Short Perspective

Relationship between Bacillus Calmette Guerin Vaccination Policy and Coronavirus Disease-2019 (COVID-19) Incidence


Bacillus Calmette Guerin (BCG) was designed for protecting children against tuberculosis. Also, it can protect against other infectious diseases through the induction of trained immunity. Due to its heterologous protective effects, the BCG vaccine has been proposed as atreatment option for coronavirus disease-2019 (COVID-19). Epidemiological studies have found that countries without BCG vaccination policy have experienced higher mortality rates related toCOVID-19 infection than those with BCG vaccination policy. However, there are some confounding factors such as age, population intensity, immigration, the pandemic phase, and data accuracy that may affect these results. Therefore, this hypothesis should be evaluated by clinical trial studies. Large-scale clinical trials are in progress to investigate ifthe BCG vaccine could be used as a useful tool for protection against COVID-19 infection. 

1. Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and corona virus disease-2019 (COVID-19): the epidemic and the challenges. Int J Antimicrob Agents. 2020:105924.
2. Hassan SA, Sheikh FN, Jamal S, Ezeh JK, Akhtar A. Coronavirus (COVID-19): a review of clinical features, diagnosis, and treatment. Cureus. 2020;12(3).
3. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020:102433.
4. Dzobo M, Chitungo I, Dzinamarira T. COVID-19: a perspective for lifting lockdown in Zimbabwe. Pan Afr Med J. 2020;35(13).
5. Guo YR, Cao QD, Hong ZS, Tan YY, Chen SD, Jin HJ, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak–an update on the status. Mil Med Res. 2020;7(1):1-0.
6. Le TT, Andreadakis Z, Kumar A, Roman RG, Tollefsen S, Saville M, et al. The COVID-19 vaccine development landscape. Nat Rev Drug Discov. 2020;19:305-6.
7. Miller A, Reandelar MJ, Fasciglione K, Roumenova V, Li Y, Otazu GH. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. MedRxiv. 2020.
8. Sala G, Miyakawa T. Association of BCG vaccination policy with prevalence and mortality of COVID-19. MedRxiv. 2020.
9. Berg MK, Yu Q, Salvador CE, Melani I, Kitayama S. Mandated Bacillus Calmette-Guérin (BCG) vaccination predicts flattened curves for the spread of COVID-19. Medrxiv. 2020; 6(32):eabc1463.
10. Dayal D, Gupta S. Connecting BCG vaccination and COVID-19: additional data. MedRxiv. 2020.
11. Thysen SM, Benn CS, Gomes VF, Rudolf F, Wejse C, Roth A, et al. Neonatal BCG vaccination and child survival in TB-exposed and TB-unexposed children: a prospective cohort study. BMJ open.2020;10(2):e035595.
12. Moorlag SJ, Arts RJ, van Crevel R, Netea MG. Non-specific effects of BCG vaccine on viral infections. Clin Microbiol Infect. 2019;25(12):1473-8.
13. Kristensen I, Fine P, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West AfricaCommentary: an unexpected finding that needs confirmation or rejection. BMJ. 2000;321(7274):1435.
14. Nemes E, Geldenhuys H, Rozot V, et al. Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination. N Engl J Med. 2018;379(2):138-49.
15. O'Neill LAJ, Netea MG. BCG-induced trained immunity: can it offer protection against COVID-19? Nat Rev Immunol. 2020;20(6):335-37.
16. Arts RJ, Novakovic B, ter Horst R, Carvalho A, Bekkering S, Lachmandas E, et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. 2016;24(6):807-19.
17. Buffen K, Oosting M, Quintin J, Ng A, Kleinnijenhuis J, Kumar V, et al. Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer. PLoS Pathog. 2014;10(10).
18. Berendsen ML, Van Gijzel SW, Smits J, De Mast Q, Aaby P, Benn CS, et al. BCG vaccination is associated with reduced malaria prevalence in children under the age of 5 years in sub-Saharan Africa. BMJ Glob Health. 2019;4(6).
19. Pereira LI, Dorta ML, Pereira AJ, Bastos RP, Oliveira MA, Pinto SA, et al. Increase of NK cells and proinflammatory monocytes are associated with the clinical improvement of diffuse cutaneous leishmaniasis after immunochemotherapy with BCG/Leishmania antigens. Am J Trop Med Hyg. 2009;81(3):378-83.
20. Alyasin S, Katibeh P, Asadi S. The relationship between tuberculin response, BCG vaccine scar and asthma. Iran J Allergy Asthma Immunol. 2009;8(4):205-10.
21. Berg RE, Cordes CJ, Forman J. Contribution of CD8+ T cells to innate immunity: IFN‐γ secretion induced by IL‐12 and IL‐18. Eur J Immunol. 2002;32(10):2807-16.
22. Berg RE, Crossley E, Murray S, Forman J. Memory CD8+ T cells provide innate immune protection against Listeria monocytogenes in the absence of cognate antigen. J Exp Med. 2003;198(10):1583-93.
23. Mathurin KS, Martens GW, Kornfeld H, Welsh RM. CD4 T-cell-mediated heterologous immunity between mycobacteria and poxviruses. J Virol. 2009;83(8):3528-39.
24. Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Ifrim DC, Saeed S, et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. PNAS. 2012;109(43):17537-42.
25. Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, et al. Trained immunity: a program of innate immune memory in health and disease. Science. 2016;352(6284):aaf1098.
26. Hamada A, Torre C, Drancourt M, Ghigo E. Trained immunity carried by non-immune cells. Front Microbiol. 2019;9:3225.
27. Netea MG, Latz E, Mills KH, O'neill LA. Innate immune memory: a paradigm shift in understanding host defense. Nat Immunol. 2015;16:675-9.
28. Saeed S, Quintin J, Kerstens HH, Rao NA, Aghajanirefah A, Matarese F, et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science. 2014;345(6204):1251086.
29. Arts RJ, Moorlag SJ, Novakovic B, Li Y, Wang SY, Oosting M, et al. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe. 2018;23(1):89-100.
30. Arts RJ, Carvalho A, La Rocca C, Palma C, Rodrigues F, Silvestre R, et al. Immunometabolic pathways in BCG-induced trained immunity. Cell Rep. 2016;17(10):2562-71.
31. Kaufmann E, Sanz J, Dunn JL, Khan N, Mendonça LE, Pacis A, et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell. 2018;172(1-2):176-90.
32. Aronson NE, Santosham M, Comstock GW, Howard RS, Moulton LH, Rhoades ER, et al. Long-term efficacy of BCG vaccine in American Indians and Alaska Natives: a 60-year follow-up study. JAMA. 2004;291(17):2086-91.
33. Nguipdop-Djomo P, Heldal E, Rodrigues LC, Abubakar I, Mangtani P. Duration of BCG protection against tuberculosis and change in effectiveness with time since vaccination in Norway: a retrospective population-based cohort study. Lancet Infect Dis. 2016;16(2):219-26.
34. Akiyama Y, Ishida T. Relationship between COVID-19 death toll doubling time and national BCG vaccination policy. MedRxiv. 2020.
35. Singh BR, Gandharva R, Karthikeyan R, Singh SV, Yadav A, Vinodh Kumar OR et al. Epidemiological determinants of acute respiratory syndrome coronavirus-2 disease pandemic and the role of the Bacille-Calmette-Guerin vaccine in reducing morbidity and mortality. J Pure Appl Microbiol. 2020;14.
36. Green CM, Fanucchi S, Fok ET, Moorlag SJ, Dominguez-Andres J, Negishi Y, et al. COVID-19: A model correlating BCG vaccination to protection from mortality implicates trained immunity. MedRxiv. 2020.
37. Hegarty PK, Sfakianos JP, Giannarini G, DiNardo AR, Kamat AM. COVID-19 and Bacillus Calmette-Guérin: What is the link?. European Urology Oncology.Eur Urol Oncol. 2020;3(3):259-61.
38. Shet A, Ray D, Malavige N, Santosham M, Bar-Zeev N. Differential COVID-19-attributable mortality and BCG vaccine use in countries. MedRxiv. 2020.
39. Ozdemir C, Kucuksezer UC, Tamay ZU. Is BCG vaccination effecting the spread and severity of COVID‐19?. Allergy. 2020;75(7):1824-1827.
40. Singh S. BCG vaccines may not reduce COVID-19 mortality rates. MedRxiv. 2020.
41. Aksu K, Naziroğlu T, Özkan P. Factors determining COVID-19 pneumonia severity in a country with routine BCG vaccination. Clin Exp Immunol. 2020 Nov;202(2):220-225
42. Hensel J, McGrail DJ, McAndrews KM, Dowlatshahi D, LeBleu VS, Kalluri R. Exercising caution in correlating COVID-19 incidence and mortality rates with BCG vaccination policies due to variable rates of SARS CoV-2 testing. MedRxiv. 2020.
43. Hamiel U, Kozer E, Youngster I. SARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults. JAMA. 2020;323(22):2340-2341.
44. Cruz CT, Almeida B, Troster E. Systematic Review of the Non-Specific Effects of Bacillus Calmette-Guérin Vaccine on Child. Mortality. J Infec Dis Treat. 2017;3:1.
45. Zimmermann P, Curtis N. The influence of BCG on vaccine responses - a systematic review. Expert Rev Vaccines. 2018;17(6):547-554.
46. (accessed 20 September 2020)
47. Miyazaki J, Onozawa M, Takaoka E, Yano I. Bacillus Calmette-Guérin strain differences as the basis for immunotherapies against bladder cancer. Int J Urol. 2018;25(5):405-413.
48. Ladefoged A, Bunch-Christensen K, Guld J. Tuberculin sensitivity in guinea-pigs after vaccination with varying doses of BCG of 12 different strains. Bull World Health Organ. 1976;53(4):435.
49. Davids V, Hanekom WA, Mansoor N, Gamieldien H, Sebastian JG, Hawkridge A, et al. The effect of bacille Calmette-Guerin vaccine strain and route of administration on induced immune responses in vaccinated infants. J Infect Dis. 2000;193(4):531-6.
50. Miyasaka M. Is BCG vaccination causally related to reduced COVID‐19 mortality?. EMBO Mol Med. 2020;12(6):e12661.
51. Weyand CM, Goronzy JJ. Aging of the Immune System. Mechanisms and Therapeutic Targets. Ann Am Thorac Soc. 2016;5(Suppl 5):S422-S428.
52. Brewczyńska A, Depczyńska D, Borecka A, Winnicka I, Kubiak L, Skopińska-Różewska E, et al. The influence of the workplace-related biological agents on the immune systems of emergency medical personnel. Cent Eur J Immunol. 2015;40(2):243.
53. Rakshit S, Ahmed A, Adiga V, Sundararaj BK, Sahoo PN, Kenneth J, et al. BCG revaccination boosts adaptive polyfunctional Th1/Th17 and innate effectors in IGRA+ and IGRA–Indian adults. JCI Insight. 2019;4(24).
IssueVol 20 No 1 (2021) QRcode
SectionShort Perspective
COVID-19 Mycobacterium bovis

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Alyasin S, Kanannejad Z, Esmaeilzadeh H, Nabavizadeh H, Ghatee MA, Amin R. Relationship between Bacillus Calmette Guerin Vaccination Policy and Coronavirus Disease-2019 (COVID-19) Incidence. Iran J Allergy Asthma Immunol. 20(1):106-113.