key: cord-0854458-m0p70nha
authors: Raghab Mohapatra, Prasanta; Mishra, Baijayantimala; Behera, Bijayini
title: BCG vaccination induced protection from COVID-19
date: 2020-08-07
journal: Indian J Tuberc
DOI: 10.1016/j.ijtb.2020.08.004
sha: 6a82a1fb9e83693dd97efe3713ad49c32eb30582
doc_id: 854458
cord_uid: m0p70nha

There are worldwide urgency, efforts, and uncertainties for the discovery of a vaccine against SARS CoV2. If successful, it will take own time till useful for the humans. Till the specific vaccine available, there are evidences for repurposing existing other vaccine. It is observed that the countries having routine BCG vaccination programme, had shown to have lower incidence of COVID-19, suggesting some protective mechanisms of BCG against COVID-19 in such countries. Countries like India despite vast population density and other adversities, and growing numbers of COVID19 infections, the mortality rate and severity of COVID has been low in comparison to TB non-endemic countries (like Europe and USA). In addition, there are evidences that BCG vaccination offers partial protection and survival in low-income countries where tuberculosis is prevalent. The nonspecific effects (NSEs) of immune responses induced by BCG vaccination, protect against other infections are seems to be due to its immunological memory eliciting lymphocytes response and trained immunity. The protective effect on other viral infection in humans are believed to be mediated by heterologous lymphocyte activation and the initiation of innate immune memory may be applicable to SARS CoV2. The BCG vaccination at birth does not have protective effect beyond childhood against COVID-19. In adult, there might be some other factors dampening the virulence and pathogenicity of COVID-19. In the TB endemic countries like India, with high population density, similar to BCG vaccination, the environmental Mycobacteria might be imparting some immune-protection from severity and deaths of COVID-19.

The COVID-19 pandemic continues to ravage India and the world with its high transmissibility and varying degree of virulence. As the causative agent SARS CoV2 is a novel coronavirus, prior infection with other endemic coronaviruses does not confer any protection. Due to immune naivety of the population and ease of international travel, the world faces the greatest ever global pandemic of the century. While uncertainty of an effective vaccine against SARS CoV2 persists, protective attributes of century old Bacillus Calmette-Guérin (BCG) vaccine is currently the hot topic of attention.

At the beginning of the pandemic, it was predicted that the developing countries will face the maximum case fatalities because of poor health infrastructure, lack of preparedness, poor health regulations. However, till now, the number of deaths have been higher in developed nations like USA and Europe. Surprising, less number of cases are reported from Africa and majority of cases recovered with mild diseases. Even if the number are increasing in India the severity and mortality are less in in compared to some countries. In India, over 80% of the patients have mild symptoms or asymptomatic Hence, the inter-regional variation in the clinical severity and mortality of COVID-19 is speculated to be through immune response impact. It is also claimed that BCG vaccination offers partial protection and survival in low-income countries where tuberculosis is prevalent. 1 There is much variation of severity of inflammatory process of COVID-19 across geographical locations in world. The possible reasons could be individual, age and viral factors modified by population density, environment, ambient air temperature and humidity. High temperature and higher relative humidity is demonstrated to have negative effect on the spread of virus. 2, 3 The increase of temperature from spring to summer could facilitate the containment and the cold season may witness an upsurge in infections during 2020-2021 winter season. 3 In addition to geographic variation influencing COVID 19 spread and severity, there are other established factors like advanced age, inflammatory comorbidities, and immune compromised conditions for severe illness. 4 Two basic steps by which the virus overcomes host immune response are recognition and evasion of SARS-CoV-2 to circumvent the cytosolic pathogen recognition receptors (PRR) and subsequent invasion of the host. 5 SARS-CoV-2 causes severe damage rapidly by excessive cytokine production (storm) or slowly through innate immune resistance manifesting as fever in order to provoke a delayed over inflammation. 6 More severe disease have inflammation-based sequelae due to uncontrolled systemic inflammatory response resulting from the release of large amounts proinflammatory cytokines that further affects the immune system, which contributes to severity of the disease. The excessive production and secretion of cytokines like tumour necrosis factor (TNF), IL-6, and IL-1β results in a critical state which is described as a cytokine storm. The cytokine storm leads to an increased vascular (hyper)permeability, multi-organ failure, and eventually death when J o u r n a l P r e -p r o o f the cytokine concentrations are unrestricted and high over time. 7 Therefore, controlling the immune evasion of SARS-CoV-2 is an important step in management.

BCG vaccine, a live attenuated strain derived from Mycobacterium bovis, has ability to induce potent nonspecific immunity also known as so-called 'off-target' protection against bacterial and viral pathogens. BCG has shown to diminish the susceptibility to various respiratory tract infections. Such protection is mediated by the non-specific boosting of innate immunity. However the mechanisms of the beneficial effects of the BCG vaccine are now better understood. Protective effects of BCG vaccine against COVID 19 disease severity is partially explained by the different national policies respect to BCG vaccination.

The cellular and molecular mechanisms of the non-specific protective effects of BCG vaccination against various DNA and RNA viruses, including herpes and influenza viruses have been studied in mice recently. 8 BCG vaccination is also shown to protect from herpes simplex virus type 2 (HSV2) infection in new-born mice 9 . Subcutaneous injection of component of the mycobacterial cell wall (muramyl dipeptide) protects against vaccinia virus and HSV2 infections in mice. 10 Such protection is facilitated by peritoneal macrophages 10 . Above effect, suggests that there is substantial effects of BCG on the innate immune system. BCG administration acts through macrophages and have reduced viral titres of influenza A virus in the injected mice. 11 Several studies underscored reduction in respiratory tract infections and risk of pneumonia upon BCG vaccination of elderly people. 12, 13 However, limited period time of the acquired protection remains a caveat for trained immunity boosters.

A randomized study showed that BCG vaccination prior to influenza vaccination in healthy individuals resulted in a significantly higher antibody response against influenza A (H1N1) compared to placebo. 14 The effectiveness of BCG in the promotion of long-lasting T cell immunity to human respiratory syncytial virus (hRSV) antigens was experimentally demonstrated without any observable adverse effects. 15 In severe combined immunodeficiency (SCID) mice, with functionally depleted T-and B-cells, BCG vaccination had protected against a secondary non-Mycobacterial challenge, which highlights the importance of innate immune cells in protecting from diseases. 16 Several studies have shown protective action of BCG against unrelated respiratory infections both in children and adults. A comparable protection effect of BCG on respiratory infections was shown among elderly population in Indonesia 12 . Prospective clinical trial performed in Japan has J o u r n a l P r e -p r o o f shown BCG vaccine to protect from pneumonia in tuberculin negative elderly populations. 13 Randomised controlled trials have demonstrated that the BCG vaccine have immunomodulatory effects to protect partially against respiratory infections. In South Africa, BCG-Danish reduced respiratory tract infections by 73% (95% CI 39-88) in adolescents. 17 In a randomized placebo controlled trial, BCG vaccination showed to induce significant reduction in viremia in an experimental infection with live attenuated yellow fever virus vaccine strain. The level of lowering of viremia was correlated with heterologous IL1-β production which was attributed for protection induced by BCG 18 .

Miller et al 19 18 This is so far proven that the countries more prone to be severely affected SARS-CoV-2 didn't adopt universal policies of BCG vaccination like Italy and Spain. The BCG vaccine likely reduces cytokine storm after SARS-COV-2 exposure, resulting mild COVID-19 and early recovery. 23, 24 J o u r n a l P r e -p r o o f Figure-1 Vaccines excite the initiation of the adaptive immune response and the development of immunological memory. 25, 26 The immunological memory consists of the developments of antigenspecific T and B cells which protects against subsequent insult by the pathogen. This is thought to be due to secondary innate immune response induced by BCG vaccination, coined as nonspecific effects (NSEs). The efficacy to protect against other infections can be linked to its immunological memory eliciting lymphocytes response (Fig-1) and trained immunity (Fig-2 and 3) .

The protective effect on viral infection in humans are believed to be mediated by heterologous lymphocyte activation and the initiation of innate immune memory.

The NSE is a consequence of the type of non-specific immune memory induced after vaccination as part of protective "trained immunity". 27 This type of immunological memory (of past insults) is developed by innate immune cells, like monocytes, macrophages, and natural killer cells, and can be efficiently induced by BCG. 16, 28 J o u r n a l P r e -p r o o f Hence, durable epigenetic alterations to increase antiviral function of innate immune cells is observed after live vaccines, facilitating a faster and better responsiveness if exposed to reinfections. 16, 29 COVID-19: Children are protected?

The children might have some immune characteristic to incite the triggering active innate immune response to stop cytokine storm and progression to pneumonia /illness. 30 The immune dysfunction and extent of cytokine overproduction are minimal in children compared to adults. Lymphopenia in the majority of paediatric COVID-19 patients is uncommon in contrast to adults. 31 It is possible that the innate immunity plays a protective role in the pathogenesis of COVID-19 in the paediatric age group as the adaptive immunity is not well-developed in early ages. There could be a crossprotective immunity developed in response to regionally prevalent viral infections and repeated mild upper respiratory tract infections. Some protection due to an immune system activation as a result of frequent viral infections decreases the susceptibility to severe illness.

A reasonable explanation is that children of the country where routine childhood BCG vaccination is a policy and BCG vaccinated children have some degree of protection from infection with SARS-CoV-2, and less severe diseases among those who infected. Ultimately there is less transmissibility of the virus. The children also seem to be better protected from COVID-19 than adults.

In late adulthood, there is an involution of the thymus, and the decrease in regulatory T cells can be a contributory mechanism underlying severe COVID-19 illness. In older ages, generalized inability to fine-control inflammation favours propensity toward sustaining the cytokine release syndrome (CRS).

Considering the above evidences of BCG regarding its non-specific beneficial effect on non- We hypothesise on the possible mechanism behind the exact "environment-antiviral immunity"

interplay on the pathogenesis of COVID-19. 36 36 Factually these conditions impact some degree of general immunity for new infections. TB endemicity or environmental mycobacteria seems to be correlated with reduced disease burden and severity of COVID-19. 39 Like BCG it is hypothesized that environmental Mycobacteria induce prolonged alteration in the immune system that results in increased level of innate and adaptive immunity. 39 The environmental

Mycobacteria might have induced similar immunological memory eliciting lymphocytes response (Fig-1) and trained immunity (Fig-2 ) making epigenetic alterations in the similar mechanism to BCG at the promotor sites of various genes encoding inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumour necrosis factor (TNF), resulting less cytokine storms compared to naïve population. 40 It is possible that people of the TB endemic countries like India despite vast population and growing numbers of COVID19 infection, have acquired some protections from severity and deaths from COVID-19 in comparison to TB non-endemic countries (like Europe and USA). Although it appears the immunity may not able to stop COVID 19 infections, but is likely to diminish its impact on severity and mortality.

If the BCG vaccine as an inducer of trained immunity induces non-specific protection to bridge the gap before a real specific vaccine is developed, this would be an important tool in the response to COVID-19 and future pandemics. Better understandings of the molecular mechanisms are still evolving. By identifying the factors that impact the non-specific effects of BCG, can be an important step towards novel therapeutic options and vaccination strategies, which might lead to a reduction in severe morbidity and mortality associated with viral infections.

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