Bacillus Calmette–Guérin (BCG) vaccine, Bladder Cancer & More

Bacillus Calmette–Guérin (BCG) vaccine is a vaccine primarily used against tuberculosis (TB).[1]  WHO recommends BCG be given to all children born in countries with a high incidence of TB and/or high leprosy burden.[1] Additionally it is sometimes used as part of the treatment of bladder cancer.[2][3]

Serious side effects are rare. 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.[5] Between 2011 and 2014 the wholesale price was $0.16 to $1.11 USD a dose in the developing world.[6][7] In the United States it costs $100 to $200 USD.[8] As of 2004 the vaccine is given to about 100 million children per year globally.[9]

  Cancer immunotherapy, Cancer vaccine, and Coley’s toxins

Micrograph showing granulomatousinflammation 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.[26] BCG vaccine has been the “standard of care for patients with bladder cancer (NMIBC)” since 1977.[26][27] By 2014 there were more than eight different considered biosimilar agents or strains used for the treatment of non–muscle-invasive bladder cancer (NMIBC).[26] [27] A number of cancer vaccines use BCG as an additive to provide an initial stimulation of the person’s immune systems.

BCG is used in the treatment of superficial forms of bladder cancer. Since the late 1970s, evidence has become available that instillation of BCG into the bladder is an effective form of immunotherapy in this disease.[28]

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.

BCG has been evaluated in a number of studies as a therapy for colorectal cancer.[29] 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.

 How is this Vaccine made ?

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 & Co.). Pacis BCG, made from the Montréal (Institut Armand-Frappier) strain,[50] 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.[51] 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.”[52]

A weakened strain of bovine tuberculosis bacillus, Mycobacterium bovis is specially subcultured in a culture medium, usually Middlebrook 7H9. Some BCG vaccines are freeze dried and become fine powder. Sometimes the powder is 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.

French poster promoting the BCG vaccine

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 tuberculosis 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. Calmette and Guerin transferred to the Paris Pasteur Institute in 1919. The BCG vaccine was first used in humans in 1921.[59]

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.[60]

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 United States and the Netherlands (in both countries, it is felt that having a reliable Mantoux test and therefore being able to accurately detect active disease is more beneficial to society than vaccinating against a condition that is now relatively rare there).[61][62] Other names include “Vaccin Bilié de Calmette et Guérin vaccine” and “Bacille de Calmette et Guérin vaccine”.

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,[63] with greater benefit the earlier it is used.[64] BCG vaccine is in the early stages of being studied in type I diabetes.[65][66]

France: The BCG was mandatory for school children between 1950 and 2007,[38][39] 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.[40] United States: The US has never used mass immunization of BCG, relying instead on the detection and treatment of latent tuberculosis.

Discussion

The most controversial aspect of BCG in non-cancer diseases 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]

This suggests that Vitamin D naturally boosts immunity, thereby bypassing the BCG’s effect.

Interference by concurrent parasitic infection could be another explanation. 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] BCG has protective effects against some non-tuberculosis mycobacteria.  BCG has a protective effect against leprosy in the range of 20 to 80%.[1] Buruli ulcer: BCG may protect against or delay the onset of Buruli ulcer.[1][25]

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.[33] In 2007, The WHO stopped recommending BCG for infants with HIV, even if there is a high risk of exposure to TB,[34] because of the risk of disseminated BCG infection (which is approximately 400 per 100,000 in that higher risk context).[35][36]

Discussion on BCG and Cancer

The way BCG for bladder cancer works, is  via the production of liquid with the BCG medicine, and then putting it inside the bladder. And when it is in the bladder, it actually activates the patient’s immune system, turning on the immune cells – the T cells specifically – and it generally attacks the abnormal cells in the bladder that are cancerous. In that regard, it is a really clever design because you can put BCG in to the bladder and it activates the immune system, but the bladder itself serves as the perfect barrier to prevent it from getting in to the body. It is a really great treatment for patients with non-muscle invasive bladder cancer.

In bladder cancer, which group of patients should be treated with BCG?

For patients who reject the holistic approach, BCG is a better option than chemo, in particular for patients with non-muscle invasive bladder cancer. The diagnoses that we can think about when we want to use BCG are carcinoma in situ (CIS), high-grade disease or patients with T1 disease, and in cases of patients who have disease that is categorized as intermediate- or high-risk disease.

It is one of the most well studied treatments. In each case, every patient and diagnosis are unique, so this treatment also needs to be personalized.

It is nearly 40 years since Bacillus Calmette–Guérin (BCG) was first used as an immunotherapy to treat superficial bladder cancer. Despite its limitations, to dayte, with regard to Conventional oncology,  it has not been surpassed by any other treatment. As a better understanding of its mechanism of action and the clinical response to it have evolved, some of the questions around optimal dosing and treatment protocols have been answered. However, its potential for toxicity and failure to produce the desired clinical effect in a significant cohort of patients presents an ongoing challenge to conventional  clinicians and mainstream researchers alike. An extensive array of immune molecules that have been implicated in its action of mechanism.

Tentative Conclusion

From the viewpoint of holistic oncology,  the role photodynamic therapy as well as a few other credible  alternatives should be first used, saving BCG as a last resort.

 Beyond BCG, researchers are also looking at studying different ways of treating these patients using things like genetic therapy, oral or IV immunotherapy, radiation and a number of other agents. There are a number of clinical trials in progress. Recent interest in the immune check point system has led to the development of monoclonal antibodies against proteins involved with bladder cancer. However, as noted in other blogs, the immune system can attack innoncent tissues. Here too, this technique should be saved as a last option while holistic interventions that target the microbiome and the immune system should be the first line approach.

Consider scheduling a coaching session for further discussion.

Text under constellation

References

  1. “BCG vaccines: WHO position paper – February 2018″ (PDF). Releve epidemiologique hebdomadaire. 93 (8): 73–96. 23 February 2018. PMID 29474026.
  2. ^ Fuge, O; Vasdev, N; Allchorne, P; Green, JS (2015). “Immunotherapy for bladder cancer”. Research and reports in urology. 7: 65–79. doi:10.2147/RRU.S63447. PMC 4427258. PMID 26000263.
  3. ^ 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. doi:10.1111/j.1464-410x.2012.11390.x. PMID 23253618.
  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. doi:10.1136/bmj.g4643. PMC 4122754. PMID 25097193.
  5. ^ “WHO Model List of Essential Medicines (19th List)” (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
  6. ^ “Vaccine, Bcg”. International Drug Price Indicator Guide. Retrieved 6 December 2015.[permanent dead link]
  7. ^ “Vaccine, Bcg”. ERC. Archived from the original on 22 January 2018. Retrieved 13 June 2016.
  8. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 312. ISBN 9781284057560.
  9. ^ “BCG Vaccine: WHO position paper” (PDF). Weekly epidemiological record. 4(79): 25–40. Jan 23, 2004. Archived (PDF) from the original on 2015-09-21.
  10. ^ “BCG Vaccine | TB Symptoms | Tuberculin Skin Test | PPD | TB Signs”. TB Symptoms. 2013-01-18. Archived from the original on 2013-10-29. Retrieved 2014-02-02.
  11. ^ Jump up to: a b 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.
  12. ^ 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.
  13. ^ Jump up to: a b 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.
  14. ^ 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. PMID 7475776.
  15. ^ Roy A, Eisenhut M, Harris RJ, et al. (2014). “Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis”. BMJ. 349: g4643. doi:10.1136/bmj.g4643. PMC 4122754. PMID 25097193.
  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. doi:10.1001/jama.291.17.2086. PMID 15126436.
  17. ^ 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.
  18. ^ Fine PE, Carneiro IA, Milstein JB, Clements CJ (1999). “Chapter 8: Reasons for variable efficacy”. Issues relating to the use of BCG in immunization programmes (PDF). Geneva, Switzerland: World Health Organization. Archived (PDF) from the original on 2011-02-20.
  19. ^ 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.
  20. ^ 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. Archivedfrom the original on 2008-10-04.
  21. ^ 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.
  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. doi:10.1128/IAI.70.2.672-678.2002. PMC 127715. PMID 11796598.
  24. ^ Rook GAW; Dheda K; Zumla A. (2005). “Do successful tuberculosis vaccines need to be immunoregulatory rather than merely Th1-boosting?” (PDF). Vaccine. 23 (17–18): 2115–20. doi:10.1016/j.vaccine.2005.01.069. PMID 15755581. Archived (PDF) from the original on 2017-09-22.
  25. ^ 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. doi:10.1128/IAI.69.9.5403-5411.2001. PMC 98650. PMID 11500410.
  26. ^ Jump up to: a b c 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.
  27. ^ Jump up to: a b 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.
  28. ^ 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. PMID 1922207.
  29. ^ 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.
  30. ^ Nick Makwana and Andrew Riordan (2004), “Is medical therapy effective in the treatment of BCG abscesses?”, Birmingham Heartlands Hospital “Archived copy”. Archived from the original on 2007-02-16. Retrieved 2007-04-01.
  31. ^ 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. doi:10.1002/14651858.CD008300.pub2. ISSN 1469-493X. PMID 23440826.
  32. ^ Govindarajan KK, Chai FY (2011). “BCG adenitis — need for increased awareness”. Mal J Med Sci. 18 (2): 67–70. Malaysian Journal of Medical Sciences Archived 2012-03-26 at the Wayback Machine
  33. ^ 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.
  34. ^ WHO (2007). “Revised BCG vaccination guidelines for infants at risk for HIV infection”. Wkly Epidemiol Rec. 82 (21): 193–6. PMID 17526121.
  35. ^ 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.
  36. ^ 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.
  37. ^ “Archived copy”. Archived from the original on 2015-04-02. Retrieved 2015-03-12.
  38. ^ Loi n° 50-7 du 5 janvier 1950
  39. ^ décret n° 2007-1111 du 17 juillet 2007
  40. ^ “relatif à l’obligation de vaccination par le BCG des professionnels listés aux articles L” (PDF). Archived (PDF) from the original on 2012-07-30. Retrieved 2014-02-02.
  41. ^ 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.
  42. ^ “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). Archived from the original on 2017-04-16. Retrieved 2017-07-10.
  43. ^ 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#eHandbook687100Archived 2016-03-07 at the Wayback Machine
  44. ^ [1] Archived May 11, 2013, at the Wayback Machine
  45. ^ “Role Of BC Vaccination”. The National Programme for TB Control & Chest Diseases. Archived from the original on 2013-06-06.
  46. ^ “Thai Pediatrics”. Thai Pediatrics. Archived from the original on 2015-11-19.
  47. ^ 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. doi:10.1016/0041-3879(76)90015-5. PMID 1085050.
  48. ^ “School ‘TB jabs’ to be scrapped”. BBC News. July 2005. Archived from the original on 6 March 2012. Retrieved 24 September 2014.
  49. ^ “Archived copy”. Archived from the original on 2016-04-01. Retrieved 2016-03-27.
  50. ^ “Pharmaceutical Information – PACIS”. RxMed. Archived from the original on 2014-02-22. Retrieved 2014-02-02.
  51. ^ “BCG Vaccine Danish Strain 1331 – Statens Serum Institut”. Ssi.dk. 2013-09-19. Archived from the original on 2014-02-18. Retrieved 2014-02-02.
  52. ^ “Bacillus Calmette-Guérin Vaccine Supply & Demand Outlook” (PDF), UNICEF Supply Division, p. 5, December 2015, archived (PDF) from the original on 5 February 2016, retrieved 29 January 2016
  53. ^ Jump up to: a b “April 2012 Inspectional Observations (form 483)”, U.S. Food and Drug Administration, Vaccines, Blood & Biologics, 12 April 2012, archived from the original on 6 February 2016, retrieved 29 January 2016
  54. ^ “Sanofi Pasteur Product Monograph – Immucyst” (PDF). Sanofi Pasteur Canada. Retrieved 11 February 2016.
  55. ^ 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
  56. ^ 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
  57. ^ Palmer, Eric (31 March 2015), “Sanofi Canada vax plant again producing ImmuCyst bladder cancer drug”, FiercePharma, archived from the original on 5 February 2016, retrieved 29 January 2016
  58. ^ Cernuschi T, Malvolti S, Nickels E, Friede M (January 2018). “Bacillus Calmette-Guérin (BCG) vaccine: A global assessment of demand and supply balance”. Vaccine. 36 (4): 498–506. doi:10.1016/j.vaccine.2017.12.010. PMC 5777639. PMID 29254839.
  59. ^ Fine PE, Carneiro IA, Milstein JB, Clements CJ (1999). Issues relating to the use of BCG in immunization programs. Geneva: WHO.
  60. ^ Rosenthal SR. (1957). BCG vaccination against tuberculosis. Boston: Little, Brown & Co.
  61. ^ “Fact Sheets: BCG Vaccine”. Centers for Disease Control and Prevention. 28 October 2011. Archived from the original on 20 July 2013. Retrieved 18 July2013.
  62. ^ “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. Archived (PDF) from the original on 19 February 2014. Retrieved 12 July2013.
  63. ^ 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. doi:10.1093/infdis/jir240. PMID 21673035.
  64. ^ 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. doi:10.1097/inf.0b013e3182458289. PMID 22189537.
  65. ^ Kühtreiber, Willem M.; Tran, Lisa; Kim, Taesoo; Dybala, Michael; Nguyen, Brian; Plager, Sara; Huang, Daniel; Janes, Sophie; Defusco, Audrey; Baum, Danielle; Zheng, Hui & Faustman, Denise L. (2018). “Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations”. npj Vaccines. 3. doi:10.1038/s41541-018-0062-8.
  66. ^ Kowalewicz-Kulbat, M; Locht, C (July 2017). “BCG and protection against inflammatory and auto-immune diseases”. Expert review of vaccines. 16 (7): 1–10. doi:10.1080/14760584.2017.1333906. PMID 28532186.