16/04/2020
Medical Learning - Myanmar
áážá
áş(ááá)áĄáá˝ááşá¸ ááťááşáážáŹááťáŹá¸áá˛áˇ ááąá¸ááąáŤááşá¸áĄáážááş (áááŻáˇáááŻááş) BCG... B-)
áááŚá¸á
ááźáąáŹááááş ááááááŻááşá¸á Pasteur Institute áážáŹ Albert Calmette (bacteriologist) áá˛áˇ Camille Guerin (veterinarian) áááŻáˇ(á)áŚá¸á Mycobacterium bovis strain áá
áşááťááŻá¸ááᯠvirulence ááťáąáŹááşáĄáąáŹááşááŻááşááźáŽá¸ live vaccine ááŻááşáááŻáˇ ááźááŻá¸á
áŹá¸ááźááŤááá˛áˇá (áá)áážá
áşááąáŹááşááźáŹááźáŽá¸ááž áááááážáŹ vaccine áĄááźá
áş á
introduce ááŻááşáááŻááşáá˛áˇááŤáááş (bacille Calmette-Guerin = BCG áááŻááźáŽá¸ áĄáááşáá˝ááşáááşááąáŤáˇ)á á
ááŻááşá¸áááᯠorally ááąá¸áááźáŽá¸ ááááááąáŹááşáážáŹááž immunogenic áááŻááźá
áşáá˛áˇ route áááŻáá˝áąá¸áááşáááŻááźáŽá¸ intradermal (deltoid) ááźá
áşáá˝áŹá¸ááŹá፠(ááŤááąáŹááş Brazil áážáŹ áážá
áşáĄáááşááźáŹáĄáá orally ááąá¸ááąááźááŻááşá¸ááŤáá˛áˇ)á
BCG áááş TB ááᯠ100% áĄááźááşáˇáĄáááŹáá˝ááşáááŻááşáᏠáááŻááşááŤáá°á¸á Active TB áááźá
áşáĄáąáŹááş partial protection áá˛ááąá¸áááŻááşááŤáááşá áá°ááŹáááşááźáŽá¸ááŹá áá°ááźáŽá¸ pulmonary TB áááŻááŹáá˝ááşááŹáááş áááąá¸áá˝áąáážáŹ disseminated TB áááş TB meningitis áááşááᯠááŹáá˝ááşááŹááŤá áĄá
áážáŹáááşááŹá¸áááᯠprimary TB áááŻáˇ reactivation of latent TB áááŻáˇ TB person-to-person transmission áááŻáˇááᯠáááŹá¸áááŻááşááŤáá°á¸ (ááŤááźáąáŹááşáˇáááşá¸ áááŻááąáŹááşá¸áá˛áˇ TB vaccine áá˝áą áážáŹááąááźááŤáááş... áĽááᏠsubunit vaccine [attenuated viral vector or adjuvanted fusion protein], whole cell vaccine [genetically attenuated Mycobacterium tuberculosis, killed MTB or recombinant BCG])á áááŻáˇááąáŹáş epidemiologically ááąáˇááŹáážáŻáá˝áąáĄá BCG vaccine áááŻá¸ááŹá¸áá˛áˇáá°áá˝áąáážáŹ treatment response áááŻááąáŹááşá¸ááŹáááş autopsy á
á
áşááąá¸ááťááşáá˝áąáĄá BCG áááŻá¸ááŹá¸áááş pulmonary TB foci á áááŻááąá¸ááźáŽá¸ bacillary burden áááşá¸ áááşá¸ááŹááᯠáá˝áąáˇáááŤááá˛áˇá
á
áá˝ááşááŻááşá¸á TB áĄáá˝ááş vaccine áááŻááąáááşáˇ áážá
áşááźáŹááŹááŹáá˛áˇáĄááťáž áá°áˇáá˛áˇ immunomodulatory effect ááᯠááááŹáááźáŽá¸ áĄááŻáśá¸áá˝áąá
á˝ááşá
áŻáśááźá
áşááŹááŤááąáŹáˇáááşá
1. Leprosy & other nontuberculous mycobacteria
Mycobacterial antigens áá˝áąáááş T & B-cell cross-reactivity áážáááźááŹáááŻáˇ Mycobacterium tuberculosis áááŻáˇááŻááşááŹá¸áá˛áˇ BCG áááş M. leprae áááŻáááşá¸ ááááááŹááŹááŹáá˝ááşáááŻááşááŹááᯠáá˝áąáˇááźááŤáááşá ááŤáˇáĄááźááş nontuberculous mycobacterial lymphadenitis áá˛áˇ Buruli ulcer áááŻáááşá¸ ááŹáá˝ááşáááŻááşááŤááąá¸áááşá
2. Prevention of nonspecific infections
Pathogen áá
áşááŻáááşááŹáááş ááŤááᯠáááŻááşááŻááşáááŻáˇ immune response ááŹáá˛áˇáĄá፠memory system áááşá¸ ááŤááŤáááşá ááááá
áşááŤáááŻááşáá˝á˛ááᯠáážááşááŹá¸ááźáŽá¸ ááąáŹááşáĄááźáŹá¸ unrelated pathogen áááşáááşááŹááŹááąáŹááş áĄááźáŹá¸áááŻááşáá˝á˛áážáŹ áááŚá¸áážááşááŹá¸ááŹá¸ááŹááᯠááźááşáĄááŻáśá¸ááťááźáŽá¸ áááŻááąáŹááşá¸áá˛áˇ response ááŹááŹááᯠheterologous, nonspecific immunity áááŻáˇááąáŤáşááŤáááşá ááŤááťááŻá¸á BCG áážáŹ áĄááąáŹáşááááŹááŤáááşáá˛áˇá BCG áááŻá¸áááŻááşáááş innate immunity áááş epigenetic reprogramming áááş adaptive changes ááźá
áşááŹááźáŽá¸ nonspecific protection from infection ááᯠááąá¸ááŤáááşá áᎠtrained immunity áááş (á)áážá
áşáĄáá áááşáážáááąááŤáááş (ááŤááźáąáŹááşáˇáááşá¸ infant mortality ááťááŤááá˛áˇ)á BCG áááş mycobacteria ááźá
áşááźá
áş áĄááźáŹá¸áĄááąáŹááşááźá
áşááźá
áşáááşááŹáááş NK cells áááą proinflammatory cytokine production áááŻáááşá¸ ááťáŹá¸á
áąááŤáááşá ááŤáá˝áąáááş pneumonia, leishmaniasis, malaria á
ááŹáá˝áąáážáŹ áĄááťááŻá¸áážá ááŹáá˝ááşáážáŻáĄááťááŻáˇááąá¸áááŻááşáááᯠáĄááźáŹá¸ vaccines áá˝áąáááŻá¸áááşáááşá¸ vaccine response áá˝áą áááŻááąáŹááşá¸áᏠáá˝áąáˇáááŤááá˛áˇá WHO systematic review áá
áşááŻáĄá neonatal BCG vaccination áááş all-cause mortality ááᯠ30% reduction áá˛áˇ association áážáááŤáááşáááŻáˇ áááŻááŤáááşá BCG áá˛áˇ pathogen protective benefit áááş áĄá
áąáŹááŻáśá¸áĄááąáá˛áˇ áá˝áąá¸áááşá¸á
(á)áááşáážáŹááąáŹááş á
ááźáŽááźáąáŹááŤáááş (ááŤááźáąáŹááşáˇ áĄááťááŻáˇááąá¸ááŻáśáá˝áąáážáŹ áá˝áąá¸áá˝áąá¸ááťááşá¸ BCG áááŻá¸ááąá¸áá˛áˇááŻáśá
áś áážáááŤáááş)á
BCG áááŻá¸ááźáŽá¸áááş scar ááąá¸ááąáŤáşááŤáááşá áááŻá¸ááźáŽá¸ 6-8 weeks ááᯠtuberculin skin test (TST) positive ááźá
áşááŤááźáŽá BCG scar áááş tuberculin conversion áááşáááş BCG-induced cell-mediated immunity (CMI) áááźáŽáááŻáá˛áˇ áĄáááášááŹááşááŤá Scar-negative ááᯠáááşáááŻá¸áááŻáˇ á
ááşá¸á
áŹá¸áááşáˇáááşáááŻáˇáááşá¸ áááŻááźááŤáááşá
4. Immunomodulation
BCG áááş immune-mediated diseases áá˝áąáážáŹáááşá¸ áĄááťááŻá¸áážáááźááşááŤáááşá BCG áááŻá¸ááŹá¸áá˛áˇáááąá¸áá˝áąáážáŹ allergic asthma ááźá
áşáážáŻááşá¸áááşá¸ááźáŽá¸ asthma áááąá¸áá˝áąáážáŹáááşá¸ rescue medication ááŻáśá¸ááážáŻááşá¸ ááťáááşáááŻáˇ áá˝áąáˇáááŤáááşá
Neonatal BCG vaccination áááş first symptomatic neurologic episode áááą multiple sclerosis áá°á¸áá˛áˇ conversion rate ááᯠááááááŹááŹááťááąá¸áááŻááşáááşáááŻáˇ áááŻááŤáááşá
3. Antitumor effect
BCG áááş inhibitory effect on tumor growth áááŻáᏠanimal studies áá˝áąáážáŹáááᏠááźáŹáážááŤááźáŽá áááşáá˝áąáˇáážáŹáááşá¸ childhood BCG vaccination áááş leukemia, lung cancer áá˝áąáážáŹ risk reduction ááźá
áşá
áąááŤááá˛áˇá Melanoma ááźá
áşáá˛áˇáá°ááŹáá˝áąáážáŹáááşá¸ BCG áááŻá¸ááŹá¸áá°á¸áá°áá˝áąá survival áááŻááťáŹá¸ááŤááá˛áˇá áá
áşááťááŻáˇ stage III melanoma áá˝áąáážáŹ inoperable ááᯠintralesional BCG injection áááŻá¸áááş tumor ááťáŻáśáˇáá˝áŹá¸ááŹááᯠáá˝áąáˇáááŤáááşáá˛áˇá
ááąááťáŹááŹáááąáŹáˇ non-muscle invasive bladder cancer áážáŹááąáŹáˇ BCG immunotherapy á gold standard adjuvant treatment ááŤá Intravesical BCG áááş local nonspecific immunological boost áá˛áˇ antitumor activity ááᯠááąá¸áááşáááŻáˇ áá°ááááŤáááşá
Recurrent respiratory papillomatosis áážáŹáááşá¸ intralesional BCG áááş relapse rate ááᯠááťá
áąááŤáááşáá˛áˇá
4. Diagnostic tool
(á
)áážá
áşáĄáąáŹááşáááąá¸áá˝áąáážáŹ áĄááźá
áşááťáŹá¸áá˛áˇ Kawasaki disease (KD) áááş diagnosis ááŻááşá áááşáá˛ááŤáááşá áá°á¸ááźáŹá¸ááŹá KD ááźá
áşááźáŽááᯠBCG site á erythema, induration áá˝áąááąáŤáşááŹááŹáááŻáˇ indirect diagnostic tool áĄááąáá˛áˇ ááŻáśá¸áááŻáˇáááŤáááşá BCG site reaction intensity áááŻá¸ááąááą KD severity áááŻá¸ááąá¸ááąáááŻáˇáááşá¸ correlation áá˝áąáˇáááŤáááşá
5. Metabolic effect
BCG ááźáąáŹááşáˇ immune activate ááźá
áşáá˛áˇáĄá፠immune cells áá˝áąáá˛áˇ glucose consumption ááťáŹá¸ááŹááŹáááş regulatory T cells áá˝áąááťáŹá¸ááŹááŹáááş insulin autoreactive T cells ááᯠááąá
áąááŹáááş... ááŤáá˝áąááźáąáŹááşáˇ type 1 diabetes mellitus áá°ááŹáá˝áąáážáŹ glycemic control ááąáŹááşá¸á
áąáááşáááŻáˇ áá˝áąáˇááŹá¸ááŤáááşá
6. Animal models
BCG áááş cholesterol-enriched lipoprotein remnants áá˝áąááᯠliver áᎠááźááşááźááşááááşá¸á
áąáááşá intestinal cholesterol absorption ááᯠááťá
áąáááşá vessel áážáŹ foam cell formation áááŻáááşá¸á
áąáááş... ááŤáá˝áąááźáąáŹááşáˇ atherosclerosis ááᯠáážáąá¸á
áąááŤáááşáá˛áˇá BCG áááş hyperoxic lung injury áááŻáááşá¸ áááşá¸á
áąááŤáááşáá˛áˇá Non-obese diabetes áááŻáááşá¸ prevention ááŻááşááŤááá˛áˇá Alzheimer disease prevention áááşá¸ áážáááŤááá˛áˇá
ááŤááąáááşáˇ ááŤáá˝áąá animal studies áááŻáˇ áĄáááĄááťááźáąáŹáááŻáˇ áĄáŹá¸áááşá¸ááŤááąá¸áááşá
7. Impact on viral infections
BCG vaccination áááş viral infections áĄááąáŤáş positive outcome ááᯠááąá¸ááŤáááşá áĽáááŹ
- Acute lower respiratory tract infection (especially by RSV)
- Lower respiratory tract infection (bacterial or viral pneumonia) ááŤáá˝áąáá˛áˇ incidence ááᯠááťážáąáŹáˇááťááąá¸áááŻááşááŹááᯠáá˝áąáˇáááŤáááşá
- HPV ááźáąáŹááşáˇááźá
áşáá˛áˇ ge***al warts áá°ááŹáá˝áąáážáŹáááşá¸ BCG áááŻá¸ááŹá¸áááş improved clearance ááᯠáá˝áąáˇáááŤááá˛áˇá
- HSV infection ááźá
áşááŹáááŻáááşá¸ áááşá¸á
áąááŤááá˛áˇá
ááŤáá˝áąá human studies áá˝áąááŤá Animal studies áĄááááşá¸ HSV 1&2, influenza A, HBV, JBE á
áá˛áˇ viral infection áá˝áąáážáŹ survival áááŻááźááşáˇááŹááᯠáá˝áąáˇáááŤáááşá
ááąáŹááşáá
áşááŻá RCT áá
áşááŻáĄá BCG áááŻá¸ááŹá¸áá˛áˇáá°áá˝áąáážáŹ influenza vaccine áááŻá¸áááş longer sustained & increased IFN-gamma áááŻá enhanced antibody titre ááąáŤáş pandemic influenza A (H1N1) ááᯠáááŻááŹáá˝ááşáááŻááşááŹááᯠáá˝áąáˇáááŤáááşá BCG áá˛áˇ HBV vaccine áá˝á˛áááŻá¸áááşáááşá¸ HBV alone áááş cytokine production áá˝áą HBV-specific antibody áá˝áą áááŻáááşááŹááᯠáá˝áąáˇáááŤáááş (ááŽáážáŹ UCI áĄá áá˝á˛áááŻá¸ááąá¸ááąááąáŹáˇ áĄáááşááźáąááŹááąáŤáˇ)á
ááźá
áşáááŻááşáá˛áˇ mechanisms áá˝áąá
A. Heterologous lymphocyte responses
áĄááąáŤáşáážáŹááźáąáŹááŹá¸ááźáŽá¸áá˛áˇáĄáááŻááşá¸ááŤáá˛á BCG áááş enhanced immune responses to secondary unrelated pathogens áááŻáˇááŤá CD4 & CD8 memory cell activation áá˛áˇ Th1 & Th17 responses á áááşááŹááźáŽá¸ (á)áážá
áşááąáŹááşáĄááááᯠprotection ááąá¸ááŤáááşá
B. Innate immune memory
áĄááąáŤáşáážáŹááźáąáŹáá˛áˇáá˛áˇ trained immunity ááŤá BCG áááş epigenetic & metabolic rewiring áĄáŹá¸ááźááşáˇ innate immune cells áá˝áąááᯠ(e.g. NK cells, monocytes, macrophages) non-specific memory induction ááźá
áşá
áąááŤáááşá áá°áááŻáˇáá˝áąáááą pro-inflammatory cytokines (e.g. IL-1beta) áá˝áąáá˝ááşááźáŽá¸ viral infection ááᯠááŻááśááŤáááşá
áᎠnon-specific effects ááᯠprevention & treatment of viral infections & vaccination strategies áá˝áąáážáŹ áĄááŻáśá¸ááťáááŻáˇ á
ááşá¸á
áŹá¸ááŹáᏠáážá
áşáĄááąáŹáşááźáŹáá˛áˇááŤááźáŽá
1. BCG áááŻá¸ááźáŽá¸ latent virus reactivation áááŻááŹá¸áá˛áˇáĄááąáá˛áˇ ááŻáśá¸áááŹá¸?
áĽááᏠBCG áááş recurrent HSV infection ááᯠfrequency ááąáŹ duration á፠ááááááŹááŹááťááąá¸áááŻááşááŤáááşá
2. Suppression of viral growth áĄáá˝ááş ááŻáśá¸ááźáááŹá¸?
áĽááᏠBCG áááş virus-infected cells áá˝áąáᲠviral replication ááᯠááŹá¸áááŻááşááŹáááŻáˇ HIV áááŻáˇ hepatitis-associated liver disease áááŻáˇáážáŹ ááŻáśá¸ááźáááŹá¸ááąáŤáˇá
3. Global pandemics ááźá
áşáá˝ááşáážááá˛áˇ ááŤáážáááŻááş ááŹáá˝ááşááąá¸ááážáááąá¸áá˛áˇ viral infection protection áĄáá˝ááş BCG áááŻá¸áááŹá¸?
áĽááᏠBCG áááŻá¸ááźáŽá¸ influenza-related morbidity & mortality ááťáááŹá¸ááąáŤáˇá
ááŽááśááŤááş3 ááŻáśá
áśáá˛áˇ áĄáᯠCOVID-19 pandemic áážáŹ ááźáąáŹááŹááźááŹáá˝áąáááşá¸ ááźáŹá¸ááááźáážáŹááŤá (https://www.researchgate.net/publication/340224580_BCG_vaccination_may_be_protective_against_Covid-19) 2020 March 9 to 24 (áá
)áááşáĄáá˝ááşá¸ world-wide reported cases & fatalities of COVID-19 ááᯠáááŻááşááśáĄáááŻááş population vaccination programs áá˛áˇ ááťáááşáááŻá¸ááźááşáˇááŤáááşá BCG vaccination áááŤáá˛áˇáááŻááşááśáá˝áąáážáŹ COVID-19 á 358.4 per million ááźá
áşááźáŽá¸ BCG vaccination ááŤáá˛áˇáááŻááşááśáá˝áąáážáŹ 38.4 per million áᲠááźá
áşááŹááᯠáá˝áąáˇáááŤáááşá Fatality records áĄááááşá¸ BCG ááááŻá¸áá˛áˇáááŻááşááśáá˝áąáážáŹ 40 per million ááąááźááźáŽá¸ BCG áááŻá¸áá˛áˇáááŻááşááśáá˝áąáážáŹ 4.28 per million áᲠááąááźááŤáááşá Case fatality rate (CFR) áĄáááźááşáˇáááşáááşá¸ BCG ááááŻá¸áá˛áˇáááŻááşááśáá˝áąáážáŹ 0.33% áážáááźáŽá¸ BCG áááŻá¸áá˛áˇáááŻááşááśáá˝áąáážáŹ 0.13% áᲠáážáááŤáááşá Single BCG inoculation áá˛áˇ booster BCG injection (7-14 years later) áážáŹááąáŹáˇ no better outcomes ááŤáá˛áˇá áááááŹá¸á
ááŹá single time-point study áááŻáˇ confounding factors áá˝áąááᯠáĄááťáŹá¸ááźáŽá¸áááşáˇáá˝ááşáááŻáˇ áááŻááŤáááş (áĽááᏠlimited testing & reporting, stage of pandemic in each country, differences in national demographics)á ááŤááźáąáŹááşáˇáááşá¸ 2020 April 12 WHO scientific brief á "There is no evidence that the Bacille Calmette-GuĂŠrin vaccine (BCG) protects people against infection with COVID-19 virus." áááŻáˇ áźááąáŹááŹá¸ááŤáááşá Evidence-based ááźá
áşáĄáąáŹááş clinical trials ááŻááşááąááŤáááş (https://clinicaltrials.gov/ct2/show/NCT04328441 áá˛áˇ https://clinicaltrials.gov/ct2/show/NCT04327206 ááŤ)á "WHO does not recommend BCG vaccination for the prevention of COVID-19. WHO continues to recommend neonatal BCG vaccination in countries or settings with a high incidence of tuberculosis." (https://www.who.int/news-room/commentaries/detail/bacille-calmette-gu%C3%A9rin-(bcg)-vaccination-and-covid-19)
ááŤááźááşáˇáááş BCG áááŻá¸áááŻááşá¸ ááąáŹááşá¸áááŹá¸áááŻáˇ ááąá¸á
ááŹáážáááŹááŤáááşá ááąá¸áááŻáˇáá˛áˇááŻáśá¸á
áśáĄáááŻááşá¸ complications áážáá
ááźá˛ááŤá Live vaccine ááźá
áşááŹáááŻáˇ bacteremic infection ááźá
áşáá˝áŹá¸á
ááŹáĄááźáąáŹááşá¸ áážáááŤáááşá ááźááşááťáŻáśááźááşáˇáááş BCG áááŻá¸áááş 1 in 2500 á local BCG disase (BCGitis) ááźá
áşáááŻááşááźáŽá¸ 1 in 100,000 á disseminated BCG disease (BCGosis) ááźá
áşááźáŽá¸ áĄáááşáĄáášáááŹááşáĄáá áážááááŻááşááŤáááşá ááŹáááŻáˇááźá
áşáᲠáááŻááşááźáá˛áˇáĄá፠Mendelian susceptibility to mycobacterial disease (MSMD) áááŻááŹáá˝áŹá¸áá˝áąáˇááŤáááşá Inborn error of immunity ááąáŤáˇá ááąáŹááşáá
áşááŻáááąáŹáˇ live vaccine áááŻáˇáá˛áˇááŻáśá¸á
áśáĄáááŻááşá¸ immunodeficiency áážáááąáááŻáˇááŤ... áĽááᏠsevere combined immunodeficiency (SCID)á
BCG ááᯠtreatment áĄááąáá˛áˇ ááŻáśá¸ááŹáá˛áˇáĄá፠(e.g. intravesical) áááşáá˝áąáˇááŹáá˛áˇ ááźáżááŹá autoimmune phenomena áá˝áąááŤá Reiter syndrome (conjunctivitis-urethritis-arthritis), Henoch-Schoenlein purpura, Guillain Barre syndrome á
ááŹáá˝áąááźá
áşáááşááŤááá˛áˇá ááźá
áşáááŻááşááŹá autoimmune áááŻáˇáá˛áˇááŻáśá¸á
áśáĄáááŻááşá¸ molecular mimicray ááŤá
BCG áĄááźáąáŹááşá¸ reviews ááťáŹá¸
1. Non-specific effects of BCG vaccine on viral infections (2019) https://www.ncbi.nlm.nih.gov/pubmed/31055165
2. BCG: a vaccine with multiple faces (2020) https://www.ncbi.nlm.nih.gov/pubmed/31995448
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