After reading my blog posts introducing the existing drugs being tested for COVID-19 treatment, you may wonder if there are any existing vaccines being tested for prevention of COVID-19. The answer is yes. This is a vaccine for tuberculosis (TB) called Bacille Calmette Guérin (BCG) which is now being tested in several clinical trials globally.
BCG was developed in France by Albert Calmette and Camille Guérin in order to prevent TB in the last century. The two scientists made use of a strain of bacteria that caused bovine tuberculosis (Mycobacterium bovis), diminished its virulent activity, and applied it to humans.1 The application of the weakened cattle bacteria induces the generation of antibodies which can also recognize and neutralize the bacteria that causes TB in humans, Mycobacterium tuberculosis. This makes BCG very effective in preventing TB.
However, the cattle bacteria that causes TB is very different from the human virus SARS-CoV-2. The perceived benefit of the BCG vaccine for COVID-19 prevention is not based on the cross neutralizing effect of the antibody generated against the vaccine. Rather, it is the vaccine's ability to initiate an overall boost to the immune system.
BCG is a live attenuated vaccine (live but with substantially weakened virulence activity). For a long time, scientists have observed a phenomena that live attenuated vaccines have "non-specific effects", which means that the protective effect of vaccine can extend to some infectious or inflammatory diseases other than its initial specific target.2
Since the introduction of the vaccine in the 1920s, several studies reported a reduction of neonatal mortality in countries where BCG vaccines are administered to newborns. The reduction rate could not be explained only by the reduction of tuberculosis.3 Later in the 2000s in Guinea-Bissau, a random controlled trial showed that BCG vaccine administered at birth to low-birth-weight infants showed an up-to-50% reduction of mortality in young children. This reduction was suggested to be due to the protection against unrelated infectious agents that cause respiratory tract infections, septicemia (a blood poisoning which occurs when a bacterial infection elsewhere in the body, such as the lungs or skin, enters the bloodstream),4 and fever.5
Moreover, it seems that the protection from the "non-specific effects" conferred by the administration of BCG is not only limited to newborn children. A study taken from 1971 to 2010 in Denmark showed that BCG given at school entry was associated with a significant reduction in the risk of dying from natural causes before the age of 45 years.6 Additionally, a clinical trial giving the BCG vaccine to tuberculin-negative elderly in Japan showed a protection against pneumonia. This demonstrates that the BCG vaccine can also confer non-specific protection when administered late in life.7
In fact, an experimental infection provides evidence that the vaccine can reduce the severity of infections by other viruses in vivo. It is demonstrated by the finding that a BCG vaccine given 4 weeks prior to a yellow fever vaccine reduced the viraemia (the presence of a virus in bloodstream) by 71% in volunteers in the Netherlands.8 Because of its non-specific effects, the BCG vaccine is also used as adjuvant immunotherapy for patients with non-muscle-invasive bladder cancer, to induce immune-stimulating effects that slow down tumour progression.9,10
Above are some of the examples of the non-specific effects the BCG vaccine conferred. But how did the BCG vaccine correlate with COVID-19? Since the outbreak of the disease, there is a high heterogeneity of infection and mortality rates across countries, and scientists tried to find out the reasons behind this. One of the hypotheses is the vaccination coverage. When analysing the BCG and another 8 vaccines' coverages in the years of 2018, 2008, 1998 and 1988, in 125 countries around the world, a study found a significant moderate negative correlation between BCG coverage and the number of COVID-19 cases. This means the higher the BCG coverage, the less the number of COVID-19 cases per unit population.11 Some observation speculative reports also found that ratio of COVID-19 cases per population and the ratio of deaths per COVID-19 cases are significantly lower in BCG-vaccinated countries.12-14
The combination of reduced morbidity and mortality has led to the suggestion that vaccination with BCG might have a role in protecting health-care workers and other vulnerable individuals against COVID-19.
According to the data from the ClinicalTrials.org (a database of privately and publicly funded clinical studies conducted around the world), there are 18 trials registered to test the BCG vaccines on their effectiveness at protection against COVID-19.15 Among these, eight are currently in progress: randomised controlled trials in the Netherlands, South Africa, Australia, and the USA are to test whether BCG vaccination of health-care workers could protect them from COVID-19; a randomised controlled trial in Greece is to test the effect of BCG vaccination on the prevention of severe COVID-19 infection among older people; two random placebo-controlled trials in Germany are testing a genetically modified BCG vaccine, VPM1002, on health-care workers and older patients, respectively; and a clinical trial in Egypt is to check if COVID-19 cases admitted to hospitals or intensive care units had been vaccinated with BCG before.
These clinical trials are useful for us to understand whether and how the vaccine confers resistance to the causal virus of COVID-19.
References
1. S. Luca, and T. Mihaescu. History of BCG vaccine. Maedica, 2013, 8:53-58.
2. P. Aaby, and C. S. Benn. Developing the concept of beneficial non-specific effect of live vaccines with epidemiological studies. Review. Clin. Microbiol. Infect, 2019, 25(12):1459-1467.
3. Shann, F. The non-specific effects of vaccines. Arch. Dis. Child, 2010, 95, 662-667.
4. https://www.healthline.com/health/septicemia
5. P. Aaby, A. Roth, H. Ravn, et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J. Infect. Dis., 2011, 204, 245-252.
6. A. Rieckmann, M. Villumsen, S. Sorup, et al. Vaccinations against smallpox and tuberculosis are associated with better long-term survival: a Danish case-cohort study 1971-2010. Int J Epidemiol., 2017, 46: 695-705.
7. T. Ohrui, K. Nakayama, T. Fukushima, et al. Prevention of elderly pneumonia by pneumococcal, influenza and BCG vaccinations [Japanese]. Nihon Ronen Igakkai Zasshi, 2005, 42, 34-36.
8. R.J.W. Arts, S.J.C.F.M. Moorlag, B. Novakovic, 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: 89-100.
9. G. Redelman-Sidi, M.S. Glickman, and B.H. Bochner. The mechanism of action of BCG therapy for bladder cancer-a current perspective. Nat. Rev. Urol. 2014, 11, 153-162.
10. R.F. Han, and J.G. Pan. Can intravesical bacillus Calmette-Guérin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology, 2006, 67, 1216-1223.
11. A. Macedo, and C. Febra. Relation between BCG coverage rate and COVID-19 infection worldwide. Med Hypothesis, 2020 May 6;142:109816.
12. C. Ozdemir, U.C. Kucuksezer, and Z.U. Tamay. Is BCG vaccination affecting the spread and severity of COVID-19? Allergy. 2020;00:1-3.
13. A. Iwasaki, and N.D. Grubaugh. Why does Japan have so few cases of COVID-19? EMBO Molecular Medicine, 2020 May 8;12(5):e12481.
14. A. Miller, M.J. Reandelar, K. Fasciglione, et al. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. MedRxiv doi: https://doi.org/10.1101/2020.03.24.20042937
15. https://clinicaltrials.gov/ct2/results?term=bcg&cond=COVID&draw=1&rank=10#rowId9
BCG was developed in France by Albert Calmette and Camille Guérin in order to prevent TB in the last century. The two scientists made use of a strain of bacteria that caused bovine tuberculosis (Mycobacterium bovis), diminished its virulent activity, and applied it to humans.1 The application of the weakened cattle bacteria induces the generation of antibodies which can also recognize and neutralize the bacteria that causes TB in humans, Mycobacterium tuberculosis. This makes BCG very effective in preventing TB.
However, the cattle bacteria that causes TB is very different from the human virus SARS-CoV-2. The perceived benefit of the BCG vaccine for COVID-19 prevention is not based on the cross neutralizing effect of the antibody generated against the vaccine. Rather, it is the vaccine's ability to initiate an overall boost to the immune system.
BCG is a live attenuated vaccine (live but with substantially weakened virulence activity). For a long time, scientists have observed a phenomena that live attenuated vaccines have "non-specific effects", which means that the protective effect of vaccine can extend to some infectious or inflammatory diseases other than its initial specific target.2
Since the introduction of the vaccine in the 1920s, several studies reported a reduction of neonatal mortality in countries where BCG vaccines are administered to newborns. The reduction rate could not be explained only by the reduction of tuberculosis.3 Later in the 2000s in Guinea-Bissau, a random controlled trial showed that BCG vaccine administered at birth to low-birth-weight infants showed an up-to-50% reduction of mortality in young children. This reduction was suggested to be due to the protection against unrelated infectious agents that cause respiratory tract infections, septicemia (a blood poisoning which occurs when a bacterial infection elsewhere in the body, such as the lungs or skin, enters the bloodstream),4 and fever.5
Moreover, it seems that the protection from the "non-specific effects" conferred by the administration of BCG is not only limited to newborn children. A study taken from 1971 to 2010 in Denmark showed that BCG given at school entry was associated with a significant reduction in the risk of dying from natural causes before the age of 45 years.6 Additionally, a clinical trial giving the BCG vaccine to tuberculin-negative elderly in Japan showed a protection against pneumonia. This demonstrates that the BCG vaccine can also confer non-specific protection when administered late in life.7
In fact, an experimental infection provides evidence that the vaccine can reduce the severity of infections by other viruses in vivo. It is demonstrated by the finding that a BCG vaccine given 4 weeks prior to a yellow fever vaccine reduced the viraemia (the presence of a virus in bloodstream) by 71% in volunteers in the Netherlands.8 Because of its non-specific effects, the BCG vaccine is also used as adjuvant immunotherapy for patients with non-muscle-invasive bladder cancer, to induce immune-stimulating effects that slow down tumour progression.9,10
Above are some of the examples of the non-specific effects the BCG vaccine conferred. But how did the BCG vaccine correlate with COVID-19? Since the outbreak of the disease, there is a high heterogeneity of infection and mortality rates across countries, and scientists tried to find out the reasons behind this. One of the hypotheses is the vaccination coverage. When analysing the BCG and another 8 vaccines' coverages in the years of 2018, 2008, 1998 and 1988, in 125 countries around the world, a study found a significant moderate negative correlation between BCG coverage and the number of COVID-19 cases. This means the higher the BCG coverage, the less the number of COVID-19 cases per unit population.11 Some observation speculative reports also found that ratio of COVID-19 cases per population and the ratio of deaths per COVID-19 cases are significantly lower in BCG-vaccinated countries.12-14
The combination of reduced morbidity and mortality has led to the suggestion that vaccination with BCG might have a role in protecting health-care workers and other vulnerable individuals against COVID-19.
According to the data from the ClinicalTrials.org (a database of privately and publicly funded clinical studies conducted around the world), there are 18 trials registered to test the BCG vaccines on their effectiveness at protection against COVID-19.15 Among these, eight are currently in progress: randomised controlled trials in the Netherlands, South Africa, Australia, and the USA are to test whether BCG vaccination of health-care workers could protect them from COVID-19; a randomised controlled trial in Greece is to test the effect of BCG vaccination on the prevention of severe COVID-19 infection among older people; two random placebo-controlled trials in Germany are testing a genetically modified BCG vaccine, VPM1002, on health-care workers and older patients, respectively; and a clinical trial in Egypt is to check if COVID-19 cases admitted to hospitals or intensive care units had been vaccinated with BCG before.
These clinical trials are useful for us to understand whether and how the vaccine confers resistance to the causal virus of COVID-19.
References
1. S. Luca, and T. Mihaescu. History of BCG vaccine. Maedica, 2013, 8:53-58.
2. P. Aaby, and C. S. Benn. Developing the concept of beneficial non-specific effect of live vaccines with epidemiological studies. Review. Clin. Microbiol. Infect, 2019, 25(12):1459-1467.
3. Shann, F. The non-specific effects of vaccines. Arch. Dis. Child, 2010, 95, 662-667.
4. https://www.healthline.com/health/septicemia
5. P. Aaby, A. Roth, H. Ravn, et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J. Infect. Dis., 2011, 204, 245-252.
6. A. Rieckmann, M. Villumsen, S. Sorup, et al. Vaccinations against smallpox and tuberculosis are associated with better long-term survival: a Danish case-cohort study 1971-2010. Int J Epidemiol., 2017, 46: 695-705.
7. T. Ohrui, K. Nakayama, T. Fukushima, et al. Prevention of elderly pneumonia by pneumococcal, influenza and BCG vaccinations [Japanese]. Nihon Ronen Igakkai Zasshi, 2005, 42, 34-36.
8. R.J.W. Arts, S.J.C.F.M. Moorlag, B. Novakovic, 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: 89-100.
9. G. Redelman-Sidi, M.S. Glickman, and B.H. Bochner. The mechanism of action of BCG therapy for bladder cancer-a current perspective. Nat. Rev. Urol. 2014, 11, 153-162.
10. R.F. Han, and J.G. Pan. Can intravesical bacillus Calmette-Guérin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology, 2006, 67, 1216-1223.
11. A. Macedo, and C. Febra. Relation between BCG coverage rate and COVID-19 infection worldwide. Med Hypothesis, 2020 May 6;142:109816.
12. C. Ozdemir, U.C. Kucuksezer, and Z.U. Tamay. Is BCG vaccination affecting the spread and severity of COVID-19? Allergy. 2020;00:1-3.
13. A. Iwasaki, and N.D. Grubaugh. Why does Japan have so few cases of COVID-19? EMBO Molecular Medicine, 2020 May 8;12(5):e12481.
14. A. Miller, M.J. Reandelar, K. Fasciglione, et al. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. MedRxiv doi: https://doi.org/10.1101/2020.03.24.20042937
15. https://clinicaltrials.gov/ct2/results?term=bcg&cond=COVID&draw=1&rank=10#rowId9
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