Editing BCG vaccine (section)

==Medical uses==

===Tuberculosis===
{{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 |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 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.<ref name=Colditz/><ref name="Fine"/>

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 | 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 slightly 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>

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 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). 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====
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.<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 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 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.<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 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.<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 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 ===
BCG has protective effects against some nontuberculosis mycobacteria.
* Leprosy: BCG has a protective effect against leprosy in the range of 20 to 80%.<ref name=WHO2018 />
* [[Mycobacterium ulcerans|Buruli ulcer]]: BCG may protect against or delay the onset of Buruli ulcer.<ref name=WHO2018 /><ref>{{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 }}</ref>

=== Cancer ===
{{anchor|Cancer}}
{{see also|Cancer immunotherapy|Cancer vaccine|Coley's toxins}}
[[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 | 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, more than eight different considered biosimilar agents or strains used to treat nonmuscle-invasive bladder cancer.<ref name="BDG_2016" /><ref name="BCG_success_2007" />
* Several [[cancer vaccine]]s use BCG as an additive to provide an initial stimulation of the person's immune system.{{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 the 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 many 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}}