COVID-19 and BCG vaccine: is there a link?

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Abstract

The spread of the novel coronavirus infection (COVID-19) makes the search for new approaches to prevent the infection of great importance. As one of the relevant approaches, the vaccination of risk groups with BCG vaccine has recently been suggested. BCG (Mycobacterium bovis, Bacillus Calmette–Guérin) is a live vaccine for tuberculosis, which is used in many countries with a high tuberculosis prevalence and helps preventing childhood tuberculosis, primarily, military disease and tuberculosis meningitis. Whether BCG may be used to increase the protection against COVID-19 is currently a question of debates. The review considers scientific background underlying possible impact of BCG in increased protection against COVID-19. BCG is able of inducing the heterologous and trained immunity, and its capacity to stimulate antiviral immune response has been demonstrated in experimental animals and humans. Our comparison of the dynamics of COVID-19 morbidity and mortality in countries with different BCG vaccination policies has demonstrated a milder course of COVID-19 (i.e., a slower increase in disease cases and mortality) in countries where BCG vaccination is mandatory for all children. However, an association between BCG vaccination and a milder COVID-19 course is not obligatory direct. Other factors that may affect the association, such as the level of virus testing, the rigidity and the speed of quarantine implementation and others are discussed. An important argument against a role of BCG in the protection against COVID-19 is that BCG is given in childhood and may hardly induce long-lasting immunity. Because mandatory BCG vaccination is implemented in countries with high TB burden and because in these countries latent tuberculosis infection is widely spread, we suggest a hypothesis that latent tuberculosis infection may contribute to the maintenance of heterologous/trained antiviral immunity in countries with mandatory BCG vaccination. Four countries have recently initiated clinical trials to investigate whether BCG vaccination can increase the level of protection against COVID-19 in risk groups. The results of these studies, as well as COVID-19 epidemiological modeling will help understanding the impact of BCG in the level of the protection against COVID-19. Performing analogous clinical trials in Russia seems appropriate and scientifically sound.

About the authors

I. V. Lyadova

Koltzov Institute of Developmental Biology of Russian Academy of Sciences;
Pirogov Russian National Research Medical University

Author for correspondence.
Email: ivlyadova@mail.ru
ORCID iD: 0000-0003-3147-5386

Lyadova Irina V., PhD, MD (Medicine), Head of the Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of Russian Academy of Sciences; Head of the Department of Cellular Biomedicine, Pirogov Russian National Research Medical University

119334, Moscow, Vavilova str., 26

Russian Federation

A. A. Starikov

Koltzov Institute of Developmental Biology of Russian Academy of Sciences

Email: ant.starikov@gmail.com

Independent Researcher

Moscow

Russian Federation

References

  1. Илларионов А. Вакцинация БЦЖ и смертность от коронавируса на стадии эпидемического «взрыва». Персональная страница А. Илларионова. Livejournal. URL: https://aillarionov.livejournal.com/1169468.html (31.03.2020)
  2. Aaby P., Benn C.S. Saving lives by training innate immunity with Bacille Calmette–Guérin vaccine. Proc. Natl. Acad. Sci. USA, 2012, vol. 109, no. 43, pp. 17317–17318. doi: 10.1073/pnas.1215761109
  3. Arts R.J.W., Blok B.A., Aaby P., Joosten L.A.B., de Jong D., van der Meer J.W.M., Benn C.S., van Crevel R., Netea M.G. Longterm in vitro and in vivo effects of γ-irradiated BCG on innate and adaptive immunity. J. Leukoc. Biol., 2015, vol. 98, no. 6, pp. 995–1001. doi: 10.1189/jlb.4MA0215-059R
  4. Arts R.J.W., Moorlag S.J.C.F.M., Novakovic B., Li Y., Wang S.Y., Oosting M., Kumar V., Xavier R.J., Wijmenga C., Joosten L.A.B., Reusken C.B.E.M., Benn C.S., Aaby P., Koopmans M.P., Stunnenberg H.G., van Crevel R., Netea M.G. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe, 2018, vol. 23, no. 1, pp. 89–100. doi: 10.1016/j.chom.2017.12.010
  5. Bansal M. Cardiovascular disease and COVID-19. Diabetes Metab. Syndr., 2020, vol. 14, no. 3, pp. 247–250. doi: 10.1016/j.dsx.2020.03.013
  6. Covián C., Fernández-Fierro A., Retamal-Díaz A., Díaz F.E., Vasquez A.E., Lay M.K., Riedel C.A., González P.A., Bueno S.M., Kalergis A.M. BCG-induced cross-protection and development of trained immunity: implication for vaccine design. Front Immunol., 2019, vol. 10: 2806. doi: 10.3389/fimmu.2019.02806
  7. COVID-19 Coronavirus Pandemic. Worldometer. URL: https://www.worldometers.info/coronavirus (21.04.2020)
  8. De Bree L.C.J., Koeken V.A.C.M., Joosten L.A.B., Aaby P., Benn C.S., van Crevel R., Netea M.G. Non-specific effects of vaccines: current evidence and potential implications. Semin. Immunol., 2018, vol. 39, pp. 35–43. doi: 10.1016/j.smim.2018.06.002
  9. De Bree L.C.J., Marijnissen R.J., Kel J.M., Rosendahl Huber S.K., Aaby P., Benn C.S., Wijnands M.V.W., Diavatopoulos D.A., van Crevel R., Joosten L.A.B., Netea M.G., Dulos J. Bacillus Calmette–Guérin-induced trained immunity is not protective for experimental influenza A/Anhui/1/2013 (H7N9) infection in mice. Front Immunol., 2018, vol. 9: 869. doi: 10.3389/fimmu.2018.00869
  10. De Castro M.J., Pardo-Seco J., Martinón-Torres F. Nonspecific (heterologous) protection of neonatal BCG vaccination against hospitalization due to respiratory infection and sepsis. Clin. Infect. Dis., 2015, vol. 60, no. 11, pp. 1611–1619. doi: 10.1093/cid/civ144
  11. De Vriez J. Can a century-old TB vaccine steel the immune system against the new coronavirus. Science, 2020, March 23. doi: 10.1126/science.abb8297
  12. Ford N.D., Patel S.A., Venkat Narayan K.M. Obesity in low- and middle-income countries: burden, driversm and emerging challenges. Annu. Rev. Public Health., 2017, vol. 38, no. 1, pp. 145–164. doi: 10.1146/annurev-publhealth-031816-044604
  13. Kapina M.A., Shepelkova G.S., Mischenko V.V., Sayles P., Bogacheva P., Winslow G., Apt A.S., Lyadova I.V. CD27low CD4 T lymphocytes that accumulate in the mouse lungs during mycobacterial infection differentiate from CD27high precursors in situ, produce IFN-gamma, and protect the host against tuberculosis infection. J. Immunol., 2007, vol. 178, no. 2, pp. 976–985. doi: 10.4049/jimmunol.178.2.976
  14. Kleinnijenhuis J., Quintin J., Preijers F., Benn C.S., Joosten L.A., Jacobs C., van Loenhout J., Xavier R.J., Aaby P., van der Meer J.W., van Crevel R., Netea M.G. Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J. Innate Immun., 2014, vol. 6, no. 2, pp. 152–158. doi: 10.1159/000355628
  15. Kleinnijenhuis J., Quintin J., Preijers F., Joosten L.A., Ifrim D.C., Saeed S., Jacobs C., van Loenhout J., de Jong D., Stunnenberg H.G., Xavier R.J., van der Meer J.W., van Crevel R., Netea M.G. Bacille Calmette–Guérin induces NOD2- dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc. Natl. Acad. Sci. USA, 2012, vol. 109, no. 43, pp. 17537–17542. doi: 10.1073/pnas.1202870109
  16. Kleinnijenhuis J., Quintin J., Preijers F., Joosten L.A.B., Jacobs C., Xavier R.J., van der Meer J.W., van Crevel R., Netea M.G. BCG-induced trained immunity in NK cells: role for non-specific protection to infection. Clin. Immunol., 2014, vol. 155, no. 2, pp. 213–219. doi: 10.1016/j.clim.2014.10.005
  17. Lighter J., Phillips M., Hochman S., Sterling S., Johnson D., Francois F., Stachel A. Obesity in patients younger than 60 years is a risk factor for COVID-19 hospital admission. Clin. Infect. Dis., 2020; ciaa415. doi: 10.1093/cid/ciaa415
  18. Mathurin K.S., Martens G.W., Kornfeld H., Welsh R.M. CD4 T-cell-mediated heterologous immunity between mycobacteria and poxviruses. J. Virol., 2009, vol. 83, no. 8, pp. 3528–3539. doi: 10.1128/JVI.02393-08
  19. Miller M.F., Reandelar M.J., Fasciglione K., Roumenova V., Li Y., Otazu G.H. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. medRxiv, 2020.03.24.20042937. doi: 10.1101/2020.03.24.20042937
  20. Morra M.E., Kien N.D., Elmaraezy A., Abdelaziz O.A.M., Elsayed A.L., Halhouli O., Montasr A.M., Vu T.L., Ho C., Foly A.S., Phi A.P., Abdullah W.M., Mikhail M., Milne E., Hirayama K., Huy N.T. Early vaccination protects against childhood leukemia: a systematic review and meta-analysis. Sci. Rep., 2017, vol. 7, no. 1: 15986. doi: 10.1038/s41598-017-16067-0
  21. Netea M.G., Quintin J., Van Der Meer J.W.M. Trained immunity: a memory for innate host defense. Cell Host Microbe, 2011, vol. 9, no. 5, pp. 355–361. doi: 10.1016/j.chom.2011.04.006
  22. Ng C.J., Teo C.H., Abdullah N., Tan W.P., Tan H.M. Relationships between cancer pattern, country income and geographical region in Asia. BMC Cancer, 2015, vol. 15: 613. doi: 10.1186/s12885-015-1615-0
  23. Nikitina I.Y., Panteleev A.V., Sosunova E.V., Karpina N.L., Bagdasarian T.R., Burmistrova I.A., Andreevskaya S.N., Chernousova L.N., Vasilyeva I.A., Lyadova I.V. Antigen-specific IFNγ responses correlate with the activity of M. tuberculosis infection but are not associated with the severity of tuberculosis disease. J. Immunol. Res., 2016: 7249369. doi: 10.1155/2016/7249369
  24. The BCG world atlas. 2nd edition. A database of global BCG vaccination policies and practices. 2017. URL: http://www.bcgatlas.org (21.04.2020)
  25. Weir R.E., Gorak-Stolinska P., Floyd S., Lalor M.K., Stenson S., Branson K., Blitz R., Ben-Smith A., Fine P.E.M., Dockrell H.M. Persistence of the immune response induced by BCG vaccination. BMC Infect. Dis., 2008, vol. 8: 9. doi: 10.1186/1471-2334-8-9
  26. WHO: Bacille Calmette–Guérin (BCG) vaccination and COVID-19. Scientific Brief. 12.04.2020. URL: https://www.who.int/news-room/commentaries/detail/bacille-calmette-gu%C3%A9rin-(bcg)-vaccination-and-covid-19
  27. Wout J.W., Poell R., Furth R. The Role of BCG/PPD-activated macrophages in resistance against systemic candidiasis in mice. Scand. J. Immunol., 1992, vol. 36, no. 5, pp. 713–719. doi: 10.1111/j.1365-3083.1992.tb03132.x

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