{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T02:11:51Z","timestamp":1778033511180,"version":"3.51.4"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T00:00:00Z","timestamp":1694131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The observation of reduced COVID-19 incidence and severity in populations receiving neonatal intradermal BCG vaccination vaccine raised the question of whether BCG can induce non-specific protection against the SARS-CoV-2 (SCV2) virus. Subsequent epidemiologic studies and clinical trials have largely failed to support this hypothesis. Furthermore, in small animal model studies all investigators have failed to observe resistance to viral challenge in response to BCG immunization by the conventional and clinically acceptable intradermal or subcutaneous routes. Nevertheless, BCG administered by the intravenous (IV) route has been shown to strongly protect both hamsters and mice against SCV2 infection and disease. In this Perspective, we review the current data on the effects of BCG vaccination on resistance to COVID-19 as well as summarize recent work in rodent models on the mechanisms by which IV administered BCG promotes resistance to the virus and discuss the translational implications of these findings.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1232764","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T10:30:50Z","timestamp":1694169050000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["BCG mediated protection of the lung against experimental SARS-CoV-2 infection"],"prefix":"10.3389","volume":"14","author":[{"given":"Kerry L.","family":"Hilligan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sivaranjani","family":"Namasivayam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"Sher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00031.2021","article-title":"Trained immunity: adaptation within innate immune mechanisms","volume":"103","author":"Dominguez-Andres","year":"2023","journal-title":"Physiol Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41585-018-0055-4","article-title":"Mechanisms of BCG immunotherapy and its outlook for bladder cancer","volume":"15","author":"Pettenati","year":"2018","journal-title":"Nat Rev Urol"},{"key":"B3","doi-asserted-by":"publisher","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-Sorensen","year":"2017","journal-title":"Clin Infect Dis"},{"key":"B4","doi-asserted-by":"publisher","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":"B5","doi-asserted-by":"publisher","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":"Giamarellos-Bourboulis","year":"2020","journal-title":"Cell"},{"key":"B6","doi-asserted-by":"publisher","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":"B7","doi-asserted-by":"publisher","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":"B8","doi-asserted-by":"publisher","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":"B9","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2021.1885280","article-title":"A review of the BCG vaccine and other approaches toward tuberculosis eradication","volume":"17","author":"Cho","year":"2021","journal-title":"Hum Vaccin Immunother"},{"key":"B10","article-title":"Essai d'immunisation contre l'infection tuberculeuse","volume":"91","author":"Calmette","year":"1924","journal-title":"Bull Acad Med"},{"key":"B11","doi-asserted-by":"publisher","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":"B12","doi-asserted-by":"publisher","first-page":"962","DOI":"10.1016\/j.chom.2023.05.006","article-title":"Airway T cells are a correlate of i.v. 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