cord-000153-134qz0aw	2009	Our previous results showed that Bacillus Calmette Guerin (BCG), a mycobacterium used as a model to investigate the immune response against MTB, stimulates the induction of TNF-α via mitogen-activated protein kinase (MAPK) in human blood monocytes. Since MAPK is regulated by MKP-1 in response to LPS and the activation of MAPK is important in BCGinduced cytokine expression, we hypothesize that MKP-1 plays a critical role in the immune regulation of BCG in human monocytes. The results revealed that MKP-1 plays a role in the induction of TNF-α expression upon BCG stimulation, which may be different from that of its conventional functions in which MKP-1 acts as a negative regulator in LPS-induced signaling pathways [7] . Similar to the results of cytokine expression, phosphorylation of both p38 MAPK and ERK1/2 in response to BCG was decreased in monocytes transfected with MKP-1 siRNA instead of the expected increase in phosphorylation ( Figure 5 ).
cord-002058-rppsmirp	2010	The novel ligands are chaperone protein DnaK, 60 kDa chaperonin-1 (Cpn60.1), glyceraldehyde-3 phosphate dehydrogenase (GAPDH) and lipoprotein lprG. bovis BCG can bind to dendritic-cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN/CD209) to promote entry into human dendritic cells (DCs) and alveolar macrophages Maeda et al., 2003; Tailleux et al., 2003; Pitarque et al., 2005; Appelmelk et al., 2008) . However, the form of this protein identified after capture by the affinity column was not glycosylated at this position, and it is therefore very unlikely that DC-SIGN binds to this ligand via its Ca 2+ -dependent lectin activity. bovis BCG lysate incubated with either 125 I-DC-SIGN or 125 I-DC-SIGNR revealed that DC-SIGN and DC-SIGNR both bind the same protein at around 27 kDa, which corresponds to lprG in our SDS-PAGE system, and is the only ligand detected by this method. DC-SIGN and DC-SIGNR binding to lprG can therefore still occur when the mycobacterial protein has been denatured by SDS-PAGE.
cord-003504-wjab4y0g	2019	Finally, an in vivo immunisation model showed that BCG vaccination under PD-L1 blockade could enhance antigen-specific memory CD4 T-cell responses. Here, we show for the first time that BCG can induce the up-regulation of PD-L1 on both macrophages and dendritic cells (DCs) via autocrine/paracrine secretion of STAT3-activating cytokines, chiefly IL-6 and IL-10. Upon infection with BCG, both APC types expressed high levels of PD-L1 compared to the unstimulated control at 24 h and 48 h (p < 0.0001), and a dose trend was observed for increasing MOI in macrophages at 48 h. To confirm that STAT3 was mediating the up-regulation of PD-L1 expression by BCG, cells were then pre-treated with Stattic or a vehicle control for 2 hours before infection with a low dose of bacteria (Fig. 5C) . BCG vaccine mediated reduction in the MHC-II expression of macrophages and dendritic cells is reversed by activation of Toll-like receptors 7 and 9
cord-005882-iodfgzjf	2005	Elucidation of the genetic mechanisms underlying susceptibility and protective immune mechanisms in resistant individuals that prevent disease outbreak in face of ongoing infection, as well as identification of the pathogen genes that promote transformation of latent infection into active tuberculosis, will facilitate rational design of a postexposure vaccine 27, 28, 31 . Generally, subunit vaccines crucially depend on appropriate adjuvants 38 that stimulate T helper type 1 (T H 1) immune responses by the different T cell populations required for protection against tuberculosis. Despite previous reluctance, a recent expert group meeting has strongly advocated development of viable recombinant vaccines against tuberculosis because they are the most potent stimulators of protective immune responses that perform better than BCG in experimental animal models 60 . In humans, therapeutic vaccination would probably be used to stimulate T cell responses in HIV-infected people whose virus was well controlled by antiretroviral drugs, with the aim of terminating antiretroviral therapy (ART) once the T cell levels were boosted.
cord-014712-5u4e00q6	2014	Ege University Faculty of Medicine, Dept of Pediatric Immunology, Izmir, Turkey Ig class switch recombination deficiencies are rare PIDs (1:500,000 births) with normal or elevated serum IgM and low IgG, IgA and IgE levels, defective or normal somatic hypermutation, defective T/B cooperation (50%), intrinsic B cell defect (50%), susceptibility to bacterial infections begining from the first year of age (impaired B cell immunity) and lack of germinal centres in secondary lymphoid organs. Great North Children''s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, and Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK Even following the introduction of biologic disease modifying antirheumatic drugs (DMARDs), a small number of children suffering from severe, refractory autoimmune (AI), rheumatic and/or autoinflammatory disorders will not get into clinical remission (CR) and will potentially further suffer from multiple side-effects of combined and long-term immunosuppressive and anti-inflammatory therapies, in particular severe infections (Marodi L, Casanova JL.
cord-018737-1h84yi2i	2019	Activation of antigen-presenting cells by live-attenuated bacterial vectors leads to adaptive immune response: Various pathogen-associated molecular patterns present in the liveattenuated bacterial vectors interact with Toll-like receptors expressed on the surface or in endosomal membranes. Live-attenuated microbes exhibit superior ability to deliver vaccine antigens to the mucosal immune system, as many of them are derived from natural mucosal pathogens, including Salmonella spp., Lm, E. Adaptation of the endogenous Salmonella enterica serovar Typhi clyA-encoded hemolysin for antigen export enhances the immunogenicity of anthrax protective antigen domain 4 expressed by the attenuated live-vector vaccine strain CVD 908-htrA Immune responses to recombinant pneumococcal PspA antigen delivered by live attenuated Salmonella enterica serovar typhimurium vaccine Regulated delayed expression of rfc enhances the immunogenicity and protective efficacy of a heterologous antigen delivered by live attenuated Salmonella enterica vaccines Attenuated deltaguaBA Salmonella typhi vaccine strain CVD 915 as a live vector utilizing prokaryotic or eukaryotic expression systems to deliver foreign antigens and elicit immune responses
cord-024716-1waejlwb	2020	Heterologous protection offered by BCG through production of trained immunity, epigenetic reprogramming of monocytes, non-specific activation of NK cells, and increase of pro-inflammatory cytokines (particularly, tumor necrosis factor [TNF]-alpha and interleukin 1 beta) production may be the mechanism behind its crossprotection against the novel coronavirus. The countries where universal BCG vaccination is practiced have a mean COVID-19 positive cases of 131.1 (standard deviation 208.7) per 1 million population with a median of 40. The countries where universal BCG vaccination is practiced have a mean COVID-19 positive cases of 131.1 (standard deviation 208.7) per 1 million population with a median of 40. The countries where universal BCG vaccination is not practiced have a mean COVID-19 deaths of 80.7 (standard deviation 180.8) per 1 million population with a median of 18. The countries where universal BCG vaccination is practiced have a mean COVID-19 positive deaths of 4 (standard deviation 7.6) per 1 million population with a median of 1.
cord-208177-m8q6dyfx	2020	Instead, this paper takes advantage of a rare nationwide natural experiment that took place in Sweden in 1975, where discontinuation of newborns BCG vaccination led to a dramatic fall of the BCG coverage rate from 92% to 2% , thus allowing us to estimate the BCG''s effect without all the biases associated with cross-country comparisons. We used regression discontinuity to assess the effect of BCG vaccination on Covid-19 related outcomes. found that countries with universal Bacillus Calmette-Guérin (BCG) childhood vaccination policies tend to be less affected by the COVID-19 pandemic, in terms of their number of cases and deaths 3 . In this study, we took advantage of a change in vaccination policy in Sweden to investigate the link between BCG vaccination in infancy and Covid-19 cases, hospitalizations and deaths, using a regression discontinuity approach.
cord-252855-xtsnlu1f	2017	In this review, we highlight recent findings in in vitro and in vivo models of the gut, lung, oral cavity, mammary gland, and liver infections that provide experimental evidence supporting the therapeutic role of human and bovine Lf in promoting some parameters of inflammation and protecting against the deleterious effects of bacterial, viral, fungal and protozoan-associated inflammation. However, this is not always the case because studies on intestinal epithelial-barrier function and mucosal inflammation carried out in a Caco-2 cells model and macrophages activated with lipopolysaccharide (LPS) showed that both Lf forms effectively inhibited the pro-inflammatory response. In a mice model of hepatitis induced by intraperitoneal co-administration of LPS and zymosan, orally administered bLf decreased the serum aspartate aminotransferase activity (a marker of liver inflammation), and increased in the small intestine the production of IL-11, an anti-inflammatory cytokine with a role in the amelioration of inflammatory response [153, 164] .
cord-256642-payjduek	2019	BACKGROUND: Reactivation of the Bacillus Calmette-Guérin (BCG), manifesting as erythema, induration, ulceration or crust formation at a previous BCG inoculation site, is a common and highly specific feature of Kawasaki disease (KD). CONCLUSIONS: This case report highlights the rare finding of BCG reactivation in a child with confirmed measles infection, and suggests that this clinical manifestation may occasionally occur in children with infections or conditions other than KD. Reactivation of the BCG, manifesting as erythema, induration, ulceration or crust formation at the BCG site months or years after inoculation, has been described as an important feature of Kawasaki disease (KD) [5, 6] . Here, we present a case report of a 7-month old infant with laboratory-confirmed measles who presented with erythema and induration at the BCG inoculation site. Apart from those to confirm the measles infection, no laboratory investigations were undertaken to determine if additional viral pathogens were present in the patient and contributed to the development of the BCG reactivation.
cord-258742-li71b9e0	2020	Based on a subset of Covid-19 Wave 1 cases at a time point near TZ+3m (April, 2020), we perform an analysis of the influencing factors for the epidemics impacts with several different statistical methods. The intent of the work is to repeat similar analysis at several different points in the time series of cases that would allow to make a confident conclusion about the epidemiological and social factors with strong influence on the course of the epidemics. The purpose of the analysis is to develop and verify the methods that would allow to identify the main factors, different and in addition to the known ones, that have significant influence on the course and the impact of the epidemics based on the available data. As can be see seen, the combination of three factors: policy, BCG immunization and smoking has the highest correlation and the lowest linear regression error for the resulting effect.
cord-258877-6hy37qxa	2020	The intent of this work was to analyze publicly available Covid-19 epidemiological data by reporting national and subnational jurisdictions with respect to the hypothesized induced immunity population-scale protection resulting from a universal BCG vaccination policy (UBIP), current or previous, and attempt both qualitative and quantitative analysis of the hypothesis of correlation between a current or previous UBIP in the jurisdiction and a milder scenario of Covid-19 epidemics; to verify the assumptions, results and conclusions of the earlier studies [1, 2, [4] [5] [6] with a specific objective to determine, in a quantitative analysis, the constraints and confidence of the correlation and null hypotheses. We use qualitative methods such as case comparison, trend analysis and quantitative ones such evaluation of statistical parameters to analyze trends in development of the epidemiological situation across monitored jurisdictions with the intent to evaluate the significance of the correlation hypothesis between the impact of Covid-19 epidemics and a record of universal BCG immunization.
cord-260826-1n96pz86	2020	Using publicly available data we built a simple log-linear regression model to assess the association of BCG use and COVID-19-attributable mortality per 1 million population after adjusting for confounders including country economic status (GDP per capita), and proportion of elderly among the population. Notwithstanding limitations due to testing constraints in LMICs, case ascertainment bias and a plausible rise of cases as countries progress along the epidemiological trajectory, these analyses provide intriguing observations that urgently warrant mobilization of resources for prospective randomized interventional studies and institution of systematic disease surveillance, particularly in LMICs. Novel SARS-CoV2 continues to wreak global havoc. To evaluate the effect of BCG vaccine on mortality attributable to COVID-19, we built a simple log-linear regression model using crude COVID-19-attributable mortality data per 1 million population for each country as outcome, BCG vaccine inclusion in the national immunization schedule as exposure, and adjusted for the effects of the following variables on mortality: country-specific GDP per capita, the percentage of population 65 years and above, and the relative position of each country on the epidemic timeline (days since 100 th case reported as of 29 March 2020).
cord-263455-dquztf5l	2020	More chemoprophylaxis research is needed on: enhanced medication regimens; interventions in varying (epidemiological) settings, including focal mass drug administration (fMDA); specific approaches per contact type; combinations with screening variations and field-friendly rapid tests, if available in the future; community and health staff education; ongoing antibiotic resistance surveillance; and administering chemoprophylaxis with SDR-PEP prior to BCG administration. But, given the evidence for the effectiveness of SDR-PEP and the WHO guidelines for its use, the ethics of testing new post-exposure immunoprophylactic approaches for leprosy prevention without combining them with chemoprophylaxis in both the intervention and control group needs to be discussed. The combined effect of chemoprophylaxis with single dose rifampicin and immunoprophylaxis with BCG to prevent leprosy in contacts of newly diagnosed leprosy cases: a cluster randomized controlled trial (MALTALEP study)
cord-265472-b1s4stvz	2015	In conclusion, there are several case reports of autoimmune diseases following vaccines, however, due to the limited number of cases, the different classifications of symptoms and the long latency period of the diseases, every attempt for an epidemiological study has so far failed to deliver a connection. We can infer that a similar response may be associated with different safety in relation to the development of autoimmune reactions to vaccines, particularly in the patients with genetic predisposition to an enhanced response to vaccine inoculation [85] . HSP was associated with seasonal influenza, influenza A (H1N1), pneumococcal and meningococcal disease, hepatitis A virus (HAV), HBV, anti-human papilloma virus (HPV) vaccines, and following multiple combinations of vaccines, such as typhoid, cholera and yellow fever [139, [171] [172] [173] . Hepatitis B vaccination and undifferentiated connective tissue disease: another brick in the wall of the autoimmune/inflammatory syndrome induced by adjuvants (Asia)
cord-266549-g8060w8v	2020	This report underscores the lack of major differences in the clinical features of severe acute respiratory syndrome coronavirus 2 and other types of CoV or influenza infections among infants despite limited clinical features reported. S. pneumoniae was codetected in the CoV-infected infants who died in Pneumo-study while bacterial co-detection was not reported by Wei et al. The incidence of COVID-19 in infants less than 1-year-old is currently low, but studies are needed to describe the clinical features, prognosis and impact of infected infants on the COVID-19 spread. Two recent reports from China suggest that in utero infection could be possible based on the measurement of IgM levels in neonates shortly after birth but no further confirmation of this with a positive reverse transcriptase-polymerase chain reaction test. 4 To show the causality between the BCG vaccine and the severity of COVID-19, we have to confirm the following Bradford Hill criteria: specificity, temporality, reversibility, and experiment.
cord-270675-37kus7mz	2020	The non-specific beneficial effects of Bacille Calmette-Guérin (BCG) vaccination suggest that this vaccine might play a role in protecting individuals against severe coronavirus disease (COVID-19).Several studies propose that BCG vaccination may increase the body''s immunity, thereby preventing respiratory infections caused by other respiratory pathogens. As the number of deaths due to COVID-19 is increasing rapidly and there is no specific treatment available to date, scientists are evaluating the effectiveness of already approved drugs as therapies against COVID-19, and the results were found to vary widely: from no significant effect being observed to a reduction in the time taken for clinical improvement. Therefore, these non-specific beneficial effects of BCG vaccination suggest that the vaccine could play a role in protecting individuals against severe coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [5] . A controlled study to evaluate the efficacy of BCG vaccination in protecting against COVID-19 is warranted for several reasons, the most important of which is the non-specific b.
cord-271734-1cfhjuxi	2020	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. The objective of this work was to investigate the immune regulatory mechanism responsible for the induction of an ''immunological'' type granuloma in the draining lymph node after BCG vaccination in guinea pigs and their early resolution in contrast to that observed with another mycobacterium, M. The effects of injected BCG and M leprae on the stimulation index (T/C) measured in the post auricular and cervical lymph node cell preparations cultured with PPD, leprosin, concavalin A, or BCG: live, heat killed or co-irr were compared using student''s t-test for means comparison. leprae injected guinea pigs, cells from the cervical lymph nodes draining BCG induced granuloma did not respond in vitro to soluble mycobacterial antigens, PPD and leprosin, though they responded to whole BCG organisms.
cord-276351-cv5th7hd	2020	BCG vaccination trials for reducing SARS-CoV-2 infection are underway, but concerns have been raised regarding the potential harm of strong innate immune responses. To investigate the safety of BCG vaccination, we retrospectively assessed coronavirus disease 2019 (COVID-19) and related symptoms in three cohorts of healthy volunteers who either received BCG in the last five years or not. In conclusion, recent BCG vaccination is safe and large randomized trials are needed to reveal if BCG reduces the incidence and/or severity of SARS-CoV-2 infection. The incidence of self-reported sickness ( Figure 4B ) as well as the 252 incidence of symptoms ( Figure 4C and D, Figure S6 ) was not significantly different between 253 responders and non-responders, indicating that a strong trained immunity profile is not 254 associated with increased sickness or severity of symptoms during the COVID-19 pandemic. COVID-19: A model correlating BCG vaccination to protection from 696 mortality implicates trained immunity.
cord-276495-q22jnkn2	2020	This type of immunological memory or epigenetic programming to a pre-activated state allows the generation of a sustained and more effective non-specific response, even after years, although in the protocols of these studies, the innate immunity was evaluated after 3 months (2). Various clinical trials are underway to evaluate trained immunity through BCG vaccination in healthy volunteers under the coordination of Dr. Mihail Netea (Radboud University Medical Center, Nijmegen, the Netherlands). To our knowledge, there are no published articles or clinical evidences that show that BCG immunization protects against SARS-CoV-2 in Brazil. The journal The Lancet, in May 2020, published the results of an observational, longitudinal, and retrospective clinical study based on medical records of COVID-19 patient cohorts treated across 6 countries and 671 hospitals, with different technical capabilities and diverse drug protocols (13) .
cord-278417-ty4wbtkv	2020	Keywords: Coronavirus, Covid-19, Vaccine, SARS-CoV-2 World Health Organisation discussed the "Top Threats to Human Health in 2019," and developed a strategic plan to meet the challenges. Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-Cov-2) has caused a pandemic of Coronavirus disease -19 (Covid-19) with global public health and economic crisis. Since the WHO notification of first case of this disease on 31st Dec, 2019 and a complete genome sequence of the virus on Jan 5, 2020, global attempts to produce a suitable vaccine are ongoing in scores of laboratories. Phase I: Vaccines are given to a limited number of human volunteers with emphasis on safety and also to monitor the immune response. RNA vaccine stimulates immune system to produce protective antibodies against viral S protein. Pandemic preparedness: Developing vaccines and therapeutic antibodies for COVID-19 The early landscape of COVID-19 vaccine development in the UK and rest of the world BCG-induced trained immunity: can it offer protection against COVID-19?
cord-279620-ckh4uke6	2020	A number of hypotheses may explain the low susceptibility of children to COVID-19 virus [2] viz, (i) immaturity and limited function of angiotensin-converting enzyme 2 (ACE2) receptors in children, as undifferentiated cells that express low levels of ACE2 are not readily infected by SARS-CoV; (ii) the immature innate immune system in young children results in less inflammation and consequently fewer symptoms; and, (iii) possible crossreactivity of antibodies against other viruses (influenza, adenovirus, respiratory syncytial virus etc.) with the SARS-CoV-2, which could provide partial protection. In patients hospitalized in French pediatric units in recent weeks, the chest computed tomography (CT) scans have often been pathological, even in children with limited respiratory sign with associated decline in lung function (unpublished data). Recently, there has been a buzz about the protective effect of Bacille Calmette-Guérin (BCG) vaccine in COVID-19. Based on epidemiological correlations, many unpublished preprints hypothesized that the BCG vaccine may offer protection against COVID-19. The basis of the possible use of the BCG vaccine against COVID-19 lies in its non-specific effects (NSEs) over the immune system [3] .
cord-281354-sa27k8o3	2020	title: Role of Latent Tuberculosis Infections in Reduced COVID-19 Mortality: Evidence from an Instrumental Variable Method Analysis However, these studies ignore an important fact: according to World Health Organization estimates, about a quarter of the world''s population may have latent tuberculosis infection (LTBI), a condition in which there is no evidence of clinically active tuberculosis but persistent immune responses are stimulated by Mycobacterium tuberculosis antigens. However, such studies ignore the important fact that about one-quarter of the world''s population may have latent TB infection (LTBI), a condition in which there is no evidence of clinically active TB but persistent immune responses are stimulated by Mycobacterium tuberculosis antigens. As explained above, the logarithm of the number of TB infections per 100,000 individuals (lntb10) can be used as a proxy variable for LTBIs. For this regression analysis to be statistically accurate, the explanatory variable X must first be correlated with the error term u (i.e., the covariance of X and u must be zero).
cord-283603-d6ult65u	2020	The Bacillus Calmette-Guérin (BCG) vaccine induces some level of protection against Mycobacterium tuberculosis (Mtb) while stimulating trained immunity that correlates with lower mortality and increased protection against unrelated pathogens. PBMCs from volunteers vaccinated with gamma-irradiated BCG (γBCG) only demonstrated increased cytokine production in response to Mtb antigens, with no significant trained immunity effects observed after two weeks and three months [18] . Stimulation of macrophages deficient in NOD2 with BCG did not result in increased cytokine production following heterologous stimulation, demonstrating the critical importance of this signaling pathway in establishing trained immunity [23] . tuberculosis Vaccine Candidate (MTBVAC), the first genetically modified, live attenuated vaccine based on Mtb which has demonstrated safety and efficacy in initial clinical trials, induces trained immunity effects in vitro through shifts in metabolism and epigenetic changes at proinflammatory promoters, and can protect subcutaneously vaccinated mice from lethal intranasal doses of Streptococcus pneumoniae [62] .
cord-285306-leu2hygk	2020	Finally, we also analysed the peak Z score reflecting increases in total mortality from historical averages reported by EuroMOMO (Euromomo.eu), Results: Following adjustment for the effects of population size, median age, population density, the proportion of population living in an urban setting, life-expectancy, the elderly dependency ratio (or proportion over 65 years), net migration, days from day 1 to lockdown and case-fatality rate, only BCG vaccination score remained significantly associated with Covid-19 mortality at day 30. Following adjustment for the effects of population size, median age, population density, the proportion of population living in an urban setting, life-expectancy, the elderly dependency ratio (or proportion over 65 years), net migration, days from day 1 to lockdown and case-fatality rate, BCG vaccination score remained significantly associated with Covid 19 mortality at day 30.
cord-288618-01hxgcds	2020	INTERPRETATION The adjustment of a Gaussian to daily data of COVID-19 in each country reveals the different propagation dynamics, properly characterized by the parameters proposed here. Column 1: country; Column 2: population in thousand inhabitants; Column 3: Number of applied COVID-19 tests; Column 4: Test density (ratio between the last two columns); Column 5: accumulated number of positive tests; Column 6: accumulated number of deaths; Column 7: percentage of mortality (based on the ration of the two previous columns); Column 8: BCG vaccination status; Column 9: Maximum of fitting Gaussian; Column 10: FWHM of the fitting Gaussian; Column 11: Figure of merit proposed in this paper. Despite fluctuations in the daily cases of COVID-19, it is possible in general to adjust a Gaussian function to high density sets of data pointing to a possible mathematical description of the evolution of the pandemic in different countries, as shown in Figs.
cord-289008-c4cu3vrp	2020	Patients with muscle-invasive bladder cancer are at risk of disease progression, with radical cystectomy delays beyond 12 wk from diagnosis or completion of neoadjuvant chemotherapy. To this end, PubMed was searched from inception until April 2, 2020 to identify studies examining the association between delays in treatment and clinical outcomes, including upstaging, recurrence, and mortality for patients with bladder cancer (BC; both muscle-invasive and non-muscle-invasive disease), prostate cancer (PCa), kidney cancer, upper tract urothelial cancer, germ cell tumors, and penile cancer. Where radiotherapy is planned to be administered, a recent Cochrane Database systematic review and meta-analysis of 10 studies including 8278 patients demonstrated that for those with intermediate-and high-risk PCa, hypofractionation is associated with equivalent oncologic outcomes (MFS, disease-specific survival, and OS), as well as functional outcomes [64] .
cord-289742-1usxeo9a	2020	Indeed, in murine models, stimuli that induce trained immunity in circulating monocytes, including Western type diet feeding, BCG vaccination, or administration of β-glucan, were found to trigger a persistent inflammatory reprogramming of myeloid progenitor cells in the bone marrow (Christ et al., 2018; Mitroulis et al., 2018) . Finally, additional proof for a role of glycolysis in trained immunity stems from the observations that in cohorts of healthy subjects, single nucleotide polymorphisms (SNPs) in key glycolytic enzymes are associated with the induction of cytokine production capacity by training of the cells ex vivo; this was reported for SNPs in hexokinase 2 (HK2) and phosphofructokinase, platelet (PFKP) for training with BCG . When innate immune cells, such as monocytes, are stimulated by growth signals or inflammatory stimuli, e.g. lipopolysaccharide, the TCA cycle shifts function to provide intermediary metabolites for biosynthetic pathways, including the production of amino acids and lipids, which is termed cataplerosis.
cord-291719-1ku6cmwj	2020	METHODS: We developed and employed a systems biology workflow capable of identifying small-molecule antiviral drugs and vaccines that can boast immunity and affect a wide variety of viral disease pathways to protect from the fatal consequences of emerging viruses. RESULTS: Our analysis demonstrates that BCG vaccine affects the production and maturation of naïve T cells resulting in enhanced, long-lasting trained innate immune responses that can provide protection against novel viruses. Herein, we describe a unique drug and vaccine repurposing workflow, and list high confidence proteins and pharmacological classes of compounds, that work as BCG mimics at the system level by inducing beneficial long lasting trained immune response. Earlier studies suggested that the documented beneficial off-target effects of BCG in protecting from non-TB infections, including perhaps COVID-19, involve a potentiation of innate immune responses through epigenetic mechanisms (56) (57) (58) .
cord-291722-xnfdjriz	2020	We believe that the low occurrence/fatality of Covid-19 may be due to the existing vaccination status and endemicity of other infections which might have enhanced their immune system to face the challenges of COVID-19. Countries with a high prevalence of infections with dengue, chikungunya, malaria etc., have a low occurrence of COVID-19 makes one to hypothesize that endemic infections may protect through interferon which retard subsequent illness/disease through viral interference (11, 12) . Previous experimental studies have revealed that beta coronaviruses are capable of inducing immune responses against one another by way of generating neutralizing antibodies which cross-react against other SARS-CoV viruses (15, 16) . Overall the organisms and individuals based on previous exposure to vaccines and infections come from the environment, internal sensors, memorized experience, and genome prefer to develop pathways in a goal-directed manner and improve the behavioural traits and phenotypic variability so as to protect and survive from infectious agents. Non-specific effects of BCG vaccine on viral infections
cord-292128-8o20mcur	2020	title: Bacille Calmette Guérin (BCG) and new TB vaccines: specific, cross-mycobacterial and off-target effects An 192 interesting randomised placebo-controlled study in 30 healthy male adults (not previously 193 BCG immunised) compared the immune response to a yellow fever immunisation as a "viral 194 challenge model" one month after BCG immunisation. tuberculosis Erdman 6 to 10 months after BCG 329 immunisation, macaques that had received intravenous BCG showed superior protection The vaccine is also being tested in trials in several other settings in adults for prevention of 443 disease and recurrence, and also for its off-target effects on bladder cancer. The efficacy of bacillus Calmette-Guérin 517 vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses 518 of the published literature Effect of BCG vaccination against 520 Mycobacterium tuberculosis infection in children: systematic review and meta-521 analysis Non-specific effect of Bacille Calmette-Guerin 631 vaccine on the immune response to routine immunisations
cord-292372-kn27ghlv	2020	Instead, this paper takes advantage of a rare nationwide natural experiment that took place in Sweden in 1975, where discontinuation of newborns BCG vaccination led to a dramatic fall of the BCG coverage rate, thus allowing us to estimate the BCG''s effect without the biases associated with cross-country comparisons. found that countries with universal Bacillus Calmette-Guérin (BCG) childhood vaccination policies tend to be less affected by the COVID-19 pandemic, in terms of their number of cases and deaths [7] . In this study, we took advantage of a change in vaccination policy in Sweden to investigate the link between BCG vaccination in infancy and Covid-19 cases, hospitalizations and deaths, using a regression discontinuity approach. For instance, this study estimates the effect of universal BCG vaccination for individuals born around April 1st 1975, who are in their mid-forties during the COVID-19 pandemic, and cannot be generalized to the entire population.
cord-294302-hboc3xcz	2020	Here, we illustrate the immunological mechanism to train the immune system towards a more effective and less symptomatic T-helper 1 (Th1) immune response, thanks to a subcutaneous vaccine containing lysates of Corynebacterium parvum (synonym for Propionibacterium acnes), a Gram-positive bacterium able to evoke a strong Th1 response. parvum vaccine protection against a coronavirus (mouse hepatitis virus type 3), dating back to 1981 murine model by Schindler and colleagues, is also reported [31] . parvum vaccine (point 3), it is theoretically possible to train and calibrate the immune system towards a T h 1 response (point 4), able to prevent COVID-19 or to keep the disease under control in a paucisymptomatic or asymptomatic way thanks to activated reticuloendothelial system, NK, T c and dendritic cells. Efficacy of BCG vaccination in the prevention of COVID19 via the strengthening of innate immunity in health care workers
cord-298867-hzshnq7b	2020	At early times during COVID-19 pandemic heterogeneous immunity towards (SARS-CoV-2), was hypothesized and statistical correlation between of BCG vaccination practices and COVID-19 mortality variances among countries was statistically proved . Through applying stem-leaf plot for exploring data screening behavior concerning Covid-19 Mortality for obsolescence duration of cessation of mass BCG vaccination programs, as well as (nonlinear regression of compound model) for predicted shape behavior for that group. Results: Slope value shows highly significant effectiveness of obsolescence of cessation of mass BCG vaccination programs on Covid -19 mortality at P-value<0.000. . https://doi.org/10.1101/2020.08.20.20178889 doi: medRxiv preprint CoV-2) by different way that is the cessation duration of BCG programs in countries which stopped BCG vaccinations programs.
cord-298945-0sm0r4v8	2020	A possible association between national Bacille Calmette-Guerin (BCG) vaccination policy and lower COVID-19 incidence has been suggested in some preprint papers. . https://doi.org/10.1101/2020.05.13.20100156 doi: medRxiv preprint Abstract A possible association between national Bacille Calmette-Guérin (BCG) vaccination policy and lower COVID-19 incidence has been suggested in some preprint papers. Using publicly accessible databases, I explored associations of national BCG vaccination policy with COVID-19 epidemiology in 78 countries. The mixed effect model revealed national BCG policy decreases in the country-specific risk of death by COVID-19, correspond to odds ratio of 0.446 (95% confidence interval 0.323 -0.614, P=1×10 −5 ). The mixed effect model revealed national BCG policy decreases in the country-specific risk of death by COVID-19, correspond to odds ratio of 0.446 (95% confidence interval 0.323 -0.614, P=1×10 −5 ). A possible association between national Bacille Calmette-Guérin (BCG) vaccination policy and lower COVID-19 incidence has been suggested in some preprint papers.
cord-299676-6wt9rn1a	2020	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. Using this "disease stage normalized" data, there was still a highly significant difference between countries that adhered to national BCG vaccination policy versus those that had ceases/never had a national programme ( Figure 1C ). The duration of BCG-induced trained immunity or how different vaccine strains compare in terms of longevity of induced innate memory is not known. 7 Since the persistence and immunostimulatory properties of BCG strains differ, their potential to induce trained immunity in vaccinated individuals could also vary. When we analyzed available data on BCG vaccine strains used in different countries BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity
cord-300338-duhyb754	2020	We therefore aimed to explore whether recent BCG vaccine coverage is associated with COVID-19 morbidity and/or mortality rates, using linear regression models to explore associations between the two continuous random variables adjusted for a variety of potential confounders, such as median age and body mass index (BMI) in individual countries through this ecological study. As a result, ''≥60 years of age'' (p < 0.001) and ''BCG vaccine coverage'' (p = 0.002) remained significant factors associated with COVID-19 mortality, even after adjustment for morbidity and PCR-tests. As a result, ''≥60 years of age'' (p < 0.001) and ''BCG vaccine coverage'' (p = 0.002) remained significant factors associated with COVID-19 mortality, even after adjustment for morbidity and PCR-tests.
cord-300729-35meen0h	2020	Most of the countries with low-income levels (17/18) reported zero deaths attributed to COVID-19 and have universal BCG policies in place consistent with a protective role of BCG vaccination. In contrast, middle high and high income countries that never had a universal BCG policy (5 countries) had a larger mortality rate, with 16.39 ± 7.33 deaths per million people. We wondered if countries that established a universal BCG policy earlier would have a reduced mortality rate, as older people that are more severely affected by COVID-19 would be protected. Consistent with a role of BCG in slowing spread of COVID-19, middle high and high income countries that never had a universal BCG policy (5 countries) had about 4 times the number of cases per million inhabitants, with 264.90± 134.88. . https://doi.org/10.1101/2020.03.24.20042937 doi: medRxiv preprint Figure 3 : Higher number of COVID-19 cases were presented in countries that never implemented a universal BCG vaccination policy.
cord-304108-kn9v8qmz	2020	While the rate of cases vaccinated with BCG is lower (68.5% vs 88.2%; p=.026), the mean age (54.0 ± 11.5 years vs 38.3 ±10.7 years; p <.001), diabetes (32.6% vs 5.9%; p=.002) and low income (84.3% vs 52.9% p<.001) are higher in patients with severe disease compared to those with mild disease. Comparison of characteristics of BCG-vaccinated andunvaccinated COVID-19 pneumonia patients revealed that, mean age and low income rate were significantly higher in BCG-unvaccinated subjects compared to BCG-vaccinated subjects. Mean age, rate of diabetes, low-income and BCGvaccination status were the parameters differed significantly between mild and severe COVID-19 pneumonia patients ( Table 3 ). 12, 13 The study population consisted of BCG-vaccinated and -unvaccinated COVID-19 pneumonia cases in order to compare the severity of the disease in the two groups. Accordingly, logistic analysis revealed that increasing age and low income level were predictive of severe disease, whereas BCG vaccination status is not related to the severity of COVID-19 pneumonia.
cord-305264-0uhabgsr	2020	In this study, we reviewed 120 consecutive adult patients (≥18 years old) with COVID-19 at a major federally qualified health centre in Rhode Island, United States from 19 March to 29 April 2020. To determine if BCG vaccination provided protection from COVID-19, we reviewed a predominately Latino/Hispanic population receiving care at the major federally qualified health centre (FQHC) in Providence, Rhode Island, United States. COVID-19 patients with BCG vaccination were less likely to be hospitalised during the disease course (3.7% vs. A recent population-based study examining the cohort of Israeli adults aged 35−41 years found that the BCG vaccine may not reduce the likelihood of acquiring SARS-CoV-2 (difference, 1.3%; 95% CI −0.3% to 2.9%; P = 0.09) [10] . However, the lower hospitalisation rate among BCG-vaccinated patients from our prospective cohort study suggests the potential of BCG in preventing more severe COVID-19 among those who acquired SARS-CoV-2.
cord-309888-93rdcwrh	2020	First of all, we would like to underline the potential protective effect of Bacillus Calmette Guerin (BCG) vaccination against Covid-19 [4] . Based on these findings, the Murdoch Children''s Research Institute in Australia and the Radboud University in the Netherland have launched prospective clinical trials enrolling health care workers, to assess whether BCG vaccination protects against Sars-CoV-2 infection or reduces its severity [11, 12] . All these considerations raise some interesting questions: (1) is androgen deprivation therapy able to downregulate TMPRSS2 in lung epithelial cells, and if so is it able to affect the susceptibility and/or severity of Covid-19 infection? (2) Is the known male predominance of Sars-CoV-2 infection/Covid-19 severity related to the androgen-dependent regulation of TMPRSS2 gene? (3) Does individual variability of TMPRSS2 expression (e.g. caused by polymorphism) have any impact on Sars-CoV-2 infection/ Covid-19 severity?
cord-314121-ez62fx9p	2020	Instead, this paper takes advantage of a rare nationwide natural experiment that took place in Sweden in 1975, where discontinuation of newborns BCG vaccination led to a dramatic fall of the BCG coverage rate from 92% to 2% , thus allowing us to estimate the BCG''s effect without all the biases associated with cross-country comparisons. found that countries with universal Bacillus Calmette-Guérin (BCG) childhood vaccination policies tend to be less affected by the COVID-19 pandemic, in terms of their number of cases and deaths 3 . This suggests that universal BCG vaccination has no effect on the number of COVID-19 cases per 1000 inhabitants for individuals born in 1975. In this study, we took advantage of a change in vaccination policy in Sweden to investigate the link between BCG vaccination in infancy and Covid-19 cases, hospitalizations and deaths, using a regression discontinuity approach.
cord-315101-7mim3yl6	2020	Recent reports have suggested that BCG vaccination might have protective effects against COVID-19, however it is highly unlikely that BCG vaccine in its current form can offer complete protection against SARS-CoV-2 infection due to the lack of specific immunity. Nonetheless, recombinant BCG strains expressing antigens of SARS-CoV-2 may offer protection against COVID-19 due to the activation of innate as well as specific adaptive immune response. In this review we discuss about the heterologous effects of BCG, induction of trained immunity and its implication in development of a potential vaccine against COVID-19 pandemic. BCG Vaccination Protects against Experimental Viral Infection in Humans through 370 the Induction of Cytokines Associated with Trained Immunity BCG-Induced Cross-Protection and Development of Trained 376 Immunity: Implication for Vaccine Design BCG-induced trained immunity in NK cells: Role for non-specific protection to 416 infection Long-Lasting Effects of 483 BCG Vaccination on Both Heterologous Th1/Th17 Responses and Innate Trained Immunity
cord-318542-785hnh19	2020	In this review, we aim to summarize what is known about the immunologic mechanisms of COVID-19, the current recommendations, mechanisms of action and adverse effects of intravesical BCG in bladder cancer and determine if This article is part of the Topical Collection on Covid-19 * Ahmed Kotb drahmedfali@gmail.com intravesical BCG is safe in patients that are suspected or confirmed to have COVID-19. We reviewed relevant articles focusing on the mechanism of action of intravesical BCG and chemotherapy, including systemic outcomes and side effects from intravesical treatment, and its safety and efficacy in immunocompromised patients or those with acute immunological disorders. Search terms included "SARS-CoV-2" or "COVID-19" combined with "immune response", "intravesical BCG" combined with "bladder cancer", "urothelial carcinoma", "adverse events", "side effects", "mechanism of action", "immunocompromised" and "immunological disease". With knowledge of the recent SARS-CoV-2 pandemic, and the risk for severe complications such as ARDS, it is necessary to review the side effects of intravesical treatment in an attempt to determine its safety in COVID-19 and immunocompromised patients.
cord-323141-6z750avb	2020	5 On the other hand, the Centre for Disease Control and Prevention and the Royal College of Obstetricians and Gynecologists recommend breast-feeding with strict contact precautions based on the fact that so far there is no evidence that the virus can be transferred via breast milk. 4 To show the causality between the BCG vaccine and the severity of COVID-19, we have to confirm the following Bradford Hill criteria: specificity, temporality, reversibility, and experiment. Based on this background, we analyzed the data concerning all pediatric patients with COVID-19 (0-18 years old) admitted to the San Matteo Hospital of Pavia until April 4. As of today (April 11), 17 children had COVID-19 diagnosis based on clinical data and positive swab (RT-PCR analysis). Analyzing the data concerning the whole Lombardy population, 29.3% of patients with COVID-19 had home isolation, 21.5% required low-medium-intensity care, 2.3% ICU admission, and 18.3% died.
cord-325966-0g7a9s5z	2020	Some candidate drugs targeting different levels and stages of human responses against COVID-19 such as cell membrane fusion, RNA-dependent RNA polymerase, viral protease inhibitor, interleukin 6 blocker, and convalescent plasma may improve the clinical outcomes of critical COVID-19 patients. However, these clinical, laboratory, and imaging findings are nonspecific and cannot differentiate COVID-19 from other viral respiratory infections; viral diagnostic methods specific for SARS-CoV-2 should be applied for disease confirmation. An open-label study published in 2004 suggested, by comparison with a control group that received only ribavirin, that the addition of lopinavir-ritonavir (400 mg and 100 mg, respectively) to ribavirin reduced the risk of adverse clinical outcomes (acute respiratory distress syndrome or death) and viral load among patients with SARS [29] . Some available candidate drugs targeting different levels of human responses to COVID-19, such as cell membrane fusion, RNA-dependent RNA polymerase, viral protease inhibitor, IL-6 blocker and convalescent plasma, may improve the clinical outcomes of critical COVID-19 patients.
cord-328262-hw8swbt5	2020	Bacillus Calmette–Guérin (BCG) vaccination has been reported to decrease susceptibility to respiratory tract infections, an effect proposed to be mediated by the general long-term boosting of innate immune mechanisms, also termed trained immunity. This effect was mediated by peritoneal macrophages 10 Bacillus Calmette-Guérin (BCG) vaccination has been reported to decrease susceptibility to respiratory tract infections, an effect proposed to be mediated by the general long-term boosting of innate immune mechanisms, also termed trained immunity. Here, we discuss the non-specific beneficial effects of BCG against viral infections and whether this vaccine may afford protection to COVID-19. Here, we discuss the non-specific beneficial effects of BCG against viral infections and whether this vaccine may afford protection to COVID-19. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity
cord-328623-ud8vz3zu	2020	Results: The results show with robust statistical support that standerized TB prevalence to BCG coverage is significantly associated with reduced COVID-19 mortality and malaria incidence have an additional highly significant effect in reducing COVID-19 mortality. This study will test COVID-19 mortality in malarious countries against malaria incidence and TB prevalence calibrated by BCG coverage to look for statistical associations and significances. (3) , and regarding to composite regression estimate''s factors (i.e. the standardized TB/100000 by BCG vaccination coverage 2018 as direct effect, and malaria incidence for 2018/1000 population as indirect effect) results shows a meaningful composite linear regression tested in two tailed alternative statistical hypothesis of studied factor is playing effective role for reducing "Covid-19 death /1 M." rates as a function of the previous factors. Malaria which possibly induce immunological response similar to TB as we suggest in one way or another is significantly associated with reduction in COVID-19 mortality in this study.
cord-330203-7xen4nlm	2020	RESULTS: The countries that had ≤70% coverage of BCG vaccine reported 6.5 (95% CI: −8.4 to −4.5) less COVID-19 infections per 10,000 population as compared to countries that reported no coverage. 3 Data on BCG vaccination status when analysed at a national-level along with incident cases of COVID-19, can give us an ecological idea of a possible protective effect, if any. 4 Data on BCG vaccination coverage was obtained from the WHO Global Health Observatory. 6 We included 160 countries that reported official data on BCG vaccination coverage (%) and COVID-19 confirmed cases until May 31, 2020. The countries that had ≤70% coverage of BCG vaccine reported 6.5 (95% CI: −8.4 to −4.5) less COVID-19 infections per 10,000 population as compared to countries that reported no coverage (p < 0.001). Irrespective of the level of coverage, the East Asia and Pacific region countries reported 4 less infections per 10,000 population, as compared to countries without BCG vaccination strategy.
cord-331477-2x9szmjc	2020	Oral health professionals are at risk of developing COVID 19 infection as they come into close contact with patients and accompanying relatives who may be carrying the virus. Knowledge of these symptoms would help the dental surgery staff to triage patients when it comes to spotting COVID-19-infected persons. When booking emergency dental appointments, having a checklist of COVID-19 symptoms at the reception may help to inform the dentist about symptomatic patients, to postpone non-urgent therapies and to direct such patients to hospital centres equipped for handling infected subjects and their relatives, living together. For undertaking any direct patient care, dentists and dental surgery assistants and other oral health professionals are advised to wear, disposable gloves, aprons, eye protection and face shields where there is a risk of saliva, blood, other body fluids, secretions or excretions splashing into the face and eyes. Coronavirus Disease 2019 (COVID-19): Emerging and Future Challenges for Dental and Oral Medicine
cord-334550-xb0alubj	2020	These include some ongoing mutations that can alter the virulence of the circulating SARS-CoV-2 strains, host factors like innate immunity, genetic diversity in immune responses, epigenetic factors, genetic polymorphisms of ACE2 receptors, micro RNAs and universal BCG vaccination, and environmental factors like high temperature and humidity which may alter the viability and transmissibility of the strain. Researchers from Translational Bioinformatics Group at International Center for Genetic Engineering and Biotechnology (ICGEB) in collaboration with the Department of Biochemistry, Jamia Hamdard, New Delhi, India, performed an integrated mutational analysis of SARS-CoV-2 genomes from different geographical locations, including India, Italy, United States, Nepal and Wuhan, and observed a novel mutation in S protein (A930V, 24351C>T) of the Indian strain, which was absent in other strains (Sardar et al., 2020) . While this apparent protection among Indians is largely attributed to non-heritable influences as discussed earlier, a safe and effective vaccine against SARS-CoV-2 can reduce disease severity, control transmission, and prevent future infections across all populations.
cord-338498-3238fz73	2020	Bacterial "new old friends" such as Bacille Calmette-Guérin (BCG) or Mycobacterium obuense have the ability to elevate basal systemic levels of type 1 cytokines and immune cells, correlating with increased protection against diverse and unrelated infectious agents, called "trained immunity." Here we describe dysfunctional immune responses induced by coronaviruses, representing potentially difficult to overcome obstacles to safe, effective vaccine development for COVID-19, and outline how trained immunity could help protect high risk populations through immunomodulation with BCG and other "new old friends." One recent example of the need for continued vigilance is a study using Chinese macaques indicating cause for concern by showing that vaccine-induced, S-specific immunity in the form of anti-spike IgG resulted in severe ALI by skewing macrophage responses during subsequent, acute infection with closely related SARS-CoV (139) .
cord-340532-fpmd9nzf	2020	Conclusions: Relying on a very large dataset and a wide array of control variables, our study confirms a strong and robust association between Covid-19 diffusion and mortality with BCG vaccination and a set socio-economic factors, opening new perspectives for clinical speculations and public health policies. In particular Tobit regressions, estimating both the impacts of covariates on the probability of a country reporting more than 100 cases as of April 17 th , and their effect on relative diffusion, was our preferred estimation method. Table 2 shows large and strongly significant effects for per capita gross domestic product and Human Freedom Index (positive) and for the summer season and BCG vaccination (negative), even controlling for more vaccinations. To the best of our knowledge, this is the first study assessing the impact of BCG vaccination on the diffusion and mortality of Covid-19 at the global level by controlling for a comprehensive set of social, economic, geographic and demographic variables.
cord-342847-sjcanw19	2008	Using this approach, in tandem with DNA resequencing, we have identified six novel large sequence polymorphisms including four deletions and two duplications in specific BCG strains. Importantly, these polymorphisms affect genes encoding established virulence factors including cell wall complex lipids, ESX secretion systems, and the PhoP-PhoR two-component system. Our study demonstrates that major virulence factors are different among BCG strains, which provide molecular mechanisms for important vaccine phenotypes including adverse effect profile, tuberculin reactivity and protective efficacy. Subsequent analyses of multiple vaccine strains have uncovered extensive genome diversity including both deletions and duplications in BCG substrains [18, [20] [21] [22] . We have used NimbleGen tiling arrays to analyze the genomic variability of 13 BCG strains, including BCG-Russia, -Japan, -Moreau, -Sweden, -Birkhaug, -China, -Prague, -Glaxo, -Danish, -Tice, -Phipps, -Frappier and -Pasteur. Our sequence analysis revealed a number of polymorphisms in the phoP-phoR locus in various BCG strains compared to the genome sequence of M.
cord-344553-uya1j94u	2020	In this study, we ascertain the associations between BCG vaccination policies and progression of COVID-19 through analysis of various time-adjusted indicators either directly extracted from the incidence and death reports, or estimated as parameters of disease progression models. The associations between BCG vaccination policy and COVID-19 disease progression have also been a subject to controversy in data analysis, with some studies claiming significant effects on the number of cases and case fatality rates (Miller et al., 2020; Berg et al., 2020) , while others criticizing weaknesses of those studies and claiming no statistically significant differences (Szigeti et al., 2020; Hensel et al., 2020; Fukui et al., 2020; Singh, 2020) . In this study, we have estimated a variety of indicators characteristic for different stages of COVID-19 epidemics, also adjusting for time since the beginning of the epidemics in each country, and found that several key indicators show weak, but statistically significant, associations with BCG vaccination status.
cord-345114-b06uz0sj	2020	The analysis of countries according to an age-group partition reveals that the strongest correlation is attributed to the coverage in BCG vaccination of the young population (0–24 years). Due to the varying effect of each age group on the viral spread in the population, we next investigated the relevance of age groups to the observation showing that years of BCG administration are strongly correlated with better COVID-19 outcomes. Due to the varying effect of each age group on the viral spread in the population, we next investigated the relevance of age groups to the observation showing that years of BCG administration are strongly correlated with better COVID-19 outcomes. The histogram (d-f) shows the statistical significance of the correlation of BCG years of administration for the 4 different COVID-19 outcomes according to the 3 age groups marked as: young (d) middle age (e) and elderly (f).
cord-350103-liwvhuzj	2020	OBJECTIVES: To summarize the available literature regarding bacillus Calmette‐Guerin (BCG) administration, severe acute respiratory syndrome conoravirus‐2 (SARS‐CoV‐2), and the resulting clinical condition coronavirus disease (COVID‐19) in light of recent epidemiologic work suggesting decreased infection severity in BCG immunized populations while highlighting the potential role of the urologist in clinical trials and ongoing research efforts. Specifically, the epidemiologic evidence for decreased COVID‐19 morbidity in countries with BCG vaccination programs, current clinical trials for BCG vaccination to protect against COVID‐19, potential mechanisms and rationale for this protection, and the role of the urologist and urology clinic in providing support and/or leading ongoing efforts. 18 In both animal and human studies, BCG vaccination provides a non-specific benefit to the immune system, relative protection against, and reduced mortality from infections by other microbes (bacteria and viruses) which may occur by epigenetic reprogramming and induction of trained immunity.
cord-351002-msjurww1	2020	Results : Countries that never had universal BCG vaccination policy have a higher mortality (correlated to performed diagnostic tests) attributed to SARS-CoV-2 infection (p<0.001). Countries that never had universal BCG vaccination policy have a higher mortality (correlated to performed diagnostic tests) attributed to SARS-CoV-2 infection (p<0.001). For countries that started the BCG vaccination after 1960, countries with current policies have lower mortality attributed to SARS-CoV-2 infection than countries that have stopped immunization (p=0.047). For countries that started the BCG vaccination after 1960, countries with current policies have lower mortality attributed to SARS-CoV-2 infection than countries that have stopped immunization (p=0.047). Based on these observations, we hypothesized that countries which have an early start of universal BCG vaccination policy would have a reduced morbidity and mortality attributed to SARS-CoV-2 infection. Or results revealed that countries that never had universal BCG vaccination policy have a higher mortality (correlated to performed diagnostic tests) attributed to SARS-CoV-2 infection.
cord-354972-nc496v6s	2020	As of 8 August 2020, there have been over 1.2 million confirmed cases of COVID-19 in Africa, with 29,833 deaths reported (Africa CDC) There is concern that the pandemic may pose an even greater risk to countries in Africa owing to their weak health-care infrastructure, large burden of co-infections, including HIV-1 and tuberculosis, and ongoing outbreaks of emerging and re-emerging infections such as Ebola virus (Democratic Republic of Congo) and Lassa haemorrhagic fever (Nigeria) that will divert much-needed resources away from the fight against COVID-19 (ref. Given the optimistic development timeline of 12-18 months before any vaccines could be available for widespread use, it is clear that these efforts will not Box 1 | Potential impact of climate on SArS-coV-2 dissemination the comparatively low incidence of coronavirus disease-2019 (COviD19) in africa has raised the possibility that climate could influence the spread of severe acute respiratory syndrome coronavirus 2 (sars-Cov-2).
cord-355384-qa7grviy	2020	PURPOSE: Bacillus Calmette–Guerin (BCG) is a live attenuated vaccine with the potential of causing severe iatrogenic complications in patients with primary immunodeficiency diseases (PID) before and after hematopoietic stem cell transplantation (HSCT). Since BCG is a live attenuated vaccine, complication rates are significantly increased in immunodeficient individuals [3, [6] [7] [8] [9] [10] [11] , especially so in patients with T cell defects, mendelian susceptibility to mycobacterial disease (MSMD), or chronic granulomatous disease (CGD) [5] [6] [7] 11] , reflecting the main mechanisms of defense against mycobacteria. Thirty-six pediatric patients who underwent HSCT for phagocytic and T cell defects in Hadassah medical center between 2007 and 2019, and had received the BCG vaccine prior to transplant, were included in this study (Table 1) .
cord-355926-24z5lhet	2020	To explore this hypothesis, we assessed the correlation of COVID-19 burden at three different time points (14 April, 29 April, and 13 May 2020) with year-wise BCG coverage among the countries with universal BCG vaccination policy over past four decades . Out of 170 countries for which data on BCG vaccination and COVID-19 was available, we excluded 28 countries (<100 cases as on May 13, 2020). Among the countries with universal BCG vaccination policy (n-142), a weak but positive correlation (spearmen rho-0.1-0.5, p < 0.05) was observed between COVID-19 cases and deaths per million population and BCG vaccination coverage rates (Supplementary Table 1 ). We further explored the relationship by adjusting for covariates (age > 65 y, cardiovascular disease death rate, diabetes, GDP per capita, beds per thousand population, and the number of tests done per million population) and didn''t find any consistent and significant relationship between BCG vaccination rates and COVID-19 burden. These results suggest against any meaningful relationship between country''s BCG vaccination coverage and COVID-19 burden.