Bacillus Calmette-Guérin

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The Bacille Calmette-Guérin ( BCG ) is a weakened virulent ( attenuated ) developed by the French Albert Calmette (1863–1933) and Camille Guérin (1872–1961) at the beginning of the 20th century from the wild type of the mycobacterium Mycobacterium bovis through repeated breeding ) Bacterium used as a live vaccine against tuberculosis (TB) in 173 countries . The BCG vaccine is on the World Health Organization's list of Essential Medicines .

The current application of BCG in Germany is in the area of bladder instillation . Mycobacterium bovis -BCG is classified in risk group 3 (RG 3) in Germany - with the exception of a single strain.

history

The French microbiologist Albert Calmette and the veterinarian Camille Guérin worked at the Pasteur Institute in Lille in 1908 . Her work included the creation of tuberculosis cultures and the testing of various nutrient media. They found that continuous subculturing using a nutrient medium based on glycerine , bile and potatoes weakened the virulence of the tubercleosis bacteria. Therefore, they investigated the question of whether repeated breeding could develop an attenuated vaccine.

The research lasted until 1919, whereby the vaccination with the reduced virulent bacteria could not stop the tuberculosis in test animals. In 1919 Calmette and Guérin transferred to the Pasteur Institute in Paris , where they developed the BCG vaccine for human use in 1921.

In 1928 this vaccine was accepted by the League of Nations Health Council . Due to the actions of vaccine opponents , it was not used extensively until after World War II . Aid organizations vaccinated around 8 million babies in Eastern Europe between 1945 and 1948, thus preventing the increase in tuberculosis incidence predicted after a major war. In Germany, as a result of the Lübeck vaccination accident , in which 77 of 256 vaccinated infants died, vaccination was only introduced after the Second World War.

Use as a vaccination

Main indication

The main indication for BCG is vaccination in newborns and young children to reduce the risk of miliary tuberculosis and tuberculous meningitis.

Selective indications

  • In countries with a high incidence of tuberculosis and high levels of leprosy , the World Health Organization recommends vaccinating all newborns at birth.
  • In countries with a low prevalence of tuberculosis and leprosy, the WHO recommends vaccinating only newborns in special risk groups with BCG. Which includes:
    • Newborns of parents (or other close contacts / relatives) with a current or previous tuberculosis - or leprosy disease infection
    • Newborns in households with contacts to countries with high tuberculosis -Inzidenz or leprosy -load
    • Newborns in other locally identified risk groups with tuberculosis and / or leprosy diseases.
  • Countries with falling tuberculosis rates should regularly assess their epidemiological situation and consider changing their vaccination strategy from universal vaccination to more selective.

BCG vaccinations in selected states

In accordance with these WHO recommendations, BCG immunization is only used in risk groups in most European countries and North America . The Switzerland ended the routine BCG immunization in 1987, Austria in 1989 and Germany in 1998. The BCG vaccination is since 1998 by the Standing Committee on Vaccination (STIKO) at the Robert Koch Institute no longer recommended ( "Reasons: favorable epidemiological situation in Germany with little Risk of infection in the population, a protective effectiveness of 50–80% depending on age and the type of illness, and not infrequently undesirable side effects (attenuated live vaccine). ”).

Lack of effectiveness of the vaccination

The BCG vaccination protects children and adults in most cases from the worst forms of the disease, but not from the most common form of tuberculosis, pulmonary tuberculosis, and has therefore not been able to contain tuberculosis worldwide.

Technique of vaccination

The vaccination must be administered strictly intradermally by a professional trained in this technique.

Effects on other mycobacteria

The BCG vaccination protects against Mycobacterium ulcerans , non-tuberculosis mycobacteria (NTM) and M. leprae to a limited extent .

Unspecific vaccination effects

Vaccination with BCG has non-specific effects (heterologous effects) and also makes vaccinated people less sensitive to other infections. In a small study it was shown that the immune cells in the blood of vaccinated individuals secrete significantly more cytokines than in non- vaccinated individuals. The vaccination also activated genes in immune cells that are necessary for increased cytokine production. Cytokines strengthen the immune system.

In a double-blind, randomized clinical study (“ACTIVATE” study) in seniors (average age 80 years) after a BCG vaccination, infectious diseases, especially respiratory infections, occurred less frequently in the first 12 months. The vaccination was also safe; adverse events did not occur more frequently than in the placebo group. Here, too, an increased cytokine production could be demonstrated in the BCG vaccinees.

Risk groups of the pathogen

The hazard classification of microorganisms for the EU is specified in EU Directive 2000/54 / EC . If necessary, this classification is modified by national regulations and laws that take precedence over the EU directive. According to German law, Mycobacterium bovis belongs to risk group 3 (RG 3) . After examination, the Committee for Biological Agents (ABAS), which advises the German Federal Institute for Occupational Safety and Health , found that BCG, which has been cultivated on various continents for many decades, has produced heterogeneous strains and that these strains are no more similar to Mycobacterium bovis than Mycobacterium tuberculosis (RG 3). In his justification paper for the classification (Decision 14/2013 of the ABAS of 3 December 2013), the Committee points on it that investigations even greater similarity with laboratory-adapted Mycobacterium tuberculosis strains than with recent isolates of bovis Mycobacterium or Mycobacterium tuberculosis have shown , and also classified the BCG strains in RG 3 and therefore more stringent than the EU directive. The only exception is the BCG Pasteur 1173P2 strain (RG 2; ABAS resolution 15/2013 of December 3, 2013), which has been better researched and characterized than the other BCG strains and which has additional DNA compared to numerous other BCG strains -Regions are missing whose genes or gene products play a role in the pathogenicity and infectivity of the pathogen.

The classification of Mycobacterium bovis as RG 3 (now without exception of the BCG strains) was published by the ABAS in the TRBA 466 of 2010 and 2015 and in the joint ministerial sheets (GMBl) of the Federal Institute for Occupational Safety and Health (BAuA) and the ABAS (December 2010 edition; supplement April 2012, GMBl No. 15–20 of April 25, 2012, p. 380 and August 2015 edition of GMBl 2015, No. 46–50 of August 25, 2015).

In general, a lower classification of daughter strains may only be made if it has been scientifically proven that the pathogenicity, immunogenicity and virulence of the strain to be evaluated justify this.

The biological protection level (S or BSL) under which work must be carried out with it depends on the risk group of a microorganism : RG 3 = S 3. With a lower protection level than specified by the risk group, only one pathogen is allowed to work if the laboratory construction guarantees identical safety conditions for employees and the environment.

Meaningfulness of the tuberculin test

Vaccination with BCG causes a false positive tuberculin test . Since tuberculosis can occur despite BCG vaccination, the tuberculin test in BCG-vaccinated people is not suitable for excluding current tuberculosis.

Use outside of TB and leprosy

Use in bladder cancer

Another indication of BCG from the manufacturer medac is the treatment of superficial bladder cancer . In the late 1980s, BCG bladder instillation was shown to be an effective form of cancer immunotherapy for this disease. Although the exact mechanisms have still not been researched, BCG apparently causes a local immune reaction against the tumor. A possible BCG treatment scheme is described by the DKFZ .

Alzheimer's disease

A study in patients with bladder cancer, published in 2019 and not yet confirmed by replication , found that instillation of BCG into the bladder reduced the incidence of Alzheimer's disease in the following years .

Bronchial cancer

Childhood vaccination is associated with a lower risk of lung cancer among indigenous peoples in the United States and Canada .

Side effects

The safety of using BCG in bladder cancer is limited by the possibility of side effects similar to those of tuberculosis. The infestation mostly affects the local area near the bladder, but can rarely affect other organs. Then Mycobacterium bovis can be detected. The main symptoms in acute cases are fever and night sweats. This so-called BCG disease or BCGitis occurs rarely, but can be life-threatening, especially in the case of immune incompetence. It is usually treated with triple anti-tubercular therapy. A differentiated notification to the health department makes sense, but unlike tuberculosis, it is not mandatory.

VPM1002

At the Max Planck Institute for Infection Biology in Berlin, BCG was modified with the help of genetic engineering with the aim of improving safety and effectiveness. The product was licensed in 2004 by Vakzine Projektmanagement GmbH in Hanover and was given the name VPM1002.

VPM1002 against tuberculosis

A phase I study with VPM1002 was tested in Neuss in 2009 and 2010 with 80 test persons, after which the tolerability was rated as good. By 2020, VPM's Indian parent company will test VPM1002 in a phase II / III study on 2000 people in India. 500 employees from clinics in Nijmegen , the Netherlands , were vaccinated with BCG and compared against a non-vaccinated control group. The experiment is to be repeated with VPM1002 on 1000 employees in German clinics.

VPM1002 against SARS-CoV-2

Numerous studies are still being investigated, and there are initial indications of whether a BCG vaccination can reduce the morbidity and mortality of COVID-19 diseases. However, the WHO advises caution. In April 2020, after evaluating the studies available at the time, she summarized that there were no studies on whether BCG vaccinations protect against infection with SARS-CoV-2; therefore she did not recommend such vaccinations for this purpose. Vakzine Projektmanagement GmbH, on the other hand, is also investigating whether VPM1002 can alleviate the course of COVID-19 diseases . This is intended to serve as an interim solution until a specific SARS-CoV-2 vaccine is available. Due to the unspecific effect of VPM1002, it is hoped that the preparation will also be effective against any variants of SARS-CoV-2.

See also

literature

  • P. Andersen, TM Doherty: The success and failure of BCG - implications for a novel tuberculosis vaccine. In: Nat. Rev. Microbiol. Volume 3, Number 8, August 2005, pp. 656-662, doi: 10.1038 / nrmicro1211 . PMID 16012514 . (Review).

Web links

Individual evidence

  1. ↑ a b BCG World Atlas: A DATABASE OF GLOBAL BCG VACCINATION POLICIES AND PRACTICES. Retrieved February 23, 2018 .
  2. ↑ a b WHO SAGE BCG Working Group: Report on BCG vaccine use for protection against mycobacterial infections including tuberculosis, leprosy, and other nontuberculous mycobacteria (NTM) infections. SAGE, October 22, 2017, accessed February 23, 2018 .
  3. ^ WHO Model Lists of Essential Medicines. (PDF) In: WHO. 2019, accessed April 4, 2020 .
  4. ↑ a b c d e WHO .: BCG vaccines: WHO position paper - February 2018. In: Weekly Epidemiological Record, 23 February 2018, vol. 93, 08 (pp. 73-96). Retrieved February 23, 2018 .
  5. ↑ Tuberculosis vaccination in Germany? What options are there if the vaccination is required for a stay abroad? In: RKI. January 3, 2018, accessed March 11, 2020 .
  6. ↑ Towards a New Tuberculosis Vaccine. Max Planck Society , March 23, 2015, accessed on March 11, 2020 .
  7. ^ Julian PT Higgins et al .: Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review . In: BMJ (Clinical research ed.) . tape 355 , October 13, 2016, p. i5170 , doi : 10.1136 / bmj.i5170 , PMID 27737834 , PMC 5063034 (free full text).
  8. ↑ Chee Fu Yung: Non-specific effects of childhood vaccines . In: BMJ . tape 355 , October 13, 2016, doi : 10.1136 / bmj.i5434 , PMID 27737824 .
  9. ↑ Deeva Uthayakumar et al .: Non-specific Effects of Vaccines Illustrated Through the BCG Example: From Observations to Demonstrations . In: Frontiers in Immunology . tape 9 , December 4, 2018, p. 2869 , doi : 10.3389 / fimmu.2018.02869 , PMID 30564249 , PMC 6288394 (free full text).
  10. ↑ a b Why the TB vaccine also makes recipients less sensitive to other infections. In: Deutsches Ärzteblatt . August 4, 2020, accessed August 16, 2020 .
  11. ↑ Branko Cirovic et al .: BCG vaccination in Humans elicits Trained Immunity via the Hematopoietic Progenitor compartment . In: Cell Host & Microbe . tape 28 , no. 2 , August 12, 2020, p. 322–334.e5 , doi : 10.1016 / j.chom.2020.05.014 .
  12. ↑ Evangelos J. Giamarellos-Bourboulis et al .: Activate: Randomized Clinical Trial of BCG vaccination against infection in the Elderly . In: Cell . tape 0 , no. 0 , August 31, 2020, doi : 10.1016 / j.cell.2020.08.051 , PMID 32941801 .
  13. ↑ https://www.baua.de/de/Themen-von-AZ/Biologische-Arbeitsstoffe/TRBA/pdf/Mycobacterium-bovis.pdf?__blob=publicationFile&v=4
  14. ↑ https://www.baua.de/de/Themen-von-AZ/Biologische-Arbeitsstoffe/TRBA/pdf/Mycobacterium-bovis-BCG-Pasteur-1173P2.pdf?__blob=publicationFile&v=3
  15. ↑ Roland Brosch et al .: Genome plasticity of BCG and impact on vaccine efficacy . In: Proceedings of the National Academy of Sciences of the United States of America . tape 104 , no. 13 , March 27, 2007, p. 5596-5601 , doi : 10.1073 / pnas.0700869104 , PMID 17372194 , PMC 1838518 (free full text).
  16. ↑ http://www.baua.de/cae/servlet/contentblob/672886/publicationFile/48583/TRBA-466.pdf
  17. ^ R. De Jager et al .: Long-term complete remission in bladder carcinoma in situ with intravesical TICE bacillus Calmette Guerin. Overview analysis of six phase II clinical trials . In: Urology . tape 38 , no. 6 , December 1991, pp. 507-513 , doi : 10.1016 / 0090-4295 (91) 80166-5 , PMID 1836081 .
  18. ↑ BCG treatment
  19. ↑ https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224433
  20. ↑ Nicholas T. Usher et al .: Association of BCG Vaccination in Childhood With Subsequent Cancer Diagnoses: A 60-Year Follow-up of a Clinical Trial . In: JAMA network open . tape 2 , no. 9 , September 4, 2019, p. e1912014 , doi : 10.1001 / jamanetworkopen.2019.12014 , PMID 31553471 , PMC 6763973 (free full text).
  21. ↑ Robert Koch Institute (ed.): Epidemiological Bulletin 18/2006 . May 5, 2006, doi : 10.25646 / 4231 .
  22. ↑ Epidemiological Bulletin 18/2006. In: RKI. May 5, 2006, accessed March 10, 2020 .
  23. ↑ L. Grode et al .: Safety and immunogenicity of the recombinant BCG vaccine VPM1002 in a phase 1 open-label randomized clinical trial . In: Vaccine . 2012, doi : 10.1016 / j.vaccine.2012.12.053 , PMID 23290835 .
  24. ↑ NCT03152903 ClinicalTrials.gov
  25. ↑ MPG: Vaccine candidate against tuberculosis in phase II / III study
  26. ↑ Johann Grolle: Alarm in the whole body . In: Der Spiegel . No. 14 , 2020, p. 104-106 ( online - March 28, 2020 ).
  27. ↑ Martha K. Berg et al .: Mandated Bacillus Calmette-Guérin (BCG) vaccination predicts flattened curves for the spread of COVID-19 . In: Science Advances . tape 6 , no. 32 , August 1, 2020, p. eabc1463 , doi : 10.1126 / sciadv.abc1463 .
  28. ↑ Uri Hamiel, Eran Kozer, Ilan Youngster: SARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults . In: JAMA . tape 323 , no. 22 , June 9, 2020, p. 2340-2341 , doi : 10.1001 / jama.2020.8189 .
  29. ↑ Luke AJ O'Neill and Mihai G. Netea: BCG-induced trained immunity: can it offer protection against COVID-19? In: Nature Reviews Immunology . tape 20 , no. 6 , June 2020, p. 335-337 , doi : 10.1038 / s41577-020-0337-y .
  30. ↑ Luis E. Escobar et al .: BCG vaccine protection from severe coronavirus disease 2019 (COVID-19) . In: Proceedings of the National Academy of Sciences . tape 117 , no. 30 , 28 July 2020, p. 17720-17726 , doi : 10.1073 / pnas.2008410117 , PMID 32647056 .
  31. ↑ Lars Fischer: Coronavirus vaccination: Why BCG could work against Covid-19. In: Spektrum.de. May 14, 2020, accessed July 30, 2020 .
  32. ↑ WHO: Bacille Calmette-Guérin (BCG) vaccination and COVID-19 , Scientic Brief, online April 12, 2020, accessed July 30, 2020
  33. ↑ Tuberculosis vaccine to protect doctors and nurses from Corona: The interim solution in the fight against Covid-19. In: Frankfurter Allgemeine Zeitung Online, updated on April 3, 2020
  34. ↑ Defense forces - immune booster against Sars COV2. Attempt: Strengthening the immune system. Article in the heute-journal on April 6, 2020, video, 2 min.