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BCG vaccine

bcg vaccine, bcg vaccine side effects
Bacillus Calmette–Guérin BCG vaccine is a vaccine primarily used against tuberculosis1 In countries where tuberculosis is common, one dose is recommended in healthy babies as close to the time of birth as possible1 Babies with HIV/AIDS should not be vaccinated2 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 treated1 Adults who do not have tuberculosis and have not been previously immunized but are frequently exposed to drug-resistant tuberculosis may be immunized as well1 The vaccine is also often used as part of the treatment of bladder cancer3

Rates of protection against tuberculosis infection vary widely and protection lasts between ten and twenty years1 Among children it prevents about 20% from getting infected and among those who do get infected it protects half from developing disease4 The vaccine is given by injection into the skin1 Additional doses are not supported by evidence1 It may also be used in the treatment of some types of bladder cancers5

Serious side effects are rare1 Often there is redness, swelling, and mild pain at the site of injection1 A small ulcer may also form with some scarring after healing1 Side effects are more common and potentially more severe in those with poor immune function1 It is not safe for use during pregnancy1 The vaccine was originally developed from Mycobacterium bovis which is commonly found in cows1 While it has been weakened, it is still live1

The BCG vaccine was first used medically in 19211 It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system6 Between 2011 and 2014 the wholesale price was $016 to $111 USD a dose in the developing world78 In the United States it costs $100 to $200 USD9 As of 2004 the vaccine is given to about 100 million children per year globally1

Contents

  • 1 Medical uses
    • 11 Tuberculosis
      • 111 Reasons
    • 12 Mycobacteria
    • 13 Cancer
    • 14 Method of administration
  • 2 Adverse effects
  • 3 Usage
  • 4 Manufacturer
    • 41 BCG supply shortage 2012–
    • 42 Preparation
    • 43 Dried
  • 5 History
  • 6 Research
  • 7 Other tuberculosis vaccines
  • 8 References
  • 9 External links

Medical usesedit

Tuberculosisedit

The main use of BCG is for vaccination against tuberculosis BCG vaccine can be administered after birth intradermally10 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 equator1112

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 medium1314

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 efficacy16

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 negligible17

Reasonsedit

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 BCG18

  1. Genetic variation in BCG strains: Genetic variation in the BCG strains used may explain the variable efficacy reported in different trials19
  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 hypothesis20
  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 Malawi21 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 known22 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 hypothesis23
  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 BCG24

Mycobacteriaedit

  • 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%2526 However BCG vaccine is not used specifically to control leprosy
  • Buruli ulcer: BCG may protect against or delay the onset of Buruli ulcer27

Canceredit

See also: Cancer immunotherapy, Cancer vaccine, and Coley's toxins 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 immunotherapies28 BCG vaccine has been the "standard of care for patients with bladder cancer NMIBC" since 19772829 By 2014 there were more than eight different considered biosimilar agents or strains used for the treatment of non–muscle-invasive bladder cancer NMIBC28 29

  • 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 disease30 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 cancer31 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

Method of administrationedit

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 weeks32

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 effectsedit

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 scarce33

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 complications34

If BCG is accidentally given to an immunocompromised patient eg, 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 given35 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 context3738

Usageedit

The age of the person 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 meningitis39
  • Brazil: Brazil introduced universal BCG immunization in 1967–1968, and the practice continues until now According to Brazilian law, BCG is given again to professionals of the health sector and to people close to patients with tuberculosis or leprosy
  • Central and South America: Most countries in Central and South America have universal BCG immunizations In Ecuador, a child cannot receive their birth certificate without having the BCG vaccine in their medical record along with other vaccinations40
  • France: The BCG was mandatory for school children between 1950 and 2007,4142 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 basis43
  • India and Pakistan: India and Pakistan introduced BCG mass immunization in 1948, the first countries outside Europe to do so44
  • Japan: In Japan, BCG is administered between five and eight months after birth, and no later than a child's first birthday BCG was administered no later than the fourth birthday until 2005, and no later than six months from birth from 2005 to 2012; the schedule was changed in 2012 due to reports of osteitis side effects from vaccinations at 3-4 months Some municipalities recommend an earlier immunization schedule45
  • Mongolia: All newborns are vaccinated with BCG Previously, the vaccine was also given at ages 8 and 15, although this is no longer common practice46
  • Norway: In Norway the BCG vaccine was mandatory from 1947 to 1995 It is still available and recommended for high-risk groups47
  • Philippines: BCG vaccine started in the Philippines in 1979 with the Expanded Program on Immunization
  • South Africa: In South Africa, the BCG Vaccine is given routinely at birth, to all newborns, except those with clinically symptomatic AIDS The vaccination site in the right shoulder48
  • Sri Lanka: In Sri Lanka, The National Policy of Sri Lanka is to give BCG vaccination to all newborn babies immediately after birth BCG vaccination is carried out under the Expanded Programme of Immunisation EPI49
  • Thailand: In Thailand, the BCG Vaccine is given routinely at birth50
  • United Kingdom: The UK introduced universal BCG immunization in 1953, and until July 2005, the UK policy was to immunize all school children between 10 and 14 years of age, and all neonates born into high-risk groups The injection was given only once during an individual's lifetime as there is no evidence of additional protection from more than one vaccination BCG was also given to protect people who had been exposed to tuberculosis The peak of tuberculosis incidence is in adolescence and early adulthood, and the MRC trial showed efficacy lasted a maximum of 15 years51 Routine immunization with BCG for all school children was scrapped in July 2005 because of falling cost-effectiveness: whereas in 1953, 94 children would have to be immunized to prevent one case of TB, by 1988, the annual incidence of TB in the UK had fallen so much, 12,000 children would have to be immunized to prevent one case of TB52 The vaccine is still given to certain healthcare professionals, however53
  • United States: The US has never used mass immunization of BCG, relying instead on the detection and treatment of latent tuberculosis
  • Other countries: In some countries, such as the former Soviet Union, BCG was given regularly throughout life In South Korea, Singapore, Taiwan and Malaysia, BCG was given at birth and again at age 12 But in Malaysia and Singapore, from 2001, this policy was changed to once only at birth South Korea also stopped the re-vaccination in 2008 In the Canadian province of Quebec, the BCG vaccine was provided to children until the early 1960s

Manufactureredit

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 grown13

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 133155 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 1522 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–edit

In the fall of 2011 the Sanofi Pasteur plant flooded causing problems with mold57 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 drug58 By April 2012 the FDA had found dozens of documented problems with sterility at the plant including mold, nesting birds and rusted electrical conduits57 The resulting closure of the plant for over two years resulting in shortages of bladder cancer and tuberculosis vaccines5960 On October 29, 2014 Health Canada gave the permission for Sanofi to resume production of BCG61

Preparationedit

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

Driededit

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

Historyedit

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 192162

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 vaccine63

Dr RG 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 there6465

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

Researchedit

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 used67

Other tuberculosis vaccinesedit

See: Tuberculosis vaccines

Referencesedit

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  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 
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  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:101093/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:101097/inf0b013e3182458289 

External linksedit

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

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