Editing BCG vaccine (section)

====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>