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{{Short description|Vaccine primarily used against tuberculosis}}
{{Short description|Vaccine primarily used against tuberculosis}}
{{Use dmy dates|date=February 2023}}
{{Use dmy dates|date=July 2024}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
{{Infobox drug
| type = vaccine
| image = Mycobacterium bovis BCG ZN.jpg
| image = Mycobacterium bovis BCG ZN.jpg
| alt =
| caption = Microscopic image of the Calmette–Guérin bacillus, [[Ziehl–Neelsen stain]], magnification: 1,000nn
| caption = Microscopic image of the Calmette–Guérin bacillus, [[Ziehl–Neelsen stain]], magnification: 1,000nn


<!-- Vaccine data -->
<!-- Vaccine data -->
| type = vaccine
| target = ''[[Mycobacterium tuberculosis]]''
| target = ''[[Mycobacterium tuberculosis]]''
| vaccine_type = attenuated
| vaccine_type = attenuated
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| tradename = BCG Vaccine, BCG Vaccine AJV
| tradename = BCG Vaccine, BCG Vaccine AJV
| Drugs.com = {{drugs.com|ppa|bcg-vaccine-immunization}}
| Drugs.com = {{drugs.com|ppa|bcg-vaccine-immunization}}
| MedlinePlus = a682809
| DailyMedID = BCG_Vaccine
| DailyMedID = BCG Vaccine
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_category =
| pregnancy_category =
| routes_of_administration = Percutaneous, intravesical, intradermal
| routes_of_administration = [[Percutaneous]], [[Intravesical drug delivery|intravesical]], [[Intradermal injection|intradermal]]
| ATC_prefix = J07
| ATC_prefix = J07
| ATC_suffix = AN01
| ATC_suffix = AN01
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<!-- Legal status -->
<!-- Legal status -->
| legal_AU = S4
| legal_AU = S4
| legal_AU_comment =<ref>{{cite web | url=http://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=70CAA712EBEFD8B3CA257EA000422A9F&agid=(PrintDetailsPublic)&actionid=1 | title=Summary for ARTG Entry:53569 BCG VACCINE Mycobacterium bovis (Mycobacterium bovis (Bacillus Calmette and Guerin (BCG) strain) (BCG) strain) 1.5mg powder for injection multidose vial with diluent vial | publisher=[[Therapeutic Goods Administration]] (TGA) }}{{Dead link|date=October 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>
| legal_AU_comment =<ref>{{cite web | url=https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=53569&agid=(PrintDetailsPublic)&actionid=1 | title=Summary for ARTG Entry:53569 BCG VACCINE Mycobacterium bovis (Mycobacterium bovis (Bacillus Calmette and Guerin (BCG) strain) (BCG) strain) 1.5mg powder for injection multidose vial with diluent vial | publisher=[[Therapeutic Goods Administration]] (TGA) | access-date=31 July 2024 | archive-date=5 September 2024 | archive-url=https://web.archive.org/web/20240905050852/https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=53569&agid=(PrintDetailsPublic)&actionid=1 | url-status=live }}</ref>
| legal_CA = Rx-only
| legal_CA = Rx-only
| legal_CA_comment = /&nbsp;Schedule D<ref>{{cite web | title=Regulatory Decision Summary - Verity-BCG | website=Health Canada | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00744 | access-date=5 June 2022}}</ref><ref>{{cite web | title=Verity-BCG Product information | website=Health Canada | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=99797 | access-date=5 June 2022}}</ref>
| legal_CA_comment = /&nbsp;Schedule D<ref>{{cite web | title=Regulatory Decision Summary - Verity-BCG | website=[[Health Canada]] | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00744 | access-date=5 June 2022 | archive-date=5 June 2022 | archive-url=https://web.archive.org/web/20220605182527/https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00744 | url-status=live }}</ref><ref>{{cite web | title=Verity-BCG Product information | website=[[Health Canada]] | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=99797 | access-date=5 June 2022 | archive-date=5 September 2024 | archive-url=https://web.archive.org/web/20240905050743/https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=99797 | url-status=live }}</ref>
| legal_UK = POM
| legal_UK = POM
| legal_UK_comment =<ref>{{cite web | title=BCG Vaccine AJV - Summary of Product Characteristics (SmPC) | website=(emc) | url=https://www.medicines.org.uk/emc/product/9890 | access-date=21 September 2020}}</ref>
| legal_UK_comment =<ref>{{cite web | title=BCG Vaccine AJV - Summary of Product Characteristics (SmPC) | website=(emc) | url=https://www.medicines.org.uk/emc/product/9890 | access-date=21 September 2020 | archive-date=10 August 2020 | archive-url=https://web.archive.org/web/20200810163558/https://www.medicines.org.uk/emc/product/9890 | url-status=live }}</ref>
| legal_US = Rx-only
| legal_US = Rx-only
| legal_US_comment =<ref>{{cite web | title=BCG Vaccine- bacillus Calmette–Guerin substrain TICE live antigen injection, powder, lyophilized, for solution | website=DailyMed | date=3 September 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a83f0b99-9038-4c5a-aaac-8792b32838fe | access-date=21 September 2020}}</ref>
| legal_US_comment =<ref>{{cite web | title=BCG Vaccine- bacillus Calmette–Guerin substrain TICE live antigen injection, powder, lyophilized, for solution | website=DailyMed | date=3 September 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a83f0b99-9038-4c5a-aaac-8792b32838fe | access-date=21 September 2020 | archive-date=5 September 2024 | archive-url=https://web.archive.org/web/20240905050744/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a83f0b99-9038-4c5a-aaac-8792b32838fe | url-status=live }}</ref><ref>{{cite web | title=BCG Vaccine | website=U.S. [[Food and Drug Administration]] (FDA) | date=21 February 2018 | url=https://www.fda.gov/vaccines-blood-biologics/vaccines/bcg-vaccine | access-date=5 September 2024 | archive-date=24 February 2021 | archive-url=https://web.archive.org/web/20210224162301/http://www.fda.gov/vaccines-blood-biologics/vaccines/bcg-vaccine | url-status=live }}</ref>
| legal_status = Rx-only<ref name="Japan label" /><ref>{{cite journal | vauthors = Yamamoto S, Yamamoto T | title = Historical review of BCG vaccine in Japan | journal = Japanese Journal of Infectious Diseases | volume = 60 | issue = 6 | pages = 331–336 | date = November 2007 | pmid = 18032829 | doi = 10.7883/yoken.JJID.2007.331}}</ref>
| legal_status = JP: Rx-only<ref name="Japan label" /><ref>{{cite journal | vauthors = Yamamoto S, Yamamoto T | title = Historical review of BCG vaccine in Japan | journal = Japanese Journal of Infectious Diseases | volume = 60 | issue = 6 | pages = 331–336 | date = November 2007 | pmid = 18032829 | doi = 10.7883/yoken.JJID.2007.331}}</ref>


<!-- Identifiers -->
<!-- Identifiers -->
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<!-- Definition and medical uses -->
<!-- Definition and medical uses -->
'''Bacillus Calmette–Guérin''' ('''BCG''') '''vaccine''' is a [[vaccine]] primarily used against [[tuberculosis]] (TB).<ref name=WHO2018>{{cite journal | vauthors = ((World Health Organization)) | title = BCG vaccines: WHO position paper – February 2018 | journal = Weekly Epidemiological Record | volume = 93 | issue = 8 | pages = 73–96 | date = February 2018 | pmid = 29474026 | hdl = 10665/260307 | hdl-access=free }}</ref> It is named after its inventors [[Albert Calmette]] and [[Camille Guérin]].<ref>{{cite journal | vauthors = Hawgood BJ | title = Albert Calmette (1863-1933) and Camille Guérin (1872-1961): the C and G of BCG vaccine | journal = Journal of Medical Biography | volume = 15 | issue = 3 | pages = 139–146 | date = August 2007 | pmid = 17641786 | doi = 10.1258/j.jmb.2007.06-15 | s2cid = 41880560 }}</ref><ref>{{cite journal | vauthors = Luca S, Mihaescu T | title = History of BCG Vaccine | journal = Maedica | volume = 8 | issue = 1 | pages = 53–58 | date = March 2013 | pmid = 24023600 | pmc = 3749764 }}</ref> In countries where tuberculosis or [[leprosy]] is common, one dose is recommended in healthy babies as soon after birth as possible.<ref name=WHO2018/> In areas where tuberculosis is not common, only children at high risk are typically immunized, while suspected cases of tuberculosis are individually tested for and treated.<ref name=WHO2018/> Adults who do not have tuberculosis and have not been previously immunized, but are frequently exposed, may be immunized, as well.<ref name=WHO2018/> BCG also has some effectiveness against [[Buruli ulcer]] infection and other [[nontuberculous mycobacteria]]l infections.<ref name=WHO2018 /> Additionally, it is sometimes used as part of the treatment of [[bladder cancer]].<ref>{{cite journal | vauthors = Fuge O, Vasdev N, Allchorne P, Green JS | title = Immunotherapy for bladder cancer | journal = Research and Reports in Urology | volume = 7 | pages = 65–79 | date = May 2015 | pmid = 26000263 | pmc = 4427258 | doi = 10.2147/RRU.S63447 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Houghton BB, Chalasani V, Hayne D, Grimison P, Brown CS, Patel MI, Davis ID, Stockler MR | display-authors = 6 | title = Intravesical chemotherapy plus bacille Calmette-Guérin in non-muscle invasive bladder cancer: a systematic review with meta-analysis | journal = BJU International | volume = 111 | issue = 6 | pages = 977–983 | date = May 2013 | pmid = 23253618 | doi = 10.1111/j.1464-410X.2012.11390.x | s2cid = 24961108 }}</ref>
The '''Bacillus Calmette–Guérin''' ('''BCG''') '''vaccine''' is a [[vaccine]] primarily used against [[tuberculosis]] (TB).<ref name=WHO2018>{{cite journal | vauthors = ((World Health Organization)) | title = BCG vaccines: WHO position paper – February 2018 | journal = Weekly Epidemiological Record | volume = 93 | issue = 8 | pages = 73–96 | date = February 2018 | pmid = 29474026 | hdl = 10665/260307 | hdl-access=free }}</ref> It is named after its inventors [[Albert Calmette]] and [[Camille Guérin]].<ref>{{cite journal | vauthors = Hawgood BJ | title = Albert Calmette (1863-1933) and Camille Guérin (1872-1961): the C and G of BCG vaccine | journal = Journal of Medical Biography | volume = 15 | issue = 3 | pages = 139–146 | date = August 2007 | pmid = 17641786 | doi = 10.1258/j.jmb.2007.06-15 | s2cid = 41880560 }}</ref><ref name="pmid 24023600">{{cite journal | vauthors = Luca S, Mihaescu T | title = History of BCG Vaccine | journal = Maedica | volume = 8 | issue = 1 | pages = 53–58 | date = March 2013 | pmid = 24023600 | pmc = 3749764 }}</ref> In countries where tuberculosis or [[leprosy]] is common, one dose is recommended in healthy babies as soon after birth as possible.<ref name=WHO2018/> In areas where tuberculosis is not common, only children at high risk are typically immunized, while suspected cases of tuberculosis are individually tested for and treated.<ref name=WHO2018/> Adults who do not have tuberculosis and have not been previously immunized, but are frequently exposed, may be immunized, as well.<ref name=WHO2018/> BCG also has some effectiveness against [[Buruli ulcer]] infection and other [[nontuberculous mycobacteria]]l infections.<ref name=WHO2018 /> Additionally, it is sometimes used as part of the treatment of [[bladder cancer]].<ref>{{cite journal | vauthors = Fuge O, Vasdev N, Allchorne P, Green JS | title = Immunotherapy for bladder cancer | journal = Research and Reports in Urology | volume = 7 | pages = 65–79 | date = May 2015 | pmid = 26000263 | pmc = 4427258 | doi = 10.2147/RRU.S63447 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Houghton BB, Chalasani V, Hayne D, Grimison P, Brown CS, Patel MI, Davis ID, Stockler MR | title = Intravesical chemotherapy plus bacille Calmette-Guérin in non-muscle invasive bladder cancer: a systematic review with meta-analysis | journal = BJU International | volume = 111 | issue = 6 | pages = 977–983 | date = May 2013 | pmid = 23253618 | doi = 10.1111/j.1464-410X.2012.11390.x | s2cid = 24961108 }}</ref>


<!-- Effectiveness and administration -->
<!-- Effectiveness and administration -->
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<!-- History, society and culture -->
<!-- History, society and culture -->
The BCG vaccine was first used medically in 1921.<ref name=WHO2018 /> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref><ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> {{As of|2004}}, the vaccine is given to about 100 million children per year globally.<ref name=WHO2004>{{cite journal|date=23 January 2004|title=BCG Vaccine: WHO position paper|url=https://www.who.int/wer/2004/en/wer7904.pdf|journal=Weekly Epidemiological Record|volume=4|issue=79|pages=25–40|url-status=live|archive-url=https://web.archive.org/web/20150921165240/http://www.who.int/wer/2004/en/wer7904.pdf|archive-date=21 September 2015}}</ref>
The BCG vaccine was first used medically in 1921.<ref name=WHO2018 /> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> {{As of|2004}}, the vaccine is given to about 100 million children per year globally.<ref name=WHO2004>{{cite journal|date=January 2004|title=BCG Vaccine: WHO position paper|journal=Weekly Epidemiological Record|volume=4|issue=79|pages=27–38|hdl=10665/232372 | hdl-access=free }}</ref> However, it is not commonly administered in the United States.<ref name="pmid 8602127" /><ref>{{cite journal | vauthors = Vaudry W |title="To BCG or not to BCG, that is the question!". The challenge of BCG vaccination: Why can't we get it right? |journal=Paediatrics & Child Health |date=March 2003 |volume=8 |issue=3 |pages=141–144 |doi=10.1093/pch/8.3.141|pmid=20020010 |pmc=2792660 }}</ref>
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{{TOC limit}}


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{{see also|Tuberculosis vaccines}}
{{see also|Tuberculosis vaccines}}


The main use of BCG is for vaccination against [[tuberculosis]]. BCG vaccine can be administered after birth intradermally.<ref name="Japan label">{{cite web |title=FREEZE - DRIED GLUTAMATE BCG VACCINE (JAPAN) FOR INTRADERMAL USE |url=https://www.who.int/immunization_standards/vaccine_quality/68_bcg.pdf |archive-url=https://web.archive.org/web/20211019034749/https://www.who.int/immunization_standards/vaccine_quality/68_bcg.pdf |archive-date=19 October 2021 |url-status=live |publisher=World Health Organization |access-date=18 November 2021 |language=English}}</ref> BCG vaccination can cause a [[false positive]] [[Mantoux test]].<ref>{{cite web| title=Tuberculin Skin Testing Fact Sheet | date=12 July 2023| url=https://www.cdc.gov/tb/publications/factsheets/testing/skintesting.htm}}</ref>
The main use of BCG is for vaccination against [[tuberculosis]]. BCG vaccine can be administered after birth intradermally.<ref name="Japan label">{{cite web |title=Freeze - dried glutamate BCG vaccine (Japan) for intradermal use |url=https://www.who.int/immunization_standards/vaccine_quality/68_bcg.pdf |archive-url=https://web.archive.org/web/20211019034749/https://www.who.int/immunization_standards/vaccine_quality/68_bcg.pdf |archive-date=19 October 2021 |publisher=World Health Organization |access-date=18 November 2021 }}</ref> BCG vaccination can cause a [[false positive]] [[Mantoux test]].<ref>{{cite web| title=Tuberculin Skin Testing Fact Sheet| date=12 July 2023| url=https://www.cdc.gov/tb/publications/factsheets/testing/skintesting.htm| access-date=9 June 2023| archive-date=9 January 2017| archive-url=https://web.archive.org/web/20170109022127/https://www.cdc.gov/tb/publications/factsheets/testing/skintesting.htm| url-status=live}}</ref>


The most controversial aspect of BCG is the variable efficacy found in different clinical trials, which appears to depend on geography. Trials conducted in the UK have consistently shown a protective effect of 60 to 80%, but those conducted elsewhere have shown no protective effect, and efficacy appears to fall the closer one gets to the equator.<ref name=Colditz/><ref name="Fine"/>
The most controversial aspect of BCG is the variable efficacy found in different clinical trials, which appears to depend on geography. Trials conducted in the UK have consistently shown a protective effect of 60 to 80%, but those conducted elsewhere have shown no protective effect, and efficacy appears to fall the closer one gets to the equator.<ref name=Colditz/><ref name="Fine"/>
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A 1994 systematic review found that BCG reduces the risk of getting tuberculosis by about 50%.<ref name=Colditz>{{cite journal | vauthors = Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV, Mosteller F | title = Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature | journal = JAMA | volume = 271 | issue = 9 | pages = 698–702 | date = March 1994 | pmid = 8309034 | doi = 10.1001/jama.1994.03510330076038 }}</ref> Differences in effectiveness depend on region, due to factors such as genetic differences in the populations, changes in environment, exposure to other bacterial infections, and conditions in the laboratory where the vaccine is grown, including genetic differences between the strains being cultured and the choice of growth medium.<ref name="Venkataswamy"/><ref name=Fine>{{cite journal | vauthors = Fine PE | title = Variation in protection by BCG: implications of and for heterologous immunity | journal = Lancet | volume = 346 | issue = 8986 | pages = 1339–1345 | date = November 1995 | pmid = 7475776 | doi = 10.1016/S0140-6736(95)92348-9 | s2cid = 44737409 }}</ref>
A 1994 systematic review found that BCG reduces the risk of getting tuberculosis by about 50%.<ref name=Colditz>{{cite journal | vauthors = Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV, Mosteller F | title = Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature | journal = JAMA | volume = 271 | issue = 9 | pages = 698–702 | date = March 1994 | pmid = 8309034 | doi = 10.1001/jama.1994.03510330076038 }}</ref> Differences in effectiveness depend on region, due to factors such as genetic differences in the populations, changes in environment, exposure to other bacterial infections, and conditions in the laboratory where the vaccine is grown, including genetic differences between the strains being cultured and the choice of growth medium.<ref name="Venkataswamy"/><ref name=Fine>{{cite journal | vauthors = Fine PE | title = Variation in protection by BCG: implications of and for heterologous immunity | journal = Lancet | volume = 346 | issue = 8986 | pages = 1339–1345 | date = November 1995 | pmid = 7475776 | doi = 10.1016/S0140-6736(95)92348-9 | s2cid = 44737409 }}</ref>


A systematic review and meta-analysis conducted in 2014 demonstrated that the BCG vaccine reduced infections by 19–27% and reduced progression to active tuberculosis by 71%.<ref name="pmid25097193">{{cite journal | vauthors = Roy A, Eisenhut M, Harris RJ, Rodrigues LC, Sridhar S, Habermann S, Snell L, Mangtani P, Adetifa I, Lalvani A, Abubakar I | display-authors = 6 | title = Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis | journal = BMJ | volume = 349 | pages = g4643 | date = August 2014 | pmid = 25097193 | pmc = 4122754 | doi = 10.1136/bmj.g4643 }}</ref> The studies included in this review were limited to those that used [[interferon gamma release assay]].
A systematic review and meta-analysis conducted in 2014 demonstrated that the BCG vaccine reduced infections by 19–27% and reduced progression to active tuberculosis by 71%.<ref name="pmid25097193">{{cite journal | vauthors = Roy A, Eisenhut M, Harris RJ, Rodrigues LC, Sridhar S, Habermann S, Snell L, Mangtani P, Adetifa I, Lalvani A, Abubakar I | title = Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis | journal = BMJ | volume = 349 | pages = g4643 | date = August 2014 | pmid = 25097193 | pmc = 4122754 | doi = 10.1136/bmj.g4643 }}</ref> The studies included in this review were limited to those that used [[interferon gamma release assay]].


The duration of protection of BCG is not clearly known. In those studies showing a protective effect, the data are inconsistent. The MRC study showed protection waned to 59% after 15 years and to zero after 20 years; however, a study looking at Native Americans immunized in the 1930s found evidence of protection even 60 years after immunization, with only a slight waning in efficacy.<ref>{{cite journal | vauthors = Aronson NE, Santosham M, Comstock GW, Howard RS, Moulton LH, Rhoades ER, Harrison LH | title = Long-term efficacy of BCG vaccine in American Indians and Alaska Natives: A 60-year follow-up study | journal = JAMA | volume = 291 | issue = 17 | pages = 2086–2091 | date = May 2004 | pmid = 15126436 | doi = 10.1001/jama.291.17.2086 }}</ref>
The duration of protection of BCG is not clearly known. In those studies showing a protective effect, the data are inconsistent. The MRC study showed protection waned to 59% after 15 years and to zero after 20 years; however, a study looking at Native Americans immunized in the 1930s found evidence of protection even 60 years after immunization, with only a slight waning in efficacy.<ref>{{cite journal | vauthors = Aronson NE, Santosham M, Comstock GW, Howard RS, Moulton LH, Rhoades ER, Harrison LH | title = Long-term efficacy of BCG vaccine in American Indians and Alaska Natives: A 60-year follow-up study | journal = JAMA | volume = 291 | issue = 17 | pages = 2086–2091 | date = May 2004 | pmid = 15126436 | doi = 10.1001/jama.291.17.2086 }}</ref>
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BCG seems to have its greatest effect in preventing [[miliary tuberculosis]] or tuberculosis meningitis, so it is still extensively used even in countries where efficacy against pulmonary tuberculosis is negligible.<ref>{{cite journal | vauthors = Rodrigues LC, Diwan VK, Wheeler JG | title = Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis | journal = International Journal of Epidemiology | volume = 22 | issue = 6 | pages = 1154–1158 | date = December 1993 | pmid = 8144299 | doi = 10.1093/ije/22.6.1154 }}</ref>
BCG seems to have its greatest effect in preventing [[miliary tuberculosis]] or tuberculosis meningitis, so it is still extensively used even in countries where efficacy against pulmonary tuberculosis is negligible.<ref>{{cite journal | vauthors = Rodrigues LC, Diwan VK, Wheeler JG | title = Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis | journal = International Journal of Epidemiology | volume = 22 | issue = 6 | pages = 1154–1158 | date = December 1993 | pmid = 8144299 | doi = 10.1093/ije/22.6.1154 }}</ref>


The 100th anniversary of BCG was in 2021. It remains the only vaccine licensed against tuberculosis, which is an ongoing [[pandemic]]. [[Tuberculosis elimination]] is a goal of the [[World Health Organization]] (WHO), although the development of new vaccines with greater efficacy against adult pulmonary tuberculosis may be needed to make substantial progress.<ref>{{Cite web|url=http://theconversation.com/tuberculosis-kills-as-many-people-each-year-as-covid-19-its-time-we-found-a-better-vaccine-151590|title=Tuberculosis kills as many people each year as COVID-19. It's time we found a better vaccine| vauthors = Kupz A |website=The Conversation|date=14 January 2021 }}</ref>
The 100th anniversary of the BCG vaccine was in 2021.<ref name="pmid 24023600" /> It remains the only vaccine licensed against tuberculosis, which is an ongoing [[pandemic]]. [[Tuberculosis elimination]] is a goal of the [[World Health Organization]] (WHO), although the development of new vaccines with greater efficacy against adult pulmonary tuberculosis may be needed to make substantial progress.<ref>{{Cite web|url=https://theconversation.com/tuberculosis-kills-as-many-people-each-year-as-covid-19-its-time-we-found-a-better-vaccine-151590|title=Tuberculosis kills as many people each year as COVID-19. It's time we found a better vaccine|vauthors=Kupz A|website=The Conversation|date=14 January 2021|access-date=18 June 2021|archive-date=24 June 2021|archive-url=https://web.archive.org/web/20210624201633/https://theconversation.com/tuberculosis-kills-as-many-people-each-year-as-covid-19-its-time-we-found-a-better-vaccine-151590|url-status=live}}</ref>


====Efficacy====
====Efficacy====
A number of possible reasons for the variable efficacy of BCG in different countries have been proposed. None has been proven, some have been disproved, and none can explain the lack of efficacy in both low tuberculosis-burden countries (US) and high tuberculosis-burden countries (India). The reasons for variable efficacy have been discussed at length in a WHO document on BCG.<ref>{{cite report | vauthors = Fine PE, Carneiro IA, Milstein JB, Clements CJ | chapter = Chapter 8: Reasons for variable efficacy | title = Issues relating to the use of BCG in immunization programmes: a discussion document | chapter-url = http://whqlibdoc.who.int/hq/1999/WHO_V&B_99.23.pdf | year = 1999 | publisher = World Health Organization | location = Geneva, Switzerland | hdl=10665/66120 | hdl-access=free | id=WHO/V&B/99.23 }}</ref>
A number of possible reasons for the variable efficacy of BCG in different countries have been proposed. None has been proven, some have been disproved, and none can explain the lack of efficacy in both low tuberculosis-burden countries (US) and high tuberculosis-burden countries (India). The reasons for variable efficacy have been discussed at length in a WHO document on BCG.<ref name="WHO 1999">{{cite report | vauthors = Fine PE, Carneiro IA, Milstein JB, Clements CJ | chapter = Chapter 8: Reasons for variable efficacy | title = Issues relating to the use of BCG in immunization programmes: a discussion document | year = 1999 | publisher = World Health Organization | location = Geneva, Switzerland | hdl = 10665/66120 | hdl-access = free | id = WHO/V&B/99.23 }}</ref>
# Genetic variation in BCG strains: [[Genetic variation]] in the BCG strains used may explain the variable efficacy reported in different trials.<ref>{{cite journal | vauthors = Brosch R, Gordon SV, Garnier T, Eiglmeier K, Frigui W, Valenti P, Dos Santos S, Duthoy S, Lacroix C, Garcia-Pelayo C, Inwald JK, Golby P, Garcia JN, Hewinson RG, Behr MA, Quail MA, Churcher C, Barrell BG, Parkhill J, Cole ST | display-authors = 6 | title = Genome plasticity of BCG and impact on vaccine efficacy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 13 | pages = 5596–5601 | date = March 2007 | pmid = 17372194 | pmc = 1838518 | doi = 10.1073/pnas.0700869104 | doi-access = free | bibcode = 2007PNAS..104.5596B }}</ref>
# Genetic variation in BCG strains: [[Genetic variation]] in the BCG strains used may explain the variable efficacy reported in different trials.<ref>{{cite journal | vauthors = Brosch R, Gordon SV, Garnier T, Eiglmeier K, Frigui W, Valenti P, Dos Santos S, Duthoy S, Lacroix C, Garcia-Pelayo C, Inwald JK, Golby P, Garcia JN, Hewinson RG, Behr MA, Quail MA, Churcher C, Barrell BG, Parkhill J, Cole ST | title = Genome plasticity of BCG and impact on vaccine efficacy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 13 | pages = 5596–5601 | date = March 2007 | pmid = 17372194 | pmc = 1838518 | doi = 10.1073/pnas.0700869104 | doi-access = free | bibcode = 2007PNAS..104.5596B }}</ref>
# Genetic variation in populations: Differences in genetic make-up of different populations may explain the difference in efficacy. The Birmingham BCG trial was published in 1988. The trial, based in [[Birmingham]], United Kingdom, examined children born to families who originated from the Indian subcontinent (where vaccine efficacy had previously been shown to be zero). The trial showed a 64% protective effect, which is very similar to the figure derived from other UK trials, thus arguing against the genetic variation hypothesis.<ref>{{cite journal | vauthors = Packe GE, Innes JA | title = Protective effect of BCG vaccination in infant Asians: a case-control study | journal = Archives of Disease in Childhood | volume = 63 | issue = 3 | pages = 277–281 | date = March 1988 | pmid = 3258499 | pmc = 1778792 | doi = 10.1136/adc.63.3.277 }}</ref>
# Genetic variation in populations: Differences in genetic make-up of different populations may explain the difference in efficacy. The Birmingham BCG trial was published in 1988. The trial, based in [[Birmingham]], United Kingdom, examined children born to families who originated from the Indian subcontinent (where vaccine efficacy had previously been shown to be zero). The trial showed a 64% protective effect, which is very similar to the figure derived from other UK trials, thus arguing against the genetic variation hypothesis.<ref>{{cite journal | vauthors = Packe GE, Innes JA | title = Protective effect of BCG vaccination in infant Asians: a case-control study | journal = Archives of Disease in Childhood | volume = 63 | issue = 3 | pages = 277–281 | date = March 1988 | pmid = 3258499 | pmc = 1778792 | doi = 10.1136/adc.63.3.277 }}</ref>
# Interference by nontuberculous mycobacteria: Exposure to environmental mycobacteria (especially [[Mycobacterium avium]], [[Mycobacterium marinum]] and [[Mycobacterium intracellulare]]) results in a nonspecific immune response against mycobacteria. Administering BCG to someone who already has a nonspecific immune response against mycobacteria does not augment the response already there. BCG will, therefore, appear not to be efficacious because that person already has a level of immunity and BCG is not adding to that immunity. This effect is called masking because the effect of BCG is masked by environmental mycobacteria. Clinical evidence for this effect was found in a series of studies performed in parallel in adolescent school children in the UK and Malawi.<ref>{{cite journal | vauthors = Black GF, Weir RE, Floyd S, Bliss L, Warndorff DK, Crampin AC, Ngwira B, Sichali L, Nazareth B, Blackwell JM, Branson K, Chaguluka SD, Donovan L, Jarman E, King E, Fine PE, Dockrell HM | display-authors = 6 | title = BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malawi and the UK: two randomised controlled studies | journal = Lancet | volume = 359 | issue = 9315 | pages = 1393–1401 | date = April 2002 | pmid = 11978337 | doi = 10.1016/S0140-6736(02)08353-8 | s2cid = 24334622 }}</ref> In this study, the UK school children had a low baseline cellular immunity to mycobacteria which was increased by BCG; in contrast, the Malawi school children had a high baseline cellular immunity to mycobacteria and this was not significantly increased by BCG. Whether this natural immune response is protective is not known.<ref>{{cite journal | vauthors = Palmer CE, Long MW | title = Effects of infection with atypical mycobacteria on BCG vaccination and tuberculosis | journal = The American Review of Respiratory Disease | volume = 94 | issue = 4 | pages = 553–568 | date = October 1966 | pmid = 5924215 | doi = 10.1164/arrd.1966.94.4.553 | doi-broken-date = 31 January 2024 }}</ref> An alternative explanation is suggested by mouse studies; immunity against mycobacteria stops BCG from replicating and so stops it from producing an immune response. This is called the block hypothesis.<ref>{{cite journal | vauthors = Brandt L, Feino Cunha J, Weinreich Olsen A, Chilima B, Hirsch P, Appelberg R, Andersen P | title = Failure of the Mycobacterium bovis BCG vaccine: some species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to tuberculosis | journal = Infection and Immunity | volume = 70 | issue = 2 | pages = 672–678 | date = February 2002 | pmid = 11796598 | pmc = 127715 | doi = 10.1128/IAI.70.2.672-678.2002 }}</ref>
# Interference by nontuberculous mycobacteria: Exposure to environmental mycobacteria (especially ''[[Mycobacterium avium]]'', ''[[Mycobacterium marinum]]'' and ''[[Mycobacterium intracellulare]]'') results in a nonspecific immune response against mycobacteria. Administering BCG to someone who already has a nonspecific immune response against mycobacteria does not augment the response already there. BCG will, therefore, appear not to be efficacious because that person already has a level of immunity and BCG is not adding to that immunity. This effect is called masking because the effect of BCG is masked by environmental mycobacteria. Clinical evidence for this effect was found in a series of studies performed in parallel in adolescent school children in the UK and Malawi.<ref>{{cite journal | vauthors = Black GF, Weir RE, Floyd S, Bliss L, Warndorff DK, Crampin AC, Ngwira B, Sichali L, Nazareth B, Blackwell JM, Branson K, Chaguluka SD, Donovan L, Jarman E, King E, Fine PE, Dockrell HM | title = BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malawi and the UK: two randomised controlled studies | journal = Lancet | volume = 359 | issue = 9315 | pages = 1393–1401 | date = April 2002 | pmid = 11978337 | doi = 10.1016/S0140-6736(02)08353-8 | s2cid = 24334622 }}</ref> In this study, the UK school children had a low baseline cellular immunity to mycobacteria which was increased by BCG; in contrast, the Malawi school children had a high baseline cellular immunity to mycobacteria and this was not significantly increased by BCG. Whether this natural immune response is protective is not known.<ref>{{cite journal | vauthors = Palmer CE, Long MW | title = Effects of infection with atypical mycobacteria on BCG vaccination and tuberculosis | journal = The American Review of Respiratory Disease | volume = 94 | issue = 4 | pages = 553–568 | date = October 1966 | doi = 10.1164/arrd.1966.94.4.553 | doi-broken-date = 1 November 2024 | pmid = 5924215 | url = https://www.atsjournals.org/doi/abs/10.1164/arrd.1966.94.4.553 | access-date = 14 June 2024 | archive-date = 25 July 2024 | archive-url = https://web.archive.org/web/20240725192844/https://www.atsjournals.org/doi/abs/10.1164/arrd.1966.94.4.553 | url-status = live }}</ref> An alternative explanation is suggested by mouse studies; immunity against mycobacteria stops BCG from replicating and so stops it from producing an immune response. This is called the block hypothesis.<ref>{{cite journal | vauthors = Brandt L, Feino Cunha J, Weinreich Olsen A, Chilima B, Hirsch P, Appelberg R, Andersen P | title = Failure of the Mycobacterium bovis BCG vaccine: some species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to tuberculosis | journal = Infection and Immunity | volume = 70 | issue = 2 | pages = 672–678 | date = February 2002 | pmid = 11796598 | pmc = 127715 | doi = 10.1128/IAI.70.2.672-678.2002 }}</ref>
# Interference by concurrent parasitic infection: In another hypothesis, simultaneous infection with parasites changes the immune response to BCG, making it less effective. As [[T helper cell|Th1]] response is required for an effective immune response to tuberculous infection, concurrent infection with various parasites produces a simultaneous Th2 response, which blunts the effect of BCG.<ref>{{cite journal | vauthors = Rook GA, Dheda K, Zumla A | title = Do successful tuberculosis vaccines need to be immunoregulatory rather than merely Th1-boosting? | journal = Vaccine | volume = 23 | issue = 17–18 | pages = 2115–2120 | date = March 2005 | pmid = 15755581 | doi = 10.1016/j.vaccine.2005.01.069 | url = http://discovery.ucl.ac.uk/295/1/Rook_VACCINE_paper.pdf | url-status = live | author-link3 = Alimuddin Zumla | archive-url = https://web.archive.org/web/20170922153759/http://discovery.ucl.ac.uk/295/1/Rook_VACCINE_paper.pdf | archive-date = 22 September 2017 }}</ref>
# Interference by concurrent parasitic infection: In another hypothesis, simultaneous infection with parasites such as [[helminthiasis]] changes the immune response to BCG, making it less effective.<ref>{{cite journal | vauthors = Natukunda A, Zirimenya L, Nassuuna J, Nkurunungi G, Cose S, Elliott AM, Webb EL | title = The effect of helminth infection on vaccine responses in humans and animal models: A systematic review and meta-analysis | journal = Parasite Immunology | volume = 44 | issue = 9 | pages = e12939 | date = September 2022 | pmid = 35712983 | pmc = 9542036 | doi = 10.1111/pim.12939 }}</ref> As [[T helper cell|Th1]] response is required for an effective immune response to tuberculous infection, concurrent infection with various parasites produces a simultaneous Th2 response, which blunts the effect of BCG.<ref>{{cite journal | vauthors = Rook GA, Dheda K, Zumla A | title = Do successful tuberculosis vaccines need to be immunoregulatory rather than merely Th1-boosting? | journal = Vaccine | volume = 23 | issue = 17–18 | pages = 2115–2120 | date = March 2005 | pmid = 15755581 | doi = 10.1016/j.vaccine.2005.01.069 | url = https://discovery.ucl.ac.uk/id/eprint/295/1/Rook_VACCINE_paper.pdf | url-status = live | author-link3 = Alimuddin Zumla | archive-url = https://web.archive.org/web/20170922153759/http://discovery.ucl.ac.uk/295/1/Rook_VACCINE_paper.pdf | archive-date = 22 September 2017 }}</ref>


=== Mycobacteria ===
=== Mycobacteria ===
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[[Image:Granulomatous inflammation of bladder neck.jpg|thumb|right|[[Micrograph]] showing [[granuloma]]tous [[inflammation]] of bladder neck tissue due to Bacillus Calmette–Guérin used to treat [[bladder cancer]], [[H&E stain]]]]
[[Image:Granulomatous inflammation of bladder neck.jpg|thumb|right|[[Micrograph]] showing [[granuloma]]tous [[inflammation]] of bladder neck tissue due to Bacillus Calmette–Guérin used to treat [[bladder cancer]], [[H&E stain]]]]


BCG has been one of the most successful immunotherapies.<ref name="BDG_2016">{{cite journal | vauthors = Rentsch CA, Birkhäuser FD, Biot C, Gsponer JR, Bisiaux A, Wetterauer C, Lagranderie M, Marchal G, Orgeur M, Bouchier C, Bachmann A, Ingersoll MA, Brosch R, Albert ML, Thalmann GN | display-authors = 6 | title = Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy | journal = European Urology | volume = 66 | issue = 4 | pages = 677–688 | date = October 2014 | pmid = 24674149 | doi = 10.1016/j.eururo.2014.02.061 }}</ref> BCG vaccine has been the "standard of care for patients with [[bladder cancer]] (NMIBC)" since 1977.<ref name="BDG_2016" /><ref name="BCG_success_2007">{{cite journal | vauthors = Brandau S, Suttmann H | title = Thirty years of BCG immunotherapy for non-muscle invasive bladder cancer: a success story with room for improvement | journal = Biomedicine & Pharmacotherapy | volume = 61 | issue = 6 | pages = 299–305 | date = July 2007 | pmid = 17604943 | doi = 10.1016/j.biopha.2007.05.004 }}<!--|access-date=29 January 2016 --></ref> By 2014 there were more than eight different considered biosimilar agents or strains used for the treatment of nonmuscle-invasive bladder cancer.<ref name="BDG_2016" />
BCG has been one of the most successful immunotherapies.<ref name="BDG_2016">{{cite journal | vauthors = Rentsch CA, Birkhäuser FD, Biot C, Gsponer JR, Bisiaux A, Wetterauer C, Lagranderie M, Marchal G, Orgeur M, Bouchier C, Bachmann A, Ingersoll MA, Brosch R, Albert ML, Thalmann GN | title = Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy | journal = European Urology | volume = 66 | issue = 4 | pages = 677–688 | date = October 2014 | pmid = 24674149 | doi = 10.1016/j.eururo.2014.02.061 }}</ref> BCG vaccine has been the "standard of care for patients with [[bladder cancer]] (NMIBC)" since 1977.<ref name="BDG_2016" /><ref name="BCG_success_2007">{{cite journal | vauthors = Brandau S, Suttmann H | title = Thirty years of BCG immunotherapy for non-muscle invasive bladder cancer: a success story with room for improvement | journal = Biomedicine & Pharmacotherapy | volume = 61 | issue = 6 | pages = 299–305 | date = July 2007 | pmid = 17604943 | doi = 10.1016/j.biopha.2007.05.004 }}<!--|access-date=29 January 2016 --></ref> By 2014 there were more than eight different considered biosimilar agents or strains used for the treatment of nonmuscle-invasive bladder cancer.<ref name="BDG_2016" />
<ref name="BCG_success_2007" />
<ref name="BCG_success_2007" />
* A number of [[cancer vaccine]]s use BCG as an additive to provide an initial stimulation of the person's immune systems.{{citation needed|date=December 2022}}
* A number of [[cancer vaccine]]s use BCG as an additive to provide an initial stimulation of the person's immune systems.{{citation needed|date=December 2022}}
* BCG is [[BCG as a treatment for bladder cancer|used in the treatment]] of superficial forms of bladder cancer. Since the late 1970s, evidence has become available that instillation of BCG into the bladder is an effective form of [[immunotherapy]] in this disease.<ref>{{cite journal | vauthors = Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA, Sullivan J, Sarosdy MF | display-authors = 6 | title = A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder | journal = The New England Journal of Medicine | volume = 325 | issue = 17 | pages = 1205–1209 | date = October 1991 | pmid = 1922207 | doi = 10.1056/NEJM199110243251703 | doi-access = free }}</ref> While the mechanism is unclear, it appears a local immune reaction is mounted against the tumor. Immunotherapy with BCG prevents recurrence in up to 67% of cases of superficial bladder cancer.{{citation needed|date=February 2023}}
* BCG is [[BCG as a treatment for bladder cancer|used in the treatment]] of superficial forms of bladder cancer. Since the late 1970s, evidence has become available that instillation of BCG into the bladder is an effective form of [[immunotherapy]] in this disease.<ref>{{cite journal | vauthors = Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA, Sullivan J, Sarosdy MF | title = A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder | journal = The New England Journal of Medicine | volume = 325 | issue = 17 | pages = 1205–1209 | date = October 1991 | pmid = 1922207 | doi = 10.1056/NEJM199110243251703 | doi-access = free }}</ref> While the mechanism is unclear, it appears a local immune reaction is mounted against the tumor. Immunotherapy with BCG prevents recurrence in up to 67% of cases of superficial bladder cancer.{{citation needed|date=February 2023}}
* BCG has been evaluated in a number of studies as a therapy for [[colorectal cancer]].<ref>{{cite journal | vauthors = Mosolits S, Nilsson B, Mellstedt H | title = Towards therapeutic vaccines for colorectal carcinoma: a review of clinical trials | journal = Expert Review of Vaccines | volume = 4 | issue = 3 | pages = 329–350 | date = June 2005 | pmid = 16026248 | doi = 10.1586/14760584.4.3.329 | s2cid = 35749038 | title-link = therapeutic vaccine }}</ref> The US biotech company [[Vaccinogen]] is evaluating BCG as an adjuvant to autologous tumour cells used as a cancer vaccine in stage II [[colon cancer]].{{citation needed|date=December 2022}}
* BCG has been evaluated in a number of studies as a therapy for [[colorectal cancer]].<ref>{{cite journal | vauthors = Mosolits S, Nilsson B, Mellstedt H | title = Towards therapeutic vaccines for colorectal carcinoma: a review of clinical trials | journal = Expert Review of Vaccines | volume = 4 | issue = 3 | pages = 329–350 | date = June 2005 | pmid = 16026248 | doi = 10.1586/14760584.4.3.329 | s2cid = 35749038 | title-link = therapeutic vaccine }}</ref> The US biotech company [[Vaccinogen]] is evaluating BCG as an adjuvant to autologous tumour cells used as a cancer vaccine in stage II [[colon cancer]].{{citation needed|date=December 2022}}


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[[Image:BCG apparatus ja2.jpg|thumb|An apparatus (4–5 cm length, with 9 short needles) used for BCG vaccination in Japan, shown with ampules of BCG and saline]]
[[Image:BCG apparatus ja2.jpg|thumb|An apparatus (4–5 cm length, with 9 short needles) used for BCG vaccination in Japan, shown with ampules of BCG and saline]]


A pre-injection [[tuberculin skin test]] is usually carried out before administering BCG. A reactive [[tuberculin]] skin test is a contraindication to BCG due to the risk of severe local inflammation and scarring; it does not indicate any immunity. BCG is also contraindicated in certain people who have [[Interleukin-12|IL-12]] receptor pathway defects.{{citation needed|date=December 2022}}
A pre-injection [[tuberculin skin test]] is usually carried out before administering BCG. A reactive [[tuberculin]] skin test is a contraindication to BCG due to the risk of severe local inflammation and scarring; it does not indicate any immunity. BCG is also contraindicated in certain people who have [[Interleukin-12|IL-12]] receptor pathway defects.<ref name="Tuberculosis Vaccine Development: P">{{cite journal | vauthors = Sable SB, Posey JE, Scriba TJ | title = Tuberculosis Vaccine Development: Progress in Clinical Evaluation | journal = Clinical Microbiology Reviews | volume = 33 | issue = 1 | date = December 2019 | pmid = 31666281 | pmc = 6822991 | doi = 10.1128/CMR.00100-19 }}</ref>


BCG is given as a single [[intradermal]] injection at the insertion of the [[Deltoid muscle|deltoid]]. If BCG is accidentally given [[Subcutaneous injection|subcutaneous]]ly, then a local abscess may form (a "BCG-oma") that can sometimes ulcerate, and may require treatment with [[antibiotics]] immediately, otherwise without treatment it could spread the infection, causing severe damage to vital organs. An abscess is not always associated with incorrect administration, and it is one of the more common complications that can occur with the vaccination. Numerous medical studies on treatment of these abscesses with antibiotics have been done with varying results, but the consensus is once pus is aspirated and analysed, provided no unusual bacilli are present, the abscess will generally heal on its own in a matter of weeks.<ref>{{Cite web|title=BestBets: Is medical therapy effective in the treatment of BCG abscesses?|url=https://bestbets.org/bets/bet.php?id=00797|access-date=15 August 2022|website=bestbets.org}}</ref>
BCG is given as a single [[intradermal]] injection at the insertion of the [[Deltoid muscle|deltoid]]. If BCG is accidentally given [[Subcutaneous injection|subcutaneous]]ly, then a local abscess may form (a "BCG-oma") that can sometimes ulcerate, and may require treatment with [[antibiotics]] immediately, otherwise without treatment it could spread the infection, causing severe damage to vital organs. An abscess is not always associated with incorrect administration, and it is one of the more common complications that can occur with the vaccination. Numerous medical studies on treatment of these abscesses with antibiotics have been done with varying results, but the consensus is once pus is aspirated and analysed, provided no unusual bacilli are present, the abscess will generally heal on its own in a matter of weeks.<ref>{{Cite web|title=BestBets: Is medical therapy effective in the treatment of BCG abscesses?|url=https://bestbets.org/bets/bet.php?id=00797|access-date=15 August 2022|website=bestbets.org|archive-date=25 July 2024|archive-url=https://web.archive.org/web/20240725192819/https://bestbets.org/bets/bet.php?id=00797|url-status=live}}</ref>


The characteristic raised scar that BCG immunization leaves is often used as proof of prior immunization. This scar must be distinguished from that of [[smallpox vaccination]], which it may resemble.{{citation needed|date=December 2022}}
The characteristic raised scar that BCG immunization leaves is often used as proof of prior immunization. This scar must be distinguished from that of [[smallpox vaccination]], which it may resemble.<ref name="Tuberculosis Vaccine Development: P"/>


When given for bladder cancer, the vaccine is not injected through the skin, but is instilled into the bladder through the urethra using a soft catheter.<ref>{{Cite web|title=Intravesical Therapy for Bladder Cancer|url=https://www.cancer.org/cancer/bladder-cancer/treating/intravesical-therapy.html|access-date=15 August 2022|website=www.cancer.org|language=en}}</ref>
When given for bladder cancer, the vaccine is not injected through the skin, but is instilled into the bladder through the urethra using a soft catheter.<ref>{{Cite web|title=Intravesical Therapy for Bladder Cancer|url=https://www.cancer.org/cancer/bladder-cancer/treating/intravesical-therapy.html|access-date=15 August 2022|website=www.cancer.org|archive-date=30 March 2020|archive-url=https://web.archive.org/web/20200330152144/https://www.cancer.org/cancer/bladder-cancer/treating/intravesical-therapy.html|url-status=live}}</ref>


==Adverse effects==
==Adverse effects==
BCG immunization generally causes some pain and scarring at the site of injection. The main adverse effects are [[keloid]]s—large, raised scars. The insertion to the [[deltoid muscle]] is most frequently used because the local complication rate is smallest when that site is used. Nonetheless, the buttock is an alternative site of administration because it provides better cosmetic outcomes.{{citation needed|date=December 2022}}
BCG immunization generally causes some pain and scarring at the site of injection. The main adverse effects are [[keloid]]s—large, raised scars. The insertion to the [[deltoid muscle]] is most frequently used because the local complication rate is smallest when that site is used. Nonetheless, the buttock is an alternative site of administration because it provides better cosmetic outcomes.<ref name="Tuberculosis Vaccine Development: P"/>


BCG vaccine should be given intradermally. If given subcutaneously, it may induce local infection and spread to the regional [[lymph nodes]], causing either suppurative (production of [[pus]]) and nonsuppurative [[lymphadenitis]]. Conservative management is usually adequate for nonsuppurative lymphadenitis. If suppuration occurs, it may need [[needle aspiration]]. For nonresolving suppuration, [[surgical excision]] may be required. Evidence for the treatment of these complications is scarce.<ref>{{cite journal | vauthors = Cuello-García CA, Pérez-Gaxiola G, Jiménez Gutiérrez C | title = Treating BCG-induced disease in children | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 1 | pages = CD008300 | date = January 2013 | pmid = 23440826 | pmc = 6532703 | doi = 10.1002/14651858.CD008300.pub2 }}</ref>
BCG vaccine should be given intradermally. If given subcutaneously, it may induce local infection and spread to the regional [[lymph nodes]], causing either suppurative (production of [[pus]]) and nonsuppurative [[lymphadenitis]]. Conservative management is usually adequate for nonsuppurative lymphadenitis. If suppuration occurs, it may need [[needle aspiration]]. For nonresolving suppuration, [[surgical excision]] may be required. Evidence for the treatment of these complications is scarce.<ref>{{cite journal | vauthors = Cuello-García CA, Pérez-Gaxiola G, Jiménez Gutiérrez C | title = Treating BCG-induced disease in children | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 1 | pages = CD008300 | date = January 2013 | pmid = 23440826 | pmc = 6532703 | doi = 10.1002/14651858.CD008300.pub2 }}</ref>
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</ref>
</ref>


When BCG is used for bladder cancer, around 2.9% of treated patients discontinue immunotherapy due to a genitourinary or systemic BCG-related infection,<ref>{{cite journal | vauthors = Nummi A, Järvinen R, Sairanen J, Huotari K | title = A retrospective study on tolerability and complications of bacillus Calmette-Guérin (BCG) instillations for non-muscle-invasive bladder cancer | journal = Scandinavian Journal of Urology | volume = 53 | issue = 2–3 | pages = 116–122 | date = 4 May 2019 | pmid = 31074322 | doi = 10.1080/21681805.2019.1609080 | s2cid = 149444603 }}</ref> however while symptomatic bladder BCG infection is frequent, the involvement of other organs is very uncommon.<ref>{{cite journal | vauthors = Liu Y, Lu J, Huang Y, Ma L | title = Clinical Spectrum of Complications Induced by Intravesical Immunotherapy of Bacillus Calmette-Guérin for Bladder Cancer | journal = Journal of Oncology | volume = 2019 | pages = 6230409 | date = 10 March 2019 | pmid = 30984262 | pmc = 6431507 | doi = 10.1155/2019/6230409 | doi-access = free }}</ref> When systemic involvement occurs, liver and lungs are the first organs to be affected (1 week [median] after the last BCG instillation).<ref>{{cite journal | vauthors = Cabas P, Rizzo M, Giuffrè M, Antonello RM, Trombetta C, Luzzati R, Liguori G, Di Bella S | display-authors = 6 | title = BCG infection (BCGitis) following intravesical instillation for bladder cancer and time interval between treatment and presentation: A systematic review | journal = Urologic Oncology | volume = 39 | issue = 2 | pages = 85–92 | date = February 2021 | pmid = 33308969 | doi = 10.1016/j.urolonc.2020.11.037 | s2cid = 229179250 }}</ref>
When BCG is used for bladder cancer, around 2.9% of treated patients discontinue immunotherapy due to a genitourinary or systemic BCG-related infection,<ref>{{cite journal | vauthors = Nummi A, Järvinen R, Sairanen J, Huotari K | title = A retrospective study on tolerability and complications of bacillus Calmette-Guérin (BCG) instillations for non-muscle-invasive bladder cancer | journal = Scandinavian Journal of Urology | volume = 53 | issue = 2–3 | pages = 116–122 | date = 4 May 2019 | pmid = 31074322 | doi = 10.1080/21681805.2019.1609080 | s2cid = 149444603 }}</ref> however while symptomatic bladder BCG infection is frequent, the involvement of other organs is very uncommon.<ref>{{cite journal | vauthors = Liu Y, Lu J, Huang Y, Ma L | title = Clinical Spectrum of Complications Induced by Intravesical Immunotherapy of Bacillus Calmette-Guérin for Bladder Cancer | journal = Journal of Oncology | volume = 2019 | pages = 6230409 | date = 10 March 2019 | pmid = 30984262 | pmc = 6431507 | doi = 10.1155/2019/6230409 | doi-access = free }}</ref> When systemic involvement occurs, liver and lungs are the first organs to be affected (1 week [median] after the last BCG instillation).<ref>{{cite journal | vauthors = Cabas P, Rizzo M, Giuffrè M, Antonello RM, Trombetta C, Luzzati R, Liguori G, Di Bella S | title = BCG infection (BCGitis) following intravesical instillation for bladder cancer and time interval between treatment and presentation: A systematic review | journal = Urologic Oncology | volume = 39 | issue = 2 | pages = 85–92 | date = February 2021 | pmid = 33308969 | doi = 10.1016/j.urolonc.2020.11.037 | s2cid = 229179250 }}</ref>


If BCG is accidentally given to an immunocompromised patient (e.g., an infant with [[severe combined immune deficiency]]), it can cause disseminated or life-threatening infection. The documented incidence of this happening is less than one per million immunizations given.<ref>{{cite journal | vauthors = ((Centers for Disease Control and Prevention)) | title = The role of BCG vaccine in the prevention and control of tuberculosis in the United States. A joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices | journal = MMWR. Recommendations and Reports | volume = 45 | issue = RR-4 | pages = 1–18 | date = April 1996 | pmid = 8602127 | url = https://www.cdc.gov/mmwr/PDF/rr/rr4504.pdf }}</ref> In 2007, the WHO stopped recommending BCG for infants with [[Human immunodeficiency virus|HIV]], even if the risk of exposure to tuberculosis is high,<ref>{{cite journal | vauthors = ((World Health Organization)) | title = Revised BCG vaccination guidelines for infants at risk for HIV infection | journal = Weekly Epidemiological Record | volume = 82 | issue = 21 | pages = 193–196 | date = May 2007 | pmid = 17526121 | hdl = 10665/240940 | hdl-access = free }}</ref> because of the risk of disseminated BCG infection (which is roughly 400 per 100,000 in that higher risk context).<ref>{{cite journal | vauthors = Trunz BB, Fine P, Dye C | title = Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness | journal = Lancet | volume = 367 | issue = 9517 | pages = 1173–1180 | date = April 2006 | pmid = 16616560 | doi = 10.1016/S0140-6736(06)68507-3 | s2cid = 40371125 }}</ref><ref>{{cite journal | vauthors = Mak TK, Hesseling AC, Hussey GD, Cotton MF | title = Making BCG vaccination programmes safer in the HIV era | journal = Lancet | volume = 372 | issue = 9641 | pages = 786–787 | date = September 2008 | pmid = 18774406 | doi = 10.1016/S0140-6736(08)61318-5 | s2cid = 6702107 }}</ref>
If BCG is accidentally given to an immunocompromised patient (e.g., an infant with [[severe combined immune deficiency]]), it can cause disseminated or life-threatening infection. The documented incidence of this happening is less than one per million immunizations given.<ref name="pmid 8602127">{{cite journal | vauthors = ((Centers for Disease Control and Prevention)) | title = The role of BCG vaccine in the prevention and control of tuberculosis in the United States. A joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices | journal = MMWR. Recommendations and Reports | volume = 45 | issue = RR-4 | pages = 1–18 | date = April 1996 | pmid = 8602127 | url = https://www.cdc.gov/mmwr/PDF/rr/rr4504.pdf | access-date = 6 January 2020 | archive-date = 6 January 2020 | archive-url = https://web.archive.org/web/20200106203240/https://www.cdc.gov/mmwr/PDF/rr/rr4504.pdf | url-status = live }}</ref> In 2007, the WHO stopped recommending BCG for infants with [[Human immunodeficiency virus|HIV]], even if the risk of exposure to tuberculosis is high,<ref>{{cite journal | vauthors = ((World Health Organization)) | title = Revised BCG vaccination guidelines for infants at risk for HIV infection | journal = Weekly Epidemiological Record | volume = 82 | issue = 21 | pages = 193–196 | date = May 2007 | pmid = 17526121 | hdl = 10665/240940 | hdl-access = free }}</ref> because of the risk of disseminated BCG infection (which is roughly 400 per 100,000 in that higher risk context).<ref>{{cite journal | vauthors = Trunz BB, Fine P, Dye C | title = Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness | journal = Lancet | volume = 367 | issue = 9517 | pages = 1173–1180 | date = April 2006 | pmid = 16616560 | doi = 10.1016/S0140-6736(06)68507-3 | s2cid = 40371125 }}</ref><ref>{{cite journal | vauthors = Mak TK, Hesseling AC, Hussey GD, Cotton MF | title = Making BCG vaccination programmes safer in the HIV era | journal = Lancet | volume = 372 | issue = 9641 | pages = 786–787 | date = September 2008 | pmid = 18774406 | doi = 10.1016/S0140-6736(08)61318-5 | s2cid = 6702107 }}</ref>


==Usage==
==Usage==
The age of the person and the frequency with which BCG is given has always varied from country to country. The WHO currently recommends childhood BCG for all countries with a high incidence of tuberculosis and/or high leprosy burden.<ref name="WHO2018" /> This is a partial list of historic and current BCG practice around the globe. A complete atlas of past and present practice has been generated.<ref name=BCGA/>
The age of the person and the frequency with which BCG is given has always varied from country to country. The WHO recommends childhood BCG for all countries with a high incidence of tuberculosis and/or high leprosy burden.<ref name="WHO2018" /> This is a partial list of historic and active BCG practice around the globe. A complete atlas of past and present practice has been generated.<ref name=BCGA/> As of 2022, 155 countries offer the BCG vaccine in their schedule.<ref>{{cite journal | vauthors = Kaur G, Danovaro-Holliday MC, Mwinnyaa G, Gacic-Dobo M, Francis L, Grevendonk J, Sodha SV, Sugerman C, Wallace A | title = Routine Vaccination Coverage - Worldwide, 2022 | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 72 | issue = 43 | pages = 1155–1161 | date = October 2023 | pmid = 37883326 | pmc = 10602616 | doi = 10.15585/mmwr.mm7243a1 | doi-access = free | url = https://www.cdc.gov/mmwr/volumes/72/wr/pdfs/mm7243a1-H.pdf | access-date = 5 September 2024 | archive-date = 5 September 2024 | archive-url = https://web.archive.org/web/20240905050740/https://www.cdc.gov/mmwr/volumes/72/wr/pdfs/mm7243a1-H.pdf | url-status = live }}</ref>


===Americas===
===Americas===
* Brazil introduced universal BCG immunization in 1967–1968, and the practice continues until now. According to Brazilian law, BCG is given again to professionals of the health sector and to people close to patients with tuberculosis or [[leprosy]].{{citation needed|date=December 2022}}
* Brazil introduced universal BCG immunization in 1967–1968, and the practice continues until now. According to Brazilian law, BCG is given again to professionals of the health sector and to people close to patients with tuberculosis or [[leprosy]].{{citation needed|date=December 2022}}
* Canadian Indigenous communities currently receive the BCG vaccine,<ref>{{cite web |title=Bacille Calmette–Guerin (BCG) Information for Health Professionals |url=https://www.toronto.ca/community-people/health-wellness-care/information-for-healthcare-professionals/communicable-disease-info-for-health-professionals/tuberculosis-information-for-health-professionals/bacille-calmette-guerin-bcg-information-for-health-professionals/ |website=toronto.ca |access-date=8 April 2020 |date=January 2020}}</ref> and in the province of Quebec the vaccine was offered to children until the mid-70s.<ref>{{cite journal | vauthors = Rousseau MC, Conus F, Kâ K, El-Zein M, Parent MÉ, Menzies D | title = Bacillus Calmette-Guérin (BCG) vaccination patterns in the province of Québec, Canada, 1956-1974 | journal = Vaccine | volume = 35 | issue = 36 | pages = 4777–4784 | date = August 2017 | pmid = 28705514 | doi = 10.1016/j.vaccine.2017.06.064 | doi-access = free }}</ref>
* Canadian Indigenous communities receive the BCG vaccine,<ref>{{cite web |title=Bacille Calmette–Guerin (BCG) Information for Health Professionals |url=https://www.toronto.ca/community-people/health-wellness-care/information-for-healthcare-professionals/communicable-disease-info-for-health-professionals/tuberculosis-information-for-health-professionals/bacille-calmette-guerin-bcg-information-for-health-professionals/ |website=toronto.ca |access-date=8 April 2020 |date=January 2020 |archive-date=6 May 2020 |archive-url=https://web.archive.org/web/20200506111602/https://www.toronto.ca/community-people/health-wellness-care/information-for-healthcare-professionals/communicable-disease-info-for-health-professionals/tuberculosis-information-for-health-professionals/bacille-calmette-guerin-bcg-information-for-health-professionals/ |url-status=live }}</ref> and in the province of Quebec the vaccine was offered to children until the mid-70s.<ref>{{cite journal | vauthors = Rousseau MC, Conus F, Kâ K, El-Zein M, Parent MÉ, Menzies D | title = Bacillus Calmette-Guérin (BCG) vaccination patterns in the province of Québec, Canada, 1956-1974 | journal = Vaccine | volume = 35 | issue = 36 | pages = 4777–4784 | date = August 2017 | pmid = 28705514 | doi = 10.1016/j.vaccine.2017.06.064 | doi-access = free }}</ref>
* Most countries in Central and South America have universal BCG immunizations.<ref>{{cite web |url=http://www.siise.gob.ec/siiseweb/PageWebs/SALUD/ficsal_S21.htm |title=Ficha metodológica |access-date=12 March 2015 |url-status=dead |archive-url=https://web.archive.org/web/20150402152751/http://www.siise.gob.ec/siiseweb/PageWebs/SALUD/ficsal_S21.htm |archive-date=2 April 2015 }}</ref>
* Most countries in Central and South America have universal BCG immunizations,<ref>{{cite web |url=http://www.siise.gob.ec/siiseweb/PageWebs/SALUD/ficsal_S21.htm |title=Ficha metodológica |access-date=12 March 2015 |url-status=dead |archive-url=https://web.archive.org/web/20150402152751/http://www.siise.gob.ec/siiseweb/PageWebs/SALUD/ficsal_S21.htm |archive-date=2 April 2015}}</ref> as does Mexico.<ref>{{cite web |url=https://www.gob.mx/salud/en/articulos/esquema-de-vacunacion |title=Esquema de Vacunación |access-date=28 May 2024 |archive-date=25 July 2024 |archive-url=https://web.archive.org/web/20240725192848/https://www.gob.mx/salud/en/articulos/esquema-de-vacunacion |url-status=live }}</ref>
* The United States has never used mass immunization of BCG due to the rarity of tuberculosis in the US, relying instead on the detection and treatment of [[latent tuberculosis]].{{citation needed|date=December 2022}}
* The United States has never used mass immunization of BCG due to the rarity of tuberculosis in the US, relying instead on the detection and treatment of [[latent tuberculosis]].<ref name="CDC BCG">{{cite web | title=Bacille Calmette-Guérin (BCG) Vaccine for Tuberculosis | website=Tuberculosis (TB) | date=11 July 2024 | url=https://www.cdc.gov/tb/hcp/vaccines/ | access-date=5 September 2024}}</ref><ref name="CDC Tuberculosis">{{cite web | title=Tuberculosis Vaccine | website=Tuberculosis (TB) | date=11 July 2024 | url=https://www.cdc.gov/tb/vaccines/ | access-date=5 September 2024 | archive-date=5 September 2024 | archive-url=https://web.archive.org/web/20240905041249/https://www.cdc.gov/tb/vaccines/ | url-status=live }}</ref>


===Europe===
===Europe===
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| {{flaglist|Austria}}<ref name=BCGA>{{Cite web | url=http://www.bcgatlas.org/| title= Database of Global BCG Vaccination Policies and Practices|publisher=The BCG World Atlas|access-date=21 October 2020}}</ref>
| {{flaglist|Austria}}<ref name=BCGA>{{Cite web|url=http://www.bcgatlas.org/|title=Database of Global BCG Vaccination Policies and Practices|publisher=The BCG World Atlas|access-date=21 October 2020|archive-date=12 June 2009|archive-url=https://web.archive.org/web/20090612044328/http://www.bcgatlas.org/|url-status=live}}</ref>
|{{na}}
|{{na}}
|{{ya}}
|{{ya}}
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| {{flaglist|Armenia}}<ref name=BCGA>{{Cite web|url=http://www.bcgatlas.org/|title=Database of Global BCG Vaccination Policies and Practices|publisher=The BCG World Atlas|access-date=21 October 2020|archive-date=12 June 2009|archive-url=https://web.archive.org/web/20090612044328/http://www.bcgatlas.org/|url-status=live}}</ref>
| {{flaglist|Belgium}}<ref name=BCGA/><ref>{{cite web|url=https://www.sciensano.be/en/health-topics/tuberculosis/prevention|title=Prevention|website=sciensano.be}}</ref>
|{{ya}}
|{{ya}}
|?–present (reintroduced in 1998)
|-

| {{flaglist|Belgium}}<ref name=BCGA/><ref>{{cite web|url=https://www.sciensano.be/en/health-topics/tuberculosis/prevention|title=Prevention|website=sciensano.be|access-date=8 April 2020|archive-date=6 May 2020|archive-url=https://web.archive.org/web/20200506074815/https://www.sciensano.be/en/health-topics/tuberculosis/prevention|url-status=live}}</ref>
|{{na}}
|{{na}}
|{{na}}
|{{na}}
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| {{flaglist|Denmark}}<ref name=BCGA/><ref>{{cite journal | vauthors = Rieckmann A, Villumsen M, Sørup S, Haugaard LK, Ravn H, Roth A, Baker JL, Benn CS, Aaby P | display-authors = 6 | title = Vaccinations against smallpox and tuberculosis are associated with better long-term survival: a Danish case-cohort study 1971-2010 | journal = International Journal of Epidemiology | volume = 46 | issue = 2 | pages = 695–705 | date = April 2017 | pmid = 27380797 | pmc = 5837789 | doi = 10.1093/ije/dyw120 | s2cid = 3792173 }}</ref>
| {{flaglist|Denmark}}<ref name=BCGA/><ref>{{cite journal | vauthors = Rieckmann A, Villumsen M, Sørup S, Haugaard LK, Ravn H, Roth A, Baker JL, Benn CS, Aaby P | title = Vaccinations against smallpox and tuberculosis are associated with better long-term survival: a Danish case-cohort study 1971-2010 | journal = International Journal of Epidemiology | volume = 46 | issue = 2 | pages = 695–705 | date = April 2017 | pmid = 27380797 | pmc = 5837789 | doi = 10.1093/ije/dyw120 | s2cid = 3792173 }}</ref>
|{{na}}
|{{na}}
|{{ya}}
|{{ya}}
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| {{flaglist|Finland}}<ref name=BCGA/><ref>{{cite web |title=THL |url=https://thl.fi/fi/web/infektiotaudit-ja-rokotukset/rokotteet-a-o/bcg-eli-tuberkuloosirokote |website=BCG- eli tuberkuloosirokote |publisher=THL |access-date=16 April 2020}}</ref>
| {{flaglist|Finland}}<ref name=BCGA/><ref>{{cite web |title=THL |url=https://thl.fi/fi/web/infektiotaudit-ja-rokotukset/rokotteet-a-o/bcg-eli-tuberkuloosirokote |website=BCG- eli tuberkuloosirokote |publisher=THL |access-date=16 April 2020 |archive-date=23 April 2020 |archive-url=https://web.archive.org/web/20200423180931/https://thl.fi/fi/web/infektiotaudit-ja-rokotukset/rokotteet-a-o/bcg-eli-tuberkuloosirokote |url-status=live }}</ref>
|{{na}}
|{{na}}
|{{ya}}
|{{ya}}
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| {{flaglist|Germany}}<ref name=BCGA/><ref>{{cite web |last1=BCG World Atlas |url=http://www.bcgatlas.org |archive-url=https://web.archive.org/web/20090612044328/http://www.bcgatlas.org/ |url-status=dead |archive-date=12 June 2009 |title=A Database of Global BCG Vaccination Policies and Practices |access-date=4 April 2020 }}</ref>
| {{flaglist|Germany}}<ref name=BCGA/><ref>{{cite web | work =BCG World Atlas |url=http://www.bcgatlas.org |archive-url=https://web.archive.org/web/20090612044328/http://www.bcgatlas.org/ |url-status=dead |archive-date=12 June 2009 |title=A Database of Global BCG Vaccination Policies and Practices |access-date=4 April 2020 }}</ref>
|{{na}}
|{{na}}
|{{ya}}
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| {{flaglist|Greece}}<ref name=BCGA/><ref>{{cite journal | vauthors = Gabriele F, Katragkou A, Roilides E | title = BCG vaccination policy in Greece: time for another review? | journal = The International Journal of Tuberculosis and Lung Disease | volume = 18 | issue = 10 | pages = 1258 | date = October 2014 | pmid = 25216844 | doi = 10.5588/ijtld.14.0282 }}</ref><ref>{{Cite web|url=https://www.moh.gov.gr/articles/health/dieythynsh-dhmosias-ygieinhs/emboliasmoi/alles-systaseis-ths-ethnikhs-epitrophs-emboliasmwn/6358-diakoph-ths-efarmoghs-katholikoy-antifymatikoy-emboliasmoy-embolio-bcg-sta-paidia-ths-a-dhmotikoy-2016|title=Διακοπή της εφαρμογής καθολικού αντιφυματικού εμβολιασμού (εμβόλιο BCG) στα παιδιά της Α΄ Δημοτικού 2016|website=Υπουργείο Υγείας}}</ref>
| {{flaglist|Greece}}<ref name=BCGA/><ref>{{cite journal | vauthors = Gabriele F, Katragkou A, Roilides E | title = BCG vaccination policy in Greece: time for another review? | journal = The International Journal of Tuberculosis and Lung Disease | volume = 18 | issue = 10 | pages = 1258 | date = October 2014 | pmid = 25216844 | doi = 10.5588/ijtld.14.0282 }}</ref><ref>{{Cite web|url=https://www.moh.gov.gr/articles/health/dieythynsh-dhmosias-ygieinhs/emboliasmoi/alles-systaseis-ths-ethnikhs-epitrophs-emboliasmwn/6358-diakoph-ths-efarmoghs-katholikoy-antifymatikoy-emboliasmoy-embolio-bcg-sta-paidia-ths-a-dhmotikoy-2016|title=Διακοπή της εφαρμογής καθολικού αντιφυματικού εμβολιασμού (εμβόλιο BCG) στα παιδιά της Α΄ Δημοτικού 2016|website=Υπουργείο Υγείας|access-date=26 December 2020|archive-date=8 May 2021|archive-url=https://web.archive.org/web/20210508081156/https://www.moh.gov.gr/articles/health/dieythynsh-dhmosias-ygieinhs/emboliasmoi/alles-systaseis-ths-ethnikhs-epitrophs-emboliasmwn/6358-diakoph-ths-efarmoghs-katholikoy-antifymatikoy-emboliasmoy-embolio-bcg-sta-paidia-ths-a-dhmotikoy-2016|url-status=live}}</ref>
|{{na}}
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| {{flaglist|Hungary}}<ref name=BCGA/><ref>{{cite web|url=https://www.antsz.hu/felso_menu/temaink/jarvany/jarvany_archivum/oltasbiztonsag/BCG_hatteranyag.html|title=A tuberkulózis és a tuberkulózis elleni védőoltás (BCG) |trans-title=Tuberculosis and tuberculosis vaccination |date=17 July 2015|website=ÁNTSZ}}</ref><ref>{{Cite web |title=Integrált Jogvédelmi Szolgálat |url=http://www.ijsz.hu/UserFiles/000989_eszi_honlapra_20151215.pdf |archive-url=https://web.archive.org/web/20190716050327/http://www.ijsz.hu/UserFiles/000989_eszi_honlapra_20151215.pdf |archive-date=16 July 2019 |url-status=live |access-date=20 October 2022 |website=Integrált Jogvédelmi Szolgálat |language=Hungarian}}</ref>
| {{flaglist|Hungary}}<ref name=BCGA/><ref>{{cite web|url=https://www.antsz.hu/felso_menu/temaink/jarvany/jarvany_archivum/oltasbiztonsag/BCG_hatteranyag.html|title=A tuberkulózis és a tuberkulózis elleni védőoltás (BCG)|trans-title=Tuberculosis and tuberculosis vaccination|date=17 July 2015|website=ÁNTSZ|access-date=5 April 2020|archive-date=11 April 2020|archive-url=https://web.archive.org/web/20200411140436/https://www.antsz.hu/felso_menu/temaink/jarvany/jarvany_archivum/oltasbiztonsag/BCG_hatteranyag.html|url-status=live}}</ref><ref>{{Cite web |title=Integrált Jogvédelmi Szolgálat |url=http://www.ijsz.hu/UserFiles/000989_eszi_honlapra_20151215.pdf |archive-url=https://web.archive.org/web/20190716050327/http://www.ijsz.hu/UserFiles/000989_eszi_honlapra_20151215.pdf |archive-date=16 July 2019 |url-status=live |access-date=20 October 2022 |website=Integrált Jogvédelmi Szolgálat |language=Hungarian}}</ref>
|{{ya}}
|{{ya}}
|{{ya}}
|{{ya}}
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| {{flaglist|Ireland}}<ref>{{cite news|url=https://www.irishtimes.com/news/health/coronavirus-more-striking-evidence-bcg-vaccine-might-protect-against-covid-19-1.4222110|title=Coronavirus: More "striking" evidence BCG vaccine might protect against Covid-19| vauthors = O'Sullivan K |newspaper=The Irish Times|access-date=6 April 2020}}</ref>
| {{flaglist|Ireland}}<ref>{{cite news|url=https://www.irishtimes.com/news/health/coronavirus-more-striking-evidence-bcg-vaccine-might-protect-against-covid-19-1.4222110|title=Coronavirus: More "striking" evidence BCG vaccine might protect against Covid-19|vauthors=O'Sullivan K|newspaper=The Irish Times|access-date=6 April 2020|archive-date=7 April 2020|archive-url=https://web.archive.org/web/20200407140758/https://www.irishtimes.com/news/health/coronavirus-more-striking-evidence-bcg-vaccine-might-protect-against-covid-19-1.4222110|url-status=live}}</ref>
| {{na}}
| {{na}}
|{{ya}}
|{{ya}}
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|{{ya}}
|{{ya}}
|{{ya}}
|1928–present
|?–present
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| {{flaglist|Spain}}<ref name=BCGA/><ref>{{cite web|url=https://www.vacunas.org/vacunas-disponibles-tuberculosis/|title=Vacunas disponibles {{pipe}} Vacunas / Asociación Española de Vacunología |date=20 December 2018 |trans-title=Vaccines available; Vaccines / Spanish Association of Vaccination}}</ref>
| {{flaglist|Spain}}<ref name=BCGA/><ref>{{cite web|url=https://www.vacunas.org/vacunas-disponibles-tuberculosis/|title=Vacunas disponibles {{pipe}} Vacunas / Asociación Española de Vacunología|date=20 December 2018|trans-title=Vaccines available; Vaccines / Spanish Association of Vaccination|access-date=8 April 2020|archive-date=6 May 2020|archive-url=https://web.archive.org/web/20200506040815/https://www.vacunas.org/vacunas-disponibles-tuberculosis/|url-status=live}}</ref>
|{{na}}
|{{na}}
|{{ya}}
|{{ya}}
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| {{flaglist|Sweden}}<ref name=BCGA/><ref>{{cite web|url=http://www.folkhalsomyndigheten.se/smittskydd-beredskap/vaccinationer/vacciner-a-o/tuberkulos-tb/|title=Tuberkulos (TB) – om vaccination – Folkhälsomyndigheten|website=folkhalsomyndigheten.se |date=21 February 2022 |trans-title=Tuberculosis (TB) - on vaccination - Public Health Agency}}</ref>
| {{flaglist|Sweden}}<ref name=BCGA/><ref>{{cite web|url=http://www.folkhalsomyndigheten.se/smittskydd-beredskap/vaccinationer/vacciner-a-o/tuberkulos-tb/|title=Tuberkulos (TB) – om vaccination – Folkhälsomyndigheten|website=folkhalsomyndigheten.se|date=21 February 2022|trans-title=Tuberculosis (TB) - on vaccination - Public Health Agency|access-date=11 April 2020|archive-date=13 April 2020|archive-url=https://web.archive.org/web/20200413151455/https://www.folkhalsomyndigheten.se/smittskydd-beredskap/vaccinationer/vacciner-a-o/tuberkulos-tb/|url-status=live}}</ref>
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| {{flaglist|Ukraine}}<ref name=BCGA/><ref>{{Cite web|title=ІПС ЛІГА:ЗАКОН - система пошуку, аналізу та моніторингу нормативно-правової бази.|url=https://ips.ligazakon.net/|access-date=15 August 2022|website=ips.ligazakon.net}}</ref>
| {{flaglist|Ukraine}}<ref name=BCGA/><ref>{{Cite web|title=ІПС ЛІГА:ЗАКОН - система пошуку, аналізу та моніторингу нормативно-правової бази.|url=https://ips.ligazakon.net/|access-date=15 August 2022|website=ips.ligazakon.net|archive-date=19 November 2021|archive-url=https://web.archive.org/web/20211119111851/https://ips.ligazakon.net/|url-status=live}}</ref>
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| {{flaglist|United Kingdom}}<ref name=BCGA/><ref>{{cite journal | vauthors = Styblo K, Meijer J | title = Impact of BCG vaccination programmes in children and young adults on the tuberculosis problem | journal = Tubercle | volume = 57 | issue = 1 | pages = 17–43 | date = March 1976 | pmid = 1085050 | doi = 10.1016/0041-3879(76)90015-5 }}</ref><ref>{{cite news|url=http://news.bbc.co.uk/2/hi/health/4655355.stm |title=School "TB jabs" to be scrapped |date=6 July 2005|work=BBC News Online |url-status=live|archive-url=https://web.archive.org/web/20120306040753/http://news.bbc.co.uk/1/hi/health/4655355.stm|archive-date=6 March 2012|access-date=24 September 2014}}</ref><ref>{{cite web|url=http://www.nhs.uk/conditions/vaccinations/pages/bcg-tuberculosis-tb-vaccine.aspx|title=BCG tuberculosis (TB) vaccine overview|website=[[NHS.uk]]|url-status=live|archive-url=https://web.archive.org/web/20160401103926/http://www.nhs.uk/Conditions/vaccinations/Pages/bcg-tuberculosis-TB-vaccine.aspx|archive-date=1 April 2016|access-date=27 March 2016}}</ref><ref>{{cite news |last1=McKie |first1=Robin |title=Coronavirus: should the UK make vaccination mandatory? |url=https://www.theguardian.com/society/2022/jan/09/coronavirus-should-the-uk-make-vaccination-mandatory |access-date=24 April 2024 |work=The Observer |date=9 January 2022}}</ref>
| {{flaglist|United Kingdom}}<ref name=BCGA/><ref>{{cite journal | vauthors = Styblo K, Meijer J | title = Impact of BCG vaccination programmes in children and young adults on the tuberculosis problem | journal = Tubercle | volume = 57 | issue = 1 | pages = 17–43 | date = March 1976 | pmid = 1085050 | doi = 10.1016/0041-3879(76)90015-5 }}</ref><ref>{{cite news|url=http://news.bbc.co.uk/2/hi/health/4655355.stm |title=School "TB jabs" to be scrapped |date=6 July 2005|work=BBC News Online |url-status=live|archive-url=https://web.archive.org/web/20120306040753/http://news.bbc.co.uk/1/hi/health/4655355.stm|archive-date=6 March 2012|access-date=24 September 2014}}</ref><ref>{{cite web|url=https://www.nhs.uk/vaccinations/bcg-vaccine-for-tuberculosis-tb/|title=BCG tuberculosis (TB) vaccine overview|website=[[NHS.uk]]|url-status=live|archive-url=https://web.archive.org/web/20160401103926/http://www.nhs.uk/Conditions/vaccinations/Pages/bcg-tuberculosis-TB-vaccine.aspx|archive-date=1 April 2016|access-date=27 March 2016}}</ref><ref>{{cite news |vauthors=McKie R |title=Coronavirus: should the UK make vaccination mandatory? |url=https://www.theguardian.com/society/2022/jan/09/coronavirus-should-the-uk-make-vaccination-mandatory |access-date=24 April 2024 |work=The Observer |date=9 January 2022 |archive-date=25 July 2024 |archive-url=https://web.archive.org/web/20240725192852/https://www.theguardian.com/society/2022/jan/09/coronavirus-should-the-uk-make-vaccination-mandatory |url-status=live }}</ref>
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* China: Introduced in 1930s. Increasingly widespread after 1949. Majority inoculated by 1979.<ref>{{cite journal | vauthors = Chen ZR, Wei XH, Zhu ZY | title = BCG in China | journal = Chinese Medical Journal | volume = 95 | issue = 6 | pages = 437–442 | date = June 1982 | pmid = 6813052 }}</ref>
* China: Introduced in 1930s. Increasingly widespread after 1949. Majority inoculated by 1979.<ref>{{cite journal | vauthors = Chen ZR, Wei XH, Zhu ZY | title = BCG in China | journal = Chinese Medical Journal | volume = 95 | issue = 6 | pages = 437–442 | date = June 1982 | pmid = 6813052 }}</ref>
* South Korea, Singapore, Taiwan and Malaysia. In these countries, BCG was given at birth and again at age 12. In Malaysia and Singapore from 2001, this policy was changed to once only at birth. South Korea stopped re-vaccination in 2008.
* South Korea, Singapore, Taiwan and Malaysia. In these countries, BCG was given at birth and again at age 12. In Malaysia and Singapore from 2001, this policy was changed to once only at birth. South Korea stopped re-vaccination in 2008.
* Hong Kong: BCG is given to all newborns.<ref>{{cite web |url=https://www.fhs.gov.hk/english/main_ser/child_health/child_health_recommend.html|title=Child health – Immunisation|access-date=6 January 2020}}</ref>
* Hong Kong: BCG is given to all newborns.<ref>{{cite web|url=https://www.fhs.gov.hk/english/main_ser/child_health/child_health_recommend.html|title=Child health – Immunisation|access-date=6 January 2020|archive-date=10 November 2019|archive-url=https://web.archive.org/web/20191110104131/https://www.fhs.gov.hk/english/main_ser/child_health/child_health_recommend.html|url-status=live}}</ref>
* Japan: In Japan, BCG was introduced in 1951, given typically at age 6. From 2005 it is administered between five and eight months after birth, and no later than a child's first birthday. BCG was administered no later than the fourth birthday until 2005, and no later than six months from birth from 2005 to 2012; the schedule was changed in 2012 due to reports of [[osteitis]] side effects from vaccinations at 3–4 months. Some municipalities recommend an earlier immunization schedule.<ref>{{cite web|url=http://www.mhlw.go.jp/seisakunitsuite/bunya/kenkou_iryou/kenkou/kekkaku-kansenshou/bcg/|title=結核とBCGワクチンに関するQ&A|厚生労働省 |trans-title=Q & A about tuberculosis and BCG vaccine, Ministry of Health, Labour and Welfare |website=mhlw.go.jp|language=ja|access-date=10 July 2017|url-status=live|archive-url=https://web.archive.org/web/20170416183326/http://www.mhlw.go.jp/seisakunitsuite/bunya/kenkou_iryou/kenkou/kekkaku-kansenshou/bcg/|archive-date=16 April 2017}}</ref>
* Japan: In Japan, BCG was introduced in 1951, given typically at age 6. From 2005 it is administered between five and eight months after birth, and no later than a child's first birthday. BCG was administered no later than the fourth birthday until 2005, and no later than six months from birth from 2005 to 2012; the schedule was changed in 2012 due to reports of [[osteitis]] side effects from vaccinations at 3–4 months. Some municipalities recommend an earlier immunization schedule.<ref>{{cite web|url=http://www.mhlw.go.jp/seisakunitsuite/bunya/kenkou_iryou/kenkou/kekkaku-kansenshou/bcg/|title=結核とBCGワクチンに関するQ&A|厚生労働省 |trans-title=Q & A about tuberculosis and BCG vaccine, Ministry of Health, Labour and Welfare |website=mhlw.go.jp|language=ja|access-date=10 July 2017|url-status=live|archive-url=https://web.archive.org/web/20170416183326/http://www.mhlw.go.jp/seisakunitsuite/bunya/kenkou_iryou/kenkou/kekkaku-kansenshou/bcg/|archive-date=16 April 2017}}</ref>
* Thailand: In Thailand, the BCG vaccine is given routinely at birth.<ref>{{cite web|url=http://www.pidst.net/A385.html|title=Thai Pediatrics|website=Thai Pediatrics|url-status=live|archive-url=https://web.archive.org/web/20151119183506/http://www.pidst.net/A385.html|archive-date=19 November 2015}}</ref>
* Thailand: In Thailand, the BCG vaccine is given routinely at birth.<ref>{{cite web|url=http://www.pidst.net/A385.html|title=Thai Pediatrics|website=Thai Pediatrics|url-status=live|archive-url=https://web.archive.org/web/20151119183506/http://www.pidst.net/A385.html|archive-date=19 November 2015}}</ref>
* India and Pakistan: India and Pakistan introduced BCG mass immunization in 1948, the first countries outside Europe to do so.<ref>{{cite journal|vauthors=Mahler HT, Mohamed Ali P|year=1955|title=Review of mass B.C.G. project in India|url=http://openmed.nic.in/804/|url-status=dead|journal=Ind J Tuberculosis|volume=2|issue=3|pages=108–16|archive-url=https://web.archive.org/web/20070213202749/http://openmed.nic.in/804/|archive-date=13 February 2007}}</ref> In 2015, millions of infants were denied BCG vaccine in Pakistan for the first time due to shortage globally.<ref>{{cite news | vauthors = Chaudhry A |title=Millions of infants denied anti-TB vaccination |url=https://www.dawn.com/news/1165534 |access-date=8 April 2020 |work=Dawn|location=Pakistan |date=24 February 2015 }}</ref>
* India and Pakistan: India and Pakistan introduced BCG mass immunization in 1948, the first countries outside Europe to do so.<ref>{{cite journal|vauthors=Mahler HT, Mohamed Ali P|year=1955|title=Review of mass B.C.G. project in India|url=http://openmed.nic.in/804/|url-status=dead|journal=Ind J Tuberculosis|volume=2|issue=3|pages=108–16|archive-url=https://web.archive.org/web/20070213202749/http://openmed.nic.in/804/|archive-date=13 February 2007}}</ref> In 2015, millions of infants were denied BCG vaccine in Pakistan for the first time due to shortage globally.<ref>{{cite news |vauthors=Chaudhry A |title=Millions of infants denied anti-TB vaccination |url=https://www.dawn.com/news/1165534 |access-date=8 April 2020 |work=Dawn |location=Pakistan |date=24 February 2015 |archive-date=6 May 2020 |archive-url=https://web.archive.org/web/20200506144007/https://www.dawn.com/news/1165534 |url-status=live }}</ref>
* Mongolia: All newborns are vaccinated with BCG. Previously, the vaccine was also given at ages 8 and 15, although this is no longer common practice.<ref>{{cite journal | vauthors = Rauniyar SK, Munkhbat E, Ueda P, Yoneoka D, Shibuya K, Nomura S | title = Timeliness of routine vaccination among children and determinants associated with age-appropriate vaccination in Mongolia | journal = Heliyon | volume = 6 | issue = 9 | pages = e04898 | date = September 2020 | pmid = 32995607 | pmc = 7505765 | doi = 10.1016/j.heliyon.2020.e04898 | doi-access = free | bibcode = 2020Heliy...604898R }}</ref>
* Mongolia: All newborns are vaccinated with BCG. Previously, the vaccine was also given at ages 8 and 15, although this is no longer common practice.<ref>{{cite journal | vauthors = Rauniyar SK, Munkhbat E, Ueda P, Yoneoka D, Shibuya K, Nomura S | title = Timeliness of routine vaccination among children and determinants associated with age-appropriate vaccination in Mongolia | journal = Heliyon | volume = 6 | issue = 9 | pages = e04898 | date = September 2020 | pmid = 32995607 | pmc = 7505765 | doi = 10.1016/j.heliyon.2020.e04898 | doi-access = free | bibcode = 2020Heliy...604898R }}</ref>
* Philippines: BCG vaccine started in the Philippines in 1979 with the [[Expanded Program on Immunization (Philippines)|Expanded Program on Immunization]].
* Philippines: BCG vaccine started in the Philippines in 1979 with the [[Expanded Program on Immunization (Philippines)|Expanded Program on Immunization]].
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===Middle East===
===Middle East===
* Israel: BCG was given to all newborns between 1955 and 1982.<ref>{{cite journal | vauthors = Hamiel U, Kozer E, Youngster I | title = SARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults | journal = JAMA | volume = 323 | issue = 22 | pages = 2340–2341 | date = June 2020 | pmid = 32401274 | pmc = 7221856 | doi = 10.1001/jama.2020.8189 }}</ref>
* Israel: BCG was given to all newborns between 1955 and 1982.<ref>{{cite journal | vauthors = Hamiel U, Kozer E, Youngster I | title = SARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults | journal = JAMA | volume = 323 | issue = 22 | pages = 2340–2341 | date = June 2020 | pmid = 32401274 | pmc = 7221856 | doi = 10.1001/jama.2020.8189 }}</ref>
* Iran: Iran's vaccination policy implemented in 1984. Vaccination with the Bacillus Calmette–Guerin (BCG) is among the most important tuberculosis control strategies in Iran [2]. According to Iranian neonatal vaccination policy, BCG has been given as a single dose at children aged <6 years, shortly after birth or at first contact with the health services.<ref>{{cite journal | vauthors = Sadeghi-Shanbestari M, Ansarin K, Maljaei SH, Rafeey M, Pezeshki Z, Kousha A, Baradaran R, Casanova JL, Feinberg J, de Villartay JP | display-authors = 6 | title = Immunologic aspects of patients with disseminated bacille Calmette-Guerin disease in north-west of Iran | journal = Italian Journal of Pediatrics | volume = 35 | issue = 1 | pages = 42 | date = December 2009 | pmid = 20030825 | pmc = 2806263 | doi = 10.1186/1824-7288-35-42 | doi-access = free }}</ref>
* Iran: Iran's vaccination policy implemented in 1984. Vaccination with the Bacillus Calmette–Guerin (BCG) is among the most important tuberculosis control strategies in Iran [2]. According to Iranian neonatal vaccination policy, BCG has been given as a single dose at children aged <6 years, shortly after birth or at first contact with the health services.<ref>{{cite journal | vauthors = Sadeghi-Shanbestari M, Ansarin K, Maljaei SH, Rafeey M, Pezeshki Z, Kousha A, Baradaran R, Casanova JL, Feinberg J, de Villartay JP | title = Immunologic aspects of patients with disseminated bacille Calmette-Guerin disease in north-west of Iran | journal = Italian Journal of Pediatrics | volume = 35 | issue = 1 | pages = 42 | date = December 2009 | pmid = 20030825 | pmc = 2806263 | doi = 10.1186/1824-7288-35-42 | doi-access = free }}</ref>


===Africa===
===Africa===
* South Africa: In South Africa, the BCG Vaccine is given routinely at birth, to all newborns, except those with clinically symptomatic AIDS. The vaccination site is in the right shoulder.<ref>{{cite web |url=http://www.doh.gov.za/docs/programmes/2006/bcg.pdf |title=BCG |publisher=[[South African National Department of Health]] |date=2006 |archive-url=https://web.archive.org/web/20130511100236/http://www.doh.gov.za/docs/programmes/2006/bcg.pdf |archive-date=11 May 2013 }}</ref>
* South Africa: In South Africa, the BCG Vaccine is given routinely at birth, to all newborns, except those with clinically symptomatic AIDS. The vaccination site is in the right shoulder.<ref>{{cite web |url=http://www.doh.gov.za/docs/programmes/2006/bcg.pdf |title=BCG |publisher=[[South African National Department of Health]] |date=2006 |archive-url=https://web.archive.org/web/20130511100236/http://www.doh.gov.za/docs/programmes/2006/bcg.pdf |archive-date=11 May 2013 }}</ref>
* Morocco: In Morocco, the BCG was introduced in 1949. The current policy is BCG vaccination at birth, to all newborns.<ref>{{cite web|url=http://www.academie-medecine.fr/evolution-du-calendrier-vaccinal-au-maroc/|title=Évolution du calendrier vaccinal au Maroc|date=29 May 2006}}</ref>
* Morocco: In Morocco, the BCG was introduced in 1949. The policy is BCG vaccination at birth, to all newborns.<ref>{{cite web|url=http://www.academie-medecine.fr/evolution-du-calendrier-vaccinal-au-maroc/|title=Évolution du calendrier vaccinal au Maroc|date=29 May 2006|access-date=8 April 2020|archive-date=6 May 2020|archive-url=https://web.archive.org/web/20200506111823/http://www.academie-medecine.fr/evolution-du-calendrier-vaccinal-au-maroc/|url-status=live}}</ref>
* Kenya: In Kenya, the BCG Vaccine is given routinely at birth to all newborns.<ref>{{cite web |title=BCG Vaccine – Its Evolution and Importance |url=https://chskenya.org/bcg-vaccine-its-evolution-and-importance/ |website=Centre for Health Solutions - Kenya |access-date=14 February 2022 |date=12 January 2016}}</ref>
* Kenya: In Kenya, the BCG Vaccine is given routinely at birth to all newborns.<ref>{{cite web |title=BCG Vaccine – Its Evolution and Importance |url=https://chskenya.org/bcg-vaccine-its-evolution-and-importance/ |website=Centre for Health Solutions - Kenya |access-date=14 February 2022 |date=12 January 2016 |archive-date=25 July 2024 |archive-url=https://web.archive.org/web/20240725192825/https://chskenya.org/bcg-vaccine-its-evolution-and-importance/ |url-status=live }}</ref>


=== South Pacific ===
=== South Pacific ===
* Australia: BCG vaccination was used between 1950s and mid 1980. BCG is not part of routine vaccination since mid 1980.<ref>{{cite web |title=BCG vaccine for TB |url=https://www.rch.org.au/kidsinfo/fact_sheets/BCG_vaccine_for_TB/ |publisher=Royal Children's Hospital Melbourne |access-date=31 March 2020}}</ref>
* Australia: BCG vaccination was used between 1950s and mid 1980. BCG is not part of routine vaccination since mid 1980.<ref>{{cite web |title=BCG vaccine for TB |url=https://www.rch.org.au/kidsinfo/fact_sheets/BCG_vaccine_for_TB/ |publisher=Royal Children's Hospital Melbourne |access-date=31 March 2020 |archive-date=9 March 2020 |archive-url=https://web.archive.org/web/20200309063205/https://www.rch.org.au/kidsinfo/fact_sheets/BCG_vaccine_for_TB/ |url-status=live }}</ref>
* New Zealand: BCG Immunisation was first introduced for 13 yr olds in 1948. Vaccination was phased out 1963–1990.<ref name=BCGA/>
* New Zealand: BCG Immunisation was first introduced for 13 year olds in 1948. Vaccination was phased out 1963–1990.<ref name=BCGA/>


==Manufacture==
==Manufacture==
BCG is prepared from a strain of the attenuated ([[virulence]]-reduced) live bovine tuberculosis bacillus, ''[[Mycobacterium bovis]]'', that has lost its ability to cause disease in humans. It is specially subcultured in a culture medium, usually [[Middlebrook 7H9 Broth|Middlebrook 7H9]].<ref>{{cite book |title=Handbook of media for clinical microbiology | vauthors = Atlas RM, Snyder JW |year=2006 |publisher=[[CRC Press]] |isbn=978-0-8493-3795-6 }}</ref> Because the living bacilli evolve to make the best use of available nutrients, they become less well-adapted to human blood and can no longer induce disease when introduced into a human host. Still, they are similar enough to their wild ancestors to provide some degree of immunity against human tuberculosis. The BCG vaccine can be anywhere from 0 to 80% effective in preventing tuberculosis for a duration of 15 years; however, its protective effect appears to vary according to geography and the lab in which the vaccine strain was grown.<ref name="Venkataswamy">{{cite journal | vauthors = Venkataswamy MM, Goldberg MF, Baena A, Chan J, Jacobs WR, Porcelli SA | title = In vitro culture medium influences the vaccine efficacy of Mycobacterium bovis BCG | journal = Vaccine | volume = 30 | issue = 6 | pages = 1038–1049 | date = February 2012 | pmid = 22189700 | pmc = 3269512 | doi = 10.1016/j.vaccine.2011.12.044 }}</ref>
BCG is prepared from a strain of the attenuated ([[virulence]]-reduced) live bovine tuberculosis bacillus, ''[[Mycobacterium bovis]]'', that has lost its ability to cause disease in humans. It is specially subcultured in a culture medium, usually [[Middlebrook 7H9 Broth|Middlebrook 7H9]].<ref>{{cite book |title=Handbook of media for clinical microbiology | vauthors = Atlas RM, Snyder JW |year=2006 |publisher=[[CRC Press]] |isbn=978-0-8493-3795-6 }}</ref> Because the living bacilli evolve to make the best use of available nutrients, they become less well-adapted to human blood and can no longer induce disease when introduced into a human host. Still, they are similar enough to their wild ancestors to provide some degree of immunity against human tuberculosis. The BCG vaccine can be anywhere from 0 to 80% effective in preventing tuberculosis for a duration of 15 years; however, its protective effect appears to vary according to geography and the lab in which the vaccine strain was grown.<ref name="Venkataswamy">{{cite journal | vauthors = Venkataswamy MM, Goldberg MF, Baena A, Chan J, Jacobs WR, Porcelli SA | title = In vitro culture medium influences the vaccine efficacy of Mycobacterium bovis BCG | journal = Vaccine | volume = 30 | issue = 6 | pages = 1038–1049 | date = February 2012 | pmid = 22189700 | pmc = 3269512 | doi = 10.1016/j.vaccine.2011.12.044 }}</ref>


A number of different companies make BCG, sometimes using different genetic strains of the bacterium. This may result in different product characteristics. OncoTICE, used for bladder instillation for bladder cancer, was developed by Organon Laboratories (since acquired by [[Schering-Plough]], and in turn acquired by [[Merck & Co.]]). A similar application is the product of Onko BCG<ref>{{cite web |url=https://biomedlublin.com/en/produkty/onko-bcg-100/ |title=Onko BCG 100 Biomed Lublin |publisher=biomedlublin.com |access-date=3 March 2021 }}</ref> of the [[Poland|Polish]] company [[Biomed-Lublin]], which owns the Brazilian substrain M. bovis BCG Moreau which is less reactogenic than vaccines including other BCG strains. Pacis BCG, made from the Montréal (Institut Armand-Frappier) strain,<ref>{{cite web |url=http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20%28General%20Monographs-%20P%29/PACIS.html |title=Pharmaceutical Information – PACIS |publisher=RxMed |access-date=2 February 2014 |url-status=live |archive-url=https://web.archive.org/web/20140222020626/http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20%28General%20Monographs-%20P%29/PACIS.html |archive-date=22 February 2014 }}</ref> was first marketed by Urocor in about 2002. Urocor was since acquired by Dianon Systems. Evans Vaccines (a subsidiary of [[PowderJect Pharmaceuticals]]). [[Statens Serum Institut]] in Denmark markets BCG vaccine prepared using Danish strain 1331.<ref>{{cite web |url=http://www.ssi.dk/English/Vaccines/BCG%20Vaccine%20Danish%20Strain%201331.aspx |title=BCG Vaccine Danish Strain 1331 – Statens Serum Institut |publisher=Ssi.dk |date=19 September 2013 |access-date=2 February 2014 |url-status=dead |archive-url=https://web.archive.org/web/20140218233417/http://www.ssi.dk/English/Vaccines/BCG%20Vaccine%20Danish%20Strain%201331.aspx |archive-date=18 February 2014 }}</ref> Japan BCG Laboratory markets its vaccine, based on the Tokyo 172 substrain of Pasteur BCG, in 50 countries worldwide.
A number of different companies make BCG, sometimes using different genetic strains of the bacterium. This may result in different product characteristics. OncoTICE, used for bladder instillation for bladder cancer, was developed by Organon Laboratories (since acquired by [[Schering-Plough]], and in turn acquired by [[Merck & Co.]]). A similar application is the product of Onko BCG<ref>{{cite web |url=https://biomedlublin.com/en/produkty/onko-bcg-100/ |title=Onko BCG 100 Biomed Lublin |publisher=biomedlublin.com |access-date=3 March 2021 |archive-date=15 January 2021 |archive-url=https://web.archive.org/web/20210115195448/https://biomedlublin.com/en/produkty/onko-bcg-100/ |url-status=live }}</ref> of the [[Poland|Polish]] company [[Biomed-Lublin]], which owns the Brazilian substrain M. bovis BCG Moreau which is less reactogenic than vaccines including other BCG strains. Pacis BCG, made from the Montréal (Institut Armand-Frappier) strain,<ref>{{cite web |url=http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20%28General%20Monographs-%20P%29/PACIS.html |title=Pharmaceutical Information – PACIS |publisher=RxMed |access-date=2 February 2014 |url-status=live |archive-url=https://web.archive.org/web/20140222020626/http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20%28General%20Monographs-%20P%29/PACIS.html |archive-date=22 February 2014 }}</ref> was first marketed by Urocor in about 2002. Urocor was since acquired by Dianon Systems. Evans Vaccines (a subsidiary of [[PowderJect Pharmaceuticals]]). [[Statens Serum Institut]] in Denmark has marketed BCG vaccine prepared using Danish strain 1331. The production of BCG Danish strain 1331 and its distribution was later undertaken by AJVaccines company since the ownership transfer of SSI's vaccine production business to AJ Vaccines Holding A/S which took place on 16 January 2017.<ref>{{cite web |url=http://www.ssi.dk/English/Vaccines/BCG%20Vaccine%20Danish%20Strain%201331.aspx |title=BCG Vaccine Danish Strain 1331 – Statens Serum Institut |publisher=Ssi.dk |date=19 September 2013 |access-date=2 February 2014 |url-status=dead |archive-url=https://web.archive.org/web/20140218233417/http://www.ssi.dk/English/Vaccines/BCG%20Vaccine%20Danish%20Strain%201331.aspx |archive-date=18 February 2014 }}</ref><ref>{{Cite web |title=The Story of SSI |url=https://en.ssi.dk/about-us/the-story-of-ssi |access-date=2 May 2024 |website=en.ssi.dk |archive-date=2 May 2024 |archive-url=https://web.archive.org/web/20240502085011/https://en.ssi.dk/about-us/the-story-of-ssi |url-status=live }}</ref> Japan BCG Laboratory markets its vaccine, based on the Tokyo 172 substrain of Pasteur BCG, in 50 countries worldwide.


According to a [[UNICEF]] report published in December 2015, on BCG vaccine supply security, global demand increased in 2015 from 123 to 152.2&nbsp;million doses. To improve security and to [diversify] sources of affordable and flexible supply," UNICEF awarded seven new manufacturers contracts to produce BCG. Along with supply availability from existing manufacturers, and a "new WHO prequalified vaccine" the total supply will be "sufficient to meet both suppressed 2015 demand carried over to 2016, as well as total forecast demand through 2016–2018."<ref name="UNICEF_2015">{{citation |title=Bacillus Calmette–Guérin Vaccine Supply & Demand Outlook |work=UNICEF Supply Division |date=December 2015 |access-date=29 January 2016 |url=http://www.unicef.org/supply/files/BCG_Supply_Status_December_2015.pdf |page=5 |url-status=live |archive-url=https://web.archive.org/web/20160205111702/http://www.unicef.org/supply/files/BCG_Supply_Status_December_2015.pdf |archive-date=5 February 2016 }}</ref>
According to a [[UNICEF]] report published in December 2015, on BCG vaccine supply security, global demand increased in 2015 from 123 to 152.2&nbsp;million doses. To improve security and to [diversify] sources of affordable and flexible supply," UNICEF awarded seven new manufacturers contracts to produce BCG. Along with supply availability from existing manufacturers, and a "new WHO prequalified vaccine" the total supply will be "sufficient to meet both suppressed 2015 demand carried over to 2016, as well as total forecast demand through 2016–2018."<ref name="UNICEF_2015">{{citation |title=Bacillus Calmette–Guérin Vaccine Supply & Demand Outlook |work=UNICEF Supply Division |date=December 2015 |access-date=29 January 2016 |url=http://www.unicef.org/supply/files/BCG_Supply_Status_December_2015.pdf |page=5 |archive-url=https://web.archive.org/web/20160205111702/http://www.unicef.org/supply/files/BCG_Supply_Status_December_2015.pdf |archive-date=5 February 2016 }}</ref>


===Supply shortage===
===Supply shortage===
<!-- Any change to this section title should be reflected in its linking at [[Sanofi Pasteur#2012 BCG supply shortage]] -->
<!-- Any change to this section title should be reflected in its linking at [[Sanofi Pasteur#2012 BCG supply shortage]] -->
In 2011, the [[Sanofi Pasteur]] plant flooded, causing problems with mold.<ref name="FDA_2012">{{citation |url=https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm310376.htm |series=Vaccines, Blood & Biologics |title=April 2012 Inspectional Observations (form 483) |work=U.S. Food and Drug Administration |date=12 April 2012 |access-date=29 January 2016 |url-status=live |archive-url=https://web.archive.org/web/20160206161441/https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm310376.htm |archive-date=6 February 2016 }}</ref> The facility, located in Toronto, Ontario, Canada, produced BCG vaccine products made with substrain Connaught such as a tuberculosis vaccine and ImmuCYST, a BCG immunotherapeutic and bladder cancer drug.<ref>{{cite web|title=Sanofi Pasteur Product Monograph – Immucyst|url=https://hemonc.org/docs/packageinsert/bacilluscalmetteguerin.pdf |archive-url=https://web.archive.org/web/20200914231710/https://hemonc.org/docs/packageinsert/bacilluscalmetteguerin.pdf |archive-date=14 September 2020 |url-status=live |website=Sanofi Pasteur Canada|access-date=11 February 2016}}</ref> By April 2012 the [[FDA]] had found dozens of documented problems with sterility at the plant including mold, nesting birds and rusted electrical conduits.<ref name="FDA_2012" /> The resulting closure of the plant for over two years caused shortages of bladder cancer and tuberculosis vaccines.<ref name="Sanofi_2014_BCG_vaccine">{{cite news | vauthors = Palmer E |title= UPDATED: Merck again shipping BCG cancer treatment but Sanofi still is not |url=https://www.fiercepharma.com/supply-chain/updated-merck-again-shipping-bcg-cancer-treatment-but-sanofi-still-not |work=FiercePharma |date=10 September 2014 }}</ref> On 29 October 2014 [[Health Canada]] gave the permission for Sanofi to resume production of BCG.<ref name="FiercePharma_mar_2015">{{citation |title=Sanofi Canada vax plant again producing ImmuCyst bladder cancer drug |url=http://www.fiercepharmamanufacturing.com/story/sanofi-vaccine-plant-canada-again-producing-immucyst-bladder-drug/2015-03-31 |date=31 March 2015 |access-date=29 January 2016 | vauthors = Palmer E |work=FiercePharma |url-status=live |archive-url=https://web.archive.org/web/20160205081244/http://www.fiercepharmamanufacturing.com/story/sanofi-vaccine-plant-canada-again-producing-immucyst-bladder-drug/2015-03-31 |archive-date=5 February 2016 }}</ref> A 2018 analysis of the global supply concluded that the supplies are adequate to meet forecast BCG vaccine demand, but that risks of shortages remain, mainly due to dependence of 75 percent of WHO pre-qualified supply on just two suppliers.<ref name="pmid29254839">{{cite journal | vauthors = Cernuschi T, Malvolti S, Nickels E, Friede M | title = Bacillus Calmette-Guérin (BCG) vaccine: A global assessment of demand and supply balance | journal = Vaccine | volume = 36 | issue = 4 | pages = 498–506 | date = January 2018 | pmid = 29254839 | pmc = 5777639 | doi = 10.1016/j.vaccine.2017.12.010 }}</ref>
In 2011, the [[Sanofi Pasteur]] plant flooded, causing problems with mold.<ref name="FDA_2012">{{citation |url=https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm310376.htm |series=Vaccines, Blood & Biologics |title=April 2012 Inspectional Observations (form 483) |work=U.S. Food and Drug Administration |date=12 April 2012 |access-date=29 January 2016 |url-status=live |archive-url=https://web.archive.org/web/20160206161441/https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm310376.htm |archive-date=6 February 2016 }}</ref> The facility, located in Toronto, Ontario, Canada, produced BCG vaccine products made with substrain Connaught such as a tuberculosis vaccine and ImmuCYST, a BCG immunotherapeutic and bladder cancer drug.<ref>{{cite web|title=Sanofi Pasteur Product Monograph – Immucyst|url=https://hemonc.org/docs/packageinsert/bacilluscalmetteguerin.pdf |archive-url=https://web.archive.org/web/20200914231710/https://hemonc.org/docs/packageinsert/bacilluscalmetteguerin.pdf |archive-date=14 September 2020 |url-status=live |website=Sanofi Pasteur Canada|access-date=11 February 2016}}</ref> By April 2012 the [[FDA]] had found dozens of documented problems with sterility at the plant including mold, nesting birds and rusted electrical conduits.<ref name="FDA_2012" /> The resulting closure of the plant for over two years caused shortages of bladder cancer and tuberculosis vaccines.<ref name="Sanofi_2014_BCG_vaccine">{{cite news |vauthors=Palmer E |title=UPDATED: Merck again shipping BCG cancer treatment but Sanofi still is not |url=https://www.fiercepharma.com/supply-chain/updated-merck-again-shipping-bcg-cancer-treatment-but-sanofi-still-not |work=FiercePharma |date=10 September 2014 |access-date=12 July 2020 |archive-date=12 July 2020 |archive-url=https://web.archive.org/web/20200712155207/https://www.fiercepharma.com/supply-chain/updated-merck-again-shipping-bcg-cancer-treatment-but-sanofi-still-not |url-status=live }}</ref> On 29 October 2014 [[Health Canada]] gave the permission for Sanofi to resume production of BCG.<ref name="FiercePharma_mar_2015">{{citation |title=Sanofi Canada vax plant again producing ImmuCyst bladder cancer drug |url=http://www.fiercepharmamanufacturing.com/story/sanofi-vaccine-plant-canada-again-producing-immucyst-bladder-drug/2015-03-31 |date=31 March 2015 |access-date=29 January 2016 | vauthors = Palmer E |work=FiercePharma |url-status=live |archive-url=https://web.archive.org/web/20160205081244/http://www.fiercepharmamanufacturing.com/story/sanofi-vaccine-plant-canada-again-producing-immucyst-bladder-drug/2015-03-31 |archive-date=5 February 2016 }}</ref> A 2018 analysis of the global supply concluded that the supplies are adequate to meet forecast BCG vaccine demand, but that risks of shortages remain, mainly due to dependence of 75 percent of WHO pre-qualified supply on just two suppliers.<ref name="pmid29254839">{{cite journal | vauthors = Cernuschi T, Malvolti S, Nickels E, Friede M | title = Bacillus Calmette-Guérin (BCG) vaccine: A global assessment of demand and supply balance | journal = Vaccine | volume = 36 | issue = 4 | pages = 498–506 | date = January 2018 | pmid = 29254839 | pmc = 5777639 | doi = 10.1016/j.vaccine.2017.12.010 }}</ref>


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==History==
==History==
[[File:BCG advert.jpg|thumb|French poster promoting the BCG vaccine]]
[[File:BCG advert.jpg|thumb|French poster promoting the BCG vaccine]]
The history of BCG is tied to that of [[smallpox]]. By 1865 [[Jean Antoine Villemin]] had demonstrated that rabbits could be infected with tuberculosis from humans;<ref>{{cite journal | vauthors = Villemin JA |title=Cause et nature de la tuberculose |journal=Bulletin de l'Académie Impériale de Médecine |date=1865 |volume=31 |pages=211–216 |url=https://babel.hathitrust.org/cgi/pt?id=hvd.32044103060562&view=1up&seq=215 |trans-title=Cause and nature of tuberculosis |language=fr}}</ref> by 1868 he had found that rabbits could be infected with tuberculosis from cows, and that rabbits could be infected with tuberculosis from other rabbits.<ref>{{cite book | vauthors = Villemin JA |title=Études sur la Tuberculose |trans-title=Studies of Tuberculosis |date=1868 |publisher=J.-B. Baillière et fils |location=Paris, France |pages=528–597 |url=https://books.google.com/books?id=lIpawDQYwtwC&pg=PA528 |language=fr}} (§ ''"Seizième Étude: La tuberculose est inoculable"'' (Sixteenth study: Tuberculosis can be transmitted by inoculation))</ref> Thus, he concluded that tuberculosis was transmitted via some unidentified microorganism (or ''"virus"'', as he called it).<ref>(Villemin, 1868), pp. 598–631. From p. 598: ''"La tuberculose est inoculable, voilà maintenant un fait incontestable. Désormais cette affection devra se placer parmi les maladies ''virulentes'', ... "'' (Tuberculosis [can be transmitted by] inoculation; that's now an incontestable fact. Henceforth this malady should be placed among the ''virulent'' maladies [i.e., those diseases that are transmitted via microorganisms], ... ) From p. 602: ''"Les virus, comme les parasites, se multiplient eux-même, nous ne leur fournissons que les moyens de vivre et de se reproduire, jamais nous les créons."'' (Viruses, like parasites, multiply themselves; we merely furnish them with the means of living and reproducing; we never create them.)</ref><ref>{{cite book | vauthors = Villemin JA |title=De la virulence et de la spécificité de la tuberculose |trans-title=On the virulence [i.e., infectious nature] and specificity of tuberculosis |date=1868a |publisher=Victor Masson et fils |location=Paris, France |url=https://archive.org/details/b30568602 |language=fr}}</ref> In 1882 [[Robert Koch]] regarded human and bovine tuberculosis as identical.<ref>{{cite journal | vauthors = Koch R |title=Die Aetologie der Tuberculose |journal=Berliner Klinische Wochenschrift |date=10 April 1882 |volume=19 |issue=15 |pages=221–230 |url=https://babel.hathitrust.org/cgi/pt?id=mdp.39015020075001&view=1up&seq=235 |trans-title=The etiology of tuberculosis |language=de}} From p. 230: ''"Die Perlsucht ist identisch mit der Tuberculose des Menschen und also eine auf diesen übertragbare Krankheit."'' (Pearl disease [i.e., bovine tuberculosis] is identical with the tuberculosis of humans and thus [is] a disease that can be transmitted to them.)</ref> But in 1895, [[Theobald Smith]] presented differences between human and bovine tuberculosis, which he reported to Koch.<ref>{{cite journal | vauthors =Smith T |title=Investigations of diseases of domesticated animals |journal=Annual Report of the Bureau of Animal Industry| publisher = U.S. Department of Agriculture |date=1895 |volume=12/13 |pages=119–185 |url=https://books.google.com/books?id=bZkp_4YTdu0C&pg=PA149}} See § "Two varieties of the tubercle bacillus from mammals." pp. 149-161.
The history of BCG is tied to that of [[smallpox]]. By 1865 [[Jean Antoine Villemin]] had demonstrated that rabbits could be infected with tuberculosis from humans;<ref>{{cite journal |vauthors=Villemin JA |title=Cause et nature de la tuberculose |journal=Bulletin de l'Académie Impériale de Médecine |date=1865 |volume=31 |pages=211–216 |url=https://babel.hathitrust.org/cgi/pt?id=hvd.32044103060562&view=1up&seq=215 |trans-title=Cause and nature of tuberculosis |language=fr |access-date=8 October 2020 |archive-date=9 December 2021 |archive-url=https://web.archive.org/web/20211209200251/https://babel.hathitrust.org/cgi/pt?id=hvd.32044103060562&view=1up&seq=215 |url-status=live }}</ref> by 1868 he had found that rabbits could be infected with tuberculosis from cows, and that rabbits could be infected with tuberculosis from other rabbits.<ref>{{cite book |vauthors=Villemin JA |title=Études sur la Tuberculose |trans-title=Studies of Tuberculosis |date=1868 |publisher=J.-B. Baillière et fils |location=Paris, France |pages=528–597 |url=https://books.google.com/books?id=lIpawDQYwtwC&pg=PA528 |language=fr |access-date=8 October 2020 |archive-date=25 July 2024 |archive-url=https://web.archive.org/web/20240725193904/https://books.google.com/books?id=lIpawDQYwtwC&pg=PA528#v=onepage&q&f=false |url-status=live }} (§ ''"Seizième Étude: La tuberculose est inoculable"'' (Sixteenth study: Tuberculosis can be transmitted by inoculation))</ref> Thus, he concluded that tuberculosis was transmitted via some unidentified microorganism (or ''"virus"'', as he called it).<ref>(Villemin, 1868), pp. 598–631. From p. 598: ''"La tuberculose est inoculable, voilà maintenant un fait incontestable. Désormais cette affection devra se placer parmi les maladies ''virulentes'', ... "'' (Tuberculosis [can be transmitted by] inoculation; that's now an incontestable fact. Henceforth this malady should be placed among the ''virulent'' maladies [i.e., those diseases that are transmitted via microorganisms], ... ) From p. 602: ''"Les virus, comme les parasites, se multiplient eux-même, nous ne leur fournissons que les moyens de vivre et de se reproduire, jamais nous les créons."'' (Viruses, like parasites, multiply themselves; we merely furnish them with the means of living and reproducing; we never create them.)</ref><ref>{{cite book | vauthors = Villemin JA |title=De la virulence et de la spécificité de la tuberculose |trans-title=On the virulence [i.e., infectious nature] and specificity of tuberculosis |date=1868a |publisher=Victor Masson et fils |location=Paris, France |url=https://archive.org/details/b30568602 |language=fr}}</ref> In 1882 [[Robert Koch]] regarded human and bovine tuberculosis as identical.<ref>{{cite journal |vauthors=Koch R |title=Die Aetologie der Tuberculose |journal=Berliner Klinische Wochenschrift |date=10 April 1882 |volume=19 |issue=15 |pages=221–230 |url=https://babel.hathitrust.org/cgi/pt?id=mdp.39015020075001&view=1up&seq=235 |trans-title=The etiology of tuberculosis |language=de |access-date=9 October 2020 |archive-date=9 December 2021 |archive-url=https://web.archive.org/web/20211209173628/https://babel.hathitrust.org/cgi/pt?id=mdp.39015020075001&view=1up&seq=235 |url-status=live }} From p. 230: ''"Die Perlsucht ist identisch mit der Tuberculose des Menschen und also eine auf diesen übertragbare Krankheit."'' (Pearl disease [i.e., bovine tuberculosis] is identical with the tuberculosis of humans and thus [is] a disease that can be transmitted to them.)</ref> But in 1895, [[Theobald Smith]] presented differences between human and bovine tuberculosis, which he reported to Koch.<ref>{{cite journal |vauthors=Smith T |title=Investigations of diseases of domesticated animals |journal=Annual Report of the Bureau of Animal Industry |publisher=U.S. Department of Agriculture |date=1895 |volume=12/13 |pages=119–185 |url=https://books.google.com/books?id=bZkp_4YTdu0C&pg=PA149 }} See § "Two varieties of the tubercle bacillus from mammals." pp. 149-161.
* {{cite journal | vauthors = Smith T |title=Two varieties of the tubercle bacillus from mammals |journal=Transactions of the Association of American Physicians |date=1896 |volume=11 |pages=75–95 |url=https://babel.hathitrust.org/cgi/pt?id=hvd.32044103006490&view=1up&seq=109}}</ref><ref>{{cite journal | vauthors = Palmer MV, Waters WR | title = Bovine tuberculosis and the establishment of an eradication program in the United States: role of veterinarians | journal = Veterinary Medicine International | volume = 2011 | issue = 1 | pages = 816345 | date = May 2011 | pmid = 21647341 | pmc = 3103864 | doi = 10.4061/2011/816345 | s2cid = 18020962 | doi-access = free }} From p. 2: "In 1895, Smith visited Koch in Europe and described his findings."</ref> By 1901 Koch distinguished ''Mycobacterium bovis'' from ''[[Mycobacterium tuberculosis]]''.<ref>{{cite journal | vauthors = Koch R |title=An address on the combatting of tuberculosis in the light of experience that has been gained in the successful combatting of other infectious diseases. |journal=The Lancet |date=27 July 1901 |volume=158 |issue=4065 |pages=187–191 |doi=10.1016/S0140-6736(01)85122-9 |url=https://babel.hathitrust.org/cgi/pt?id=uiug.30112114890558&view=1up&seq=225}} From p. 189: "Considering all these facts, I feel justified in maintaining that human tuberculosis differs from bovine and cannot be transmitted to cattle."</ref> Following the success of [[vaccination]] in preventing smallpox, established during the 18th century, scientists thought to find a corollary in tuberculosis by drawing a parallel between bovine tuberculosis and [[cowpox]]: it was hypothesized that infection with bovine tuberculosis might protect against infection with human tuberculosis. In the late 19th century, clinical trials using ''M. bovis'' were conducted in Italy with disastrous results, because ''M. bovis'' was found to be just as virulent as ''M. tuberculosis''.{{citation needed|date=December 2022}}
* {{cite journal |vauthors=Smith T |title=Two varieties of the tubercle bacillus from mammals |journal=Transactions of the Association of American Physicians |date=1896 |volume=11 |pages=75–95 |url=https://babel.hathitrust.org/cgi/pt?id=hvd.32044103006490&view=1up&seq=109 |access-date=9 October 2020 |archive-date=25 July 2024 |archive-url=https://web.archive.org/web/20240725193929/https://babel.hathitrust.org/cgi/pt?id=hvd.32044103006490&view=1up&seq=109 |url-status=live }}</ref><ref>{{cite journal | vauthors = Palmer MV, Waters WR | title = Bovine tuberculosis and the establishment of an eradication program in the United States: role of veterinarians | journal = Veterinary Medicine International | volume = 2011 | issue = 1 | pages = 816345 | date = May 2011 | pmid = 21647341 | pmc = 3103864 | doi = 10.4061/2011/816345 | s2cid = 18020962 | doi-access = free }} From p. 2: "In 1895, Smith visited Koch in Europe and described his findings."</ref> By 1901 Koch distinguished ''Mycobacterium bovis'' from ''[[Mycobacterium tuberculosis]]''.<ref>{{cite journal |vauthors=Koch R |title=An address on the combatting of tuberculosis in the light of experience that has been gained in the successful combatting of other infectious diseases. |journal=The Lancet |date=27 July 1901 |volume=158 |issue=4065 |pages=187–191 |doi=10.1016/S0140-6736(01)85122-9 |url=https://babel.hathitrust.org/cgi/pt?id=uiug.30112114890558&view=1up&seq=225 |access-date=9 October 2020 |archive-date=25 July 2024 |archive-url=https://web.archive.org/web/20240725193926/https://babel.hathitrust.org/cgi/pt?id=uiug.30112114890558&view=1up&seq=225 |url-status=live }} From p. 189: "Considering all these facts, I feel justified in maintaining that human tuberculosis differs from bovine and cannot be transmitted to cattle."</ref> Following the success of [[vaccination]] in preventing smallpox, established during the 18th century, scientists thought to find a corollary in tuberculosis by drawing a parallel between bovine tuberculosis and [[cowpox]]: it was hypothesized that infection with bovine tuberculosis might protect against infection with human tuberculosis. In the late 19th century, clinical trials using ''M. bovis'' were conducted in Italy with disastrous results, because ''M. bovis'' was found to be just as virulent as ''M. tuberculosis''.<ref>{{cite journal | vauthors = Mitermite M, Elizari JM, Ma R, Farrell D, Gordon SV | title = Exploring virulence in Mycobacterium bovis: clues from comparative genomics and perspectives for the future | journal = Irish Veterinary Journal | volume = 76 | issue = Suppl 1 | pages = 26 | date = September 2023 | pmid = 37770951 | pmc = 10540498 | doi = 10.1186/s13620-023-00257-6 | doi-access = free }}</ref>


[[Albert Calmette]], a French physician and bacteriologist, and his assistant and later colleague, [[Camille Guérin]], a veterinarian, were working at the [[Institut Pasteur de Lille]] ([[Lille]], France) in 1908. Their work included subculturing virulent strains of the tuberculosis bacillus and testing different culture media. They noted a glycerin-bile-potato mixture grew bacilli that seemed less virulent, and changed the course of their research to see if repeated subculturing would produce a strain that was attenuated enough to be considered for use as a vaccine. The BCG strain was isolated after subculturing 239 times during 13 years from virulent strain on glycerine potato medium. The research continued throughout World War I until 1919, when the now avirulent bacilli were unable to cause tuberculosis disease in research animals. Calmette and Guerin transferred to the Paris [[Pasteur Institute]] in 1919. The BCG vaccine was first used in humans in 1921.<ref>{{cite book |vauthors=Fine PE, Carneiro IA, Milstein JB, Clements CJ | title=Issues relating to the use of BCG in immunization programs | publisher=[[World Health Organization]] (WHO) | year=1999 | location=Geneva }}</ref>
[[Albert Calmette]], a French physician and bacteriologist, and his assistant and later colleague, [[Camille Guérin]], a veterinarian, were working at the [[Institut Pasteur de Lille]] ([[Lille]], France) in 1908. Their work included subculturing virulent strains of the tuberculosis bacillus and testing different culture media. They noted a glycerin-bile-potato mixture grew bacilli that seemed less virulent, and changed the course of their research to see if repeated subculturing would produce a strain that was attenuated enough to be considered for use as a vaccine. The BCG strain was isolated after subculturing 239 times during 13 years from virulent strain on glycerine potato medium. The research continued throughout World War I until 1919, when the now avirulent bacilli were unable to cause tuberculosis disease in research animals. Calmette and Guerin transferred to the Paris [[Pasteur Institute]] in 1919. The BCG vaccine was first used in humans in 1921.<ref name="WHO 1999" />


Public acceptance was slow, and the [[Lübeck disaster]], in particular, did much to harm it. Between 1929 and 1933 in [[Lübeck]], 251 infants were vaccinated in the first 10 days of life; 173 developed tuberculosis and 72 died. It was subsequently discovered that the BCG administered there had been contaminated with a virulent strain that was being stored in the same incubator, which led to legal action against the manufacturers of the vaccine.<ref>{{cite book | vauthors = Rosenthal SR | title=BCG vaccination against tuberculosis | publisher=Little, Brown & Co. | location=Boston | year=1957 }}</ref>
Public acceptance was slow, and the [[Lübeck disaster]], in particular, did much to harm it. Between 1929 and 1933 in [[Lübeck]], 251 infants were vaccinated in the first 10 days of life; 173 developed tuberculosis and 72 died. It was subsequently discovered that the BCG administered there had been contaminated with a virulent strain that was being stored in the same incubator, which led to legal action against the manufacturers of the vaccine.<ref>{{cite book | vauthors = Rosenthal SR | title=BCG vaccination against tuberculosis | publisher=Little, Brown & Co. | location=Boston | year=1957 }}</ref>


Dr. [[R. G. Ferguson]], working at the [[Fort San, Saskatchewan|Fort Qu'Appelle Sanatorium]] in Saskatchewan, was among the pioneers in developing the practice of vaccination against tuberculosis. In Canada, more than 600 children from [[Canadian Indian residential school system|residential schools]] were used as involuntary participants in BCG vaccine trials between 1933 and 1945.<ref>{{Cite news| vauthors = Blackburn M |date=24 July 2013|title=First Nation infants subject to "human experimental work" for TB vaccine in 1930s-40s|url=https://www.aptnnews.ca/national-news/first-nation-infants-subject-to-human-experimental-work-for-tb-vaccine-in-1930s-40s/|access-date=31 March 2021|website=APTN News|language=en-US}}</ref> In 1928, BCG was adopted by the Health Committee of the [[League of Nations]] (predecessor to the [[World Health Organization]] (WHO)). Because of opposition, however, it only became widely used after World War II. From 1945 to 1948, relief organizations (International Tuberculosis Campaign or Joint Enterprises) vaccinated over eight million babies in eastern Europe and prevented the predicted typical increase of tuberculosis after a major war.{{citation needed|date=December 2022}}
Dr. [[R. G. Ferguson]], working at the [[Fort San, Saskatchewan|Fort Qu'Appelle Sanatorium]] in Saskatchewan, was among the pioneers in developing the practice of vaccination against tuberculosis. In Canada, more than 600 children from [[Canadian Indian residential school system|residential schools]] were used as involuntary participants in BCG vaccine trials between 1933 and 1945.<ref>{{Cite news|vauthors=Blackburn M|date=24 July 2013|title=First Nation infants subject to "human experimental work" for TB vaccine in 1930s-40s|url=https://www.aptnnews.ca/national-news/first-nation-infants-subject-to-human-experimental-work-for-tb-vaccine-in-1930s-40s/|access-date=31 March 2021|website=APTN News|archive-date=26 April 2021|archive-url=https://web.archive.org/web/20210426093642/https://www.aptnnews.ca/national-news/first-nation-infants-subject-to-human-experimental-work-for-tb-vaccine-in-1930s-40s/|url-status=live}}</ref> In 1928, the BCG vaccine was adopted by the Health Committee of the [[League of Nations]] (predecessor to the [[World Health Organization]] (WHO)). Because of opposition, however, it only became widely used after World War II. From 1945 to 1948, relief organizations (International Tuberculosis Campaign or Joint Enterprises) vaccinated over eight million babies in eastern Europe and prevented the predicted typical increase of tuberculosis after a major war.<ref>{{cite journal | vauthors = Brimnes N | title = Vikings against tuberculosis: the International Tuberculosis Campaign in India, 1948-1951 | journal = Bulletin of the History of Medicine | volume = 81 | issue = 2 | pages = 407–430 | date = 2007 | pmid = 17844722 | doi = 10.1353/bhm.2007.0022 }}</ref>


BCG is very efficacious against [[tuberculous meningitis]] in the pediatric age group, but its efficacy against pulmonary tuberculosis appears to be variable. Some countries have removed BCG from routine vaccination. Two countries that have never used it routinely are the United States and the Netherlands (in both countries, it is felt that having a reliable [[Mantoux test]] and therefore being able to accurately detect active disease is more beneficial to society than vaccinating against a condition that is now relatively rare there).<ref>{{cite web |url=https://www.cdc.gov/tb/publications/factsheets/prevention/bcg.htm |title=Fact Sheets: BCG Vaccine |date=28 October 2011 |publisher=Centers for Disease Control and Prevention |access-date=18 July 2013 |url-status=live |archive-url=https://web.archive.org/web/20130720080800/http://www.cdc.gov/tb/publications/factsheets/prevention/BCG.htm |archive-date=20 July 2013 }}</ref><ref>{{cite book |year=2011 |title=Vaccination of young children against tuberculosis |issue=2011/04 |publisher=The Hague:Health Council of the Netherlands |isbn=978-90-5549-844-4 |url=http://www.gezondheidsraad.nl/sites/default/files/Summary_vaccine_tegen_tuberculose.pdf |access-date=12 July 2013 |url-status=live |archive-url=https://web.archive.org/web/20140219093821/http://www.gezondheidsraad.nl/sites/default/files/Summary_vaccine_tegen_tuberculose.pdf |archive-date=19 February 2014 }}</ref>
The BCG vaccine is very efficacious against [[tuberculous meningitis]] in the pediatric age group, but its efficacy against pulmonary tuberculosis appears to be variable. Some countries have removed the BCG vaccine from routine vaccination. Two countries that have never used it routinely are the United States and the Netherlands (in both countries, it is felt that having a reliable [[Mantoux test]] and therefore being able to accurately detect active disease is more beneficial to society than vaccinating against a condition that is relatively rare).<ref name="CDC BCG" /><ref name="CDC Tuberculosis" /><ref>{{cite book |year=2011 |title=Vaccination of young children against tuberculosis |issue=2011/04 |publisher=The Hague:Health Council of the Netherlands |isbn=978-90-5549-844-4 |url=http://www.gezondheidsraad.nl/sites/default/files/Summary_vaccine_tegen_tuberculose.pdf |access-date=12 July 2013 |url-status=live |archive-url=https://web.archive.org/web/20140219093821/http://www.gezondheidsraad.nl/sites/default/files/Summary_vaccine_tegen_tuberculose.pdf |archive-date=19 February 2014 }}</ref>


Other names include "Vaccin Bilié de Calmette et Guérin vaccine" and "Bacille de Calmette et Guérin vaccine".{{citation needed|date=December 2022}}
Other names include "Vaccin Bilié de Calmette et Guérin vaccine" and "Bacille de Calmette et Guérin vaccine".<ref>{{Cite web |title=🔎 Vaccin Bilié de Calmette et Guérin - Définition et Explications |url=https://www.techno-science.net/glossaire-definition/Vaccin-Bilie-de-Calmette-et-Guerin.html |access-date=27 June 2024 |website=Techno-Science.net |language=fr |archive-date=27 June 2024 |archive-url=https://web.archive.org/web/20240627120910/https://www.techno-science.net/glossaire-definition/Vaccin-Bilie-de-Calmette-et-Guerin.html |url-status=live }}</ref>


== Research ==
== Research ==
Tentative evidence exists for a beneficial [[non-specific effect of vaccines|non-specific effect]] of BCG vaccination on overall mortality in low income countries, or for its reducing other health problems including [[sepsis]] and respiratory infections when given early,<ref>{{cite journal | vauthors = Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM, Stensballe L, Diness BR, Lausch KR, Lund N, Biering-Sørensen S, Whittle H, Benn CS | display-authors = 6 | title = Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? | journal = The Journal of Infectious Diseases | volume = 204 | issue = 2 | pages = 245–252 | date = July 2011 | pmid = 21673035 | doi = 10.1093/infdis/jir240 | doi-access = free }}</ref> with greater benefit the earlier it is used.<ref>{{cite journal | vauthors = Biering-Sørensen S, Aaby P, Napirna BM, Roth A, Ravn H, Rodrigues A, Whittle H, Benn CS | display-authors = 6 | title = Small randomized trial among low-birth-weight children receiving bacillus Calmette-Guérin vaccination at first health center contact | journal = The Pediatric Infectious Disease Journal | volume = 31 | issue = 3 | pages = 306–308 | date = March 2012 | pmid = 22189537 | doi = 10.1097/inf.0b013e3182458289 | s2cid = 1240058 | doi-access = free }}</ref>
Tentative evidence exists for a beneficial [[non-specific effect of vaccines|non-specific effect]] of BCG vaccination on overall mortality in low income countries, or for its reducing other health problems including [[sepsis]] and respiratory infections when given early,<ref>{{cite journal | vauthors = Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM, Stensballe L, Diness BR, Lausch KR, Lund N, Biering-Sørensen S, Whittle H, Benn CS | title = Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? | journal = The Journal of Infectious Diseases | volume = 204 | issue = 2 | pages = 245–252 | date = July 2011 | pmid = 21673035 | doi = 10.1093/infdis/jir240 | doi-access = free }}</ref> with greater benefit the earlier it is used.<ref>{{cite journal | vauthors = Biering-Sørensen S, Aaby P, Napirna BM, Roth A, Ravn H, Rodrigues A, Whittle H, Benn CS | title = Small randomized trial among low-birth-weight children receiving bacillus Calmette-Guérin vaccination at first health center contact | journal = The Pediatric Infectious Disease Journal | volume = 31 | issue = 3 | pages = 306–308 | date = March 2012 | pmid = 22189537 | doi = 10.1097/inf.0b013e3182458289 | s2cid = 1240058 | doi-access = free }}</ref>


In [[rhesus macaque]]s, BCG shows improved rates of protection when given [[intravenous injection|intravenously]].<ref name=rh-iv>{{cite journal | vauthors = Darrah PA, Zeppa JJ, Maiello P, Hackney JA, Wadsworth MH, Hughes TK, Pokkali S, Swanson PA, Grant NL, Rodgers MA, Kamath M, Causgrove CM, Laddy DJ, Bonavia A, Casimiro D, Lin PL, Klein E, White AG, Scanga CA, Shalek AK, Roederer M, Flynn JL, Seder RA | display-authors = 6 | title = Prevention of tuberculosis in macaques after intravenous BCG immunization | journal = Nature | volume = 577 | issue = 7788 | pages = 95–102 | date = January 2020 | pmid = 31894150 | pmc = 7015856 | doi = 10.1038/s41586-019-1817-8 | doi-access = free | bibcode = 2020Natur.577...95D }}</ref><ref>{{cite journal | vauthors = Behar SM, Sassetti C | title = Tuberculosis vaccine finds an improved route | journal = Nature | volume = 577 | issue = 7788 | pages = 31–32 | date = January 2020 | pmid = 31894152 | doi = 10.1038/d41586-019-03597-y | s2cid = 209528484 | bibcode = 2020Natur.577...31B | doi-access = free }}</ref> Some risks must be evaluated before it can be translated to humans.<ref>{{cite journal | vauthors = | title = The trick that could inject new life into an old tuberculosis vaccine | journal = Nature | volume = 577 | issue = 7789 | pages = 145 | date = January 2020 | pmid = 31911698 | doi = 10.1038/d41586-020-00003-w | s2cid = 210044794 | bibcode = 2020Natur.577..145. | doi-access = free }}</ref>
In [[rhesus macaque]]s, BCG shows improved rates of protection when given [[intravenous injection|intravenously]].<ref name=rh-iv>{{cite journal | vauthors = Darrah PA, Zeppa JJ, Maiello P, Hackney JA, Wadsworth MH, Hughes TK, Pokkali S, Swanson PA, Grant NL, Rodgers MA, Kamath M, Causgrove CM, Laddy DJ, Bonavia A, Casimiro D, Lin PL, Klein E, White AG, Scanga CA, Shalek AK, Roederer M, Flynn JL, Seder RA | title = Prevention of tuberculosis in macaques after intravenous BCG immunization | journal = Nature | volume = 577 | issue = 7788 | pages = 95–102 | date = January 2020 | pmid = 31894150 | pmc = 7015856 | doi = 10.1038/s41586-019-1817-8 | doi-access = free | bibcode = 2020Natur.577...95D }}</ref><ref>{{cite journal | vauthors = Behar SM, Sassetti C | title = Tuberculosis vaccine finds an improved route | journal = Nature | volume = 577 | issue = 7788 | pages = 31–32 | date = January 2020 | pmid = 31894152 | doi = 10.1038/d41586-019-03597-y | s2cid = 209528484 | bibcode = 2020Natur.577...31B | doi-access = free }}</ref> Some risks must be evaluated before it can be translated to humans.<ref>{{cite journal | vauthors = | title = The trick that could inject new life into an old tuberculosis vaccine | journal = Nature | volume = 577 | issue = 7789 | pages = 145 | date = January 2020 | pmid = 31911698 | doi = 10.1038/d41586-020-00003-w | s2cid = 210044794 | bibcode = 2020Natur.577..145. | doi-access = free }}</ref>


The [[University of Oxford]] [[Jenner Institute]] is conducting a study comparing the efficacy of injected versus inhaled BCG vaccine in already-vaccinated adults.<ref>{{cite web | url=https://www.ox.ac.uk/news/2024-01-15-novel-inhaled-tb-vaccine | title=Novel inhaled TB vaccine &#124; University of Oxford | date=15 January 2024 }}</ref>
The [[University of Oxford]] [[Jenner Institute]] is conducting a study comparing the efficacy of injected versus inhaled BCG vaccine in already-vaccinated adults.<ref>{{cite web | url=https://www.ox.ac.uk/news/2024-01-15-novel-inhaled-tb-vaccine | title=Novel inhaled TB vaccine &#124; University of Oxford | date=15 January 2024 | access-date=16 January 2024 | archive-date=16 January 2024 | archive-url=https://web.archive.org/web/20240116061129/https://www.ox.ac.uk/news/2024-01-15-novel-inhaled-tb-vaccine | url-status=live }}</ref>


=== Type 1 diabetes ===
=== Type 1 diabetes ===
{{As of|2017}}, BCG vaccine is in the early stages of being studied in [[type 1 diabetes]] (T1D).<ref>{{cite journal | vauthors = Kühtreiber WM, Tran L, Kim T, Dybala M, Nguyen B, Plager S, Huang D, Janes S, Defusco A, Baum D, Zheng H, Faustman DL | display-authors = 6 | title = Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations | journal = npj Vaccines | volume = 3 | pages = 23 | year = 2018 | pmid = 29951281 | pmc = 6013479 | doi = 10.1038/s41541-018-0062-8 }}</ref><ref>{{cite journal | vauthors = Kowalewicz-Kulbat M, Locht C | title = BCG and protection against inflammatory and auto-immune diseases | journal = Expert Review of Vaccines | volume = 16 | issue = 7 | pages = 699–708 | date = July 2017 | pmid = 28532186 | doi = 10.1080/14760584.2017.1333906 | s2cid = 4723444 }}</ref>
{{As of|2017}}, BCG vaccine is in the early stages of being studied in [[type 1 diabetes]] (T1D).<ref>{{cite journal | vauthors = Kühtreiber WM, Tran L, Kim T, Dybala M, Nguyen B, Plager S, Huang D, Janes S, Defusco A, Baum D, Zheng H, Faustman DL | title = Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations | journal = npj Vaccines | volume = 3 | pages = 23 | year = 2018 | pmid = 29951281 | pmc = 6013479 | doi = 10.1038/s41541-018-0062-8 }}</ref><ref>{{cite journal | vauthors = Kowalewicz-Kulbat M, Locht C | title = BCG and protection against inflammatory and auto-immune diseases | journal = Expert Review of Vaccines | volume = 16 | issue = 7 | pages = 699–708 | date = July 2017 | pmid = 28532186 | doi = 10.1080/14760584.2017.1333906 | s2cid = 4723444 }}</ref>


=== COVID-19 ===
=== COVID-19 ===
Use of the BCG vaccine may provide protection against COVID-19.<ref>{{cite journal | vauthors = Gong W, Mao Y, Li Y, Qi Y | title = BCG Vaccination: A potential tool against COVID-19 and COVID-19-like Black Swan incidents | journal = International Immunopharmacology | volume = 108 | issue = 108 | pages = 108870 | date = July 2022 | pmid = 35597119 | pmc = 9113676 | doi = 10.1016/j.intimp.2022.108870 }}</ref><ref>{{cite journal | vauthors = Faustman DL, Lee A, Hostetter ER, Aristarkhova A, Ng NC, Shpilsky GF, Tran L, Wolfe G, Takahashi H, Dias HF, Braley J, Zheng H, Schoenfeld DA, Kühtreiber WM | display-authors = 6 | title = Multiple BCG vaccinations for the prevention of COVID-19 and other infectious diseases in type 1 diabetes | language = English | journal = Cell Reports. Medicine | volume = 3 | issue = 9 | pages = 100728 | date = September 2022 | pmid = 36027906 | pmc = 9376308 | doi = 10.1016/j.xcrm.2022.100728 }}</ref> However, epidemiologic observations in this respect are ambiguous.<ref>{{cite journal | vauthors = Szigeti R, Kellermayer D, Trakimas G, Kellermayer R | title = BCG epidemiology supports its protection against COVID-19? A word of caution | journal = PLOS ONE | volume = 15 | issue = 10 | pages = e0240203 | date = 7 October 2020 | pmid = 33027297 | pmc = 7540851 | doi = 10.1371/journal.pone.0240203 | doi-access = free | bibcode = 2020PLoSO..1540203S }}</ref> The WHO does not recommend its use for prevention {{as of|2021|1|12|lc=yes}}.<ref>{{Cite web|date=13 April 2020|title=Situation Report 13 April 2020 – COVID-19|url=https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200413-sitrep-84-covid-19.pdf?sfvrsn=44f511ab_2|access-date=14 April 2020|website=World Health Organisation}}</ref>
Use of the BCG vaccine may provide protection against COVID-19.<ref>{{cite journal | vauthors = Gong W, Mao Y, Li Y, Qi Y | title = BCG Vaccination: A potential tool against COVID-19 and COVID-19-like Black Swan incidents | journal = International Immunopharmacology | volume = 108 | issue = 108 | pages = 108870 | date = July 2022 | pmid = 35597119 | pmc = 9113676 | doi = 10.1016/j.intimp.2022.108870 }}</ref><ref>{{cite journal | vauthors = Faustman DL, Lee A, Hostetter ER, Aristarkhova A, Ng NC, Shpilsky GF, Tran L, Wolfe G, Takahashi H, Dias HF, Braley J, Zheng H, Schoenfeld DA, Kühtreiber WM | title = Multiple BCG vaccinations for the prevention of COVID-19 and other infectious diseases in type 1 diabetes | language = English | journal = Cell Reports. Medicine | volume = 3 | issue = 9 | pages = 100728 | date = September 2022 | pmid = 36027906 | pmc = 9376308 | doi = 10.1016/j.xcrm.2022.100728 }}</ref> However, epidemiologic observations in this respect are ambiguous.<ref>{{cite journal | vauthors = Szigeti R, Kellermayer D, Trakimas G, Kellermayer R | title = BCG epidemiology supports its protection against COVID-19? A word of caution | journal = PLOS ONE | volume = 15 | issue = 10 | pages = e0240203 | date = 7 October 2020 | pmid = 33027297 | pmc = 7540851 | doi = 10.1371/journal.pone.0240203 | doi-access = free | bibcode = 2020PLoSO..1540203S }}</ref> The WHO does not recommend its use for prevention {{as of|2021|1|12|lc=yes}}.<ref>{{Cite web|date=13 April 2020|title=Situation Report 13 April 2020 – COVID-19|url=https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200413-sitrep-84-covid-19.pdf?sfvrsn=44f511ab_2|access-date=14 April 2020|website=World Health Organisation|archive-date=13 April 2020|archive-url=https://web.archive.org/web/20200413234846/https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200413-sitrep-84-covid-19.pdf?sfvrsn=44f511ab_2|url-status=live}}</ref>


{{As of|2021|1}}, twenty BCG trials are in various clinical stages.<ref>{{Cite web |date=|title=Studies found for BCG Recruiting, Active, not recruiting Studies Covid19|url=https://clinicaltrials.gov/ct2/results?term=BCG&cond=Covid19&Search=Apply&recrs=a&recrs=d&age_v=&gndr=&type=&rslt=|url-status=live|archive-url=https://web.archive.org/web/20210301004702/https://clinicaltrials.gov/ct2/results?term=BCG&cond=Covid19&Search=Apply&recrs=a&=d&age_v=&gndr=&type=&rslt= |archive-date=1 March 2021 |access-date=|website=Clinical Trials.gov}}</ref> {{As of|2022|10}}, the results are extremely mixed. A 15-month trial involving people thrice-vaccinated over the two years before the pandemic shows positive results in preventing infection in BCG-naive people with type 1 diabetes.<ref>{{cite journal | vauthors = Faustman DL, Lee A, Hostetter ER, Aristarkhova A, Ng NC, Shpilsky GF, Tran L, Wolfe G, Takahashi H, Dias HF, Braley J, Zheng H, Schoenfeld DA, Kühtreiber WM | display-authors = 6 | title = Multiple BCG vaccinations for the prevention of COVID-19 and other infectious diseases in type 1 diabetes | journal = Cell Reports. Medicine | volume = 3 | issue = 9 | pages = 100728 | date = September 2022 | pmid = 36027906 | pmc = 9376308 | doi = 10.1016/j.xcrm.2022.100728 | doi-access = free }}</ref> On the other hand, a 5-month trial shows that re-vaccinating with BCG does not help prevent infection in healthcare workers. Both of these trials were [[double-blind]] [[randomized controlled trial]]s.<ref>{{cite journal | vauthors = Upton CM, van Wijk RC, Mockeliunas L, Simonsson US, McHarry K, van den Hoogen G, Muller C, von Delft A, van der Westhuizen HM, van Crevel R, Walzl G, Baptista PM, Peter J, Diacon AH | display-authors = 6 | title = Safety and efficacy of BCG re-vaccination in relation to COVID-19 morbidity in healthcare workers: A double-blind, randomised, controlled, phase 3 trial | journal = eClinicalMedicine | volume = 48 | pages = 101414 | date = June 2022 | pmid = 35582122 | pmc = 9098089 | doi = 10.1016/j.eclinm.2022.101414 }}</ref>
{{As of|2021|1}}, 20 BCG trials are in various clinical stages.<ref>{{Cite web |date=|title=Studies found for BCG Recruiting, Active, not recruiting Studies Covid19|url=https://clinicaltrials.gov/ct2/results?term=BCG&cond=Covid19&Search=Apply&recrs=a&recrs=d&age_v=&gndr=&type=&rslt=|url-status=live|archive-url=https://web.archive.org/web/20210301004702/https://clinicaltrials.gov/ct2/results?term=BCG&cond=Covid19&Search=Apply&recrs=a&=d&age_v=&gndr=&type=&rslt= |archive-date=1 March 2021 |access-date=|website=Clinical Trials.gov}}</ref> {{As of|2022|10}}, the results are extremely mixed. A 15-month trial involving people thrice-vaccinated over the two years before the pandemic shows positive results in preventing infection in BCG-naive people with type 1 diabetes.<ref>{{cite journal | vauthors = Faustman DL, Lee A, Hostetter ER, Aristarkhova A, Ng NC, Shpilsky GF, Tran L, Wolfe G, Takahashi H, Dias HF, Braley J, Zheng H, Schoenfeld DA, Kühtreiber WM | title = Multiple BCG vaccinations for the prevention of COVID-19 and other infectious diseases in type 1 diabetes | journal = Cell Reports. Medicine | volume = 3 | issue = 9 | pages = 100728 | date = September 2022 | pmid = 36027906 | pmc = 9376308 | doi = 10.1016/j.xcrm.2022.100728 | doi-access = free }}</ref> On the other hand, a 5-month trial shows that re-vaccinating with BCG does not help prevent infection in healthcare workers. Both of these trials were [[double-blind]] [[randomized controlled trial]]s.<ref>{{cite journal | vauthors = Upton CM, van Wijk RC, Mockeliunas L, Simonsson US, McHarry K, van den Hoogen G, Muller C, von Delft A, van der Westhuizen HM, van Crevel R, Walzl G, Baptista PM, Peter J, Diacon AH | title = Safety and efficacy of BCG re-vaccination in relation to COVID-19 morbidity in healthcare workers: A double-blind, randomised, controlled, phase 3 trial | journal = eClinicalMedicine | volume = 48 | pages = 101414 | date = June 2022 | pmid = 35582122 | pmc = 9098089 | doi = 10.1016/j.eclinm.2022.101414 }}</ref>


== References ==
== References ==
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== External links ==
== External links ==
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/bcg%20vaccine | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = BCG Vaccine }}
* {{cite web | title=BCG Vaccine | website=U.S. [[Food and Drug Administration]] (FDA) | date=24 April 2019 | url=https://www.fda.gov/vaccines-blood-biologics/vaccines/bcg-vaccine }}
* [https://www.priory.com/cmol/bcg.htm Frequently Asked Questions about BCG] Professor P D O Davies, Tuberculosis Research Unit, Cardiothoracic Centre, Liverpool, UK.
* {{MeshName|BCG Vaccine}}
* {{MeshName|BCG Vaccine}}


{{vaccines}}
{{Vaccines}}
{{Portal bar | Medicine}}
{{Portal bar | Medicine}}
{{Authority control}}
{{Authority control}}

Latest revision as of 15:04, 21 November 2024

BCG vaccine
Microscopic image of the Calmette–Guérin bacillus, Ziehl–Neelsen stain, magnification: 1,000nn
Vaccine description
TargetMycobacterium tuberculosis
Vaccine typeAttenuated
Clinical data
Trade namesBCG Vaccine, BCG Vaccine AJV
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa682809
License data
Routes of
administration
Percutaneous, intravesical, intradermal
ATC code
Legal status
Legal status
Identifiers
DrugBank
ChemSpider
  • none
UNII
KEGG

The Bacillus Calmette–Guérin (BCG) vaccine is a vaccine primarily used against tuberculosis (TB).[9] It is named after its inventors Albert Calmette and Camille Guérin.[10][11] In countries where tuberculosis or leprosy is common, one dose is recommended in healthy babies as soon after birth as possible.[9] In areas where tuberculosis is not common, only children at high risk are typically immunized, while suspected cases of tuberculosis are individually tested for and treated.[9] Adults who do not have tuberculosis and have not been previously immunized, but are frequently exposed, may be immunized, as well.[9] BCG also has some effectiveness against Buruli ulcer infection and other nontuberculous mycobacterial infections.[9] Additionally, it is sometimes used as part of the treatment of bladder cancer.[12][13]

Rates of protection against tuberculosis infection vary widely and protection lasts up to 20 years.[9] Among children, it prevents about 20% from getting infected and among those who do get infected, it protects half from developing disease.[14] The vaccine is given by injection into the skin.[9] No evidence shows that additional doses are beneficial.[9]

Serious side effects are rare. Often, redness, swelling, and mild pain occur at the site of injection.[9] A small ulcer may also form with some scarring after healing.[9] Side effects are more common and potentially more severe in those with immunosuppression.[9] Although no harmful effects on the fetus have been observed, there is insufficient evidence about the safety of BCG vaccination during pregnancy and therefore the vaccine is not recommended for use during pregnancy.[9] The vaccine was originally developed from Mycobacterium bovis, which is commonly found in cattle.[9] While it has been weakened, it is still live.[9]

The BCG vaccine was first used medically in 1921.[9] It is on the World Health Organization's List of Essential Medicines.[15] As of 2004, the vaccine is given to about 100 million children per year globally.[16] However, it is not commonly administered in the United States.[17][18]

Medical uses

[edit]

Tuberculosis

[edit]

The main use of BCG is for vaccination against tuberculosis. BCG vaccine can be administered after birth intradermally.[7] BCG vaccination can cause a false positive Mantoux test.[19]

The most controversial aspect of BCG is the variable efficacy found in different clinical trials, which appears to depend on geography. Trials conducted in the UK have consistently shown a protective effect of 60 to 80%, but those conducted elsewhere have shown no protective effect, and efficacy appears to fall the closer one gets to the equator.[20][21]

A 1994 systematic review found that BCG reduces the risk of getting tuberculosis by about 50%.[20] Differences in effectiveness depend on region, due to factors such as genetic differences in the populations, changes in environment, exposure to other bacterial infections, and conditions in the laboratory where the vaccine is grown, including genetic differences between the strains being cultured and the choice of growth medium.[22][21]

A systematic review and meta-analysis conducted in 2014 demonstrated that the BCG vaccine reduced infections by 19–27% and reduced progression to active tuberculosis by 71%.[14] The studies included in this review were limited to those that used interferon gamma release assay.

The duration of protection of BCG is not clearly known. In those studies showing a protective effect, the data are inconsistent. The MRC study showed protection waned to 59% after 15 years and to zero after 20 years; however, a study looking at Native Americans immunized in the 1930s found evidence of protection even 60 years after immunization, with only a slight waning in efficacy.[23]

BCG seems to have its greatest effect in preventing miliary tuberculosis or tuberculosis meningitis, so it is still extensively used even in countries where efficacy against pulmonary tuberculosis is negligible.[24]

The 100th anniversary of the BCG vaccine was in 2021.[11] It remains the only vaccine licensed against tuberculosis, which is an ongoing pandemic. Tuberculosis elimination is a goal of the World Health Organization (WHO), although the development of new vaccines with greater efficacy against adult pulmonary tuberculosis may be needed to make substantial progress.[25]

Efficacy

[edit]

A number of possible reasons for the variable efficacy of BCG in different countries have been proposed. None has been proven, some have been disproved, and none can explain the lack of efficacy in both low tuberculosis-burden countries (US) and high tuberculosis-burden countries (India). The reasons for variable efficacy have been discussed at length in a WHO document on BCG.[26]

  1. Genetic variation in BCG strains: Genetic variation in the BCG strains used may explain the variable efficacy reported in different trials.[27]
  2. Genetic variation in populations: Differences in genetic make-up of different populations may explain the difference in efficacy. The Birmingham BCG trial was published in 1988. The trial, based in Birmingham, United Kingdom, examined children born to families who originated from the Indian subcontinent (where vaccine efficacy had previously been shown to be zero). The trial showed a 64% protective effect, which is very similar to the figure derived from other UK trials, thus arguing against the genetic variation hypothesis.[28]
  3. Interference by nontuberculous mycobacteria: Exposure to environmental mycobacteria (especially Mycobacterium avium, Mycobacterium marinum and Mycobacterium intracellulare) results in a nonspecific immune response against mycobacteria. Administering BCG to someone who already has a nonspecific immune response against mycobacteria does not augment the response already there. BCG will, therefore, appear not to be efficacious because that person already has a level of immunity and BCG is not adding to that immunity. This effect is called masking because the effect of BCG is masked by environmental mycobacteria. Clinical evidence for this effect was found in a series of studies performed in parallel in adolescent school children in the UK and Malawi.[29] In this study, the UK school children had a low baseline cellular immunity to mycobacteria which was increased by BCG; in contrast, the Malawi school children had a high baseline cellular immunity to mycobacteria and this was not significantly increased by BCG. Whether this natural immune response is protective is not known.[30] An alternative explanation is suggested by mouse studies; immunity against mycobacteria stops BCG from replicating and so stops it from producing an immune response. This is called the block hypothesis.[31]
  4. Interference by concurrent parasitic infection: In another hypothesis, simultaneous infection with parasites such as helminthiasis changes the immune response to BCG, making it less effective.[32] As Th1 response is required for an effective immune response to tuberculous infection, concurrent infection with various parasites produces a simultaneous Th2 response, which blunts the effect of BCG.[33]

Mycobacteria

[edit]

BCG has protective effects against some nontuberculosis mycobacteria.

  • Leprosy: BCG has a protective effect against leprosy in the range of 20 to 80%.[9]
  • Buruli ulcer: BCG may protect against or delay the onset of Buruli ulcer.[9][34]

Cancer

[edit]

Micrograph showing granulomatous inflammation of bladder neck tissue due to Bacillus Calmette–Guérin used to treat bladder cancer, H&E stain

BCG has been one of the most successful immunotherapies.[35] BCG vaccine has been the "standard of care for patients with bladder cancer (NMIBC)" since 1977.[35][36] By 2014 there were more than eight different considered biosimilar agents or strains used for the treatment of nonmuscle-invasive bladder cancer.[35] [36]

  • A number of cancer vaccines use BCG as an additive to provide an initial stimulation of the person's immune systems.[citation needed]
  • BCG is used in the treatment of superficial forms of bladder cancer. Since the late 1970s, evidence has become available that instillation of BCG into the bladder is an effective form of immunotherapy in this disease.[37] While the mechanism is unclear, it appears a local immune reaction is mounted against the tumor. Immunotherapy with BCG prevents recurrence in up to 67% of cases of superficial bladder cancer.[citation needed]
  • BCG has been evaluated in a number of studies as a therapy for colorectal cancer.[38] The US biotech company Vaccinogen is evaluating BCG as an adjuvant to autologous tumour cells used as a cancer vaccine in stage II colon cancer.[citation needed]

Method of administration

[edit]
An apparatus (4–5 cm length, with 9 short needles) used for BCG vaccination in Japan, shown with ampules of BCG and saline

A pre-injection tuberculin skin test is usually carried out before administering BCG. A reactive tuberculin skin test is a contraindication to BCG due to the risk of severe local inflammation and scarring; it does not indicate any immunity. BCG is also contraindicated in certain people who have IL-12 receptor pathway defects.[39]

BCG is given as a single intradermal injection at the insertion of the deltoid. If BCG is accidentally given subcutaneously, then a local abscess may form (a "BCG-oma") that can sometimes ulcerate, and may require treatment with antibiotics immediately, otherwise without treatment it could spread the infection, causing severe damage to vital organs. An abscess is not always associated with incorrect administration, and it is one of the more common complications that can occur with the vaccination. Numerous medical studies on treatment of these abscesses with antibiotics have been done with varying results, but the consensus is once pus is aspirated and analysed, provided no unusual bacilli are present, the abscess will generally heal on its own in a matter of weeks.[40]

The characteristic raised scar that BCG immunization leaves is often used as proof of prior immunization. This scar must be distinguished from that of smallpox vaccination, which it may resemble.[39]

When given for bladder cancer, the vaccine is not injected through the skin, but is instilled into the bladder through the urethra using a soft catheter.[41]

Adverse effects

[edit]

BCG immunization generally causes some pain and scarring at the site of injection. The main adverse effects are keloids—large, raised scars. The insertion to the deltoid muscle is most frequently used because the local complication rate is smallest when that site is used. Nonetheless, the buttock is an alternative site of administration because it provides better cosmetic outcomes.[39]

BCG vaccine should be given intradermally. If given subcutaneously, it may induce local infection and spread to the regional lymph nodes, causing either suppurative (production of pus) and nonsuppurative lymphadenitis. Conservative management is usually adequate for nonsuppurative lymphadenitis. If suppuration occurs, it may need needle aspiration. For nonresolving suppuration, surgical excision may be required. Evidence for the treatment of these complications is scarce.[42]

Uncommonly, breast and gluteal abscesses can occur due to haematogenous (carried by the blood) and lymphangiomatous spread. Regional bone infection (BCG osteomyelitis or osteitis) and disseminated BCG infection are rare complications of BCG vaccination, but potentially life-threatening. Systemic antituberculous therapy may be helpful in severe complications.[43]

When BCG is used for bladder cancer, around 2.9% of treated patients discontinue immunotherapy due to a genitourinary or systemic BCG-related infection,[44] however while symptomatic bladder BCG infection is frequent, the involvement of other organs is very uncommon.[45] When systemic involvement occurs, liver and lungs are the first organs to be affected (1 week [median] after the last BCG instillation).[46]

If BCG is accidentally given to an immunocompromised patient (e.g., an infant with severe combined immune deficiency), it can cause disseminated or life-threatening infection. The documented incidence of this happening is less than one per million immunizations given.[17] In 2007, the WHO stopped recommending BCG for infants with HIV, even if the risk of exposure to tuberculosis is high,[47] because of the risk of disseminated BCG infection (which is roughly 400 per 100,000 in that higher risk context).[48][49]

Usage

[edit]

The age of the person and the frequency with which BCG is given has always varied from country to country. The WHO recommends childhood BCG for all countries with a high incidence of tuberculosis and/or high leprosy burden.[9] This is a partial list of historic and active BCG practice around the globe. A complete atlas of past and present practice has been generated.[50] As of 2022, 155 countries offer the BCG vaccine in their schedule.[51]

Americas

[edit]
  • Brazil introduced universal BCG immunization in 1967–1968, and the practice continues until now. According to Brazilian law, BCG is given again to professionals of the health sector and to people close to patients with tuberculosis or leprosy.[citation needed]
  • Canadian Indigenous communities receive the BCG vaccine,[52] and in the province of Quebec the vaccine was offered to children until the mid-70s.[53]
  • Most countries in Central and South America have universal BCG immunizations,[54] as does Mexico.[55]
  • The United States has never used mass immunization of BCG due to the rarity of tuberculosis in the US, relying instead on the detection and treatment of latent tuberculosis.[56][57]

Europe

[edit]
BCG vaccine in Europe
Country Mandatory now Mandatory in the past Years vaccine was mandatory
 Austria[50] No Yes 1952–1990
 Armenia[50] Yes Yes ?–present (reintroduced in 1998)
 Belgium[50][58] No No N/A
 Bosnia and Herzegovina[50] Yes Yes 1950–present
 Bulgaria[50][59] Yes Yes 1951–present
 Croatia[50] Yes Yes 1948–present
 Czech Republic[50][60] No Yes 1953–2010
 Denmark[50][61] No Yes 1946–1986
 Estonia[50] Yes Yes ?–present
 Finland[50][62] No Yes 1941–2006
 France[50][63][64][65] No Yes 1950–2007
 Germany[50][66] No Yes 1961–1998 (East Germany began 1951)
 Greece[50][67][68] No Yes ?–2016
 Hungary[50][69][70] Yes Yes 1953–present
 Ireland[71] No Yes 1950s–2015
 Italy[50] No No N/A
 Latvia[50] Yes Yes 1940s–present
 Lithuania[50] Yes Yes ?–present
 Moldova[50] Yes Yes ?–present
 Netherlands[50] No Yes ?-1979
 North Macedonia[50] Yes Yes 1950–present
 Norway[50][72] No Yes 1947–1995, voluntary 1995–2009
 Poland[50] Yes Yes 1955–present
 Portugal[50][73] No Yes ?–2016
 Romania[50][74] Yes Yes 1928–present
 Russia[50] Yes Yes 1962–present
 Serbia[50] Yes Yes 1928–present
 Slovakia[50][9] No Yes 1953–2012
 Slovenia[50] No Yes 1947–2005
 Spain[50][75] No Yes 1965–1981
 Sweden[50][76] No Yes 1940–1975
 Switzerland[50] No Yes 1960s–1987
 Turkey[50][77] Yes Yes 1952–present
 Ukraine[50][78] Yes Yes ?–present
 United Kingdom[50][79][80][81][82] No No N/A

Asia

[edit]
  • China: Introduced in 1930s. Increasingly widespread after 1949. Majority inoculated by 1979.[83]
  • South Korea, Singapore, Taiwan and Malaysia. In these countries, BCG was given at birth and again at age 12. In Malaysia and Singapore from 2001, this policy was changed to once only at birth. South Korea stopped re-vaccination in 2008.
  • Hong Kong: BCG is given to all newborns.[84]
  • Japan: In Japan, BCG was introduced in 1951, given typically at age 6. From 2005 it is administered between five and eight months after birth, and no later than a child's first birthday. BCG was administered no later than the fourth birthday until 2005, and no later than six months from birth from 2005 to 2012; the schedule was changed in 2012 due to reports of osteitis side effects from vaccinations at 3–4 months. Some municipalities recommend an earlier immunization schedule.[85]
  • Thailand: In Thailand, the BCG vaccine is given routinely at birth.[86]
  • India and Pakistan: India and Pakistan introduced BCG mass immunization in 1948, the first countries outside Europe to do so.[87] In 2015, millions of infants were denied BCG vaccine in Pakistan for the first time due to shortage globally.[88]
  • Mongolia: All newborns are vaccinated with BCG. Previously, the vaccine was also given at ages 8 and 15, although this is no longer common practice.[89]
  • Philippines: BCG vaccine started in the Philippines in 1979 with the Expanded Program on Immunization.
  • Sri Lanka: In Sri Lanka, The National Policy of Sri Lanka is to give BCG vaccination to all newborn babies immediately after birth. BCG vaccination is carried out under the Expanded Programme of Immunisation (EPI).[90]

Middle East

[edit]
  • Israel: BCG was given to all newborns between 1955 and 1982.[91]
  • Iran: Iran's vaccination policy implemented in 1984. Vaccination with the Bacillus Calmette–Guerin (BCG) is among the most important tuberculosis control strategies in Iran [2]. According to Iranian neonatal vaccination policy, BCG has been given as a single dose at children aged <6 years, shortly after birth or at first contact with the health services.[92]

Africa

[edit]
  • South Africa: In South Africa, the BCG Vaccine is given routinely at birth, to all newborns, except those with clinically symptomatic AIDS. The vaccination site is in the right shoulder.[93]
  • Morocco: In Morocco, the BCG was introduced in 1949. The policy is BCG vaccination at birth, to all newborns.[94]
  • Kenya: In Kenya, the BCG Vaccine is given routinely at birth to all newborns.[95]

South Pacific

[edit]
  • Australia: BCG vaccination was used between 1950s and mid 1980. BCG is not part of routine vaccination since mid 1980.[96]
  • New Zealand: BCG Immunisation was first introduced for 13 year olds in 1948. Vaccination was phased out 1963–1990.[50]

Manufacture

[edit]

BCG is prepared from a strain of the attenuated (virulence-reduced) live bovine tuberculosis bacillus, Mycobacterium bovis, that has lost its ability to cause disease in humans. It is specially subcultured in a culture medium, usually Middlebrook 7H9.[97] Because the living bacilli evolve to make the best use of available nutrients, they become less well-adapted to human blood and can no longer induce disease when introduced into a human host. Still, they are similar enough to their wild ancestors to provide some degree of immunity against human tuberculosis. The BCG vaccine can be anywhere from 0 to 80% effective in preventing tuberculosis for a duration of 15 years; however, its protective effect appears to vary according to geography and the lab in which the vaccine strain was grown.[22]

A number of different companies make BCG, sometimes using different genetic strains of the bacterium. This may result in different product characteristics. OncoTICE, used for bladder instillation for bladder cancer, was developed by Organon Laboratories (since acquired by Schering-Plough, and in turn acquired by Merck & Co.). A similar application is the product of Onko BCG[98] of the Polish company Biomed-Lublin, which owns the Brazilian substrain M. bovis BCG Moreau which is less reactogenic than vaccines including other BCG strains. Pacis BCG, made from the Montréal (Institut Armand-Frappier) strain,[99] was first marketed by Urocor in about 2002. Urocor was since acquired by Dianon Systems. Evans Vaccines (a subsidiary of PowderJect Pharmaceuticals). Statens Serum Institut in Denmark has marketed BCG vaccine prepared using Danish strain 1331. The production of BCG Danish strain 1331 and its distribution was later undertaken by AJVaccines company since the ownership transfer of SSI's vaccine production business to AJ Vaccines Holding A/S which took place on 16 January 2017.[100][101] Japan BCG Laboratory markets its vaccine, based on the Tokyo 172 substrain of Pasteur BCG, in 50 countries worldwide.

According to a UNICEF report published in December 2015, on BCG vaccine supply security, global demand increased in 2015 from 123 to 152.2 million doses. To improve security and to [diversify] sources of affordable and flexible supply," UNICEF awarded seven new manufacturers contracts to produce BCG. Along with supply availability from existing manufacturers, and a "new WHO prequalified vaccine" the total supply will be "sufficient to meet both suppressed 2015 demand carried over to 2016, as well as total forecast demand through 2016–2018."[102]

Supply shortage

[edit]

In 2011, the Sanofi Pasteur plant flooded, causing problems with mold.[103] The facility, located in Toronto, Ontario, Canada, produced BCG vaccine products made with substrain Connaught such as a tuberculosis vaccine and ImmuCYST, a BCG immunotherapeutic and bladder cancer drug.[104] By April 2012 the FDA had found dozens of documented problems with sterility at the plant including mold, nesting birds and rusted electrical conduits.[103] The resulting closure of the plant for over two years caused shortages of bladder cancer and tuberculosis vaccines.[105] On 29 October 2014 Health Canada gave the permission for Sanofi to resume production of BCG.[106] A 2018 analysis of the global supply concluded that the supplies are adequate to meet forecast BCG vaccine demand, but that risks of shortages remain, mainly due to dependence of 75 percent of WHO pre-qualified supply on just two suppliers.[107]

Dried

[edit]

Some BCG vaccines are freeze dried and become fine powder. Sometimes the powder is sealed with vacuum in a glass ampoule. Such a glass ampoule has to be opened slowly to prevent the airflow from blowing out the powder. Then the powder has to be diluted with saline water before injecting.[108]

History

[edit]
French poster promoting the BCG vaccine

The history of BCG is tied to that of smallpox. By 1865 Jean Antoine Villemin had demonstrated that rabbits could be infected with tuberculosis from humans;[109] by 1868 he had found that rabbits could be infected with tuberculosis from cows, and that rabbits could be infected with tuberculosis from other rabbits.[110] Thus, he concluded that tuberculosis was transmitted via some unidentified microorganism (or "virus", as he called it).[111][112] In 1882 Robert Koch regarded human and bovine tuberculosis as identical.[113] But in 1895, Theobald Smith presented differences between human and bovine tuberculosis, which he reported to Koch.[114][115] By 1901 Koch distinguished Mycobacterium bovis from Mycobacterium tuberculosis.[116] Following the success of vaccination in preventing smallpox, established during the 18th century, scientists thought to find a corollary in tuberculosis by drawing a parallel between bovine tuberculosis and cowpox: it was hypothesized that infection with bovine tuberculosis might protect against infection with human tuberculosis. In the late 19th century, clinical trials using M. bovis were conducted in Italy with disastrous results, because M. bovis was found to be just as virulent as M. tuberculosis.[117]

Albert Calmette, a French physician and bacteriologist, and his assistant and later colleague, Camille Guérin, a veterinarian, were working at the Institut Pasteur de Lille (Lille, France) in 1908. Their work included subculturing virulent strains of the tuberculosis bacillus and testing different culture media. They noted a glycerin-bile-potato mixture grew bacilli that seemed less virulent, and changed the course of their research to see if repeated subculturing would produce a strain that was attenuated enough to be considered for use as a vaccine. The BCG strain was isolated after subculturing 239 times during 13 years from virulent strain on glycerine potato medium. The research continued throughout World War I until 1919, when the now avirulent bacilli were unable to cause tuberculosis disease in research animals. Calmette and Guerin transferred to the Paris Pasteur Institute in 1919. The BCG vaccine was first used in humans in 1921.[26]

Public acceptance was slow, and the Lübeck disaster, in particular, did much to harm it. Between 1929 and 1933 in Lübeck, 251 infants were vaccinated in the first 10 days of life; 173 developed tuberculosis and 72 died. It was subsequently discovered that the BCG administered there had been contaminated with a virulent strain that was being stored in the same incubator, which led to legal action against the manufacturers of the vaccine.[118]

Dr. R. G. Ferguson, working at the Fort Qu'Appelle Sanatorium in Saskatchewan, was among the pioneers in developing the practice of vaccination against tuberculosis. In Canada, more than 600 children from residential schools were used as involuntary participants in BCG vaccine trials between 1933 and 1945.[119] In 1928, the BCG vaccine was adopted by the Health Committee of the League of Nations (predecessor to the World Health Organization (WHO)). Because of opposition, however, it only became widely used after World War II. From 1945 to 1948, relief organizations (International Tuberculosis Campaign or Joint Enterprises) vaccinated over eight million babies in eastern Europe and prevented the predicted typical increase of tuberculosis after a major war.[120]

The BCG vaccine is very efficacious against tuberculous meningitis in the pediatric age group, but its efficacy against pulmonary tuberculosis appears to be variable. Some countries have removed the BCG vaccine from routine vaccination. Two countries that have never used it routinely are the United States and the Netherlands (in both countries, it is felt that having a reliable Mantoux test and therefore being able to accurately detect active disease is more beneficial to society than vaccinating against a condition that is relatively rare).[56][57][121]

Other names include "Vaccin Bilié de Calmette et Guérin vaccine" and "Bacille de Calmette et Guérin vaccine".[122]

Research

[edit]

Tentative evidence exists for a beneficial non-specific effect of BCG vaccination on overall mortality in low income countries, or for its reducing other health problems including sepsis and respiratory infections when given early,[123] with greater benefit the earlier it is used.[124]

In rhesus macaques, BCG shows improved rates of protection when given intravenously.[125][126] Some risks must be evaluated before it can be translated to humans.[127]

The University of Oxford Jenner Institute is conducting a study comparing the efficacy of injected versus inhaled BCG vaccine in already-vaccinated adults.[128]

Type 1 diabetes

[edit]

As of 2017, BCG vaccine is in the early stages of being studied in type 1 diabetes (T1D).[129][130]

COVID-19

[edit]

Use of the BCG vaccine may provide protection against COVID-19.[131][132] However, epidemiologic observations in this respect are ambiguous.[133] The WHO does not recommend its use for prevention as of 12 January 2021.[134]

As of January 2021, 20 BCG trials are in various clinical stages.[135] As of October 2022, the results are extremely mixed. A 15-month trial involving people thrice-vaccinated over the two years before the pandemic shows positive results in preventing infection in BCG-naive people with type 1 diabetes.[136] On the other hand, a 5-month trial shows that re-vaccinating with BCG does not help prevent infection in healthcare workers. Both of these trials were double-blind randomized controlled trials.[137]

References

[edit]
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