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]

 More later

Text under construction

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