by Antonino NapoleoneGiuseppe ScarlataDomenico Gangemi |June 8, 2020

The impact and spread of Coronavirus Infectious Disease 2019 (COVID-19) reached 188 countries worldwide and the confirmed case numbers continuing to rise rapidly, with 7,049,649 cases reported on June 8, 2020. Mathematical and epidemiological models are constantly updated, but understanding and predicting the spread of the virus is becoming more difficult, even months after the beginning of the pandemic. Some countries in Europe are beginning to approach a clear descending phase of contagion, as a result of the lockdown measures adopted, but in different areas of the world, there is a wave of cases that are now strongly affecting Russia, South America, the Middle East, and South-East Asia. The comparison of the characteristics of the outbreaks between the various countries is widely debated and is presumed to be influenced by factors related to the average age of the population, the health system management of the pandemic, climatic and environmental factors. Looking at the data, the lethality rate (number of deaths per confirmed cases) varies widely between countries, and it is difficult to find a valid and unequivocal explanation. One of the hypotheses that emerged to explain the pandemic articulated pattern between the European countries and the developing countries has been attributed to the different national policies for childhood tuberculosis (TB) vaccination.

The BCG vaccine and the Trained Immunity

The Bacillus of Calmette and Guerin (BCG) derives from an attenuated bacterial strain (Mycobacterium bovis) and is used as a vaccine to prevent TBC, a serious lung infection that still affects about 10 million people every year. It has been seen that the BCG vaccine indirectly offers protection against other respiratory infections including the Syncytial Respiratory Virus (RSV), Influenza A Virus, and Herpes Simplex Virus-2 (HSV2). This indirect protection has long been studied and has been reported for the first time in Nature as a mechanism of trained immunity induced by BCG vaccination (Figure 1) since it can bring indirect benefits to the immune system against other pathogens (to learn more: https://www.nature.com/articles/s41577-020-0337-y).

Figure 1. a | Bacillus Calmette–Guérin (BCG) vaccination has been shown to protect against multiple viral pathogens, including respiratory syncytial virus (RSV), influenza A virus, and herpes simplex virus type 2 (HSV2). Will it protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)? b | Trained immunity leading to enhanced innate immune responses to different pathogens after vaccination is mediated by metabolic and epigenetic rewiring in innate immune cells, which leads to increased gene transcription and improved host defense.

Hence, without discriminating between bacterial or viral infection, the hypothesis has been spread that countries that have extended BCG vaccination to the entire population, such as India in 1948, have an indirect protective effect towards COVID-19. Indeed, the unpredictability of SARS-CoV-2 has not only generated fear and concern but has triggered an avalanche of hypotheses and theories based on simplistic, sometimes trivial, and not properly proven studies. In the European countries most affected by COVID-19 and with high lethality rates, such as Italy, Spain, France, the United Kingdom, and Sweden, the TB vaccination plan was discontinued decades ago due to a shortage of cases among the population. The COVID-19 pandemic initially spread to China and then spread to Europe with well-known effects and consequences, so rapidly that disoriented scientists and epidemiologists. According to official data, the same wave did not affect the same way and at the same time the countries close to China and where the BCG vaccination has been extended to the entire population. But this observation is certainly not sufficient to demonstrate any correlation between the BCG vaccine and the number of cases/lethality rate of COVID-19. The position of the World Health Organisation (WHO) is clear, recommending the use of the BCG vaccine only to prevent TB in countries with a high incidence of TB, especially in children.

So in the absence of scientific evidence, it is good to be cautious in supporting this correlation, for several reasons:

  • There are two major ongoing clinical trials in Australia and the Netherlands (http://clinicaltrials.gov/show/NCT04327206 and http://clinicaltrials.gov/show/NCT04328441) to investigate the correlation between BCG vaccination and clinical course of COVID-19 infection, but until proven evidence, WHO recommendations prevail;
  • BCG vaccination carried out in childhood is unlikely to offer current protection in adults and elderly people many years later. Moreover, the concomitant administration of other vaccines makes it even more difficult to establish unequivocal conclusions;
  • It was recently reported in The Lancet that the BCG vaccine (against a mycobacterium) is not directly effective against SARS-CoV-2. Vaccines are developed to be antigen-specific and there is no common antigen between the TB mycobacterium and the Coronavirus;
  • Currently, there is a trend of COVID-19 spread that is heavily affecting the Russian, Indian, Middle East and South American area where the BCG vaccine is mandatory/recommended, with peaks exceeding 10,000 infected and 200 deaths per day, according to official COVID-19 data;
  • TB vaccination is mandatory mainly in developing countries, where health and intensive care facilities, as well as COVID-19 data collection systems and the number of diagnostics tests carried out, are extremely low or insufficient, and this greatly alters the rate of spread and lethality.

The study from JAMA

A study recently published in the well-known medical journal JAMA analyzed 72,060 swab results from a cohort of 35- to 41-year-old adults vaccinated for TB and unvaccinated in Israel. It has been found that individuals vaccinated for TB were associated with a virus-positive and lethal rate similar to non-vaccinated individuals. This analysis carried out on a large number of individuals does not support the hypothesis that the BCG vaccine in childhood has a protective effect against COVID-19 in adulthood, although results and confirmations of further ongoing clinical studies are awaited.

Conclusions

There are too many factors to consider to have a clear idea of how the spread of SARS-CoV-2 is progressing, but this should not justify speculation or false information. The TB is endemic in many areas of the world (Figure 2) Approximately 130 million people are vaccinated for TB annually, with a sharp reduction in the TB mortality rate of more than 11% worldwide from 2015 to date. The discovery that the immune system can benefit from BCG vaccination through the trained immunity mechanism has provided further confirmation of the importance of continuing research and vaccination campaigns against diseases such as TB. There is a future of expectations and answers from researchers, to meet the increasingly urgent need for a therapeutic solution or hopefully a specific and effective vaccine against SARS-CoV-2 to be extended worldwide, to be integrated and not a replacement for TB vaccination. Share and have faith in medical science rather than the media, we all need to work together to stop all of this.

Figure 2. Estimated Tuberculosis incidence rates, 2018.

References:

  1. Moorlag, S. J. C. F. M., Arts, R. J. W., van Crevel, R. & Netea, M. G. Non-specific effects of BCG vaccine on viral infections. Clin. Microbiol. Infect. 25, 1473–1478 (2019).
  2. Centis, R. & Sc, M. c or r e sp ondence Multidrug-Resistant Tuberculosis. 4–6 (2012) doi:10.1056/NEJMc1210001.
  3. WHO global tuberculosis report 2019.
  4. UNICEF Bacillus Calmette-Guérin Vaccine Supply and Demand Update – August 2019.
  5.  Leentjens, J., Kox, M., Stokman, R., et al. (2015). BCG vaccination enhances the immunogenicity of subsequent influenza vaccination in healthy volunteers: A randomized, placebo-controlled pilot study. Journal of Infectious Diseases, 212(12), 1930–1938.
  6. Curtis, N., Sparrow, A., Ghebreyesus, T. A., & Netea, M. G. (2020). Considering BCG vaccination to reduce the impact of COVID-19. The Lancet, 395(10236), 1545–1546.
  7. O’Neill, L. A. J., & Netea, M. G. (2020). BCG-induced trained immunity: can it offer protection against COVID-19? Nature Reviews Immunology, 1–3. https://doi.org/10.1038/s41577-020-0337-y
  8. https://gisanddata.maps.arcgis.com/
  9. Gursel, M., & Gursel, I. (2020). Is global BCG vaccination-induced trained immunity relevant to the progression of the SARS-CoV-2 pandemic? Allergy, 0–3.
  10. https://www.nytimes.com/2020/04/03/health/coronavirus-bcg-vaccine.html

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