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.