BCG vaccine

From Wikipedia, the free encyclopedia
BCG vaccine
Vaccine description
Target disease Tuberculosis
Type Live bacteria
Clinical data
AHFS/Drugs.com FDA Professional Drug Information
Pregnancy cat. C (US)
Legal status ℞-only (US)
Routes Percutaneous
Identifiers
ATC code J07AN01
Microscopic image of the Calmette-Guérin bacillus, Ziehl–Neelsen stain, magnification:1,000

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 that is prepared from a strain of the attenuated (weakened) live bovine tuberculosis bacillus, Mycobacterium bovis, that has lost its virulence in humans by being specially subcultured in a culture medium, usually Middlebrook 7H9. Because the living bacilli evolve to make the best use of the available nutrients, they become less well adapted to their traditional environment, human blood, and can no longer induce the disease when introduced into a human host. Still, they are similar enough to their wild ancestors to provide some degree of immunity against human tuberculosis. The BCG vaccine can be anywhere from 0 to 80% effective in preventing tuberculosis for a duration of 15 years; however, its protective effect appears to vary according to geography and the lab in which the vaccine strain was grown.[1]

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. 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.[2]

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 had been contaminated with a virulent strain that was being stored in the same incubator, and led to legal action being taken against the manufacturers of BCG.[3]

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 1928, BCG was adopted by the Health Committee of the League of Nations (predecessor to the WHO). Because of opposition, however, it did not become widely used until after World War II. From 1945 to 1948, relief organizations (International Tuberculosis Campaign or Joint Enterprises) vaccinated over 8 million babies in 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. The USA and the Netherlands have never used it routinely. In both countries, BCG vaccination is not routinely given to adults because 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 in those countries.[4][5] Recent research by the Imperial College London has focused instead 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.[6]

Variable 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.[7][8]

A 1994 systematic review found that the BCG reduces the risk of getting TB by about 50%.[7] 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][9]

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.[10]

BCG seems to have its greatest effect in preventing miliary TB or TB meningitis,[11] 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, but none have been proven, 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.[12]

  1. Genetic variation in BCG strains: Genetic variation in the BCG strains used may explain the variable efficacy reported in different trials.[13]
  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.[14]
  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.[15] 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.[16] 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.[17]
  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.[18]
  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.[19] 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.

Uses

Tuberculosis: The main use of BCG is for vaccination against tuberculosis. BCG vaccine can be implemented after the birth intradermally.[20] BCG vaccination is recommended to be given intradermally by a nurse skilled in the technique. 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.[21]
  • United States: The US has never used mass immunization of BCG, relying instead on the detection and treatment of latent tuberculosis.
  • France: The BCG was mandatory for school children between 1950 (Loi n° 50-7 du 5 janvier 1950) and 2007 (décret n° 2007-1111 du 17 juillet 2007) 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.[22]
  • United Kingdom: The UK introduced universal BCG immunization in 1953, and until 2005, the UK policy was to immunize all school children at the age of 13, and all neonates born into high-risk groups. The injection was only given 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 only 15 years at most. Styblo and Meijer argued neonatal immunization protected against miliary TB and other noncontagious forms of TB, and not pulmonary TB which was a disease of adults, and that mass immunization campaigns with BCG would therefore not be expected to have a significant public health impact.[23] For these and other reasons, BCG was therefore given to time with the peak incidence of pulmonary disease. Routine immunization with BCG was withdrawn in 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.
  • India and Pakistan: India and Pakistan introduced BCG mass immunization in 1948, the first countries outside Europe to do so.[24]
  • 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.
  • Norway: In Norway the BCG vaccine was mandatory from 1947 to 1995. It is still available and recommended for high-risk groups.
  • 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.[25]
  • Other countries: In some countries, such as the former USSR, 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.

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 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. However, it is important to note an abscess is not always associated with incorrect administration, and it is one of the more common complications that can occur with the vaccination. Numerous medical studies on treatment of these abscesses with antibiotics have been done with varying results, but the consensus is once pus is aspirated and analysed, provided no unusual bacilli are present, the abscess will generally heal on its own in a matter of weeks.[26]

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

Micrograph showing granulomatous inflammation of bladder neck tissue due to Bacillus Calmette-Guérin used to treat bladder cancer, H&E stain
  • 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%.[27][28] However BCG vaccine is not used specifically to control leprosy.
  • Buruli ulcer: BCG may protect against or delay the onset of Buruli ulcer.[29]
  • Cancer immunotherapy/cancer vaccine: A number of cancer vaccines use BCG as an adjuvant to provide an initial stimulation of the patients' immune systems.
    • BCG is used in the treatment of superficial forms of bladder cancer. Since the late 1980s, evidence has become available that instillation of BCG into the bladder is an effective form of immunotherapy in this disease.[30] 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.
    • Colorectal cancer[31]
    • Lung cancer
    • Melanoma
    • MPNST
    • Equine sarcoid (in horses)
  • 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.[32] Studies using mice have shown a similar treatment results in a permanent cure for about one-third of the test subjects.[33]
  • Interstitial cystitis (IC) or painful bladder syndrome (PBS): BCG has been useful in treating some people with IC and/or PBS, which are chronic inflammatory bladder problems with unknown etiology. It is instilled directly into the bladder. How it works is unclear, but is likely immunotherapeutic, as the chronic inflammation could be the result of an autoimmune problem.[citation needed]
  • Multiple sclerosis: In humans, BCG has been shown to substantially reduce recurrence of symptoms in multiple sclerosis patients.[34] The frequency of new enhancing lesions as detected by Gd-enhanced MRI was reduced by more than half in 12 patients, comparing the six-month run-in phase to the six-month post-BCG phase of the experiment. Persistence at subsequent MR scan was reduced from 18 lesions to one lesion, and evolution to black holes was reduced from 28 to six lesions.[35] The conventional explanation of such protection is parasites (including bacteria) modulate the sensitivity of the immune system. BCG appears safe as a treatment for multiple sclerosis,[34][36] although it is not commonly used.
  • Parkinson's disease: In a mouse model of Parkinson's disease, BCG vaccination partially preserved striatal dopaminergic markers. The neuroprotective effect is associated with suppression in microglial activation and proliferation in mouse mid-brain area.[37] The neuroprotective effect was later found to be positively associated with regulatory T cell induced by BCG vaccination.[38]

Adverse effects

BCG is one of the most widely used vaccines in the world, with an unparalleled safety record[citation needed]. 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 is required, but not incision. 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.[39]

If BCG is accidentally given to an immunocompromised patient (e.g., an infant with SCID), it can cause disseminated or life-threatening infection. The documented incidence of this happening is less than one per million immunizations given.[40] In 2007, The WHO stopped recommending BCG for infants with HIV, even if there is a high risk of exposure to TB,[41] because of the risk of disseminated BCG infection (which is approximately 400 per 100,000).[42][43]

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,[44] 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.[45] 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,[46] were recalled in July 2012 due to noncompliance in the manufacturing process.

Other tuberculosis vaccines

See: Tuberculosis vaccines

See also

References

  1. ↑ 1.0 1.1 Venkataswamy, Manjunatha M.; Goldberg, Michael F.; Baena, Andres; Chan, John; Jacobs, William R., Jr.; Porcelli, Steven A. (1 February 2012). "In vitro culture medium influences the vaccine efficacy of Mycobacterium bovis BCG". Vaccine 30 (6): 1038–1049. doi:10.1016/j.vaccine.2011.12.044. PMC 3269512. PMID 22189700. Retrieved 18 July 2013. 
  2. ↑ Fine PEM, Carneiro IAM, Milstein JB, Clements CJ. (1999). Issues relating to the use of BCG in immunization programs. Geneva: WHO. 
  3. ↑ Rosenthal SR. (1957). BCG vaccination against tuberculosis. Boston: Little, Brown & Co. 
  4. ↑ "Fact Sheets: BCG Vaccine". Centers for Disease Control and Prevention. 28 October 2011. Retrieved 18 July 2013. 
  5. ↑ Vaccination of young children against tuberculosis (2011/04). The Hague:Health Council of the Netherlands. 17 March 2011. ISBN 978-90-5549-844-4. Retrieved 12 July 2013. 
  6. ↑ "Tuberculosis vaccine target found". BBC News. 19 March 2011. 
  7. ↑ 7.0 7.1 Colditz, Graham A.; Brewer, TF; Berkey, CS; Wilson, ME; Burdick, E; Fineberg, HV; Mosteller, F (1994). "Efficacy of BCG Vaccine in the Prevention of Tuberculosis". JAMA 271 (9): 698–702. doi:10.1001/jama.1994.03510330076038. PMID 8309034. 
  8. ↑ Fine PEM (1995). "Variation in protection by BCG: implications of and for heterologous immunity". Lancet 346 (8986): 1339–45. doi:10.1016/S0140-6736(95)92348-9. PMID 7475776. 
  9. ↑ FINE, P (1 November 1995). "Variation in protection by BCG: implications of and for heterologous immunity". The Lancet 346 (8986): 1339–1345. doi:10.1016/S0140-6736(95)92348-9. 
  10. ↑ Aronson NE, Santosham M, Comstock GW (2004). "Long-term efficacy of BCG vaccine in American Indians and Alaska Natives: A 60-year follow-up study". JAMA 291 (17): 2086–91. doi:10.1001/jama.291.17.2086. PMID 15126436. 
  11. ↑ Rodrigues LC, Diwan VK, Wheeler JG (1993). "Protective Effect of BCG against Tuberculous Meningitis and Miliary Tuberculosis: A Meta-Analysis". Int J Epidemiol 22 (6): 1154–8. doi:10.1093/ije/22.6.1154. PMID 8144299. 
  12. ↑ Fine PEM, Carneiro IAM, Milstein JB, Clements CJ (1999). "Chapter 8: Reasons for variable efficacy". Issues relating to the use of BCG in immunization programmes. Geneva, Switzerland: World Health Organization. 
  13. ↑ Brosch R, Gordon SV, Garnier T, Eiglmeier K (2007). "Genome plasticity of BCG and impact on vaccine efficacy". Proceedings of the National Academy of Sciences of the United States of America 104 (13): 5596–601. doi:10.1073/pnas.0700869104. PMC 1838518. PMID 17372194. 
  14. ↑ Packe GE, Innes JA. (1988). "Protective effect of BCG vaccination in infant Asians: a case-control study". Archives of Disease in Childhood 63 (3): 277–281. doi:10.1136/adc.63.3.277. PMC 1778792. PMID 3258499. 
  15. ↑ Black GF, Weir RE, Floyd S (2002). "BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malai and the UK: two randomized controlled studies". Lancet 359 (9315): 1393–401. doi:10.1016/S0140-6736(02)08353-8. PMID 11978337. 
  16. ↑ Palmer CE, Long MW. (1966). "Effects of infection with atypical mycobacteria on BCG vaccination and tuberculosis". Am Rev Respir Dis: 553–68. 
  17. ↑ Brandt L, Feino Cunha J, Weinreich Olsen A (2002). "Failure of Mycobacterium bovis BCG vaccine: some species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to tuberculosis". Infection and Immunity 70 (2): 672–78. doi:10.1128/IAI.70.2.672-678.2002. PMC 127715. PMID 11796598. 
  18. ↑ Rook GAW; Dheda K; Zumla A. (2005). "Do successful tuberculosis vaccines need to be immunoregulatory rather than merely Th1-boosting?". Vaccine 23 (17–18): 2115–20. doi:10.1016/j.vaccine.2005.01.069. PMID 15755581. 
  19. ↑ Jeevan A, Sharma AK, McMurray DN (November 2009). "Ultraviolet radiation reduces resistance to Mycobacterium tuberculosis infection in BCG-vaccinated guinea pigs". Tuberculosis (Edinb) 89 (6): 431–8. doi:10.1016/j.tube.2009.09.004. PMID 19850524. 
  20. ↑ Name * (2013-01-18). "BCG Vaccine | TB Symptoms | Tuberculin Skin Test | PPD | TB Signs". TB Symptoms. Retrieved 2014-02-02. 
  21. ↑ WHO (2004). WHO Position Paper on BCG Vaccination. Geneva: WHO. 
  22. ↑ "relatif à l'obligation de vaccination par le BCG des professionnels listés aux articles L" (PDF). Retrieved 2014-02-02. 
  23. ↑ Styblo K, Meijer J. (1976). "Impact of BCG vaccination programs in children and young adults on the tuberculosis problem". Tubercle 57 (1): 17–43. doi:10.1016/0041-3879(76)90015-5. PMID 1085050. 
  24. ↑ Mahler HT, Mohamed Ali P (1955). "Review of mass B.C.G. project in India". Ind J Tuberculosis 2 (3): 108–16. 
  25. ↑
  26. ↑ Nick Makwana and Andrew Riordan (2004), "Is medical therapy effective in the treatment of BCG abscesses?", Birmingham Heartlands Hospital
  27. ↑ Setia MS, Steinmaus C, Ho CS, Rutherford GW. (2006). "The role of BCG in prevention of leprosy: a meta-analysis". Lancet Infect Dis 6 (3): 162–70. doi:10.1016/S1473-3099(06)70412-1. PMID 16500597. 
  28. ↑ Merle, Corinne SC; Cunha, Sergio S; Rodrigues, Laura C (2010). "BCG vaccination and leprosy protection: Review of current evidence and status of BCG in leprosy control". Expert Review of Vaccines 9 (2): 209–22. doi:10.1586/ERV.09.161. PMID 20109030. 
  29. ↑ Tanghe, A., J. Content, J. P. Van Vooren, F. Portaels, and K. Huygen (2001). "Protective efficacy of a DNA vaccine encoding antigen 85A from Mycobacterium bovis BCG against Buruli ulcer". Infection and Immunity 69 (9): 5403–11. doi:10.1128/IAI.69.9.5403-5411.2001. PMC 98650. PMID 11500410. 
  30. ↑ Lamm DL, Blumenstein BA, Crawford ED (1991). "A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional-cell carcinoma of the bladder". N Engl J Med 325 (2): 1205–9. doi:10.1056/NEJM199110243251703. PMC 1164610. PMID 1922207. 
  31. ↑ Mosolits S, Nilsson B, Mellstedt H. (2005). "Towards therapeutic vaccines for colorectal carcinoma: a review of clinical trials". Expert Rev Vaccines 4 (3): 329–50. doi:10.1586/14760584.4.3.329. PMID 16026248. 
  32. ↑ Faustman, DL; Wang L, Okubo Y, Burger D, Ban L, Man G, Zheng H, Schoenfeld D, Pompei R, Avruch J, Nathan D (Aug 2012). "Proof-of-Concept, Randomized, Controlled Clinical Trial of Bacillus-Calmette-Guerin for Treatment of Long-Term Type 1 Diabetes". In Doherty, T. Mark. PLoS ONE 7 (8): e41756. doi:10.1371/journal.pone.0041756. PMC 3414482. PMID 22905105. 
  33. ↑ "Human trials to begin on 'diabetes cure' after terminally ill mice are returned to health". Daily Mail (London). 14 March 2008. 
  34. ↑ 34.0 34.1 Ristori, G; Buzzi MG, Sabatini U, Giugni E, Bastianello S, Viselli F, Buttinelli C, Ruggieri S, Colonnese C, Pozzilli C, Salvetti M (Oct 1999). "Use of Bacille Calmette-Guèrin (BCG) in multiple sclerosis". Neurology 53 (7): 1588–9. doi:10.1212/WNL.53.7.1588. PMID 10534275. 
  35. ↑ Paolillo, A; Buzzi MG, Giugni E, Sabatini U, Bastianello S, Pozzilli C, Salvetti M, Ristori G. (February 2003). "The effect of Bacille Calmette-Guérin on the evolution of new enhancing lesions to hypointense T1 lesions in relapsing remitting MS". J Neurol 250 (2): 247–8. doi:10.1007/s00415-003-0967-6. PMID 12622098. 
  36. ↑ Rutschmann, OT; McCrory, DC; Matchar, DB; Immunization Panel of the Multiple Sclerosis Council for Clinical Practice Guidelines (Dec 2002). "Immunization and MS: a summary of published evidence and recommendations". Neurology 59 (12): 1837–43. doi:10.1212/WNL.59.12.1837. PMID 12499473. 
  37. ↑ Yong, J; Goran Lacan, Hoa Dang, Terry Hsieh, Blake Middleton, Clive Wasserfall, Jide Tian, William P. Melega, Daniel L. Kaufman (Jan 2011). "BCG Vaccine-Induced Neuroprotection in a Mouse Model of Parkinson's Disease". In Zimmer, Jacques. PLoS ONE 6 (1): e16610. doi:10.1371/journal.pone.0016610. PMC 3031604. PMID 21304945. 
  38. ↑ Laćan, Goran; Dang, Hoa; Middleton, Blake; Horwitz, Marcus A.; Tian, Jide; Melega, William P.; Kaufman, Daniel L. (2013). "Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease". Journal of Neuroscience Research 91 (10): 1292–302. doi:10.1002/jnr.23253. PMID 23907992. 
  39. ↑ Govindarajan KK, Chai FY (2011). "BCG adenitis — need for increased awareness". Mal J Med Sci 18 (2): 67–70.  Malaysian Journal of Medical Sciences
  40. ↑ Centers for Disease Control and Prevention (1996). "The role of BCG vaccine in the prevention and control of tuberculosis in the United States: a joint statement of the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices". MMWR Recomm Rep 45 (RR-4): 1–18. PMID 8602127. 
  41. ↑ WHO (2007). "Revised BCG vaccination guidelines for infants at risk for HIV infection". Wkly Epidemiol Rec 82 (21): 193–6. PMID 17526121. 
  42. ↑ Trunz BB, Fine P, Dye C (2006). "Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness". Lancet 367 (9517): 1173–80. doi:10.1016/S0140-6736(06)68507-3. PMID 16616560. 
  43. ↑ Mak TK, Hesseling AC, Hussey GD, Cotton MF (2008). "Making BCG vaccination programs safer in the HIV era". Lancet 372 (9641): 786–7. doi:10.1016/S0140-6736(08)61318-5. PMID 18774406. 
  44. ↑ "Pharmaceutical Information - PACIS". RxMed. Retrieved 2014-02-02. 
  45. ↑ "BCG Vaccine Danish Strain 1331 - Statens Serum Institut". Ssi.dk. 2013-09-19. Retrieved 2014-02-02. 
  46. ↑ Fine, P.E.M (2004). Issues relating to the use of BCG in immunization programmes A discussion document, WHO/V&B/99.23. Geneva: WHO. 

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