Vaccination with Bacillus Calmette–Guérin (BCG) provided 100 percent protection against the development of COVID-19 infection caused by the SARS-CoV-2 coronavirus.
Why It Matters
As the COVID-19 pandemic worsened, vaccine development came to the forefront. Alas, the antigen-specific vaccines on which most clinical programs focus have struggled to keep up with new variants of the coronavirus. The ideal vaccine must be safe, effective, affordable, and provide long-lasting protection against a virus with any mutations.
Spikevax bivalent Original / Omicron (elasomeran + imelasomeran; mRNA-1273.214) by Moderna is the world’s first vaccine to protect against the Omicron variant of the SARS-CoV-2 coronavirus.
What It’s All About
The BCG vaccine produces long-term positive changes in the innate immune system as the first line of defense against any pathogen. “Trained immunity,” triggered and reinforced by the annual BCG vaccination, keeps the immune system properly activated against viruses, bacteria, and parasites. BCG reliably protects against COVID-19, regardless of any mutation of all variants of the coronavirus, including the now-dominant Omicron. In fact, BCG is a universal vaccine.
Given, first, the decidedly penny-pinching cost of BCG available to any nation and, second, the century-long history of this tuberculosis vaccine, which is one of the safest ever developed and which continues to vaccinate tens of millions of children annually, and therefore nullifies all the claims of anti-vaxxers, we have a decidedly new perspective on combating the coronavirus pandemic.
The biotechnology industry must come up with a comprehensive defense against all coronaviruses.
What is BCG
Bacillus Calmette–Guérin (BCG), first introduced into medical practice in 1921, is a vaccine used primarily to protect against tuberculosis (TB). BCG also has some activity against other non-TB mycobacterial infections (leprosy and Buruli ulcer) and is the standard treatment for bladder cancer.
BCG is a live, highly attenuated (virulence-reduced) strain of bovine-type mycobacterium (Mycobacterium bovis).
The efficacy of BCG vaccine to prevent TB is difficult to accurately evaluate due to a combination of factors, such as differences in the vaccine strains cultured and the laboratory conditions where it is grown, genetic differences in inoculated populations, changes in the environment, and exposure to other bacterial and parasitic infections.       
The BCG vaccine is thought to reduce the risk of getting TB by about 50%.  Other estimates suggest that the BCG vaccine reduces the number of infections by 19%–27% and attenuates the risk of progression to active TB by 71%. 
The duration of the protective effect of BCG is not exactly known. One study showed that vaccine protection wanes to 59% after 15 years of immunization and to zero after 20 years.  Another showed that protective efficacy was maintained even after 60 years. 
BCG remains the only approved vaccine to prevent tuberculosis, but its inconsistent efficacy is forcing the development of new TB vaccines, whose emergence is more than required because of the evolution of multidrug-resistant (MDR) Mycobacterium tuberculosis. The pharmaceutical industry has a very cool attitude to the creation of TB vaccines, understanding the lack of serious business prospects, as TB is mostly associated with poor countries.
The BCG vaccine, one of the safest vaccines ever developed, is widely used around the world, administered to newborns to prevent tuberculosis.  It is extremely affordable, ranging from 10–75 cents per dose. Numerous clinical trials and epidemiological studies have confirmed that the BCG vaccine protects against not only TB but also many other bacterial and viral infections, including upper respiratory infections (pneumonia, respiratory syncytial virus), leprosy, malaria, and sepsis.                The BCG vaccine, while providing heterologous (nonspecific) protection, has the potential to protect against immune diseases such as type 1 diabetes mellitus and multiple sclerosis.    
With the onset of the SARS-CoV-2 pandemic, some epidemiological studies have found a link between neonatal BCG vaccination and a reduction in morbidity and mortality from COVID-19 infection, even in older adults decades after immunization.                    However, in some populations that were vaccinated differently and received different BCG strains, no such benefit was observed.        
Efficacy of BCG to Protect Against COVID-19
The NCT02081326 phase 2/3 (randomized, double-blind, placebo-controlled) clinical trial verified the hypothesis suggesting that periodic vaccination with Bacillus Calmette–Guérin (BCG) has beneficial immunologic and metabolic effects in type 1 diabetes mellitus.
- The idea was that BCG stimulates the innate immune system, which activates tumor necrosis factor (TNF), which triggers the destruction of autoreactive cytotoxic T cells that destroy insulin-secreting pancreatic beta cells. The progressive autoimmune process underlying type 1 diabetes is mitigated, and the pancreas is allowed to regenerate. BCG, which resets the immune system, causes massive changes: Through an epigenetic reprogramming mechanism, all six key T-regulatory genes (Foxp3, TNFRSF18, IL2RA, IKZF2, IKZF4, CTLA4) relevant to glucose metabolism are demethylated in CD4+ T cells, reflecting a switch in the immune system from high levels of oxidative phosphorylation to enhanced early aerobic glycolysis. This systemic metabolic shift allows cells to consume large amounts of glucose in a regulated manner and safely reduce hyperglycemia to near-normal levels.   
Adult patients (n=144) were given either placebo or BCG intradermally, two doses at 4-week intervals in the first year and then one dose annually for the next four years.
When the COVID-19 pandemic began, the decision was made to study the effect of BCG vaccine on the SARS-CoV-2. This was done between early January 2020 and April 2021, when all participants had already received three doses of BCG or placebo.
BCG vaccination was found to prevent COVID-19 with 92% efficacy: in the BCG group, 1% of subjects (n=1/96) developed COVID-19 — versus 12.5% (n=6/48) in the placebo group. The diagnosis was confirmed by the presence of symptoms and antibodies against SARS-CoV-2.
When it comes to preventing COVID-19, whose diagnosis was confirmed by PCR (which is more accurate and reliable), the protective efficacy of the BCG vaccine was 100%: 0% of those who fell ill — vs. 10.4% (n=5/48).
BCG-vaccinated individuals were less likely to experience other non-SARS-CoV-2 infections (e.g., influenza, common cold, sinusitis, bladder infections), but it took two years after the first dose of vaccine to achieve a statistically significant (p=0.004) difference with the placebo group. Even if an illness occurred, the severity of its symptoms and the duration of infection were significantly milder and shorter (p=0.04).
BCG Against Coronavirus: Pros
Clinical trial NCT02081326 demonstrated that intermittent and relatively frequent BCG vaccination protected against COVID-19 with the highest efficacy comparable to the level of protection provided by Comirnaty (tozinameran; BNT162b2) and Spikevax (elasomeran; mRNA-1273), the strongest mRNA vaccines from Pfizer/BioNTech and Moderna, at the beginning of the pandemic when the coronavirus had not yet mutated.
In evaluating these impressive outcomes, there are a number of positive features of this study that should be taken into account to support the validity of the results:
- Because newborns and adults in the United States had never been routinely vaccinated with BCG, the trial adequately tested the effect of such immunization on COVID-19 risk. By the time the COVID-19 pandemic began, all tuberculosis-free and previously BCG-unimmunized participants had received three doses of BCG vaccine or placebo.
- A very potent Japanese BCG strain, Tokyo 172-1, characterized by one of the highest in vitro potency rates and high immunogenicity, was used.      Indeed, in terms of the number of COVID-19 cases or deaths per million inhabitants, Japan, as a country with mandatory BCG vaccination, does not occupy any leading position, being only in the second hundred in the ranking of countries most affected by the pandemic.
- The invited participants had type 1 diabetes mellitus, a known risk factor for infectious diseases including COVID-19.   This suggests that the BCG vaccine is effective in populations susceptible to infections.
- The study turned to rigorous molecular methods to diagnose COVID-19 cases based on PCR and/or SARS-CoV-2-directed immunoglobulin production to specific regions of the virus to confirm current or past infection.
- There was no patient dropout, which reinforced the statistical power.
- The study was conducted among people who had not previously had COVID-19 and had not been vaccinated against it. The inclusion of SARS-CoV-2 seropositives could have skewed the degree of protective effect of the BCG vaccine.
In early July 2022, the results of the ACTIVATE II (NCT04414267) phase 4 (randomized, double-blind, placebo-controlled, multicenter) clinical trial testing the BCG vaccine for protection against COVID-19 among aged (50 years and older) Greek residents (n=190) were published. The 6-month follow-up after administration of a single dose of BCG found that the risk of COVID-19 relative to placebo was reduced by 68%: odds ratio (OR) 0.32 (95% CI: 0.13–0.79; p=0.014). 
BCG Against Coronavirus: Cons
The only disadvantage of BCG vaccination to prevent COVID-19 infection is the very long period of time it takes to establish adequate and broad antiviral protection, which in this case is the off-target effect of this TB vaccine. In contrast to standard antigen-specific COVID-19 vaccines, after which immunity builds up within a few weeks, BCG immunization requires many months to do so, perhaps approximately two years is needed.     However, while the protection against SARS-CoV-2 provided by the former is generally limited to a particular variant of coronavirus and weakens over time, BCG vaccination works regardless of viral mutations, and for decades or even possibly for life.  
The slow onset of the protective effect and its prolonged persistence are due to the gradual migration of BCG microorganisms into the bone marrow, where they infect resident stem cells. The process can be accelerated by intravenous BCG administration.   
Within two to three years, BCG alters key metabolic and immune signaling pathways through gene methylation.    Chemical modifications (methylation, acetylation, etc.) of histones in gene promoters and enhancers also occur.   The slow restart of key immune genes under BCG action in almost all types of lymphoid cells, such as T cells and monocytes, indicates that prolonged immunity is multi-lineage. This may be due to remodeling of the immune system by stem cells under the influence of the synergistic nature of the microorganisms in BCG.
In general, the process of forming “trained immunity” itself is very slow. It is a concept that refutes that only adaptive immunity has a memory and believes that the innate immune system has a similar property. “Trained immunity” is realized through epigenetic reprogramming — sustained changes in gene expression and cell physiology that do not involve permanent genetic changes, such as mutations and recombinations, that are necessary for adaptive immunity. 
Previous BCG trials in the prevention of COVID-19 have failed. Thus, the BCG-CORONA (NCT04328441) phase 3 (randomized, double-blind, placebo-controlled, multicenter) clinical trial among Dutch healthcare workers (n=1171) found no benefit from BCG. 
The reasons why BCG vaccination did not work to protect against SARS-CoV-2 in a number of clinical trials are numerous. For example, latent tuberculosis infection, which is a continuum between immune memory and actively replicating mycobacteria, where infection has a profound effect on monocyte activation and polarization and on lymphocyte number and activity, while suppressing “trained immunity” processes in the bone marrow, may have intervened.    
The nonspecific immune benefits of BCG may be clinically relevant only in very young or elderly people because of the strong difference with the general population in terms of T- and B-cell compartments, proliferative capacity, sensitivity to activation and survival signals.   
We cannot rule out contributions from factors such as the status of prior BCG vaccination (whether the vaccination is primary or actually a booster vaccination after many years), the characteristics of the BCG strain (French, Danish, Japanese, Russian variants of BCG have different immune activity), the dose regimen (perhaps two or three BCG loading doses given at one-month intervals are important), and the route of administration (intravenous BCG delivery may be more effective than intradermal delivery).
We are left to await the results of the large-scale BRACE (NCT04327206) phase 3 (randomized, double-blind, placebo-controlled, multicenter) clinical trial among healthcare workers (n=6828) in Australia, Brazil, the UK, Holland, and Spain.