4 DISCUSSION
Our results indicate that BCG-CGS, key regulatory hubs and BCG-mimics identified from the CMap enrich common biological pathways important for key viral processes such as viral RNA synthesis and processing, virus-host interactions, positive regulation of viral genome replication, and are also important for the immune response mounted against the virus. Evidence from the biomedical literature confirms that BCG has many beneficial ‘off-target’ effects that can protect humans from emerging novel pathogens by boasting their innate immune responses. Our studies suggest that BCG can potentially reverse or prevent some of the detrimental consequences, caused by SARS-CoV-2 on vital regulatory processes, by promoting wide-range transcriptional and metabolic changes that are capable of producing a balanced immune response against SARS-CoV-2. BCG can accomplish that mainly by increasing the production of thymus-generated short-lived undifferentiated CD4+ cells known as naive T cells (Th0), and triggering their differentiation into the long-lived mature naive T cells (MNTs), such as CD4+ and CD8+ T cellsThese conclusions are supported by the enrichment results produced using the ‘Compare Experiment’ algorithm in MetaCore from Clarivate Analytics, which looks for significant coordinated gene expression effects across all experiments to test whether the pathway is being up- or down-regulated in a manner that is unlikely to be accounted for by random chance. The top enriched pathway map, with upregulated genes in response to BCG, is ‘Immune response T cell subsets: secreted signals’ (Figure 4B). As a validation, a recent study showed that SARS-CoV-2 reshapes central cellular pathways, such as translation, splicing, carbon metabolism and nucleic acid metabolism.
A recent publication in Lancet has questioned whether BCG’s effects can last for a long time. Our top enriched pathway map (Figure 4B) indicates that BCG’s effects can be long-lasting if the effects were exerted on thymus-generated Th0 cells, which can occur to a greater extent very early in life before reaching thymic involution by puberty. This pathway map indicates that BCG is capable of affecting both the numbers and the types of produced innate immune cells, as well as their maturation to long-lived memory T cells (i.e., what is known as trained immunity). This is very significant in the context of BCG’s protective effects from SARS-CoV-2 and other emergent novel viruses; where the individual’s ability to eradicate such viruses is dictated by the number and diversity of naive T cell reservoir And this is a clear indication that BCG protects individuals from lethality by novel pathogens by priming their trained immunity to fight such pathogens, including SARS-CoV-2.
Supporting evidence for this hypothesis is found in the literature indicating that the protective effects of the BCG against TB, can last from 15 to 60 years after vaccination, with longer lasting effects when the vaccine is administered during the first year of life. A recent study indicated that “school-aged BCG vaccination offered moderate protection against tuberculosis for at least 20 years, which is much longer than previously thought”. Another 60-year follow-up study, showed that BCG vaccine efficacy persisted for 50 to 60 years after a single dose of BCG. These studies serve as additional evidence from the literature supporting our claim that a single dose of an ‘effective’ BCG vaccination to infants can have a very long duration of protection against pathogens including SARS-CoV-2.
Our findings provided systems biology support for using BCG to prevent the fatal consequences of COVID-19. BCG is currently on WHO’s List of Essential Medicines; it is considered one of the safest and most effective medicines needed in a health system. Therefore, we propose BCG administration to all newborns will act as a protection measure from SARS-CoV-2 and other emerging pathogens. BCG can be given to newborns according to the regulations known for TB prevention. We also recommend that multiple doses of the vaccine are necessary to protect adults from COVID-19 since the protective effects of BCG are weaker if the vaccine is given after the first year of life and especially after puberty. Since this is an approved vaccine for TB, it can directly enter Phase III testing for the protection from COVID-19 caused fatalities. However, we caution that running these experiments during an active COVID-19 outbreak, might expose participants to aggravated immune responses if they contract COVID-19 during the study. We also advise that clinical study design takes into account several factors that are known to affect the performance of BCG vaccine, such as: the age of the participants, geographies, ethnicities, route of administration and the mycobacterium strain used in the vaccine. It is equally important to run experimental validation studies to evaluate the effects of BCG mimics, in preventing COVID-19 or for treating urological cancers. BCG mimics can solve problems associated with potential supply shortages of BCG, or even address some of the problems associated with the use of attenuated live vaccines.