key: cord-0748671-e0419keu
authors: Islam, Md. Zahurul; E‐Zahan, Md. Kudrat; Al‐Bari, Md. Abdul Alim
title: Convergence between global BCG vaccination and COVID‐19 pandemic
date: 2020-08-22
journal: J Med Virol
DOI: 10.1002/jmv.26450
sha: e3a04862b4d1d3a68561b4d5c938d0072f660e2f
doc_id: 748671
cord_uid: e0419keu

The novel coronavirus SARS‐CoV‐2 has kept the whole world in tenterhooks due to its severe life‐threatening infectious disease, COVID‐19. The virus is distinct its cousins, SARS‐CoV and MERS‐CoV in term of severity of the infection. The obligated killing properties of the SARS‐CoV‐2 virus is mediated by its unique structure. Efforts for developing vaccines for COVID‐19 are ongoing, but it is unlikely to be available in the immediate future. Due to the absence of precise treatment, the investigators are discovering other effective, protective and healing choices. However, the lower than predictable number of SARS‐CoV‐2 cases in countries with fragile health systems is mystifying. Recently, there has been a buzz about the protective effect of BCG vaccine in COVID‐19 through long‐term boosting of trained immunity. Based on epidemiological correlations, we link up that BCG vaccination adopted by different countries might influence the SARS‐CoV‐2 transmission patterns and/or COVID‐19 associated mortality through the vaccine's capacity to confer heterologous protection. A number of clinical studies are underway to investigate this possibility but ‐even if they prove effective‐many questions will remain. Moreover, responsible stewardship of the BCG vaccine in the context of the COVID‐19 epidemic is directly needed. This article is protected by copyright. All rights reserved.

coronaviruses typically cause respiratory and enteric infections. 9 Clinical features and risk factors are highly variable, making the clinical severity range from asymptomatic to fatal. 10 Initially, the coronavirus belongs to a family of viruses that may cause various symptoms such as pneumonia, fever, breathing difficulty, and lung infection. 11 The SARS-CoV-2 infection mainly presents flu-like symptoms such as fever, cough and asthenia, similar to other coronaviruses. 12 Susceptibility seems to be associated with age, biological sex, and other health conditions. 13 Although severe lung injury has been described at all ages, in some high-risk individuals, such as the elderly or those affected by multimorbidities, the virus is more likely to cause severe interstitial pneumonia, acute respiratory distress syndrome (ARDS) and subsequent multiorgan failure, which are responsible for severe acute respiratory failure and high death rates. Typically, affected individuals display a variable extent of dyspnoea and radiological signs. 14 The SARS-CoV-2 is a novel RNA virus, with a typical crown-like appearance under an electron microscope due to the presence of spike glycoprotein on its envelope. 15 The SARS-CoV-2 virus belongs the same family as severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV). 16 There are four genera of CoVs: α-coronavirus (αCoV), β-coronavirus (βCoV) probably present in bats and rodents; while δ-coronavirus (δCoV) and γcoronavirus (γCoV) probably represent avian species. 10, 16, 17 These viruses are common in animals worldwide, but very few cases have been known to affect humans. The sources of SARS-CoV2 may be combined natural and zoonotic origin. Two conditions that can reasonably clarify the origin of SARS-CoV2 are: (i) natural selection in a lower animal host before zoonotic transmission; and (ii) natural selection in human beings succeeding zoonotic transmission. 10, 17 In response to the outbreak, the Chinese Centre for Disease Control and Prevention (China CDC) dispatched a rapid response team to accompany health authorities of Wuhan city to conduct epidemiological and etiological investigations. The WHO confirmed that the outbreak of the coronavirus epidemic was associated with the Huanan South China Seafood Marketplace, but no specific animal association was identified. 18 Scientists immediately started to research the source of the new coronavirus, and its genome sequence of COVID-19. 19 This virus blow-out quickly throughout China within a month. After infecting and causing the death of thousands This article is protected by copyright. All rights reserved. of persons in China, the virus has spread, reaching Italy and other European countries   and the USA 20-22 with the number of confirmed new cases currently increasing every day.

In 20 th March 2020, WHO Director General said that the "greatest concern" was COVID-19 spreading in countries with fragile health systems. 23 Early evidence from the current COVID-19 pandemic suggests that the disease intensity and case fatality rate vary in different parts of the world. 25 Better understanding of the epidemiological characteristics of COVID-19, as to why people living in certain nations are more susceptible, would help us effectively control this pandemic. These understandings might putatively support vaccine development for COVID-19 treatment. These differences are attributed to differences in cultural norms, mitigation efforts, and health infrastructure. 26 These national differences in COVID-19 impact can be explained by the different national policies with respect to Bacille Calmette-Guérin (BCG) childhood vaccination. BCG is a vaccine derived from the live attenuated strain of Mycobacterium bovis for the vaccination against tuberculosis (TB) that is given to infants intradermally shortly after birth in high-risk regions. The WHO recommend neonatal BCG vaccination in countries with high incidence of tuberculosis, with BCG being one of the safest and most widely distributed vaccines worldwide. 27 Even though we are still in the midst of the coronavirus pandemic, the disproportionately smaller number of cases reported from disadvantaged/low income countries remains puzzling.

Here we hypothesize that general BCG vaccination policies adopted by different countries might have impacted the transmission patterns and/or COVID-19 associated morbidity and mortality. This article is protected by copyright. All rights reserved.

The inclusion and exclusion criteria for this study: (i) collected data of total numbers of COVID-19 infected population and death from every country in the world based on 

We compare large number of countries' BCG vaccination policies with the morbidity and mortality for COVID-19. Interestingly, countries in absence of universal policies of BCG vaccination like USA, Italy, Nederland, France have been found more severely exaggerated compared to countries having with universal and long-standing BCG policies. The countries without such universal policies on BCG vaccination are among the worst hit by COVID-19 infection. Many other countries including China, Korea, Bangladesh, India, Japan and the Russian Federation, have mandatory childhood BCG vaccines against tuberculosis. These countries have so far, a relatively low per capita death rate from COVID-19 compared to countries that have no mandatory BCG vaccines (USA, Spain, France, Italy, the Netherlands). Interestingly, the BCG vaccine strain used in Japan, Brazil, and Russia is one of the original strains, while further modified BCG strains are used for vaccination in European countries. Countries that have a late start of universal BCG policy had high mortality, consistent with the idea that BCG protects the vaccinated elderly population. 27 We also noticed that BCG vaccination also reduced the number of reported COVID-19 cases in a country. The combination of reduced morbidity and mortality makes BCG vaccination a possible new tool in the fight against COVID-19. 28 An epidemiological data summarizes national policies on BCG vaccination ( Figure 1 Table 1 in details). These data suggest that the rate of deaths per total infected cases is higher in BCG non-vaccinated countries than vaccinated countries. It can be argued that observation/ correlation does not mean causation. These data are observational and based on a single time-point and that there may be several confounding issues such as limited testing and reporting in many countries. In addition, the protective effect of BCG is found in incidence and mortality of COVID-19 between countries with and without a BCG vaccination program. 29 It might be concluded that countries with national program of whole population BCG vaccination appear to have a lower incidence and death rate from COVID-19. Similar results have also been found from other studies that epidemiological analyses of COVID-19 incidence might correlate to nation-based BCG vaccination policies. 29, 30 The observations of these studies indicate a higher COVID-19 related morbidity and mortality in those countries which do not have a current or recent, universal BCG vaccination policy. However, we cautiously visualized the data and found that these epidemiological studies are based on hypothesis generating only.

BCG is well known for its ability to induce a heterologous immunomodulatory effect on nonrelated conditions, a mechanism which is well understood and documented in the infectious disease literature. 31 There is evidence with low to moderate risk of bias that BCG vaccination prevents respiratory infections (pneumonia and influenza) in children and the elderly. This heterologous immunomodulatory effect has been shown to last up to 1 year following vaccination. 32 Trained immunity inducing agents reprogram bone marrow hematopoietic stem cells and multipotent progenitors through epigenetic and metabolic changes, resulting in a more robust response in differentiated innate immune cells, following encounter with a pathogen. Interestingly, BCG vaccine has the potential to induce epigenetic reprograming of the innate immune system, This article is protected by copyright. All rights reserved.

conferring protection against experimental infection with an attenuated yellow fever virus vaccine strain 33 and to enhance immune responses to other vaccines in general including influenza vaccination. 34 In epidemiological studies, neonatal BCG vaccination is associated with reduction in all-cause child mortality by 30%, widely thought to be related to reduction in rates of neonatal sepsis and pneumonia. 27 In mouse models, BCG was found to induce a trained immune response to avian influenza A (H7N9), however it was not associated with a clinical difference in survival, clinical scores or pulmonary inflammation. 35 Interestingly, BCG is also an effective immunotherapy in oncology. For example, intravesical BCG therapy is used for treatment of nonmuscle invasive bladder cancer, being standard of care to achieve reduction in tumor progression and recurrence. 36, 37 Children vaccinated with BCG suffer less from other respiratory illnesses; it could protect against asthma and autoimmune diseases such as type 1 diabetes. 38 The ability for BCG vaccination to induce a trained immune response to nonrelated pathogens raises the exciting possibility that it may have a role in protecting against the COVID-19 virus.

Given the widespread inconsistencies in collecting data relating to COVID-19 between countries, consideration of the stage of the COVID-19 pandemic in each country, differences in testing rates, isolation policies, national disease burden and demographics all must to taken into consideration. So, these need to be interpreted with mathematical explanation with all parameters. Moreover, the association between BCG vaccination and perveance and mortality of COVID-19 in different countries is difficult to confirm and validate due to broad differences between countries such as socioeconomic status, availability and sensitivity of diagnostic tests and the criteria for testing, time of arrival of the pandemic, demographic structure, and national control strategies to limit the spread of COVID-19. Thus, the WHO released a scientific brief cautioning against indiscriminate use of BCG in COVID-19 until appropriate evidence from ongoing clinical studies becomes available. 30 In our study, the several variables like the difference in testing strategies, demographics, nation's ability to respond to the pandemic, prevalence of co-morbidities, and different stages of the pandemic across various countries might have a significant impact on these associations/correlations and are necessarily interpreted carefully. Calculation of our studies are summarized the correlation between BCG vaccination policy and COVID-19 morbidity and mortality across countries in Table 1 . The calculation of the study indicates a significant correlation between BCG vaccination and COVID-19 frequency of cases and/or This article is protected by copyright. All rights reserved.

mortality, where countries with universal BCG vaccination policies showed fewer cases and/or deaths. The significant correlation is maintained on the basis of GDP per capita, population density and size, geographic region, net migration rate, and other factors.

We also found that the most significant confounding factor is low COVID-19 incidence and deaths where countries adopted BCG policy and suggest that BCG vaccination may be a protecting factor.

Vaccines provide protection to a particular pathogen by inducing effector mechanisms directed to that pathogen. Since introduction of the BCG vaccine in 1921, an increasing body of evidence has demonstrated its ability to exert a range of nonspecific effects (NSEs) beneficial for a range of other conditions. 39, 40 The BCG, live attenuated vaccine can protect against unrelated pathogens, some of which cause acute respiratory tract infections. 39 BCG has the ability to train the innate immune system to generate an immune memory-like response against secondary infections, a process also termed "trained immunity" which helps in faster recognition triggering a quicker inflammatory response. 33, 41 In innate immune cells, of the "trained immunity", BCG induces histone modifications and epigenetic reprogramming at the promotor sites of genes encoding inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF). 41 This trained immunity also offers protection against a variety of pathogens (Salmonella, Shigella, malaria, respiratory viruses, etc.) other than Mycobacterium tuberculosis, and forms the basis of its use in bladder cancer, melanoma etc. However, this NSE is mostly short-lived and wanes soon after the primary BCG stimulus is cleared from the body. By mechanism of the NSEs, BCG vaccine has shown to reduce the mortality in children. Though a few observational studies suggest that the NSEs may last till adulthood, but the overall evidence is still inadequate and is of low quality. 41, 42 The COVID-19 pandemic has prompted urgent need for novel vaccination or means of reducing disease morbidity and mortality in the global community. BCG vaccine's heterologous beneficial effect against non-tuberculosis infections is well known. 43 Thus, researchers want to test whether the tuberculosis vaccine could have a similar effect against the new coronavirus, either by reducing the risk of being infected, or by limiting the severity of the symptoms. It has been postulated that patients with comorbidities such as diabetes and hypertension which are treated with angiotensin converting enzyme (ACE) inhibitors are at higher risk for developing severe disease Accepted Article due to COVID-19. 44 

virus. This leads to the corollary that any drug or vaccine which has the potential to increase the level of ACE may help down regulate the expression of ACE2 receptors, thereby having some beneficial effect on the host immune system against COVID-19.

Earlier animal studies have shown that ACE-like activity increased with inflammation induced by BCG suppressed the induction of the inflammatory response in both lungs and spleen. 45 The BCG vaccine does not directly protect against the coronavirus, but provides a boost to the immune system which may lead to improved protection and a milder infection. 45 However, in COVID-19 cases, some patients have also suffered extreme immune responses, with the uncontrolled production of pro-inflammatory cytokines as called cytokine storm. In this case, BCG might help to better orchestrate this inflammatory immune response and acts as a "military exercise in peacetime" so that the body can "fight the enemy effectively in wartime". 46 The basis of the possible use of the BCG vaccine against COVID-19 can be explained via its common characteristic NSEs as 'trained immunity' over the immune system. The NSEs of BCG are mostly facilitated by potentiating trained immune response through epigenetic mechanisms. These epigenetic changes within the innate cells act as de novo enhancers to boost the immune response against a secondary challenge. 31, 34, 36 Though the epidemiological association between BCG and COVID-19 is striking, it does not prove causal relationship unless tested in well-designed clinical trials. 47 Also, we should not forget that the NSEs of the BCG vaccine has not been well-studied in human beings and their clinical relevance is unknown. 48, 49 Therefore, in the absence of evidence, the BCG vaccination for the prevention of COVID-19 cannot be recommended. The result of the ongoing RCTs shall guide us further. Several clinical trials have been recently launched to ascertain whether BCG may indeed offer protection against COVID-19, including in healthcare workers ( Table 2 ). It is noted that BCG strains that appear to be associated with lower COVID-19 mortality (e.g., BCG Japan and BCG Russia) are both early strains, whereas BCG Denmark, which seems to induce less protection against COVID-19.

The sole maker and supplier of BCG, Merck & Co., Inc. the USA is the only source of BCG to many other countries around the world. Due to the increasing global demand for BCG treatment and as the only source of OncoTICE ® BCG (is indicated for This article is protected by copyright. All rights reserved.

treatment of primary or concurrent carcinoma-in-situ of the urinary bladder) in many countries, Merck anticipates this shortage to continue throughout 2020. 50 Although the producer of BCG has increased its manufacture of BCG by more than hundred percentage and is manufacturing the vaccine to the completest extent of their producing capacity, the company is not able to sustain the cumulative world-wide demand of BCG since it is a lengthy and complex production process. This has led to supply constraints and a BCG shortage. 50 The COVID-19 treatment may also be affected by global shortages of the BCG vaccines.

It has already been proved that the BCG is a lifesaving preventive tool against TBrelated morbidity and mortality. In many high TB burden countries, BCG has routinely been administered to new-borns since the 1970s. Therefore, healthcare workers under 

In the face of a global health crisis imposed by COVID19 pandemic, several clinical trials are still ongoing to find a cure. BCG vaccination has been proposed, through epidemiological studies, as having a role in reducing the impact of this disease.

However, researchers should anticipate more BCG shortage. As well, if proven effective against COVID-19, accountable stewardship of the BCG vaccine in the context of the COVID-19 epidemic is urgently needed.

Furthermore, the more genetic screening and population-based genome-wide studies in divergent geographical regions are needed in order to better understand the hostpathogen interactions in a region-specific manner, which could pave the way for the genesis of more region-specific therapeutics and treatment regimens. Further research is needed to study the magnitude and duration of the non-specific effects of BCG vaccine on all-cause mortality before considering implications for practice and policy.

This study would reflect the current evidence that BCG vaccine protects against COVID-19. Being still in the midst of the COVID-19 pandemic, it is too early to jump to immature conclusions, where COVID-19 cases/deaths may still increase over time Accepted Article in some BCG-using countries. Thus, good evidence should be obtained from prospective randomized clinical trials (RCTs) before reflecting on practice and policy.

All of the authors thank to Faculty of Science, University of Rajshahi for technical assistance.

Transparency declarations: None to declare.

All of the authors clearly declare that they have no competing and commercial interests.

ZI designed the study. MAAB wrote, critically revised the manuscript and proofread.

KZ assisted to critically revise the manuscript. This manuscript is not under review elsewhere, and all authors read and approved the final manuscript.

The data that support the findings of this study are available on reasonable request from the corresponding author. Tables   Table 1. COVID-19 infected cases per million population with BCG vaccinated  and non-vaccinated countries on June 05, 2020 Sources: Countries with topmost infected cases with SARS-COV-2 were included. Coronavirus related statistics were based on data obtained from https://www.worldometers.info/coronavirus/ (According to the latest update on June 05, 2020, 12:59 GMT) and https://coronavirus.jhu.edu/map.html. 

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