COVID-19: Trained immunity from BCG vaccine

Would BCG vaccination really help in immunizing up against SARS-CoV-2?

Let's dig in. 

BCG is a live-attenuated strain derived from an isolate of Mycobacterium bovis used widely across the world as a vaccine for tuberculosis (TB). But that's not all, BCG vaccination is a potential goldmine against so many diseases.

Figure 1. BCG as an immunity booster against a spectrum of diseases.

Now that I have your curiosity, let's see how BCG works against SARS:

• BCG vaccine turns on the immune mechanism by inducing a non-specific, cross-protection via innate immune cells namely, monocytes and natural killer cells known as “trained immunity” 
• These trained innate immune cells can now undergo extensive metabolic and epigenetic reprogramming, which results in enhanced immune responses to heterologous re-infection. 
• Specifically, those genetic regions encoding for pro-inflammatory cytokines like IL-1B are activated which has been shown to play a vital role in antiviral immunity. 
• It also enhances IFN-gamma production from the CD4+ cells. 

And that is how live-attenuated vaccines induce a robust and long-lasting immune response, including cellular and humoral immunity to many different antigens.

Figure 2. An illustration depicting the induction of trained immunity by BCG

A study by the Center for Drug Research and Development (CDRD) of the British University in Egypt proposes that multiple-dose BCG vaccine repurposing for COVID-19 would be an uprising breakthrough of vaccine discovery with safer outcomes. Here are some of the reasons they gave to justify their proposal:

• Children vaccinated with BCG were observed to have a 50% reduction in overall mortality, which was attributed to the vaccine’s effect on reducing respiratory infections and sepsis. [1]
• BCG vaccination has been shown to produce broad protection against viral infections and sepsis [2], raising the possibility that the protective effect of BCG might be not directly related to actions on COVID-19 but on associated co-occurring infections or sepsis. [1]
• The broad use of the BCG vaccine across a population could reduce the number of carriers, and combined with other measures could act to slow down or stop the spread of COVID-19. [1]

Epidemiological proof of BCG immunization protection against COVID 19 spread

Although COVID-19 has spread to most countries in the world why is the impact of the disease different in different countries?  

A study was done by the Department of Biomedical Sciences, NYIT which gives possible explanations with epidemiological reasons and data:- 

1. Different nations have different national policies with respect to BCG childhood vaccination. Their study found that earlier a country established a BCG vaccination policy, stronger was the reduction in their number of deaths per million inhabitants. [3]
2. They also proposed that countries without universal policies of BCG vaccination like, Italy, Netherlands, USA have been more severely affected compared to those countries with universal and long-standing BCG policies. [3]
3. While countries that had a late start of universal BCG policy like Iran (1984) had high mortality, consistent with the idea that BCG protects the vaccinated elderly population. [3]
4. Countries such as Spain, France, and Switzerland, have discontinued their universal BCG vaccine policies due to comparatively low risk for developing M. bovis infections as well as the proven variable effectiveness in preventing adult TB. [3]
5. This study also points out the fact that BCG vaccination reduced the number of reported COVID-19 cases in a country. [3]
6. Japan and China have a universal BCG vaccination policy in newborns. [3] 

So why did SARS-CoV-2 spread in China despite having a universal BCG policy since the 1950s?

During the Cultural Revolution (1966-1976), tuberculosis prevention and treatment agencies were disbanded and weakened [4]. They speculated that this could have created a pool of potential hosts that would be affected by and spread COVID-19. Currently, however, the situation in China seems to be improving.

Conclusively, BCG vaccine is definitely a possible tool to curb the wildly spreading SARS-CoV-2 and guess what, there are already 2 RCTs being conducted as we speak:-

Trial 1: BCG-CORONA reducing health care workers absenteeism in SARS-CoV-2 pandemic through Bacillus Calmette-Guérin vaccination, a randomized controlled trial (BCG-CORONA)

Trial 2: BRACE - BCG Vaccination to Reduce the Impact of COVID-19 in Australian Healthcare Workers Following Coronavirus Exposure (BRACE) Trial

References

1. Ayoub, B. (2020, March 26). COVID-19 vaccination clinical trials should consider multiple doses of BCG. https://doi.org/10.31219/osf.io/h24bj 

2. Covián C, Fernández-Fierro A, Retamal-Díaz A, et al. BCG-Induced Cross-Protection and Development of Trained Immunity: Implication for Vaccine Design. Front Immunol. 2019;10:2806. Published 2019 Nov 29. doi:10.3389/fimmu.2019.02806

3. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study Aaron Miller, Mac Josh Reandelar, Kimberly Fasciglione, Violeta Roumenova, Yan Li, Gonzalo H Otazu medRxiv 2020.03.24.20042937; doi:https://doi.org/10.1101/2020.03.24.20042937

4. JIANG Shi-wen，ZHANG Hui，WANG Li-xia. Development and expectation of tuberculosis service system in China.Chinese Journal of Antituberculosis, 2012, 34(9): 557-559. Available at: http://www.zgflzz.cn/EN/Y2012/V34/I9/557. (Accessed: 24th March 2020)


Hope you guys enjoyed reading this and if you're interested in other vaccines under review for COVID -19 read this post: https://www.medicowesome.com/2020/04/covid-19-vaccines.html

Content and Illustration by Anagha Rao 

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