Can BCG vaccination induced immune programming reduce the mortality in COVID-

19 caused by SARS Cov2?

Kurthkoti Krishna1, Nandini Dasgupta2 and Gautam Das2

1
Mycobacterium Research Laboratory, Rajiv Gandhi Centre for Biotechnology,

Thiruvanathapuram.
2
Mibiome Therapeutics LLP, Mumbai.

A recent epidemiological study has provided a positive correlation between BCG vaccination

and the reduced morbidity and mortality in COVID-19 patients (Miller et al, 2020). The study

also presents details about the spectrum of COVID-19 outcomes with duration and

implementation of BCG vaccination in different countries. However, the study does not provide

a scientific basis for the observed heterologous (or cross) protection of BCG to COVID-19.

The present communication is a hypothesis that tries to bridge this gap in knowledge and may

be of use to the larger medical community.

Hypothesis:

Vaccination with BCG provides heterologous immunity by enhancing innate and adaptive

immune responses to COVID-19.

Studies:

The Bacille Calmette–Guerin (BCG) vaccine was introduced in 1921 against tuberculosis.

Growing number of studies have shown that BCG vaccination provides protection against

certain malignancies, allergy and asthma (Barlan et al., 2005) and non-mycobacterial

infections (Netea & van Crevel, 2014). Interestingly, in a small case study done in Gunie

Bissau it was observed that girl children with a history of BCG vaccination had lower incidence

of pneumonia (Stensballe et al, 2005). Further, in a more recent study done on population

from 33 lower- and middle-income countries showed that there was 17% -33% lower chances

of acute lower respiratory infection (ALRI) in children who received BCG vaccination (Hollm-

Delgado et al, 2014). This study also showed that vaccination with BCG Pasteur provided the

best protection among other BCG lineages and the benefits of BCG vaccine against ALRI

were reduced if children were exposed to wood smoke (Hollm-Delgado et al, 2014).
 Previously, it has been reported that in BCG vaccinated mice showed increased

protection to DNA and RNA viruses including influenza and herpes viruses (Moorlag et al,

2019) and a stronger and accelerated antibody response against 2009 influenza A vaccine

strain in healthy human volunteers (Leentjens et al, 2015). The cross protection of BCG to

these pathogens has been attributed to “trained immunity”. Trained immunity also referred to

as innate immune memory involves cells of the immune system such as Natural Killer (NK)

cells, innate lymphoid cells, cytokines and pattern recognition proteins (Netea et al, 2016).

The stronger response shown by innate immune memory to secondary stimuli is not specific

to particular infectious agent (in this case SARS Cov2) and involves transcriptional and

epigenetic reprogramming (Netea et al, 2016). BCG vaccination has been reported to induce

a genome-wide epigenetic reprogramming of human monocytes that correlates with protection

against experimental viral infection with an attenuated yellow fever virus vaccine strain (Arts

et al., 2018). The ability of BCG to induce innate immune memory is being considered an

approach to improve vaccine development and efficiency (Covián et al, 2019)

We hypothesize that the hetero resistance provided by BCG to fungal and bacterial pathogens

could be extended to the current respiratory virus COVID-19 causing reduced morbidity and

mortality in BCG vaccinated individuals as reported (Miller et al, 2020). Infection of COVID-19

in BCG vaccinated individuals can result in rapid NK cell expansion and activation leading to

production of cytokines providing T-cell independent protection (Sun et al, 2009).

In addition to promoting innate immune memory, BCG vaccination which is a live strain

induces adaptive immune response with activation of CD4+ and CD8+ T cells with elevated

production of interferon gamma (IFN-g). In mice, administration of IFN-g during early stages of

influenza virus infection resulted in increase in NK cells but on the other hand prevented the

infiltration of T cells during recovery ((Weiss et al, 2010)). Preventing T cell migration into the

lung reduces the inflammation and associated tissue damage that are commonly observed in

influenza virus infection. Since COVID-19 is a respiratory virus similar to influenza it is possible

that prior BCG vaccinated condition may result in higher (IFN-g) that can prevent migration of
T cells to the lung and reduce inflammation mediated tissue damage allowing better recovery

outcome.

Neonatal BCG vaccination influences cytokine responses to TLR ligands and heterologous

pathogens (heat killed bacterial and fungl pathogens). (Bridget Freyne et al., 2018). This effect

is characterized by decreased antiinflammatory cytokine and chemokine responses in the

context of higher levels of IL-6 in unstimulated samples. This supports the hypothesis that

BCG vaccination modulates the innate immune system. Further research is warranted to

determine whether there is an association between these findings and the beneficial

nonspecific (heterologous) effects of BCG vaccine on all-cause mortality. However, in this

study, all infants were also hepatitis B vaccinated.

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