BCG vaccine

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 FDA Professional Drug Information
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		 Percutaneous
ATC code
Legal status
Legal status
Identifiers
ChemSpider
  • none

Bacillus Calmette–Guérin (BCG) vaccine is a vaccine primarily used against tuberculosis.[1] In countries where tuberculosis is common, one dose is recommended in healthy babies as close to the time of birth as possible.[1] Babies with HIV/AIDS should not be vaccinated.[2] In areas where tuberculosis is not common, only children at high risk are typically immunized, while suspected cases of tuberculosis are individually tested for and treated.[1] Adults who do not have tuberculosis and have not been previously immunized but are frequently exposed to drug-resistant tuberculosis may be immunized as well.[1] The vaccine is also often used as part of the treatment of bladder cancer.[3]

Rates of protection against tuberculosis infection vary widely and protection lasts between ten and twenty years.[1] Among children it prevents about 20% from getting infected and among those who do get infected it protects half from developing disease.[4] The vaccine is given by injection into the skin.[1] Additional doses are not supported by evidence.[1] It may also be used in the treatment of some types of bladder cancers.[5]

Serious side effects are rare.[1] Often there is redness, swelling, and mild pain at the site of injection.[1] A small ulcer may also form with some scarring after healing.[1] Side effects are more common and potentially more severe in those with poor immune function.[1] It is not safe for use during pregnancy.[1] The vaccine was originally developed from Mycobacterium bovis which is commonly found in cows.[1] While it has been weakened, it is still live.[1]

The BCG vaccine was first used medically in 1921.[1] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[6] Between 2011 and 2014 the wholesale price was $0.16 to $1.11 USD a dose in the developing world.[7][8] In the United States it costs $100 to $200 USD.[9] As of 2004 the vaccine is given to about 100 million children per year globally.[1]

Medical uses

Tuberculosis

The main use of BCG is for vaccination against tuberculosis. BCG vaccine can be administered after birth intradermally.[10] 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 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.[11][12]

A 1994 systematic review found that BCG reduces the risk of getting TB by about 50%.[11] 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.[13][14]

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%.[15] 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.[16]

BCG seems to have its greatest effect in preventing miliary TB or TB meningitis, so it is still extensively used even in countries where efficacy against pulmonary tuberculosis is negligible.[17]

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.[18]

  1. Genetic variation in BCG strains: Genetic variation in the BCG strains used may explain the variable efficacy reported in different trials.[19]
  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.[20]
  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.[21] 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.[22] 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.[23]
  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.[24]

Mycobacteria

Cancer

Micrograph 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.[28] BCG vaccine has been the "standard of care for patients with bladder cancer (NMIBC)" since 1977.[28][29] By 2014 there were more than eight different considered biosimilar agents or strains used for the treatment of non–muscle-invasive bladder cancer (NMIBC).[28] [29]

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 also contraindicated in certain people who have IL-12 receptor pathway defects.

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.[32]

The characteristic raised scar 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.

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.[33]

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.[34]

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.[35] In 2007, The WHO stopped recommending BCG for infants with HIV, even if there is a high risk of exposure to TB,[36] because of the risk of disseminated BCG infection (which is approximately 400 per 100,000 in that higher risk context).[37][38]

Usage

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

Manufacturer

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. 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 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.[13]

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,[54] 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 markets BCG vaccine prepared using Danish strain 1331.[55] 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. In order 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."[56]

BCG supply shortage 2012–

In the fall of 2011 the Sanofi Pasteur plant flooded causing problems with mold.[57] The facility, located in Toronto, Ontario, Canada, produced BCG vaccine products, made with substrain Connaught, such as a tuberculosis vaccine ImmuCYST, a BCG Immunotherapeutic – a bladder cancer drug.[58] By April 2012 the FDA had found dozens of documented problems with sterility at the plant including mold, nesting birds and rusted electrical conduits.[57] The resulting closure of the plant for over two years resulting in shortages of bladder cancer and tuberculosis vaccines.[59][60] On October 29, 2014 Health Canada gave the permission for Sanofi to resume production of BCG.[61]

Preparation

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

Dried

Some BCG vaccines are freeze dried and become fine powder. Sometimes the powder are 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.

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 BCG strain was isolated after subculturing 239 times 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.[62]

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.[63]

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 only became widely used 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. 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).[64][65]

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

Research

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,[66] with greater benefit the earlier it is used.[67]

Other tuberculosis vaccines

See: Tuberculosis vaccines

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "BCG Vaccine: WHO position paper" (PDF). Weekly epidemiological record. 4 (79): 25–40. Jan 23, 2004.
  2. ↑ "Revised BCG vaccination guidelines for infants at risk for HIV infection." (PDF). Wkly Epidemiol Rec. 82 (21): 193–196. May 25, 2007. PMID 17526121.
  3. ↑ Fuge, O; Vasdev, N; Allchorne, P; Green, JS (2015). "Immunotherapy for bladder cancer.". Research and reports in urology. 7: 65–79. PMC 4427258 Freely accessible. PMID 26000263. doi:10.2147/RRU.S63447.
  4. ↑ Roy, A; Eisenhut, M; Harris, RJ; Rodrigues, LC; Sridhar, S; Habermann, S; Snell, L; Mangtani, P; Adetifa, I; Lalvani, A; Abubakar, I (5 August 2014). "Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis.". BMJ (Clinical research ed.). 349: g4643. PMC 4122754 Freely accessible. PMID 25097193. doi:10.1136/bmj.g4643.
  5. ↑ Houghton, BB; Chalasani, V; Hayne, D; Grimison, P; Brown, CS; Patel, MI; Davis, ID; Stockler, MR (May 2013). "Intravesical chemotherapy plus bacille Calmette-Guérin in non-muscle invasive bladder cancer: a systematic review with meta-analysis.". BJU international. 111 (6): 977–83. PMID 23253618. doi:10.1111/j.1464-410x.2012.11390.x.
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  8. ↑ "Vaccine, Bcg". ERC. Retrieved 13 June 2016.
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  11. 1 2 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. PMID 8309034. doi:10.1001/jama.1994.03510330076038.
  12. ↑ Fine PEM (1995). "Variation in protection by BCG: implications of and for heterologous immunity". Lancet. 346 (8986): 1339–45. PMID 7475776. doi:10.1016/S0140-6736(95)92348-9.
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  16. ↑ 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. PMID 15126436. doi:10.1001/jama.291.17.2086.
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  22. ↑ Palmer CE, Long MW (1966). "Effects of infection with atypical mycobacteria on BCG vaccination and tuberculosis". Am Rev Respir Dis: 553–68.
  23. ↑ 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. PMC 127715 Freely accessible. PMID 11796598. doi:10.1128/IAI.70.2.672-678.2002.
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  25. ↑ 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. PMID 16500597. doi:10.1016/S1473-3099(06)70412-1.
  26. ↑ 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. PMID 20109030. doi:10.1586/ERV.09.161.
  27. ↑ Tanghe, A.; J. Content; J. P. Van Vooren; F. Portaels; 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. PMC 98650 Freely accessible. PMID 11500410. doi:10.1128/IAI.69.9.5403-5411.2001.
  28. 1 2 3 Rentsch, Cyrill A.; Birkhäuser, Frédéric D.; Biot, Claire; Gsponer, Joël R.; Bisiaux, Aurélie; Wetterauer, Christian; Lagranderie, Micheline; Marchal, Gilles; Orgeur, Mickael; Bouchier, Christiane; Bachmann, Alexander; Ingersoll, Molly A.; Brosch, Roland; Albert, Matthew L.; Thalmann, George N. (1 October 2014). "Bacillus Calmette-Guérin Strain Differences Have an Impact on Clinical Outcome in Bladder Cancer Immunotherapy". European Urology. 66 (4): 677–688. doi:10.1016/j.eururo.2014.02.061.
  29. 1 2 Brandau, S.; Suttmann, H. (2007). "Thirty years of BCG immunotherapy for non-muscle invasive bladder cancer: a success story with room for improvement". Biomed Pharmacother. 61: 299–305. doi:10.1016/j.biopha.2007.05.004.
  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. PMID 1922207. doi:10.1056/NEJM199110243251703.
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  32. ↑ Nick Makwana and Andrew Riordan (2004), "Is medical therapy effective in the treatment of BCG abscesses?", Birmingham Heartlands Hospital
  33. ↑ Cuello-García, Carlos A.; Pérez-Gaxiola, Giordano; Jiménez Gutiérrez, Carlos (2013-01-01). "Treating BCG-induced disease in children". The Cochrane Database of Systematic Reviews. 1: CD008300. ISSN 1469-493X. PMID 23440826. doi:10.1002/14651858.CD008300.pub2.
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  36. ↑ WHO (2007). "Revised BCG vaccination guidelines for infants at risk for HIV infection". Wkly Epidemiol Rec. 82 (21): 193–6. PMID 17526121.
  37. ↑ 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. PMID 16616560. doi:10.1016/S0140-6736(06)68507-3.
  38. ↑ Mak TK, Hesseling AC, Hussey GD, Cotton MF (2008). "Making BCG vaccination programs safer in the HIV era". Lancet. 372 (9641): 786–7. PMID 18774406. doi:10.1016/S0140-6736(08)61318-5.
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  41. ↑ Loi n° 50-7 du 5 janvier 1950
  42. ↑ décret n° 2007-1111 du 17 juillet 2007
  43. ↑ "relatif à l'obligation de vaccination par le BCG des professionnels listés aux articles L" (PDF). Retrieved 2014-02-02.
  44. ↑ Mahler HT, Mohamed Ali P (1955). "Review of mass B.C.G. project in India". Ind J Tuberculosis. 2 (3): 108–16. Archived from the original on 2007-02-13.
  45. ↑ "結核とBCGワクチンに関するQ&A｜厚生労働省". www.mhlw.go.jp (in Japanese). Retrieved 2017-07-10.
  46. ↑ C. Oyunsolong, personal communication. Vaccine Specialist, Selenge Province Health Department, Mongolia. 14 January 2015.
  47. ↑ 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
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  50. ↑ "Thai Pediatrics". Thai Pediatrics.
  51. ↑ Styblo, K; Meijer, J (March 1976). "Impact of BCG vaccination programmes in children and young adults on the tuberculosis problem.". Tubercle. 57 (1): 17–43. PMID 1085050. doi:10.1016/0041-3879(76)90015-5.
  52. ↑ "School 'TB jabs' to be scrapped". BBC News. July 2005. Retrieved 24 September 2014.
  53. ↑ http://www.nhs.uk/conditions/vaccinations/pages/bcg-tuberculosis-tb-vaccine.aspx
  54. ↑ "Pharmaceutical Information - PACIS". RxMed. Retrieved 2014-02-02.
  55. ↑ "BCG Vaccine Danish Strain 1331 - Statens Serum Institut". Ssi.dk. 2013-09-19. Retrieved 2014-02-02.
  56. ↑ "Bacillus Calmette-Guérin Vaccine Supply & Demand Outlook" (PDF), UNICEF Supply Division, p. 5, December 2015, retrieved 29 January 2016
  57. 1 2 "April 2012 Inspectional Observations (form 483)", U.S. Food and Drug Administration, Vaccines, Blood & Biologics, 12 April 2012, retrieved 29 January 2016
  58. ↑ "Sanofi Pasteur Product Monograph - Immucyst" (PDF). Sanofi Pasteur Canada. Retrieved 11 February 2016.
  59. ↑ Palmer, Eric (10 September 2014), "Merck again shipping BCG cancer treatment but Sanofi still is not: Shortages of bladder cancer and tuberculosis treatment have persisted for two years", FiercePharma
  60. ↑ Palmer, Eric (12 July 2012), "Merck again shipping BCG cancer treatment but Sanofi still is not: Shortages of bladder cancer and tuberculosis treatment have persisted for two years", FiercePharma
  61. ↑ Palmer, Eric (31 March 2015), "Sanofi Canada vax plant again producing ImmuCyst bladder cancer drug", FiercePharma, retrieved 29 January 2016
  62. ↑ Fine PE, Carneiro IA, Milstein JB, Clements CJ (1999). Issues relating to the use of BCG in immunization programs. Geneva: WHO.
  63. ↑ Rosenthal SR. (1957). BCG vaccination against tuberculosis. Boston: Little, Brown & Co.
  64. ↑ "Fact Sheets: BCG Vaccine". Centers for Disease Control and Prevention. 28 October 2011. Retrieved 18 July 2013.
  65. ↑ "Vaccination of young children against tuberculosis" (PDF) (2011/04). The Hague:Health Council of the Netherlands. 17 March 2011. ISBN 978-90-5549-844-4. Retrieved 12 July 2013.
  66. ↑ 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 (15 July 2011). "Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period?". The Journal of Infectious Diseases. 204 (2): 245–52. PMID 21673035. doi:10.1093/infdis/jir240.
  67. ↑ Biering-Sørensen, S; Aaby, P; Napirna, BM; Roth, A; Ravn, H; Rodrigues, A; Whittle, H; Benn, CS (March 2012). "Small randomized trial among low-birth-weight children receiving bacillus Calmette-Guérin vaccination at first health center contact.". The Pediatric Infectious Disease Journal. 31 (3): 306–8. PMID 22189537. doi:10.1097/inf.0b013e3182458289.
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