Background. Coronavirus disease 2019 (COVID-19) is expected to continue to cause worldwide fatalities until the World population develops ‘herd immunity’, or until a vaccine is developed and used as a prevention. However, the vaccine may prove ineffective due to rapid changes in viral antigenic determinants. Bacillus Calmette–Guérin (BCG) vaccine has been recognized for its beneficial effects on the immune system, and it is currently in being tested in clinical trials for COVID-19. However, BCG shortages may affect clinical decisions regarding the prioritization of BCG to protect from viral infections, hence, small-molecule BCG-mimics will be valuable alternatives. Methods. We developed and applied a systems biology workflow capable of identifying antiviral drugs and vaccines that can boast immunity and impact viral disease pathways to prevent the fatal consequences of COVID-19. Results. Our results indicate that BCG and small-molecule BCG-mimics affect the production and maturation of naïve T cells, which results in enhanced long-lasting innate immune responses to tackle novel viruses. Our workflow identified several antiviral drugs including raltegravir and lopinavir as high confidence BCG mimics. Top hits including emetine and lopinavir were validated to inhibit the growth of novel coronavirus SARS-CoV-2 in vitro. Conclusions. Herein, we provide systems biology support for using BCG as a protection measure from the lethal consequences of emergent viruses including SARS-CoV-2. We also provide systems biology evidence that certain small molecule drugs could mimic the effects of BCG and serve as alternatives to BCG.

Background. Coronavirus disease 2019 (COVID-19) is expected to continue to cause worldwide fatalities until the World population develops ‘herd immunity’, or until a vaccine is developed and used as a prevention. However, the vaccine may prove ineffective due to rapid changes in viral antigenic determinants. Bacillus Calmette–Guérin (BCG) vaccine has been recognized for its beneficial effects on the immune system, and it is currently in being tested in clinical trials for COVID-19. However, BCG shortages may affect clinical decisions regarding the prioritization of BCG to protect from viral infections, hence, small-molecule BCG-mimics will be valuable alternatives. Methods. We developed and applied a systems biology workflow capable of identifying antiviral drugs and vaccines that can boast immunity and impact viral disease pathways to prevent the fatal consequences of COVID-19. Results. Our results indicate that BCG and small-molecule BCG-mimics affect the production and maturation of naïve T cells, which results in enhanced long-lasting innate immune responses to tackle novel viruses. Our workflow identified several antiviral drugs including raltegravir and lopinavir as high confidence BCG mimics. Top hits including emetine and lopinavir were validated to inhibit the growth of novel coronavirus SARS-CoV-2 in vitro. Conclusions. Herein, we provide systems biology support for using BCG as a protection measure from the lethal consequences of emergent viruses including SARS-CoV-2. We also provide systems biology evidence that certain small molecule drugs could mimic the effects of BCG and serve as alternatives to BCG.