{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:46:57Z","timestamp":1760150817189,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>While the development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines was rapid, time to development and implementation challenges remain that may impact the response to future pandemics. Trained immunity via bacille Calmette-Guerin (BCG) vaccination (an antigen agnostic strategy) offers a potential intervention against future novel pathogens via an existing, safe, and widely distributed vaccine to protect vulnerable populations and preserve health system capacity while targeted vaccines are developed and implemented.<\/jats:p>","DOI":"10.3390\/vaccines10020201","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T22:01:57Z","timestamp":1643320917000},"page":"201","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Is the BCG Vaccine an Answer to Future Pandemic Preparedness?"],"prefix":"10.3390","volume":"10","author":[{"given":"Nadia","family":"Khan","sequence":"first","affiliation":[{"name":"College of Agriculture and Life Sciences, Cornell University, Ithaca, NY 14850, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadine","family":"Rouphael","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindsey","family":"Baden","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Brigham and Women\u2019s Hospital (BWH), Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9484-8488","authenticated-orcid":false,"given":"Daniel","family":"Graciaa","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,27]]},"reference":[{"key":"ref_1","unstructured":"(2022, January 19). World Health Organization. Available online: https:\/\/covid19.who.int\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1098\/rstb.2011.0100","article-title":"Accelerating vaccine development and deployment: Report of a Royal Society satellite meeting","volume":"366","author":"Bregu","year":"2011","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1056\/NEJMoa2102214","article-title":"Efficacy of the ChAdOx1 nCoV-19 COVID-19 Vaccine against the B.1.351 Variant","volume":"384","author":"Madhi","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.chom.2021.03.009","article-title":"Infection- and vaccine-induced antibody binding and neutralization of the B.1.351 SARS-CoV-2 variant","volume":"29","author":"Edara","year":"2021","journal-title":"Cell Host Microbe"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1056\/NEJMc2102017","article-title":"Neutralizing Activity of BNT162b2-Elicited Serum","volume":"384","author":"Liu","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1093\/infdis\/jiab255","article-title":"Persistence of Antibody and Cellular Immune Responses in COVID-19 patients over Nine Months after Infection","volume":"224","author":"Yao","year":"2021","journal-title":"J. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1056\/NEJMc2103916","article-title":"Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for COVID-19","volume":"384","author":"Suthar","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7221","DOI":"10.1016\/j.vaccine.2021.11.038","article-title":"100 years of the Bacillus Calmette-Gu\u00e9rin vaccine","volume":"39","author":"Bettencourt","year":"2021","journal-title":"Vaccine"},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1016\/j.cell.2016.09.034","article-title":"beta-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance","volume":"167","author":"Novakovic","year":"2016","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/s41588-018-0298-2","article-title":"Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments","volume":"51","author":"Fanucchi","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1056\/NEJMra2028358","article-title":"Postinfectious Epigenetic Immune Modifications\u2014A Double-Edged Sword","volume":"384","author":"DiNardo","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_13","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":"2014","journal-title":"J. Innate Immun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1586\/14760584.5.2.277","article-title":"Bacillus Calmette-Gu\u00e9rin vaccination and infant mortality","volume":"5","author":"Roth","year":"2006","journal-title":"Expert Rev. Vaccines"},{"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","first-page":"993","DOI":"10.1016\/S1473-3099(20)30653-8","article-title":"BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates: An investigator-blind randomised controlled trial","volume":"21","author":"Prentice","year":"2021","journal-title":"Lancet Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1093\/infdis\/jiab306","article-title":"Neonatal BCG vaccination and infections in the first year of life: The MIS BAIR randomised controlled trial","volume":"224","author":"Messina","year":"2021","journal-title":"J. Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1093\/infdis\/jiab307","article-title":"BCG Specific and Nonspecific Effects: Different Questions, Similar Challenges","volume":"224","author":"Prentice","year":"2021","journal-title":"J. Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1093\/infdis\/jiv332","article-title":"BCG Vaccination Enhances the 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_20","first-page":"455","article-title":"Interacting, Nonspecific, Immunological Effects of Bacille Calmette-Guerin and Tetanus-diphtheria-pertussis Inactivated Polio Vaccinations: An Explorative, Randomized Trial","volume":"70","author":"Blok","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","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":"ref_22","doi-asserted-by":"crossref","first-page":"103254","DOI":"10.1016\/j.ebiom.2021.103254","article-title":"BCG vaccination improves DTaP immune responses in mice and is associated with lower pertussis incidence in ecological epidemiological studies","volume":"65","author":"Broset","year":"2021","journal-title":"EBioMedicine"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.vaccine.2019.10.034","article-title":"Stopping live vaccines after disease eradication may increase mortality","volume":"38","author":"Aaby","year":"2020","journal-title":"Vaccine"},{"key":"ref_24","unstructured":"World Health Organization (2018). Preferred Product Characteristics for New Tuberculosis Vaccines, World Health Organization."},{"key":"ref_25","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_26","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_27","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.cell.2020.08.051","article-title":"Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly","volume":"183","author":"Tsilika","year":"2020","journal-title":"Cell"},{"key":"ref_28","first-page":"185","article-title":"The efficacy of Bacillus Calmette-Guerin vaccinations for the preven-tion of acute upper respiratory tract infection in the elderly","volume":"43","author":"Sultana","year":"2011","journal-title":"Acta Med. Indones."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2736","DOI":"10.1016\/j.vaccine.2020.08.016","article-title":"The safety of BCG revaccination: A systematic review","volume":"39","author":"Bannister","year":"2021","journal-title":"Vaccine"},{"key":"ref_30","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_31","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.jinf.2020.08.013","article-title":"Impact of Routine Infant BCG Vaccination on COVID-19","volume":"81","author":"Kinoshita","year":"2020","journal-title":"J. Infect."},{"key":"ref_32","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_33","doi-asserted-by":"crossref","unstructured":"Abdulah, D.M., and Hassan, A.B. (2021). Exploration of Association Between Respiratory Vaccinations With Infection and Mortality Rates of COVID-19. Disaster Med. Public Heal. Prep., 1\u201316.","DOI":"10.1017\/dmp.2021.47"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Klinger, D., Blass, I., Rappoport, N., and Linial, M. (2020). Significantly Improved COVID-19 Outcomes in Countries with Higher BCG Vac-cination Coverage: A Multivariable Analysis. Vaccines, 8.","DOI":"10.1101\/2020.04.23.20077123"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"25203","DOI":"10.1073\/pnas.2016733117","article-title":"Lack of evidence for BCG vaccine protection from severe COVID-19","volume":"117","author":"Sette","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","first-page":"e501","article-title":"BCG vaccination in infancy does not protect against COVID-19. Evidence from a natural experiment in Sweden","volume":"72","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7300","DOI":"10.1016\/j.vaccine.2021.08.019","article-title":"Does BCG provide long-term protection against SARS-CoV-2 infection? A case-control study in Quebec, Canada","volume":"39","author":"Carignan","year":"2021","journal-title":"Vaccine"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1001\/jama.2020.8189","article-title":"SARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults","volume":"323","author":"Hamiel","year":"2020","journal-title":"JAMA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"145574","DOI":"10.1016\/j.gene.2021.145574","article-title":"Epidemiological transcriptomic data supports BCG protection in viral diseases including COVID-19","volume":"783","author":"Sharma","year":"2021","journal-title":"Gene"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Tsilika, M., Taks, E., Dolianitis, K., Kotsaki, A., Leventogiannis, K., Damoulari, C., Kostoula, M., Paneta, M., Adamis, G., and Papanikolaou, I.C. (2021). Activate-2: A double-blind randomized trial of bcg vaccination against covid19 in individuals at risk. medRxiv.","DOI":"10.1101\/2021.05.20.21257520"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Machlaurin, A., Dolk, F.C.K., Setiawan, D., Van Der Werf, T.S., and Postma, M.J. (2020). Cost-Effectiveness Analysis of BCG Vaccination against Tuberculosis in Indonesia: A Model-Based Study. Vaccines, 8.","DOI":"10.3390\/vaccines8040707"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1016\/S0140-6736(06)68507-3","article-title":"Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: A meta-analysis and assessment of cost-effectiveness","volume":"367","author":"Trunz","year":"2006","journal-title":"Lancet"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1586\/erv.11.197","article-title":"A review of the literature on the economics of vaccination against TB","volume":"11","author":"Tu","year":"2012","journal-title":"Expert Rev. Vaccines"},{"key":"ref_44","unstructured":"World Health Organization (2021, June 22). Immunization Policy: BCG. Available online: https:\/\/www.who.int\/immunization\/policy\/bcg.pdf."},{"key":"ref_45","unstructured":"The Global Fund (2022, January 19). Results Report. Available online: https:\/\/www.theglobalfund.org\/media\/11304\/corporate_2021resultsreport_report_en.pdf."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1001\/jama.2021.3199","article-title":"SARS-CoV-2 Vaccines","volume":"325","author":"Creech","year":"2021","journal-title":"JAMA"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"The Lancet Infectious Diseases (2021). COVID-19 vaccine equity and booster doses. Lancet Infect. Dis., 21, 1193.","DOI":"10.1016\/S1473-3099(21)00486-2"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1080\/21645515.2021.1872344","article-title":"Anticipated reduction in COVID-19 mortality due to population-wide BCG vac-cination: Evidence from Germany","volume":"17","author":"Nixon","year":"2021","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.3389\/fimmu.2019.02307","article-title":"Bacille Calmette-Guerin Vaccine Strain Modulates the Ontogeny of Both Mycobacteri-al-Specific and Heterologous T Cell Immunity to Vaccination in Infants","volume":"10","author":"Kiravu","year":"2019","journal-title":"Front. Immunol."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/10\/2\/201\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:08:48Z","timestamp":1760134128000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/10\/2\/201"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,27]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["vaccines10020201"],"URL":"https:\/\/doi.org\/10.3390\/vaccines10020201","relation":{},"ISSN":["2076-393X"],"issn-type":[{"type":"electronic","value":"2076-393X"}],"subject":[],"published":{"date-parts":[[2022,1,27]]}}}