BCG vaccine#Europe

{{see also|Tuberculosis vaccines}}

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

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

A 1994 systematic review found that BCG reduces the risk of getting tuberculosis by about 50%.{{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 }} 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.{{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 }}

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%.{{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 }} 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 slightly waning in efficacy.{{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 }}

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.{{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 }}

The 100th anniversary of the BCG vaccine 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). The development of new vaccines with greater efficacy against adult pulmonary tuberculosis may be needed to make substantial progress.{{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}}

Several 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 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.{{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 }}

1. Genetic variation in BCG strains: Genetic variation in the BCG strains may explain the variable efficacy reported in different trials.{{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 }}
2. Genetic variation in populations: Differences in the genetic makeup 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, similar to the figure from other UK trials, thus arguing against the genetic variation hypothesis.{{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 }}
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 with a nonspecific immune response against mycobacteria does not augment the response. 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.{{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 }} 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.{{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 }} 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.{{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 }}
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.{{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 }} 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.{{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 }}

BCG has protective effects against some nontuberculosis mycobacteria.

• Leprosy: BCG has a protective effect against leprosy in the range of 20 to 80%.
• Buruli ulcer: BCG may protect against or delay the onset of Buruli ulcer.{{cite journal | vauthors = Tanghe A, Content J, Van Vooren JP, Portaels F, Huygen K | title = Protective efficacy of a DNA vaccine encoding antigen 85A from Mycobacterium bovis BCG against Buruli ulcer | journal = Infection and Immunity | volume = 69 | issue = 9 | pages = 5403–5411 | date = September 2001 | pmid = 11500410 | pmc = 98650 | doi = 10.1128/IAI.69.9.5403-5411.2001 }}

{{anchor|Cancer}}

{{see also|Cancer immunotherapy|Cancer vaccine|Coley's toxins}}

Image:Granulomatous inflammation of bladder neck.jpg 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.{{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 }} BCG vaccine has been the "standard of care for patients with bladder cancer (NMIBC)" since 1977.{{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 }} By 2014, more than eight different considered biosimilar agents or strains used to treat nonmuscle-invasive bladder cancer.

• Several cancer vaccines use BCG as an additive to provide an initial stimulation of the person's immune system.{{citation needed|date=December 2022}}
• BCG is used in the treatment of superficial forms of bladder cancer. Since the late 1970s, evidence has become available that the instillation of BCG into the bladder is an effective form of immunotherapy in this disease.{{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 }} 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 many studies as a therapy for colorectal cancer.{{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 }} 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}}

Image:BCG apparatus ja2.jpg

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

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 the 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.{{Cite web| vauthors = Makwana N, Riordan A |title=Is medical therapy effective in the treatment of BCG abscesses?|url=https://bestbets.org/bets/bet.php?id=00797|date=23 August 2004|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}}

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.

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.{{Cite web|title=Intravesical Therapy for Bladder Cancer|url=https://www.cancer.org/cancer/bladder-cancer/treating/intravesical-therapy.html|date=30 January 2019|access-date=15 August 2022|publisher=American Cancer Society|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}}

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.

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) or nonsuppurative lymphadenitis. Conservative management is usually adequate for nonsuppurative lymphadenitis. If suppuration occurs, it may need needle aspiration. For unresolved suppuration, surgical excision may be required. Evidence for the treatment of these complications is scarce.{{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 }}

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.{{cite journal | vauthors = Govindarajan KK, Chai FY | title = BCG Adenitis-Need for Increased Awareness | journal = The Malaysian Journal of Medical Sciences | volume = 18 | issue = 2 | pages = 66–69 | date = April 2011 | pmid = 22135589 | pmc = 3216207 }} [http://www.mjms.usm.my/default.asp?tag=14&kod_volume=48 Malaysian Journal of Medical Sciences] {{webarchive|url=https://web.archive.org/web/20120326140134/http://www.mjms.usm.my/default.asp?tag=14&kod_volume=48 |date=26 March 2012 }}

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

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.{{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 }} In 2007, the WHO stopped recommending BCG for infants with HIV, even if the risk of exposure to tuberculosis is high,{{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 }} because of the risk of disseminated BCG infection (which is roughly 400 per 100,000 in that higher risk context).{{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 }}{{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 }}

The person's age and the frequency with which BCG is given have 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. This is a partial list of historic and active BCG practices around the globe. A complete atlas of past and present practice has been generated. As of 2022, 155 countries offer the BCG vaccine in their schedule.{{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 }}

• Brazil introduced universal BCG immunization in 1967–1968, and the practice continues until now. According to Brazilian law, BCG is given again to professionals in the health sector and people close to patients with tuberculosis or leprosy.{{citation needed|date=December 2022}}
• Canadian Indigenous communities receive the BCG vaccine,{{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 }} and in the province of Quebec the vaccine was offered to children until the mid-70s.{{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 }}
• Most countries in Central and South America have universal BCG immunizations,{{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}} as does Mexico.{{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 }}
• 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.{{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}}{{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 }}

• China: Introduced in the 1930s. Increasingly, it became more widespread after 1949. The majority were inoculated by 1979.{{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 }}
• 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.{{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}}
• 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.{{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}}
• Thailand: In Thailand, the BCG vaccine is given routinely at birth.{{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}}
• India and Pakistan: India and Pakistan introduced BCG mass immunization in 1948, the first countries outside Europe to do so.{{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}} In 2015, millions of infants were denied BCG vaccine in Pakistan for the first time due to shortage globally.{{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 }}
• 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.{{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 }}
• 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).{{cite web|url=http://203.94.76.60/TBWeb/web/PreventionofTB-1.html|title=Role of BC Vaccination|website=The National Programme for tuberculosis Control & Chest Diseases.|url-status=dead|archive-url=https://web.archive.org/web/20130606083222/http://203.94.76.60/TBWeb/web/PreventionofTB-1.html|archive-date=6 June 2013}}

• Israel: BCG was given to all newborns between 1955 and 1982.{{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 }}
• Iran: Iran's vaccination policy was 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 to children aged <6 years, shortly after birth or at first contact with the health services.{{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 }}

• 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 arm.{{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 }}
• Morocco: In Morocco, the BCG was introduced in 1949. The policy is BCG vaccination at birth, to all newborns.{{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}}
• Kenya: In Kenya, the BCG Vaccine is given routinely at birth to all newborns.{{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 }}

• Australia: BCG vaccination was used between the 1950s and mid-1980s. BCG has not been part of routine vaccination since the mid-1980s.{{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 }}
• New Zealand: BCG Immunisation was first introduced for 13-year-olds in 1948. Vaccination was phased out from 1963 to 1990.

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.{{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 }} 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 immunity against human tuberculosis. The BCG vaccine can be anywhere from 0 to 80% effective in preventing tuberculosis for 15 years; however, its protective effect appears to vary according to geography and the lab in which the vaccine strain was grown.{{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 }}

Several 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{{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 }} 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,{{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 }} 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 a 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.{{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 }}{{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 }} 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."{{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 }}

In 2011, the Sanofi Pasteur plant flooded, causing problems with mold.{{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=dead |archive-url=https://web.archive.org/web/20160206161441/https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm310376.htm |archive-date=6 February 2016 }} 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.{{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}} By April 2012 the FDA had found dozens of documented problems with sterility at the plant including mold, nesting birds and rusted electrical conduits. The resulting closure of the plant for over two years caused shortages of bladder cancer and tuberculosis vaccines.{{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 }} On 29 October 2014 Health Canada gave the permission for Sanofi to resume production of BCG.{{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 }} 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.{{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 }}

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.{{cite journal | vauthors = Ungar J, Muggleton PW, Dudley JA, Griffiths MI | title = Preparation and properties of a freeze-dried B.C.G. vaccine of increased stability | journal = British Medical Journal | volume = 2 | issue = 5312 | pages = 1086–1089 | date = October 1962 | pmid = 13995378 | pmc = 1926490 | doi = 10.1136/bmj.2.5312.1086 }}

File:BCG advert.jpg

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;{{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 }} 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.{{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)) Thus, he concluded that tuberculosis was transmitted via some unidentified microorganism (or "virus", as he called it).(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.){{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}} In 1882 Robert Koch regarded human and bovine tuberculosis as identical.{{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 to the tuberculosis of humans and thus [is] a disease that can be transmitted to them.) But in 1895, Theobald Smith presented differences between human and bovine tuberculosis, which he reported to Koch.{{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 |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 }}{{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." By 1901 Koch distinguished Mycobacterium bovis from Mycobacterium tuberculosis.{{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 |url-access=subscription }} From p. 189: "Considering all these facts, I feel justified in maintaining that human tuberculosis differs from bovine and cannot be transmitted to cattle." 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.{{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 }}

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 a 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.

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 vaccine's manufacturers.{{cite book | vauthors = Rosenthal SR | title=BCG vaccination against tuberculosis | publisher=Little, Brown & Co. | location=Boston | year=1957 }}

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.{{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}} 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.{{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 }}

The BCG vaccine is very efficacious against tuberculous meningitis in the pediatric age group, but its efficacy against pulmonary tuberculosis appears 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 relatively rare condition).{{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 }}

Other names include "Vaccin Bilié de Calmette et Guérin vaccine" and "Bacille de Calmette et Guérin vaccine".{{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 }}

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,{{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 }} with greater benefit the earlier it is used.{{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 }}

In rhesus macaques, BCG shows improved rates of protection when given intravenously.{{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 }}{{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 }} Some risks must be evaluated before it can be translated to humans.{{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 }}

The University of Oxford Jenner Institute is conducting a study comparing the efficacy of injected versus inhaled BCG vaccine in already-vaccinated adults.{{cite web | url=https://www.ox.ac.uk/news/2024-01-15-novel-inhaled-tb-vaccine | title=Novel inhaled TB vaccine | 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 }}

{{As of|2017}}, BCG vaccine is in the early stages of being studied in type 1 diabetes (T1D).{{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 }}{{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 }}

Use of the BCG vaccine may provide protection against COVID-19.{{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 }}{{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 }} However, epidemiologic observations in this respect are ambiguous.{{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 }} The WHO does not recommend its use for prevention {{as of|2021|1|12|lc=yes}}.{{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}}

{{As of|2021|1}}, 20 BCG trials are in various clinical stages.{{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}} {{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.{{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 }} 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.{{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 }}

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