The BCG Vaccine for COVID-19: First Verdict and Future Directions

Abstract

Despite of the rapid development of the vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it will take several months to have enough doses and the proper infrastructure to vaccinate a good proportion of the world population. In this interim, the accessibility to the Bacille Calmette-Guerin (BCG) may mitigate the pandemic impact in some countries and the BCG vaccine offers significant advantages and flexibility in the way clinical vaccines are administered. BCG vaccination is a highly cost-effective intervention against tuberculosis (TB) and many low-and lower-middle-income countries would likely have the infrastructure, and health care personnel sufficiently familiar with the conventional TB vaccine to mount full-scale efforts to administer novel BCG-based vaccine for COVID-19. This suggests the potential for BCG to overcome future barriers to vaccine roll-out in the countries where health systems are fragile and where the effects of this new coronavirus could be catastrophic. Many studies have reported cross-protective effects of the BCG vaccine toward non-tuberculosis related diseases. Mechanistically, this cross-protective effect of the BCG vaccine can be explained, in part, by trained immunity, a recently discovered program of innate immune memory, which is characterized by non-permanent epigenetic reprogramming of macrophages that leads to increased inflammatory cytokine production and consequently potent immune responses. In this review, we summarize recent work highlighting the potential use of BCG for the treatment respiratory infectious diseases and ongoing SARS-CoV-2 clinical trials. In situations where no other specific prophylactic tools are available, the BCG vaccine could be used as a potential adjuvant, to decrease sickness of SARS-CoV-2 infection and/or to mitigate the effects of concurrent respiratory infections.

Keywords: Bacille Calmette-Guerin; SARS-CoV-2; cross-protection; trained immunity; vaccination.

Figure 1

(A) BCG vaccination and Trained immunity. Bacillus Calmette-Guérin (BCG) vaccination induces trained immunity through metabolic changes and epigenetic rewiring. Trimethylation of the H3K4 histone predisposes the innate immune response to a secondary insult, leading to an increased production of pro-inflammatory cytokines. (B) Trained immunity as defense mechanism against respiratory infections. BCG vaccination is given as an initial stimulus, leading to metabolic changes and epigenetic rewiring of innate immune cells, increasing the transcription of pro-inflammatory genes and secretion cytokines. BCG vaccinated individuals display an enhanced innate immune response following a secondary challenge, which may lead to protection against subsequent viral infections such as Influenza A virus or Respiratory syncytial virus (RSV). Could BCG vaccination also protect against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)?

Figure 2

(A) Number of clinical trials BCG-COVID by country. (B) BCG strains in ongoing clinical trials.