCG Example: From Observations to Demonstrations","volume":"9","author":"Uthayakumar","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/s41577-020-0285-6","article-title":"Defining trained immunity and its role in health and disease","volume":"20","author":"Netea","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3482","DOI":"10.1172\/JCI128877","article-title":"Targeting innate immunity for tuberculosis vaccination","volume":"129","author":"Khader","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1590\/S0074-02762005000500002","article-title":"BCG Moreau Rio de Janeiro: An oral vaccine against tuberculosis\u2014Review","volume":"100","author":"Cosgrove","year":"2005","journal-title":"Mem\u00f3rias Inst. Oswaldo Cruz"},{"key":"ref_6","unstructured":"W.H.O. (2020, August 15). Global Tuberculosis Report. Available online: https:\/\/www.who.int\/tb\/publications\/global_report\/tb19_Exec_Sum_12Nov2019.pdf."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.it.2018.01.006","article-title":"New Tuberculosis Vaccine Strategies: Taking Aim at Un-Natural Immunity","volume":"39","author":"Jeyanathan","year":"2018","journal-title":"Trends Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1042\/BCJ20190324","article-title":"The Mycobacterium tuberculosis capsule: A cell structure with key implications in pathogenesis","volume":"476","author":"Kalscheuer","year":"2019","journal-title":"Biochem. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1056\/NEJMoa1714021","article-title":"Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination","volume":"379","author":"Nemes","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1016\/j.cmi.2019.02.015","article-title":"Trained innate immunity and resistance to Mycobacterium tuberculosis infection","volume":"25","author":"Koeken","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_11","first-page":"1351","article-title":"Early Clearance of Mycobacterium tuberculosis: The INFECT Case Contact Cohort Study in Indonesia","volume":"221","author":"Verrall","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1172\/JCI97508","article-title":"Mycobacterial growth inhibition is associated with trained innate immunity","volume":"128","author":"Joosten","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"i5170","DOI":"10.1136\/bmj.i5170","article-title":"Association of BCG, DTP, and measles containing vaccines with childhood mortality: Systematic review","volume":"355","author":"Higgins","year":"2016","journal-title":"BMJ"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e035595","DOI":"10.1136\/bmjopen-2019-035595","article-title":"Neonatal BCG vaccination and child survival in TB-exposed and TB-unexposed children: A prospective cohort study","volume":"10","author":"Thysen","year":"2020","journal-title":"BMJ Open"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1093\/infdis\/jir240","article-title":"Randomized Trial of BCG Vaccination at Birth to Low-Birth-Weight Children: Beneficial Nonspecific Effects in the Neonatal Period?","volume":"204","author":"Aaby","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Giamarellos-Bourboulis, E.J., Tsilika, M., Moorlag, S., Antonakos, N., Kotsaki, A., Dom\u00ednguez-Andr\u00e9s, J., Kyriazopoulou, E., Gkavogianni, T., Adami, M.-E., and Damoraki, G. (2020). Activate: Randomized Clinical Trial of BCG Vaccination Against Infection in the Elderly. Cell.","DOI":"10.1016\/j.cell.2020.08.051"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1128\/CVI.00349-16","article-title":"In VitroExperimental Model of Trained Innate Immunity in Human Primary Monocytes","volume":"23","author":"Bekkering","year":"2016","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1189\/jlb.4MA0215-059R","article-title":"Long-term in vitro and in vivo effects of \u03b3-irradiated BCG on innate and adaptive immunity","volume":"98","author":"Arts","year":"2015","journal-title":"J. Leukoc. Boil."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Namakula, R., De Bree, L.C.J., Tvedt, T.H.A., Netea, M.G., Cose, S., and Hanevik, K. (2020). Monocytes from neonates and adults have a similar capacity to adapt their cytokine production after previous exposure to BCG and \u03b2-glucan. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0229287"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1093\/infdis\/jiy069","article-title":"Neonatal BCG Vaccination Influences Cytokine Responses to Toll-like Receptor Ligands and Heterologous Antigens","volume":"217","author":"Freyne","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1093\/infdis\/jiu508","article-title":"Heterologous immunological effects of early BCG vaccination in low-birth-weight infants in Guinea-Bissau: A randomized-controlled trial","volume":"211","author":"Jensen","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"644","DOI":"10.3389\/fimmu.2017.00644","article-title":"Whole Blood Profiling of Bacillus Calmette\u2013Gu\u00e9rin-Induced Trained Innate Immunity in Infants Identifies Epidermal Growth Factor, IL-6, Platelet-Derived Growth Factor-AB\/BB, and Natural Killer Cell Activation","volume":"8","author":"Smith","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17537","DOI":"10.1073\/pnas.1202870109","article-title":"Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes","volume":"109","author":"Kleinnijenhuis","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Berendsen, M.L., Bles, P., De Bree, L.C.J., Jensen, K.J., Jensen, C.C., Wejse, C., Mendes, D.V., Netea, M.G., and Benn, C.S. (2020). BCG Vaccination Induces Trained Innate Immunity in Adults Over 50 Years of Age: A Randomized Trial in Guinea-Bissau. Ssrn Electron. J.","DOI":"10.2139\/ssrn.3611329"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1159\/000355628","article-title":"Long-lasting effects of BCG vaccination on both heterologous Th1\/Th17 responses and innate trained immunity","volume":"6","author":"Kleinnijenhuis","year":"2013","journal-title":"J. Innate Immun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"12305","DOI":"10.1038\/s41598-017-12110-2","article-title":"Anti-mycobacterial activity correlates with altered DNA methylation pattern in immune cells from BCG-vaccinated subjects","volume":"7","author":"Verma","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_27","first-page":"1342","article-title":"Early clearance of Mycobacterium tuberculosis is associated with increased innate immune responses","volume":"221","author":"Verrall","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.chom.2017.12.010","article-title":"BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity","volume":"23","author":"Arts","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1093\/infdis\/jiv332","article-title":"BCG-vaccination enhances immunogenicity of subsequent influenza vaccination in healthy volunteers: A randomized placebo-controlled pilot study","volume":"212","author":"Leentjens","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1038\/s41467-019-08659-3","article-title":"Outcomes of controlled human malaria infection after BCG vaccination","volume":"10","author":"Walk","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2015\/261864","article-title":"Gamma-Irradiated Bacille Calmette-Gu\u00e9rin Vaccination Does Not Modulate the Innate Immune Response during Experimental Human Endotoxemia in Adult Males","volume":"2015","author":"Hamers","year":"2015","journal-title":"J. Immunol. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3389\/fimmu.2017.00407","article-title":"Immune Responses to Bacillus Calmette\u2013Gu\u00e9rin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis?","volume":"8","author":"Moliva","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1093\/infdis\/jis012","article-title":"A Human Challenge Model for Mycobacterium tuberculosis Using Mycobacterium bovis Bacille Calmette-Gu\u00e9rin","volume":"205","author":"Minassian","year":"2012","journal-title":"J. Infect. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.3389\/fimmu.2020.01202","article-title":"Characterizing the BCG Induced Macrophage and Neutrophil Mechanisms for Defense against Mycobacterium tuberculosis","volume":"11","author":"Bickett","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"155135","DOI":"10.1016\/j.cyto.2020.155135","article-title":"The effect of BCG vaccination on alveolar macrophages obtained from induced sputum from healthy volunteers","volume":"133","author":"Koeken","year":"2020","journal-title":"Cytokine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5509","DOI":"10.1074\/jbc.C200673200","article-title":"Host Recognition of Bacterial Muramyl Dipeptide Mediated through NOD2","volume":"278","author":"Inohara","year":"2003","journal-title":"J. Boil. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2020\/5812743","article-title":"BCG-Induced Trained Immunity in Healthy Individuals: The Effect of Plasma Muramyl Dipeptide Concentrations","volume":"2020","author":"Mourits","year":"2020","journal-title":"J. Immunol. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.1016\/j.celrep.2016.11.011","article-title":"Immunometabolic Pathways in BCG-Induced Trained Immunity","volume":"17","author":"Arts","year":"2016","journal-title":"Cell Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1189\/jlb.6AB0914-416R","article-title":"Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes","volume":"98","author":"Arts","year":"2015","journal-title":"J. Leukoc. Boil."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.chom.2020.05.014","article-title":"BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment","volume":"28","author":"Cirovic","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.cell.2017.12.031","article-title":"BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis","volume":"172","author":"Kaufmann","year":"2018","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1016\/j.vaccine.2019.11.060","article-title":"Licensed Bacille Calmette-Gu\u00e9rin (BCG) formulations differ markedly in bacterial viability, RNA content and innate immune activation","volume":"38","author":"Angelidou","year":"2020","journal-title":"Vaccine"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Price, D.N., Kusewitt, D.F., Lino, C.A., McBride, A.A., and Muttil, P. (2016). Oral Tolerance to Environmental Mycobacteria Interferes with Intradermal, but Not Pulmonary, Immunization against Tuberculosis. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005614"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.tube.2016.09.004","article-title":"Alternative BCG delivery strategies improve protection against Mycobacterium tuberculosis in non-human primates: Protection associated with mycobacterial antigen-specific CD4 effector memory T-cell populations","volume":"101","author":"Sharpe","year":"2016","journal-title":"Tuberculosis"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41586-019-1817-8","article-title":"Prevention of tuberculosis in macaques after intravenous BCG immunization","volume":"577","author":"Darrah","year":"2020","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6283","DOI":"10.2174\/1381612822666160829143129","article-title":"New Biological Insights in the Immunomodulatory Effects of Mucosal Polybacterial Vaccines in Clinical Practice","volume":"22","author":"Palomares","year":"2016","journal-title":"Curr. Pharm. Des."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1080\/14760584.2019.1692657","article-title":"Mucosal delivery of tuberculosis vaccines: A review of current approaches and challenges","volume":"18","author":"Stylianou","year":"2019","journal-title":"Expert Rev. Vaccines"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/mi.2017.67","article-title":"PO and ID BCG vaccination in humans induce distinct mucosal and systemic immune responses and CD4+ T cell transcriptomal molecular signatures","volume":"11","author":"Hoft","year":"2017","journal-title":"Mucosal Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Guerra-Maupome, M., Vang, D.X., and McGill, J.L. (2019). Aerosol vaccination with Bacille Calmette-Guerin induces a trained innate immune phenotype in calves. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0212751"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/s41591-018-0319-9","article-title":"Prevention of tuberculosis infection and disease by local BCG in repeatedly exposed rhesus macaques","volume":"25","author":"Dijkman","year":"2019","journal-title":"Nat. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e001873","DOI":"10.1136\/bmjgh-2019-001873","article-title":"Seasonal variation in the non-specific effects of BCG vaccination on neonatal mortality: Three randomised controlled trials in Guinea-Bissau","volume":"5","author":"Jensen","year":"2020","journal-title":"BMJ Glob. Heal."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"De Bree, L.C.J., Mourits, V.P., Koeken, V.A.C.M., Moorlag, S.J., Janssen, R., Folkman, L., Barreca, D., Krausgruber, T., Fife-Gernedl, V., and Novakovic, B. (2020). Circadian rhythm influences induction of trained immunity by BCG vaccination. J. Clin. Investig.","DOI":"10.1172\/JCI133934"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Sartono, E., Lisse, I.M., Terveer, E.M., Van De Sande, P.J.M., Whittle, H., Fisker, A.B., Roth, A., Aaby, P., Yazdanbakhsh, M., and Benn, C.S. (2010). Oral Polio Vaccine Influences the Immune Response to BCG Vaccination. A Natural Experiment. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010328"},{"key":"ref_54","first-page":"455","article-title":"Interacting, Nonspecific, Immunological Effects of Bacille Calmette-Gu\u00e9rin and Tetanus-diphtheria-pertussis Inactivated Polio Vaccinations: An Explorative, Randomized Trial","volume":"70","author":"Blok","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_55","first-page":"1","article-title":"Phosphate starvation enhances phagocytosis of Mycobacterium bovis\/BCG by macrophages","volume":"21","author":"Mancilla","year":"2020","journal-title":"BMC Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1038\/mi.2017.80","article-title":"Exposure to human alveolar lining fluid enhances Mycobacterium bovis BCG vaccine efficacy against Mycobacterium tuberculosis infection in a CD8+ T-cell-dependent manner","volume":"11","author":"Moliva","year":"2017","journal-title":"Mucosal Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1038\/s41385-019-0148-2","article-title":"Selective delipidation of Mycobacterium bovis BCG enables direct pulmonary vaccination and enhances protection against Mycobacterium tuberculosis","volume":"12","author":"Moliva","year":"2019","journal-title":"Mucosal Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1586\/erv.09.47","article-title":"\u00c7i\u011fdem; G\u00fcnbeyaz, M.; \u015eenel, S. Chitosan-based systems for the delivery of vaccine antigens","volume":"8","author":"Arca","year":"2009","journal-title":"Expert Rev. Vaccines"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1080\/02652048.2017.1316325","article-title":"BCG-loaded chitosan microparticles: Interaction with macrophages and preliminaryin vivostudies","volume":"34","author":"Caetano","year":"2017","journal-title":"J. Microencapsul."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4098","DOI":"10.1021\/acs.molpharmaceut.7b00795","article-title":"Poly(I:C)-Encapsulating Nanoparticles Enhance Innate Immune Responses to the Tuberculosis Vaccine Bacille Calmette\u2013Gu\u00e9rin (BCG) via Synergistic Activation of Innate Immune Receptors","volume":"14","author":"Speth","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.3389\/fimmu.2019.01519","article-title":"Recombinant BCG With Bacterial Signaling Molecule Cyclic di-AMP as Endogenous Adjuvant Induces Elevated Immune Responses After Mycobacterium tuberculosis Infection","volume":"10","author":"Ning","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Taranc\u00f3n, R., Dom\u00ednguez-Andr\u00e9s, J., Uranga, S., Ferreira, A.V., Groh, L.A., Domenech, M., Gonz\u00e1lez-Camacho, F., Riksen, N.P., Aguilo, N., and Yuste, J. (2020). New live attenuated tuberculosis vaccine MTBVAC induces trained immunity and confers protection against experimental lethal pneumonia. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008404"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"894","DOI":"10.3389\/fimmu.2019.00894","article-title":"RUTI Vaccination Enhances Inhibition of Mycobacterial Growth ex vivo and Induces a Shift of Monocyte Phenotype in Mice","volume":"10","author":"Prabowo","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1111\/j.1365-3024.2011.01318.x","article-title":"Co-administration of rectal BCG and autoclaved Leishmania major induce protection in susceptible BALB\/c mice","volume":"33","author":"Soudi","year":"2011","journal-title":"Parasite Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3389\/fimmu.2018.00029","article-title":"Adjuvant Effect of Bacille Calmette\u2013Gu\u00e9rin on Hepatitis B Vaccine Immunogenicity in the Preterm and Term Newborn","volume":"9","author":"Scheid","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2806","DOI":"10.3389\/fimmu.2019.02806","article-title":"BCG-Induced Cross-Protection and Development of Trained Immunity: Implication for Vaccine Design","volume":"10","author":"Vasquez","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"100073","DOI":"10.1016\/j.xcrm.2020.100073","article-title":"Safety and COVID-19 symptoms in individuals recently vaccinated with BCG: A retrospective cohort study","volume":"1","author":"Moorlag","year":"2020","journal-title":"Cell Rep. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"17720","DOI":"10.1073\/pnas.2008410117","article-title":"BCG vaccine protection from severe coronavirus disease 2019 (COVID-19)","volume":"117","author":"Escobar","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1093\/infdis\/136.2.171","article-title":"Nonspecific Protection of Mice against Influenza Virus Infection by Local or Systemic Immunization with Bacille Calmette-Guerin","volume":"136","author":"Spencer","year":"1977","journal-title":"J. Infect. Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"869","DOI":"10.3389\/fimmu.2018.00869","article-title":"Bacillus Calmette\u2013Gu\u00e9rin-Induced Trained Immunity Is Not Protective for Experimental Influenza A\/Anhui\/1\/2013 (H7N9) Infection in Mice","volume":"9","author":"Marijnissen","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Mukherjee, S., Subramaniam, R., Chen, H., Smith, A., Keshava, S., and Shams, H. (2017). Boosting efferocytosis in alveolar space using BCG vaccine to protect host against influenza pneumonia. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0180143"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2936","DOI":"10.3389\/fimmu.2018.02936","article-title":"Trained Immunity-Based Vaccines: A New Paradigm for the Development of Broad-Spectrum Anti-infectious Formulations","volume":"9","author":"Conejero","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1172\/JCI122110","article-title":"Mucosal vaccine efficacy against intrarectal SHIV is independent of anti-Env antibody response","volume":"129","author":"Sui","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_74","first-page":"1000","article-title":"Respiratory Epithelial Cells Can Remember Infection: A Proof of Concept Study","volume":"221","author":"Bigot","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Reuschl, A.-K., Edwards, M.R., Parker, R., Connell, D.W., Hoang, L., Halliday, A., Jarvis, H., Siddiqui, N., Wright, C., and Bremang, S. (2017). Innate activation of human primary epithelial cells broadens the host response to Mycobacterium tuberculosis in the airways. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006577"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Tenland, E., H\u00e5kansson, G., Alaridah, N., Lutay, N., R\u00f6nnholm, A., Hallgren, O., Westergren-Thorsson, G., and Godaly, G. (2016). Innate Immune Responses after Airway Epithelial Stimulation with Mycobacterium bovis Bacille-Calmette Gu\u00e9rin. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0164431"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"299","DOI":"10.3389\/fcimb.2019.00299","article-title":"Mycobacterium tuberculosis Primary Infection and Dissemination: A Critical Role for Alveolar Epithelial Cells","volume":"9","author":"Ryndak","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_78","first-page":"50","article-title":"Comparison of sublingual therapeutic vaccine with antibiotics for the prophylaxis of recurrent urinary tract infections","volume":"5","year":"2015","journal-title":"Front. Microbiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.intimp.2009.01.004","article-title":"Polybacterial immunomodulator Respivax restores the inductive function of innate immunity in patients with recurrent respiratory infections","volume":"9","author":"Nikolova","year":"2009","journal-title":"Int. Immunopharmacol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.micinf.2016.10.006","article-title":"Intranasal administration of a polyvalent bacterial lysate induces self-restricted inflammation in the lungs and a Th1\/Th17 memory signature","volume":"18","author":"Rial","year":"2016","journal-title":"Microbes Infect."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1007\/BF02718200","article-title":"Effects of a bacterial extract on local immunity of the lung in patients with chronic bronchitis","volume":"168","author":"Emmerich","year":"1990","journal-title":"Lung"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1159\/000195827","article-title":"Local Immunity in Patients with Chronic Bronchitis and the Effects of a Bacterial Extract, Broncho-Vaxom\u00ae, on T Lymphocytes, Macrophages, Gamma-Interferon and Secretory Immunoglobulin A in Bronchoalveolar Lavage Fluid and Other Variables","volume":"57","author":"Emmerich","year":"1990","journal-title":"Respiration"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/0192-0561(89)90149-5","article-title":"Stimulation by a bacterial extract (broncho-vaxom) of the metabolic and functional activities of murine macrophages","volume":"11","author":"Kreis","year":"1989","journal-title":"Int. J. Immunopharmacol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/9\/2109\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:10:38Z","timestamp":1760177438000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/9\/2109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,16]]},"references-count":83,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["cells9092109"],"URL":"https:\/\/doi.org\/10.3390\/cells9092109","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,16]]}}}