Инфекция и иммунитет. 2020; 10: 459-468
COVID-19 и вакцинация БЦЖ: есть ли связь?
https://doi.org/10.15789/2220-7619-CAB-1472Аннотация
Распространение новой коронавируcной инфекции COVID-19 делает актуальным поиск новых эффективных путей предупреждения инфекции. В качестве одного из возможных подходов недавно было предложено проведение вакцинации уязвимых групп населения вакциной БЦЖ. БЦЖ (Mycobacterium bovis, Bacillus Calmette–Guérin), живая вакцина против туберкулеза, применяется во многих странах с высоким бременем туберкулеза и увеличивает протекцию у детей, в первую очередь, от милиарного туберкулеза и туберкулезного менингита. Вопрос, может ли вакцина от туберкулеза увеличить уровень протекции против COVID-19, является предметом научных споров. В обзоре рассматриваются научные предпосылки возможного влияния БЦЖ на протективный иммунитет против вируса, вызывающего COVID-19. Вакцина БЦЖ способна индуцировать гетерологичный и «тренированный» иммунитет, ее способность стимулировать противовирусный иммунный ответ показана в экспериментах на животных и в клинических исследованиях. Проведенное нами сравнение динамики роста заболеваемости и смертности от COVID-19 в странах с разной политикой по вакцинации БЦЖ показало более благоприятное течение COVID-19 (более медленную динамику роста заболеваемости и смертности) в странах с обязательной БЦЖ-вакцинацией всего населения. Однако ассоциация между вакцинацией БЦЖ и более мягким течением COVID-19 может быть непрямой. В статье обсуждаются другие факторы, которые могут обусловливать наличие этой ассоциации, такие как уровень тестирования, жесткость и скорость принятия карантинных мер и другие. Важным аргументом против участия БЦЖ в протекции против COVID-19 является то, что вакцина используется в детстве и вряд ли может обеспечивать длительное поддержание иммунитета. Поскольку политика обязательной БЦЖ-вакцинации применяется в странах с высоким бременем ТБ и поскольку в этих странах распространена латентная туберкулезная инфекция, мы предлагаем гипотезу, согласно которой в поддержание гетерологичного/тренированного противовирусного иммунитета в странах с обязательной политикой БЦЖ-вакцинации может вносить вклад латентная туберкулезная инфекция. В четырех странах недавно были начаты клинические исследования по изучению возможности повышения уровня протекции против COVID-19 в уязвимых группах населения путем вакцинации БЦЖ. Результаты этих исследований, а также эпидемиологическое моделирование COVID-19 помогут оценить влияние БЦЖ на уровень противовирусного иммунитета. Проведение подобных клинических исследований в России представляется целесообразным и научно обоснованным.
Список литературы
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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
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Russian Journal of Infection and Immunity. 2020; 10: 459-468
COVID-19 and BCG vaccine: is there a link?
https://doi.org/10.15789/2220-7619-CAB-1472Abstract
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.
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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
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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
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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
