BCG Protection Against COVID-19: Is it Reality or Illusion?

The COVID-19 pandemic (caused by the SARS-CoV-2 virus) has caused over 1.6 million deaths globally in 2020[1,2]. Early responses to address this crisis have involved the development of vaccines and rearranging existing drugs. Interestingly, however, some epidemiological studies linked Bacillus-Calmette-Guérin (BCG) - one of the world’s oldest vaccines - to the protection of humans against nonspecific pathogens such as SARS-CoV-2[3]. It comprises an attenuated, less virulent strain of Mycobacterium bovis, and years of data support its protective efficacy against tuberculosis, ie: its intended target. Nonspecific targets that BCG elicits protective effects ranging from Mycobacteria that causes leprosy through to non-mycobacterial prokaryotes including Staphylococcus aureus, and viruses including respiratory syncytial virus (RSV)[4-6], and those causing viral warts[7-8] and recurrent aphthous stomatitis[9]. BCG vaccine has been associated with a reduction in respiratory tract infections of vulnerable patient groups including neonates and the elderly, which has raised hopes that BCG may offer protection against COVID-19 during the second wave of epidemics[3].

Epidemiological and clinical evidence of BCG-mediated protection against nonspecific pathogens

Although little specific evidence suggested that BCG protected against the coronaviruses that caused the 2003 severe acute respiratory syndrome (SARS) and the Middle East Respiratory Syndrome (MERS) epidemics (SARS-CoV-1 and MERS-CoV, respectively), several observations suggested that it might offer protection against COVID-19. Countries routinely conducting mass vaccination programmes that included BCG have seen significantly lower mortality rates from COVID-19 than countries that administer the vaccine on a case-by-case basis following a positive Mantoux test result[3,10-12]. One study suggested that case-by-case BCG vaccinating countries (Italy, the USA, the Netherlands, Belgium) had 265 cases per million population compared with 60 in low-income countries that applied mass vaccinations[13].

Although one study did not prove a protective effect of BCG against COVID-19[14], the authors acknowledged that their observations may be confounded by reporting biases. Generally, opinion leaders believe that continued investigation is required until a consensus is reached[3,10,11]. Data from several eagerly awaited randomised clinical trials will determine how BCG affects COVID-19 infection. The BCG-CORONA (the Netherlands) and BRACE (Australia) placebo-controlled trials are studying the effects of BCG on 1500 and 10.078 healthcare workers, respectively exposed to COVID-19 patients[15-17]. Additionally, a study in the USA reported a statistically significant reduction in the number of COVID-19 disease related to hospital admissions in BCG-vaccinated participants (although the authors did not indicate when they were vaccinated)[18].This suggests that BCG vaccination deployment may reduce COVID-19 cases, hospitalisations, and deaths, a view shared by many opinion leaders.

How BCG mediates protection against nonspecific pathogens

There are several mechanisms for this putative protective effect. BCG reportedly triggers a form of nonspecific innate immune cell memory by epigenetic reprogramming - known as trained memory. PBMCs from vaccines stimulated with nonspecific pathogens produce elevated levels of proinflammatory cytokines IFN-γ, TNF-α, and IL-1β, which were also linked to the protection of T-cell- and B-cell-deficient BCG-vaccinated SCID mice against non-mycobacterial pathogens[19]. This process was accompanied by methylation of these genes[19]. Additionally, BCG-recipients subsequently vaccinated with the yellow fever vaccine had lower levels of viremia than those not unvaccinated which was also correlated with epigenetic reprogramming within proinflammatory cytokine genes[20]. Taken all together, these findings strongly implicate the presence of trained memory in BCG-mediated protection against nonspecific pathogens.

Adaptive immunity may also be playing a role. A clinical trial showed that BCG vaccination followed by influenza vaccination increased antibody titres against the latter (correlating with the protective efficacy), suggesting that it may increase B-cell responses against nonspecific respiratory viral pathogens in some settings in 200921. Additionally, the elevated proinflammatory cytokines driven by BCG were postulated to increase heterologous responses of CD4+ and CD8+ Th1 and Th17 cells[10,22]. If such responses are directed against SARS-CoV-2, it would be likely to have protective effects.

Conclusion

The combination of epidemiological data from the countries who apply mass vaccination backed up by strong immunological evidence that BCG vaccine protects against a wide range of nontuberculous mycobacteria, makes a strong case that BCG could help to control COVID-19. Consensus will be reached out and confirmed if the imminent further clinical trials will be carried to support this premise.