My last blog post introduced the BCG vaccine and its non-specific protective effects. However, we should not be too optimistic about it until a clinical result from a prospective random clinical trial comes out to prove the non-specific protection of BCG against COVID-19. This is because the evidence suggesting BCG vaccine's preventive effect against COVID-19 was drawn mainly from retrospective studies and speculative reports. The claims that universal BCG vaccination in a country results in lower morbidity and mortality rate of COVID-19 in that country, were based on observation and did not account for several factors that could also explain the discrepancies between different places.1-5 These factors include:
1. Public awareness:
The places with universal BCG vaccination policy such as South Korea, Taiwan and China have also been stricken by different epidemics in recent decades. The SARS outbreak in 2003 affected China, Taiwan and South Korea, while the MERS outbreak in 2015 seriously affected South Korea. Therefore the people and the governments of these countries have more experience and could act quickly in tackling the new infectious disease. This helps in slowing down the spread and lowering the severity of COVID-19.
2. Cultural differences which affect the effectiveness of the non-pharmaceutical interventions being adopted:
Most of the developed countries that do not have universal BCG vaccination, such as USA, UK and Italy, implemented quarantine, social distancing and isolation measures to contain and mitigate COVID-19. However, there is a higher proportion of civilians in these countries that did not obey and even protested against the measures. These reactions will have made the measures less effective.
On the other hand, the higher obedience among Asian people, such as Japanese, Korean and Chinese people, make it easier for the government to enforce the measures to contain the disease. Moreover, most of the people in these areas are conscientious and more willing to put on a face mask whenever they are outside their homes. According to WHO, the use of face masks is one of the measures that can limit the spread of COVID-19.6
3. Testing rate:
Within the first month or so from the start of the pandemic, Korea was already able to expand the detection of SARS-CoV-2, with a sensitivity rate of over 95%, to more than 10,000 people a day. This can quickly identify clusters of infections and quarantine the infected individuals.
4. Genetics of the population:
Super-spreaders can ignite a large-scale transmission. The low number of cases and deaths per population in some countries might be due to fewer super-spreaders, which may reflect genetic differences.7 Further study is needed to clarify this assumption.
5. Different countries had different onset times, consequently having different positions on the epidemic curve:
The observational studies correlating the BCG coverage with the low morbidity and mortality rate of COVID-19 were made based on the first three months of the outbreak of the disease (January to March). During that period, India and Ethiopia, which have long-standing BCG vaccination policies, were not yet affected by COVID-19. However, these two countries have been hit seriously by the pandemic since May. Therefore it was too early to correlate the BCG coverage with the low severity of COVID-19. The different onset in a pandemic between countries is largely due to the difference in frequency of travelling from the disease's outbreak epicentre, China. More people from China travel to Italy, the UK and the USA than to India and African countries, which had a later onset of the epidemic.
6. The differences in diagnosing and reporting COVID-19 cases:
Developing countries, which usually have BCG vaccination policies against tuberculosis, such as India, Indonesia and the Phillipines, have relatively less advanced medical systems. They have lower testing ability and less efficient reporting systems. This can result in lower morbidity and mortality rates on paper, and does not reflect the real figure.
7. The beneficial off-target effects of the BCG vaccine might be altered by subsequent administration of a different vaccine:8
Children are found to be less susceptible to the COVID-19 infection than adults, and their symptoms are generally milder.9-12 This may be due to the required vaccine programmes for every child having non-specific effects against COVID-19, but not necessarily the BCG vaccine. On the other hand, the beneficial off-target effects of the BCG vaccine might be altered by subsequent administration of different live attenuated vaccines.8,13
Moreover, it is unlikely that a BCG vaccine given decades ago in childhood could help in preventing COVID-19 nowadays. Whether older people could maintain a pool of trained monocytes many years after BCG vaccination is still questionable. A possible explanation for the observation is that children who have been vaccinated with BCG are less susceptible to infection with SARS-CoV-2 and therefore less likely to spread it to older populations.2
Conclusion
There is evidence that the BCG vaccine has non-specific effects against respiratory infections. However, there is currently no direct evidence that BCG vaccine protects against COVID-19. Hopefully, with the ongoing random clinical trials mentioned in my previous blog post, we can find out the answer in the near future.
If the BCG vaccine could really help in preventing COVID-19, it is important to know 1) which BCG strain is the most effective, as there are about 8 strains of BCG vaccine in the world,14,15 2) if the BCG vaccine will exacerbate COVID-19 in a minority of patients with severe disease,3 3) how long could the heterologous protective effect conferred by BCG last after vaccination,16 and 4) the optimal time in the life to vaccinate.17
*Examples of countries which do not have a universal BCG vaccination policy: Italy, the USA, Spain, Germany, and the UK. Italy has never had a national BCG programme; BCG is not recommended for generalized use in the US; and others phased theirs out as TB became less of a concern - Spain in 1981, Germany in 1998 and the UK stopped in 2005. 18 Examples of countries with long-standing universal BCG vaccination policies: South Korea, Japan, India, Ethiopia.18
References
1. Does BCG vaccination protect against acute respiratory infections and COVID-19? A rapid review of current evidence. CEBM, April 24,2020. https://www.cebm.net/covid-19/does-bcg-vaccination-protect-against-acute-respiratory-infections-and-covid-19-a-rapid-review-of-current-evidence/
2. L.A.J. O'Neill, and M.G. Netea. BCG induced trained immunity: can it offer protection against COVID-19? Nature Reviews Immunology,2020, 20, 335-337.
3. N. Curtis, A. Sparrow, T.A. Ghebreyesus, et al. Considering BCG vaccination to reduce the impact of COVID-19. Lancet, 2020 May 16;395(10236):1545-1546.
4. L. Faust, S. Huddart, E. MacLean, et al. A. Universal BCG vaccination and protection against COVID-19: critique of an ecological study. April 1, 2020. https://naturemicrobiologycommunity.nature.com/users/36050-emily-maclean/posts/64892-universal-bcg-vaccination-and-protection-against-covid-19-critique-of-an-ecological-study
5. C. Ozdemir, U.C. Kucuksezer, and Z.U. Tamay. Is BCG vaccination affecting the spread and severity of COVID-19? Allergy. 2020 Jul;75(7):1824-1827.
6. Advice on the use of masks in the context of COVID-19. Interim guidance. 6 April 2020. World Health Organization. https://apps.who.int/iris/bitstream/handle/10665/331693/WHO-2019-nCov-IPC_Masks-2020.3-eng.pdf?sequence=1&isAllowed=y
7. Akiko Iwasaki, & Nathan D Grubaugh. Why does Japan have so few cases of COVID-19? EMBO Molecular Medicine, 2020, 12: e12481. https://doi.org/10.15252/emmm.202012481
8. A.J. Pollard, A. Finn, and N, Curtis N. Non-specific effects of vaccines: plausible and potentially important, but implications uncertain. Arch Dis Child 2017; 102: 1077-1081.
9. J. Zhang, M. Litvinova, Y. Liang, et al. Changes in contact patterns shape the dynamics of the COVID-19 outbreak in China. Science, 2020 Jun 26;368(6498): 1481-1486.
10. D.F. Gudbjartsson, A. Helgason, H. Jonsson, et al. Spread of SARS-CoV-2 in the Iceland population. N. Eng. J. Med, 2020 Jun 11;382(24): 2302-2315.
11. COVID-19 National Emergency Response Center, Epidemiology and Case Management Team, Korea Centers for Disease Control and Prevention. Coronavirus disease-19: The first 7,755 cases in the Republic of Korea. Osong Public Health and Research Perspectives, 2020 Apr;11(2):85-90.
12. CDC COVID-19 Response Team. Coronavirus disease 2019 in children-United States, February 12-April 2, 2020. Morbidity and Mortality Weekly Report. 2020 Apr;69(14):422-426.
13. N. Curtis, A. Sparrow, T.A. Ghebreyesus, et al. Considering BCG vaccination to reduce the impact of COVID-19. Lancet, 2020 May 16;395(10236): 1545-1546.
14. N. Ritz, W.A. Hanekom, R. Robins-Browne R, et al. Influence of BCG vaccine strain on the immune response and protection against tuberculosis. FEMS Microbiol Rev 2008; 32: 821-841.
15. M. Miyasaka. Is BCG vaccination causally related to reduced COVID-19 mortality? EMBO Molecular Medicine, 2020, Jun 8;12(6):e12661. doi: 10.15252/emmm.202012661.
16. J. Kleinnijenhuis, J. Quintin, F. Preijers. et al. Long-lasting effects of BCG vaccination on both heterologous Th1/T H 17 responses and innate trained immunity. J. Innate Immun., 2014, 6, 152-158.
17. M.G. Hollm-Delgado, E.A. Stuart, & R.E. Black. Acute lower respiratory infection among Bacille Calmette-Guerin (BCG)-vaccinated children. Pediatrics, 2014, 133, e73-e81.
18. A. Zwerling, M.A. Behr, A. Verma, et al. The BCG World Atlas: a database of global BCG vaccination policies and practices. PLoS Med 2011;8(3):e1001012.
1. Public awareness:
The places with universal BCG vaccination policy such as South Korea, Taiwan and China have also been stricken by different epidemics in recent decades. The SARS outbreak in 2003 affected China, Taiwan and South Korea, while the MERS outbreak in 2015 seriously affected South Korea. Therefore the people and the governments of these countries have more experience and could act quickly in tackling the new infectious disease. This helps in slowing down the spread and lowering the severity of COVID-19.
2. Cultural differences which affect the effectiveness of the non-pharmaceutical interventions being adopted:
Most of the developed countries that do not have universal BCG vaccination, such as USA, UK and Italy, implemented quarantine, social distancing and isolation measures to contain and mitigate COVID-19. However, there is a higher proportion of civilians in these countries that did not obey and even protested against the measures. These reactions will have made the measures less effective.
On the other hand, the higher obedience among Asian people, such as Japanese, Korean and Chinese people, make it easier for the government to enforce the measures to contain the disease. Moreover, most of the people in these areas are conscientious and more willing to put on a face mask whenever they are outside their homes. According to WHO, the use of face masks is one of the measures that can limit the spread of COVID-19.6
3. Testing rate:
Within the first month or so from the start of the pandemic, Korea was already able to expand the detection of SARS-CoV-2, with a sensitivity rate of over 95%, to more than 10,000 people a day. This can quickly identify clusters of infections and quarantine the infected individuals.
4. Genetics of the population:
Super-spreaders can ignite a large-scale transmission. The low number of cases and deaths per population in some countries might be due to fewer super-spreaders, which may reflect genetic differences.7 Further study is needed to clarify this assumption.
5. Different countries had different onset times, consequently having different positions on the epidemic curve:
The observational studies correlating the BCG coverage with the low morbidity and mortality rate of COVID-19 were made based on the first three months of the outbreak of the disease (January to March). During that period, India and Ethiopia, which have long-standing BCG vaccination policies, were not yet affected by COVID-19. However, these two countries have been hit seriously by the pandemic since May. Therefore it was too early to correlate the BCG coverage with the low severity of COVID-19. The different onset in a pandemic between countries is largely due to the difference in frequency of travelling from the disease's outbreak epicentre, China. More people from China travel to Italy, the UK and the USA than to India and African countries, which had a later onset of the epidemic.
6. The differences in diagnosing and reporting COVID-19 cases:
Developing countries, which usually have BCG vaccination policies against tuberculosis, such as India, Indonesia and the Phillipines, have relatively less advanced medical systems. They have lower testing ability and less efficient reporting systems. This can result in lower morbidity and mortality rates on paper, and does not reflect the real figure.
7. The beneficial off-target effects of the BCG vaccine might be altered by subsequent administration of a different vaccine:8
Children are found to be less susceptible to the COVID-19 infection than adults, and their symptoms are generally milder.9-12 This may be due to the required vaccine programmes for every child having non-specific effects against COVID-19, but not necessarily the BCG vaccine. On the other hand, the beneficial off-target effects of the BCG vaccine might be altered by subsequent administration of different live attenuated vaccines.8,13
Moreover, it is unlikely that a BCG vaccine given decades ago in childhood could help in preventing COVID-19 nowadays. Whether older people could maintain a pool of trained monocytes many years after BCG vaccination is still questionable. A possible explanation for the observation is that children who have been vaccinated with BCG are less susceptible to infection with SARS-CoV-2 and therefore less likely to spread it to older populations.2
Conclusion
There is evidence that the BCG vaccine has non-specific effects against respiratory infections. However, there is currently no direct evidence that BCG vaccine protects against COVID-19. Hopefully, with the ongoing random clinical trials mentioned in my previous blog post, we can find out the answer in the near future.
If the BCG vaccine could really help in preventing COVID-19, it is important to know 1) which BCG strain is the most effective, as there are about 8 strains of BCG vaccine in the world,14,15 2) if the BCG vaccine will exacerbate COVID-19 in a minority of patients with severe disease,3 3) how long could the heterologous protective effect conferred by BCG last after vaccination,16 and 4) the optimal time in the life to vaccinate.17
*Examples of countries which do not have a universal BCG vaccination policy: Italy, the USA, Spain, Germany, and the UK. Italy has never had a national BCG programme; BCG is not recommended for generalized use in the US; and others phased theirs out as TB became less of a concern - Spain in 1981, Germany in 1998 and the UK stopped in 2005. 18 Examples of countries with long-standing universal BCG vaccination policies: South Korea, Japan, India, Ethiopia.18
References
1. Does BCG vaccination protect against acute respiratory infections and COVID-19? A rapid review of current evidence. CEBM, April 24,2020. https://www.cebm.net/covid-19/does-bcg-vaccination-protect-against-acute-respiratory-infections-and-covid-19-a-rapid-review-of-current-evidence/
2. L.A.J. O'Neill, and M.G. Netea. BCG induced trained immunity: can it offer protection against COVID-19? Nature Reviews Immunology,2020, 20, 335-337.
3. N. Curtis, A. Sparrow, T.A. Ghebreyesus, et al. Considering BCG vaccination to reduce the impact of COVID-19. Lancet, 2020 May 16;395(10236):1545-1546.
4. L. Faust, S. Huddart, E. MacLean, et al. A. Universal BCG vaccination and protection against COVID-19: critique of an ecological study. April 1, 2020. https://naturemicrobiologycommunity.nature.com/users/36050-emily-maclean/posts/64892-universal-bcg-vaccination-and-protection-against-covid-19-critique-of-an-ecological-study
5. C. Ozdemir, U.C. Kucuksezer, and Z.U. Tamay. Is BCG vaccination affecting the spread and severity of COVID-19? Allergy. 2020 Jul;75(7):1824-1827.
6. Advice on the use of masks in the context of COVID-19. Interim guidance. 6 April 2020. World Health Organization. https://apps.who.int/iris/bitstream/handle/10665/331693/WHO-2019-nCov-IPC_Masks-2020.3-eng.pdf?sequence=1&isAllowed=y
7. Akiko Iwasaki, & Nathan D Grubaugh. Why does Japan have so few cases of COVID-19? EMBO Molecular Medicine, 2020, 12: e12481. https://doi.org/10.15252/emmm.202012481
8. A.J. Pollard, A. Finn, and N, Curtis N. Non-specific effects of vaccines: plausible and potentially important, but implications uncertain. Arch Dis Child 2017; 102: 1077-1081.
9. J. Zhang, M. Litvinova, Y. Liang, et al. Changes in contact patterns shape the dynamics of the COVID-19 outbreak in China. Science, 2020 Jun 26;368(6498): 1481-1486.
10. D.F. Gudbjartsson, A. Helgason, H. Jonsson, et al. Spread of SARS-CoV-2 in the Iceland population. N. Eng. J. Med, 2020 Jun 11;382(24): 2302-2315.
11. COVID-19 National Emergency Response Center, Epidemiology and Case Management Team, Korea Centers for Disease Control and Prevention. Coronavirus disease-19: The first 7,755 cases in the Republic of Korea. Osong Public Health and Research Perspectives, 2020 Apr;11(2):85-90.
12. CDC COVID-19 Response Team. Coronavirus disease 2019 in children-United States, February 12-April 2, 2020. Morbidity and Mortality Weekly Report. 2020 Apr;69(14):422-426.
13. N. Curtis, A. Sparrow, T.A. Ghebreyesus, et al. Considering BCG vaccination to reduce the impact of COVID-19. Lancet, 2020 May 16;395(10236): 1545-1546.
14. N. Ritz, W.A. Hanekom, R. Robins-Browne R, et al. Influence of BCG vaccine strain on the immune response and protection against tuberculosis. FEMS Microbiol Rev 2008; 32: 821-841.
15. M. Miyasaka. Is BCG vaccination causally related to reduced COVID-19 mortality? EMBO Molecular Medicine, 2020, Jun 8;12(6):e12661. doi: 10.15252/emmm.202012661.
16. J. Kleinnijenhuis, J. Quintin, F. Preijers. et al. Long-lasting effects of BCG vaccination on both heterologous Th1/T H 17 responses and innate trained immunity. J. Innate Immun., 2014, 6, 152-158.
17. M.G. Hollm-Delgado, E.A. Stuart, & R.E. Black. Acute lower respiratory infection among Bacille Calmette-Guerin (BCG)-vaccinated children. Pediatrics, 2014, 133, e73-e81.
18. A. Zwerling, M.A. Behr, A. Verma, et al. The BCG World Atlas: a database of global BCG vaccination policies and practices. PLoS Med 2011;8(3):e1001012.
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