{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:36:22Z","timestamp":1790487382444,"version":"4.1.0"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2018,12,4]],"date-time":"2018-12-04T00:00:00Z","timestamp":1543881600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000785","name":"Education, Audiovisual and Culture Executive Agency","doi-asserted-by":"publisher","award":["2015-2323"],"award-info":[{"award-number":["2015-2323"]}],"id":[{"id":"10.13039\/501100000785","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"DOI":"10.3389\/fimmu.2018.02869","type":"journal-article","created":{"date-parts":[[2018,12,4]],"date-time":"2018-12-04T07:13:31Z","timestamp":1543907611000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":96,"title":["Non-specific Effects of Vaccines Illustrated Through the BCG Example: From Observations to Demonstrations"],"prefix":"10.3389","volume":"9","author":[{"given":"Deeva","family":"Uthayakumar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Paris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludivine","family":"Chapat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovic","family":"Freyburger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herv\u00e9","family":"Poulet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karelle","family":"De Luca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2018,12,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3923","DOI":"10.1016\/j.vaccine.2016.06.020","article-title":"Heterologous vaccine effects","volume":"34","author":"Saadatian-Elahi","year":"2016","journal-title":"Vaccine"},{"key":"B2","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1007\/978-1-4939-3387-7_3","article-title":"Principles of vaccination. vaccine design: methods and protocols.","volume":"1","author":"Zepp","year":"2016","journal-title":"Vaccines Hum Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1126\/science.aaa3662","article-title":"Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality","volume":"348","author":"Mina","year":"2015","journal-title":"Science"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1746","DOI":"10.1016\/j.vaccine.2004.02.054","article-title":"Childhood mortality after oral polio immunisation campaign in Guinea-Bissau","volume":"23","author":"Aaby","year":"2005","journal-title":"Vaccine"},{"key":"B5","first-page":"53","article-title":"History of BCG vaccine","volume":"8","author":"Luca","year":"2013","journal-title":"Maedica"},{"key":"B6","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/S0041-3879(49)80055-9","article-title":"BCG vaccination of indian infants in Saskatchewan.(a study carried out with financial assistance from the National Research Council of Canada.)","volume":"30","author":"Ferguson","year":"1949","journal-title":"Tubercle"},{"key":"B7","first-page":"255","article-title":"Protective vaccination against tuberculosis with special reference to BCG vaccination","volume":"58","author":"Aronson","year":"1948","journal-title":"Am Rev Tuber Pulm Dis."},{"key":"B8","first-page":"690","article-title":"BCG vaccination in tuberculous households","volume":"84","author":"Rosenthal","year":"1961","journal-title":"Am Rev Res Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1093\/ije\/20.2.474","article-title":"Childhood mortality among users and non-users of primary health care in a rural west African community","volume":"20","author":"Velema","year":"1991","journal-title":"Int J Epidemiol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1097\/01.inf.0000129693.81082.a0","article-title":"Low birth weight infants and Calmette-Guerin bacillus vaccination at birth: community study from Guinea-Bissau","volume":"23","author":"Roth","year":"2004","journal-title":"Pediatr Infect Dis J."},{"key":"B11","author":"Higgins","year":"2014","journal-title":"Systematic Review of the Non-Specific Effects of BCG, DTP and Measles Containing Vaccines"},{"key":"B12","doi-asserted-by":"publisher","first-page":"7300","DOI":"10.1016\/j.vaccine.2012.09.035","article-title":"Non-specific and sex-differential effects of vaccinations on child survival in rural western India","volume":"30","author":"Hirve","year":"2012","journal-title":"Vaccine"},{"key":"B13","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1093\/ije\/dyh262","article-title":"Benefits of routine immunizations on childhood survival in Tari, Southern Highlands Province, Papua New Guinea","volume":"34","author":"Lehmann","year":"2004","journal-title":"Int J Epidemiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1097\/01.inf.0000227829.64686.ae","article-title":"Sex differential effects of routine immunizations and childhood survival in rural Malawi","volume":"25","author":"Aaby","year":"2006","journal-title":"Pediatr Infect Dis J."},{"key":"B15","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1093\/oxfordjournals.aje.a008667","article-title":"No long-term excess mortality after measles infection: a community study from Senegal","volume":"143","author":"Aaby","year":"1996","journal-title":"Am J Epidemiol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1765","DOI":"10.1016\/S0140-6736(03)14867-2","article-title":"High-titre measles vaccine and female mortality","volume":"362","author":"Aaby","year":"2003","journal-title":"Lancet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1111\/j.1365-3156.2005.01434.x","article-title":"Evaluation of non-specific effects of infant immunizations on early infant mortality in a southern Indian population","volume":"10","author":"Moulton","year":"2005","journal-title":"Trop Med Int Health"},{"key":"B18","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1097\/INF.0b013e3182458289","article-title":"Small randomized trial among low\u2013birth-weight children receiving Bacillus Calmette-Gu\u00e9rin vaccination at first health center contact","volume":"31","author":"Biering-S\u00f8rensen","year":"2012","journal-title":"Pediatr Infect Dis J."},{"key":"B19","doi-asserted-by":"publisher","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":"B20","doi-asserted-by":"publisher","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":"B21","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1111\/jvim.12057","article-title":"Interpretation of odds and risk ratios","volume":"27","author":"O'connor","year":"2013","journal-title":"J Vet Int Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1038\/nri.2016.43","article-title":"Harnessing the beneficial heterologous effects of vaccination","volume":"16","author":"Goodridge","year":"2016","journal-title":"Nat Rev Immunol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"i4919","DOI":"10.1136\/bmj.i4919","article-title":"ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions","volume":"355","author":"Sterne","year":"2016","journal-title":"BMJ"},{"key":"B24","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1111\/j.1365-3083.1992.tb03132.x","article-title":"The Role of BCG\/PPD-Activated macrophages in resistance against systemic candidiasis in mice","volume":"36","author":"Wout","year":"1992","journal-title":"Scan J Immunol."},{"key":"B25","doi-asserted-by":"publisher","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 Nat Acad Sci USA."},{"key":"B26","first-page":"902","article-title":"Effect of Bacillus Callmette Guerin (BCG) on the receptivity of nude mice to Schistosoma mansoni","volume":"172","author":"Tribouley","year":"1978","journal-title":"C R Seances Soc Biol Fil."},{"key":"B27","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1093\/trstmh\/trv021","article-title":"BCG-associated heterologous immunity, a historical perspective: experimental models and immunological mechanisms","volume":"109","author":"Freyne","year":"2015","journal-title":"Trans R Soc Trop Med Hyg."},{"key":"B28","doi-asserted-by":"publisher","first-page":"5740","DOI":"10.1016\/j.vaccine.2009.07.040","article-title":"Immunoinformatic comparison of T-cell epitopes contained in novel swine-origin influenza A (H1N1) virus with epitopes in 2008\u20132009 conventional influenza vaccine","volume":"27","author":"De Groot","year":"2009","journal-title":"Vaccine"},{"key":"B29","doi-asserted-by":"publisher","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":"2014","journal-title":"J Innate Immun."},{"key":"B30","doi-asserted-by":"publisher","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":"B31","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1038\/s41590-018-0068-4","article-title":"Recognition of microbial viability via TLR8 drives T FH cell differentiation and vaccine responses","volume":"19","author":"Ugolini","year":"2018","journal-title":"Nat Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3844","DOI":"10.1016\/j.vaccine.2017.05.095","article-title":"Rabies vaccine is associated with decreased all-cause mortality in dogs","volume":"35","author":"Knobel","year":"2017","journal-title":"Vaccine"},{"key":"B33","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/nm.4008","article-title":"Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues","volume":"22","author":"Thome","year":"2016","journal-title":"Nat Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3098","DOI":"10.1016\/j.vaccine.2013.03.059","article-title":"Non-specific effect of Bacille Calmette-Guerin vaccine on the immune response to routine immunisations","volume":"31","author":"Ritz","year":"2013","journal-title":"Vaccine"},{"key":"B35","doi-asserted-by":"publisher","first-page":"aaf1098","DOI":"10.1126\/science.aaf1098","article-title":"Trained immunity: a program of innate immune memory in health and disease","volume":"352","author":"Netea","year":"2016","journal-title":"Science"},{"key":"B36","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/j.it.2017.03.005","article-title":"Immunological memory of group 2 innate lymphoid cells","volume":"38","author":"Martinez-Gonzalez","year":"2017","journal-title":"Trends Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1128\/CVI.00349-16","article-title":"In vitro experimental model of trained innate immunity in human primary monocytes","volume":"23","author":"Bekkering","year":"2016","journal-title":"Clin Vaccine Immunol."},{"key":"B38","doi-asserted-by":"publisher","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":"B39","doi-asserted-by":"publisher","first-page":"e105","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":"B40","doi-asserted-by":"publisher","first-page":"1250684","DOI":"10.1126\/science.1250684","article-title":"mTOR-and HIF-1\u03b1-mediated aerobic glycolysis as metabolic basis for trained immunity","volume":"345","author":"Cheng","year":"2014","journal-title":"Science"},{"key":"B41","doi-asserted-by":"publisher","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":"B42","doi-asserted-by":"publisher","first-page":"e139","DOI":"10.1016\/j.cell.2017.11.025","article-title":"Metabolic induction of trained immunity through the mevalonate pathway","volume":"172","author":"Bekkering","year":"2018","journal-title":"Cell"},{"key":"B43","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1016\/j.cmet.2016.10.008","article-title":"Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity","volume":"24","author":"Arts","year":"2016","journal-title":"Cell Metab."},{"key":"B44","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3389\/fonc.2018.00394","article-title":"Mevalonate metabolism in cancer stemness and trained immunity","volume":"8","author":"Gruenbacher","year":"2018","journal-title":"Front Oncol."},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.09.003","article-title":"The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity","author":"Dom\u00ednguez-Andr\u00e9s","year":"2018","journal-title":"Cell Metabol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1189\/jlb.5RI0315-096R","article-title":"Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines","volume":"98","author":"Blok","year":"2015","journal-title":"J Leukocyte Biol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"e1004485","DOI":"10.1371\/journal.ppat.1004485","article-title":"Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer","volume":"10","author":"Buffen","year":"2014","journal-title":"PLoS Pathog."},{"key":"B48","doi-asserted-by":"publisher","first-page":"e119","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":"B49","doi-asserted-by":"publisher","first-page":"e112","DOI":"10.1016\/j.cell.2017.11.034","article-title":"Modulation of myelopoiesis progenitors is an integral component of trained immunity","volume":"172","author":"Mitroulis","year":"2018","journal-title":"Cell"},{"key":"B50","doi-asserted-by":"publisher","first-page":"456","DOI":"10.3390\/ijms19020456","article-title":"Infectious agents as stimuli of trained innate immunity","volume":"19","author":"Rusek","year":"2018","journal-title":"Int J Mol Sci."},{"key":"B51","doi-asserted-by":"publisher","first-page":"919","DOI":"10.4049\/jimmunol.168.2.919","article-title":"Influence of Mycobacterium bovis bacillus Calmette-Guerin on antibody and cytokine responses to human neonatal vaccination","volume":"168","author":"Ota","year":"2002","journal-title":"J Immunol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"2084","DOI":"10.1016\/j.vaccine.2017.02.048","article-title":"Bacille Calmette-Gu\u00e9rin (BCG) vaccination at birth and antibody responses to childhood vaccines","volume":"35","author":"Nissen","year":"2017","journal-title":"Vaccine"},{"key":"B53","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.2217\/fmb-2018-0026","article-title":"Heterologous effects of infant BCG vaccination: potential mechanisms of immunity","volume":"13","author":"Butkeviciute","year":"2018","journal-title":"Future Microbiol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.trivac.2013.11.004","article-title":"Neonatal BCG vaccination is associated with enhanced T-helper 1 immune responses to heterologous infant vaccines","volume":"3","author":"Libraty","year":"2014","journal-title":"Trials Vaccinol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"310760","DOI":"10.1136\/archdischild-2016-310760","article-title":"BCG vaccination at birth and early childhood hospitalisation: a randomised clinical multicentre trial","volume":"2016","author":"Stensballe","year":"2016","journal-title":"Arch Dis Child"},{"key":"B56","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1007\/s10096-017-3097-2","article-title":"Bacillus Calmette-Gu\u00e9rin vaccination at birth and in vitro cytokine responses to non-specific stimulation","volume":"37","author":"Nissen","year":"2018","journal-title":". Eur J Clin Microbiol Infect Dis."},{"key":"B57","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1186\/s13063-015-0682-5","article-title":"Investigating the non-specific effects of BCG vaccination on the innate immune system in Ugandan neonates: study protocol for a randomised controlled trial","volume":"16","author":"Prentice","year":"2015","journal-title":"Trials"},{"key":"B58","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1093\/cid\/cix525","article-title":"Early BCG-Denmark and neonatal mortality among infants weighing < 2500 g: a randomized controlled trial","volume":"65","author":"Biering-S\u00f8rensen","year":"2017","journal-title":"Clin Infect Dis."},{"key":"B59","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1093\/cid\/civ144","article-title":"Nonspecific (heterologous) protection of neonatal BCG vaccination against hospitalization due to respiratory infection and sepsis","volume":"60","author":"De","year":"2015","journal-title":"Clin Infect Dis."},{"key":"B60","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1542\/peds.85.2.188","article-title":"Childhood survival in Haiti: protective effect of measles vaccination","volume":"85","author":"Holt","year":"1990","journal-title":"Pediatrics"},{"key":"B61","doi-asserted-by":"publisher","first-page":"e1002885","DOI":"10.1371\/journal.ppat.1002885","article-title":"Measles immune suppression: lessons from the macaque model","volume":"8","author":"De","year":"2012","journal-title":"PLoS Pathog."},{"key":"B62","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1093\/cid\/ciu354","article-title":"Measles vaccination in the presence or absence of maternal measles antibody: impact on child survival","volume":"59","author":"Aaby","year":"2014","journal-title":"Clin Infect Dis."},{"key":"B63","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1001\/jama.2014.470","article-title":"Live vaccine against measles, mumps, and rubella and the risk of hospital admissions for nontargeted infections","volume":"311","author":"S\u00f8rup","year":"2014","journal-title":"J Am Med Am"},{"key":"B64","doi-asserted-by":"publisher","first-page":"e000707","DOI":"10.1136\/bmjopen-2011-000707","article-title":"Testing the hypothesis that diphtheria\u2013tetanus\u2013pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries","volume":"2","author":"Aaby","year":"2012","journal-title":"BMJ Open"},{"key":"B65","doi-asserted-by":"publisher","first-page":"4737","DOI":"10.1016\/j.vaccine.2006.03.033","article-title":"Community cohort study of rotavirus and other enteropathogens: are routine vaccinations associated with sex-differential incidence rates?","volume":"24","author":"Rodrigues","year":"2006","journal-title":"Vaccine"},{"key":"B66","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.immuni.2014.06.008","article-title":"Macrophage activation and polarization: nomenclature and experimental guidelines","volume":"41","author":"Murray","year":"2014","journal-title":"Immunity"},{"key":"B67","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1016\/j.vaccine.2017.02.014","article-title":"Rationale and support for a one health program for canine vaccination as the most cost-effective means of controlling zoonotic rabies in endemic settings","volume":"35","author":"Lavan","year":"2017","journal-title":"Vaccine"},{"key":"B68","doi-asserted-by":"publisher","first-page":"384","DOI":"10.5713\/ajas.15.0141","article-title":"Effect of dietary beta-glucan on the performance of broilers and the quality of broiler breast meat","volume":"29","author":"Moon","year":"2016","journal-title":"Asian-Australas J Anim Sci."},{"key":"B69","doi-asserted-by":"publisher","first-page":"45","DOI":"10.3844\/ajisp.2017.45.49","article-title":"Glucans and the poultry immune system","volume":"13","author":"Jacob","year":"2017","journal-title":"Am J Immunol."}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fimmu.2018.02869\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T13:28:18Z","timestamp":1662557298000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fimmu.2018.02869\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,4]]},"references-count":69,"alternative-id":["10.3389\/fimmu.2018.02869"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2018.02869","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,4]]},"article-number":"2869"}}