BCG vaccine
Microscopic image of the Calmette-Guérin bacillus, Ziehl–Neelsen stain, magnification:1,000nn
Vaccine description
Target disease Tuberculosis
Type Live bacteria
Clinical data
AHFS/Drugs.com
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
Percutaneous
Identifiers
ATC code J07

Bacillus Calmette–Guérin (historically Vaccin Bilié de Calmette et Guérin commonly referred to as Bacille de Calmette et Guérin or BCG) is a vaccine against tuberculosis and for the treatment of some bladder cancers.

It is prepared from a strain of the attenuated (health system.[2]

Medical uses

The main use of BCG is for vaccination against tuberculosis. BCG vaccine can be administered after birth intradermally.[3] BCG vaccination is recommended to be given intradermally. A previous BCG vaccination can cause a false positive Mantoux test, although a very high-grade reading is usually due to active disease.

The age of the patient and the frequency with which BCG is given has always varied from country to country.

  • WHO BCG policy: The WHO recommend BCG be given to all children born in countries highly endemic for TB because it protects against miliary TB and TB meningitis.[4]
  • Brazil: 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.
  • Central and South America: Most countries in Central and South America have universal BCG immunizations. In Ecuador, a child cannot receive their birth certificate without having the BCG vaccine in their medical record along with other vaccinations.[5]
  • France: The BCG was mandatory for school children between 1950 and 2007,[6][7] and for healthcare professionals between 1947 and 2010. Vaccination is still available for French healthcare professionals and social workers but is now decided on a case by case basis.[8]
  • India and Pakistan: India and Pakistan introduced BCG mass immunization in 1948, the first countries outside Europe to do so.[9]
  • 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.[10]
  • Norway: In Norway the BCG vaccine was mandatory from 1947 to 1995. It is still available and recommended for high-risk groups.[11]
  • Philippines: BCG vaccine started in the Philippines in 1979 with the Expanded Program on Immunization
  • 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 in the right shoulder.[12]
  • Thailand: In Thailand, the BCF Vaccine is given routinely at birth. [13]
  • United Kingdom: The UK introduced universal BCG immunization in 1953, and until July 2005, the UK policy was to immunize all school children between 10 and 14 years of age, and all neonates born into high-risk groups. The injection was given only once during an individual's lifetime (as there is no evidence of additional protection from more than one vaccination). BCG was also given to protect people who had been exposed to tuberculosis. The peak of tuberculosis incidence is in adolescence and early adulthood, and the MRC trial showed efficacy lasted a maximum of 15 years.[14] Routine immunization with BCG for all school children was scrapped in July 2005 because of falling cost-effectiveness: whereas in 1953, 94 children would have to be immunized to prevent one case of TB, by 1988, the annual incidence of TB in the UK had fallen so much, 12,000 children would have to be immunized to prevent one case of TB.[15]
  • United States: The US has never used mass immunization of BCG, relying instead on the detection and treatment of latent tuberculosis.
  • Other countries: In some countries, such as the former Soviet Union, BCG was given regularly throughout life. In South Korea, Singapore, Taiwan and Malaysia, BCG was given at birth and again at age 12. But in Malaysia and Singapore, from 2001, this policy was changed to once only at birth. South Korea also stopped the re-vaccination in 2008.

Method of administration

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

Except in neonates, a tuberculin skin test should always be done before administering BCG. A reactive tuberculin skin test is a contraindication to BCG. Someone with a positive tuberculin reaction is not given BCG, because the risk of severe local inflammation and scarring is high, not because of the common misconception that tuberculin reactors "are already immune" and therefore do not need BCG. People found to have reactive tuberculin skin tests should be screened for active tuberculosis.

BCG is given as a single [16]

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

Other uses

Mycobacteria

  • Leprosy: BCG has a protective effect against leprosy in the range of 26 to 41% based on controlled trials. The protective effect is somewhat larger based on case control and cohort studies—about 60%.[17][18] However BCG vaccine is not used specifically to control leprosy.
  • Buruli ulcer: BCG may protect against or delay the onset of Buruli ulcer.[19]

Cancer immunotherapy

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

Type I diabetes

  • Diabetes, type 1: Clinical trials based on the work of Denise Faustman use BCG to induce production of TNF-α, which can kill the T-cells responsible for type 1 diabetes. In a Phase I, double-blind, placebo-controlled trial, two doses of the BCG vaccine were administered to three adults with long-term type 1 diabetes, resulting in elimination of the pancreas-harming cells, induction of regulatory T cells (Tregs) and a transient rise in C-peptide levels, suggestive of temporarily restored insulin production.[25]

Efficacy

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.[26][27]

A 1994 systematic review found that BCG reduces the risk of getting TB by about 50%.[26] There are differences in effectiveness, depending on region, due to factors such as genetic differences in the populations, changes in environment, exposure to other bacterial infections, and conditions in the lab where the vaccine is grown, including genetic differences between the strains being cultured and the choice of growth medium.[1][28]

A systematic review and meta analysis conducted in 2014 demonstrated that the BCG vaccine reduced infections by 19–27% and reduced progression to active TB by 71%.[29] 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.[30]

BCG seems to have its greatest effect in preventing miliary TB or TB meningitis,[31] so it is still extensively used even in countries where efficacy against pulmonary tuberculosis is negligible.

Reasons

A number of possible reasons for the variable efficacy of BCG in different countries have been proposed. None have been proven, some have been disproved, and none can explain the lack of efficacy in both low-TB burden countries (US) and high-TB burden countries (India). The reasons for variable efficacy have been discussed at length in a WHO document on BCG.[32]

  1. Genetic variation in BCG strains: Genetic variation in the BCG strains used may explain the variable efficacy reported in different trials.[33]
  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.[34]
  3. Interference by nontuberculous mycobacteria: Exposure to environmental mycobacteria (especially M. avium, M. marinum and M. 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.[35] 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.[36] 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.[37]
  4. Interference by concurrent parasitic infection: In another hypothesis, simultaneous infection with parasites changes the immune response to BCG, making it less effective. 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.[38]
  5. Exposure to ultraviolet light: Concentration of ultraviolet light (particularly UVB light) from the Sun may have some effect on efficacy of the BCG vaccine. UVB has been demonstrated to reduce efficacy of BCG vaccine in laboratory guinea pigs.[39] The concentration gradient of UVB light increases geographically closer to the Earth's equator. Though currently unresearched, this effect possibly occurs as a result of sunlight-dependent vitamin D production.

Adverse effects

BCG immunization generally causes some pain and scarring at the site of injection. The main adverse effects are keloids—large, raised scars. The insertion of deltoid 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 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.[40]

Uncommonly, breast and gluteal abscesses can occur due to haematogenous 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.[41]

If BCG is accidentally given to an immunocompromised patient (e.g., an infant with WHO stopped recommending BCG for infants with HIV, even if there is a high risk of exposure to TB,[43] because of the risk of disseminated BCG infection (which is approximately 400 per 100,000 in that higher risk context).[44][45]

Manufacturers

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, Inc.). Pacis® BCG, made from the Montréal (Institut Armand-Frappier) strain,[46] was first marketed by Urocor in about 2002. Urocor was since acquired by Dianon Systems. Evans Vaccines (a subsidiary of PowderJect Pharmaceuticals Plc, London: PJP). Statens Serum Institut in Denmark markets BCG vaccine prepared using Danish strain 1331.[47] Japan BCG Laboratory markets its vaccine, based on the Tokyo 172 substrain of Pasteur BCG, in 50 countries worldwide. Sanofi Pasteur's BCG vaccine products, made with the Glaxo 1077 strain,[48] were recalled in July 2012 due to noncompliance in the manufacturing process.

Preparation

A weakened strain of bovine tuberculosis bacillus, Mycobacterium bovis is specially subcultured in a culture medium, usually Middlebrook 7H9.

History

The history of BCG is tied to that of smallpox. Jean Antoine Villemin first recognized bovine tuberculosis in 1854 and transmitted it, and Robert Koch first distinguished Mycobacterium bovis from Mycobacterium tuberculosis. 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.

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 tubercle 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. BCG strain was isolated after 239 times subculturing 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. They transferred to the Paris Pasteur Institute in 1919. The BCG vaccine was first used in humans in 1921.[49]

Public acceptance was slow, and one disaster, in particular, did much to harm public acceptance of the vaccine. In the summer of 1930 in Lübeck, 240 infants were vaccinated in the first 10 days of life; almost all developed tuberculosis and 72 infants 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.[50]

eastern Europe and prevented the predicted typical increase of TB after a major war.

BCG is very efficacious against tuberculous meningitis in the pediatric age group, but its efficacy against pulmonary tuberculosis appears to be variable. As of 2006, only a few countries do not use BCG for routine vaccination. Two countries that have never used it routinely are the USA and the Netherlands (in both countries, it is felt that having a reliable Mantoux test and being able to accurately detect active disease is more beneficial to society than vaccinating against a condition that is now relatively rare there).[51][52]

Research

Recent research by the Imperial College London has focused on finding new cell-wall proteins that trigger an immune response and are suitable for use in a vaccine to provide long-term protection against M. tuberculosis. The study has revealed a few such proteins, the most promising of which has been dubbed EspC; it elicits a very strong immune reaction, and is specific to M. tuberculosis.[53]

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,[54] with greater benefit the earlier it is used.[55]

Other tuberculosis vaccines

See: Tuberculosis vaccines

References

  1. ^ a b
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  5. ^ http://www.siise.gob.ec/siiseweb/PageWebs/SALUD/ficsal_S21.htm
  6. ^ Loi n° 50-7 du 5 janvier 1950
  7. ^ décret n° 2007-1111 du 17 juillet 2007
  8. ^
  9. ^
  10. ^ C. Oyunsolong, personal communication. Vaccine Specialist, Selenge Province Health Department, Mongolia. 14 January 2015.
  11. ^ http://www.fhi.no/eway/default.aspx?pid=239&trg=Content_6493&Main_6157=6287:0:25,5501&MainContent_6287=6493:0:25,6826&Content_6493=6441:68710::0:6446:1:::0:0#eHandbook687100
  12. ^ [1] Archived May 11, 2013 at the Wayback Machine
  13. ^
  14. ^
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  16. ^ Nick Makwana and Andrew Riordan (2004), "Is medical therapy effective in the treatment of BCG abscesses?", Birmingham Heartlands Hospital [2]
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  26. ^ a b
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  41. ^ Malaysian Journal of Medical Sciences
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External links

  • Frequently Asked Questions about BCG Professor P D O Davies, Tuberculosis Research Unit, Cardiothoracic Centre, Liverpool, UK.
  • BCG World Atlas BCG policy by country, past and present.