Sequence similarity of HSP65 of Mycobacterium bovis BCG with SARS-CoV-2 spike and nuclear proteins: may it predict an antigen-dependent immune protection of BCG against COVID-19?

The Bacillus Calmette-Guérin (BCG) vaccine is known to have protective effects not only against tuberculosis but also against other unrelated infectious diseases caused by different pathogens. Several epidemiological studies have also documented the beneficial influence of BCG vaccine in reducing both susceptibility to and severity of SARS-CoV-2 infection. The protective, non-specific effects of BCG vaccination would be related to an antigen-independent enhancement of the innate immunity, termed trained immunity. However, the knowledge that heat shock protein (HSP)65 is the main antigen of Mycobacterium bovis BCG prompted us to verify whether sequence similarity existed between HSP65 and SARS-CoV-2 spike (S) and nuclear (N) proteins that could support an antigen-driven immune protection of BCG vaccine. The results of the in silico investigation showed an extensive sequence similarity of HSP65 with both the viral proteins, especially SARS-CoV-2 S, that also involved the regions comprising immunodominant epitopes. The finding that the predicted B cell and CD4+ T cell epitopes of HSP65 shared strong similarity with the predicted B and T cell epitopes of both SARS-CoV-2 S and N would support the possibility of a cross-immune reaction of HSP65 of BCG with SARS-CoV-2.

BCG turns 100: its nontraditional uses against viruses, cancer, and immunologic diseases.

First administered to a human subject as a tuberculosis (TB) vaccine on July 18, 1921, Bacillus Calmette-Guérin (BCG) has a long history of use for the prevention of TB and later the immunotherapy of bladder cancer. For TB prevention, BCG is given to infants born globally across over 180 countries and has been in use since the late 1920s. With about 352 million BCG doses procured annually and tens of billions of doses having been administered over the past century, it is estimated to be the most widely used vaccine in human history. While its roles for TB prevention and bladder cancer immunotherapy are widely appreciated, over the past century, BCG has been also studied for nontraditional purposes, which include (a) prevention of viral infections and nontuberculous mycobacterial infections, (b) cancer immunotherapy aside from bladder cancer, and (c) immunologic diseases, including multiple sclerosis, type 1 diabetes, and atopic diseases. The basis for these heterologous effects lies in the ability of BCG to alter immunologic set points via heterologous T cell immunity, as well as epigenetic and metabolomic changes in innate immune cells, a process called "trained immunity." In this Review, we provide an overview of what is known regarding the trained immunity mechanism of heterologous protection, and we describe the current knowledge base for these nontraditional uses of BCG.

Relationship between Bacillus Calmette Guerin Vaccination Policy and Coronavirus Disease-2019 (COVID-19) Incidence.

Bacillus Calmette Guerin (BCG) was designed for protecting children against tuberculosis. Also, it can protect against other infectious diseases through the induction of trained immunity. Due to its heterologous protective effects, the BCG vaccine has been proposed as atreatment option for coronavirus disease-2019 (COVID-19). Epidemiological studies have found that countries without BCG vaccination policy have experienced higher mortality rates related toCOVID-19 infection than those with BCG vaccination policy. However, there are some confounding factors such as age, population intensity, immigration, the pandemic phase, and data accuracy that may affect these results. Therefore, this hypothesis should be evaluated by clinical trial studies. Large-scale clinical trials are in progress to investigate ifthe BCG vaccine could be used as a useful tool for protection against COVID-19 infection.

The effect of Bacillus Calmette-Guérin (BCG) vaccination in preventing severe infectious respiratory diseases other than TB: Implications for the COVID-19 pandemic.

The rapid spread of the Coronavirus pandemic and its significant health and social impact urges the search for effective and readily available solutions to mitigate the damages. Thus, evaluating the effectiveness of existing vaccines like Bacillus Calmette-Guérin (BCG) has attracted attention. The aim of this review was evidence synthesis on the effect of BCG vaccine in preventing severe infectious respiratory disease including COVD-19, but not tuberculosis. We considered studies conducted on human participants of any study design from any country setting that were published in Enlgish. We did a systematic literature search in MEDLINE, Scopus and Google scholar databases and a free search on Google. The identified studies were appraised and relevant data were extracted using Joanna Briggs Institute tools. The extracted findings were synthesized with tables and narrative summary. Nine studies met the inclusion criteria. The findings indicated that BCG vaccine has a strong protective effect against both upper and lower acute respiratory tract infections. For instance in countries with universal BCG vaccination policy, the incidence of COVID-19 was lower compared to the counterparts. Addtionally, BCG vaccine was found to protect against infections like lethal influenza A virus, pandemic influenza (H1N1), and other acute respiratory tract infections. BCG improved the human body's immune response involving antigen-specific T cells and memory cells. It also induced adaptive functional reprogramming of mononuclear phagocytes that induce protective effects against different respiratory infections other than tuberculosis. In countries with universal BCG vaccination, the incidence and death from acute respiratory viral infection including COVID - 19 is significantly low. However, there is an urgent need for further evidence from well-designed studies to understand the possible role of BCG vaccination over time and across age groups, its possible benefits in special populations such as health workers and cost-savings related to a policy of universal BCG vaccination.

Biological Rationale for the Repurposing of BCG Vaccine against SARS-CoV-2.

The Bacillus Calmette-Guerin vaccine is still widely used in the developing world. The vaccination prevents infant death not only from tuberculosis but also from unrelated infectious agents, especially respiratory tract infections and neonatal sepsis. It is proposed that these off-target protective effects of the BCG vaccine are mediated by the general long-term boosting of innate immune mechanisms, also termed "trained innate immunity". Recent studies indicate that both COVID-19 incidence and total deaths are strongly associated with the presence or absence of national mandatory BCG vaccination programs and encourage the initiation of several clinical studies with the expectation that revaccination with BCG could reduce the incidence and severity of COVID-19. Here, presented results from the bioinformatics analysis of the Mycobacterium bovis (strain BCG/Pasteur 1173P2) proteome suggests four immunodominant antigens that could induce an immune response against SARS-CoV-2.

An update on COVID-19: SARS-CoV-2 life cycle, immunopathology, and BCG vaccination.

The causative agent of novel coronavirus disease (COVID-19) is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 possesses RNA as a genetic material with 79% of the match with the bat SARS-CoV genome, which became epidemic in 2002. The SARS-CoV-2 peripheral Spike-Fc protein binds specifically to the ACE2 receptors present on bronchial epithelial cells and alveolar pneumocytes to downmodulates its expression which leads to severe acute respiratory failure. The disease is super infectious from human to human and the symptoms are similar to flu. The old aged and immunocompromised population are severely affected, and healthcare providers globally applied various strategies for treatment including the repurposing of drugs including antimalarial drug, hydroxychloroquine and anti-viral drugs.Herein, we described the SARS-CoV-2 pandemic, immune responses, possible drug targets, vaccines under the trials and correlated the possibility of trained immunity induced by BCG vaccination over control of SARS-CoV-2 infection. The countries with constraint BCG vaccination policy are struggling badly compared to countries with BCG vaccination policy. The BCG vaccination policy supports either lowering the total number of COVID-19 cases or the increasing recovery rate.

Antituberculosis BCG vaccination: more reasons for varying innate and adaptive immune responses.

Bacillus Calmette-Guérin (BCG) vaccination induces variable protection against pulmonary tuberculosis (TB), and a more effective TB vaccine is needed. The potential for BCG to provide protection against heterologous infections, by induction of innate immune memory, is increasingly recognized. These nonspecific responses may substantially benefit public health, but are also variable. In this issue of the JCI, Koeken and de Bree et al. report that BCG reduces circulating inflammatory markers in males but not in females, while de Bree and Mouritis et al. describe how diurnal rhythms affect the degree of BCG-induced innate memory. These studies further delineate factors that influence the magnitude of responses to BCG and may be crucial to harnessing its potential benefits.

Bacillus Calmette-Guérin (BCG) vaccine generates immunoregulatory cells in the cervical lymph nodes in guinea pigs injected intra dermally.

This work demonstrates the presence of immune regulatory cells in the cervical lymph nodes draining Bacillus Calmette-Guérin (BCG) vaccinated site on the dorsum of the ear in guinea pigs. It is shown that whole cervical lymph node cells did not proliferate in vitro in the presence of soluble mycobacterial antigens (PPD or leprosin) despite being responsive to whole mycobacteria. Besides, T cells from these lymph nodes separated as a non-adherent fraction on a nylon wool column, proliferated to PPD in the presence of autologous antigen presenting cells. Interestingly, addition of as low as 20% nylon wool adherent cells to these, sharply decreased the proliferation by 83%. Looking into what cells in the adherent fraction suppressed the proliferation, it was found that neither the T cell nor the macrophage enriched cell fractions of this population individually showed suppressive effect, indicating that their co-presence was necessary for the suppression. Since BCG induced granulomas resolve much faster than granulomas induced by other mycobacteria such as Mycobacterium leprae the present experimental findings add to the existing evidence that intradermal BCG vaccination influences subsequent immune responses in the host and may further stress upon its beneficial role seen in Covid-19 patients.

BCG vaccine may generate cross-reactive T cells against SARS-CoV-2: In silico analyses and a hypothesis.

The world is facing the rising emergency of SARS-CoV-2. The outbreak of COVID-19 has caused a global public health and economic crisis.Recent epidemiological studies have shown that a possible association of BCG vaccination program with decreased COVID-19-related risks, suggesting that BCG may provide protection against COVID-19. Non-specific protection against viral infections is considered as a main mechanism of BCG and clinical trials to determine whether BCG vaccine can protect healthcare workers from the COVID-19 are currently underway. We hypothesized that BCG may carry similar T cell epitopes with SARS-CoV-2 and evaluated the hypothesis by utilizing publicly available database and computer algorithms predicting human leukocyte antigen (HLA) class I-binding peptides. We foundthatBCG contains similar 9-amino acid sequences with SARS-CoV-2. These closely-related peptides had moderate to high binding affinity for multiple common HLA class I molecules, suggesting that cross-reactive T cells against SARS-CoV-2 could be generated by BCG vaccination.

A cytokine super cyclone in COVID-19 patients with risk factors: the therapeutic potential of BCG immunization.

The seventh human coronavirus SARS-CoV2 belongs to the cluster of extremely pathogenic coronaviruses including SARS-CoV and MERS-CoV, which can cause fatal lower respiratory tract infection. Likewise, SARS-CoV2 infection can be fatal as the disease advances to pneumonia, followed by acute respiratory distress syndrome (ARDS). The development of lethal clinical symptons is associated with an exaggerated production of inflammatory cytokines, referred to as the cytokine storm, is a consequence of a hyperactivated immune response aginst the infection. In this article, we discuss the pathogenic consequences of the cytokine storm and its relationship with COVID-19 associated risk factors. The increased pro-inflammatory immune status in patients with risk factors (diabetes, hypertension, cardiovascular disease, COPD) exacerbates the Cytokine-storm of COVID-19 into a 'Cytokine Super Cyclone'. We also evaluate the antiviral immune responses provided by BCG vaccination and the potential role of 'trained immunity' in early protection against SARS-CoV2.

Could an Unrelated Live Attenuated Vaccine Serve as a Preventive Measure To Dampen Septic Inflammation Associated with COVID-19 Infection?

We propose the concept that administration of an unrelated live attenuated vaccine, such as MMR (measles, mumps, rubella), could serve as a preventive measure against the worst sequelae of coronavirus disease 2019 (COVID-19). There is mounting evidence that live attenuated vaccines provide nonspecific protection against lethal infections unrelated to the target pathogen of the vaccine by inducing "trained" nonspecific innate immune cells for improved host responses against subsequent infections. Mortality in COVID-19 cases is strongly associated with progressive lung inflammation and eventual sepsis. Vaccination with MMR in immunocompetent individuals has no contraindications and may be especially effective for health care workers who can easily be exposed to COVID-19. Following the lead of other countries conducting clinical trials with the live attenuated Mycobacterium bovis BCG (BCG) vaccine under a similar concept, a clinical trial with MMR in high-risk populations may provide a "low-risk-high-reward" preventive measure in saving lives during this unprecedented COVID-19 pandemic.

Is BCG vaccination causally related to reduced COVID-19 mortality?

The ongoing severe acute respiratory sickness coronavirus 2 (SARS-CoV-2) pandemic has resulted in more than 3,600,000 detected cases of COVID-19 illness and nearly 260,000 deaths worldwide as of May 6, 2020. Recently, BCG vaccination was shown to correlate with reduced COVID-19 case fatality rates (preprint: Miller et al, 2020; preprint: Sala & Miyakawa, 2020; https://www.jsatonotes.com/2020/03/if-i-were-north-americaneuropeanaustral.html). The most recent data from publicly available resources also indicate that both COVID-19 incidence and total deaths are strongly associated with the presence or absence of national mandatory BCG vaccination programs. As seen in Table 1, seven of eight countries with very low numbers of total deaths (< 40 per 1 million population) adopted a mandatory BCG vaccination program using one of a set of 6 separate BCG strains (Table 1). In contrast, COVID-19 mortality was markedly higher in countries where BCG vaccination is not widely administered or is given only to high-risk groups. COVID-19 mortality was also higher in countries where widespread BCG vaccination was discontinued more than 20 years ago and in countries that used the BCG Denmark strain regularly or temporarily. This raises the question of whether BCG vaccination and reduced COVID-19 mortality are causally related. An additional question is why different BCG strains may be variably associated with mortality.