# pos

id: cord-300729-35meen0h
pos: NNP
token:
  https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-worldbank-country-and-lending-groups

lemma:
  https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-worldbank-country-and-lending-groups


id: cord-340532-fpmd9nzf
pos: NNP
token:
  https://www.who.int/docs/defaultsource/coronaviruse/situation-reports/20200417-sitrep-88-covid-191b6cccd94f8b4f219377bff55719a6ed.pdf?sfvrsn=ebe78315_6

lemma:
  https://www.who.int/docs/defaultsource/coronaviruse/situation-reports/20200417-sitrep-88-covid-191b6cccd94f8b4f219377bff55719a6ed.pdf?sfvrsn=ebe78315_6


id: cord-340532-fpmd9nzf
pos: NNP
token:
  https://www.cato.org/sites/cato.org/files/human-freedom-index-files/human-freedom-index-2018-revised.pdf

lemma:
  https://www.cato.org/sites/cato.org/files/human-freedom-index-files/human-freedom-index-2018-revised.pdf


id: cord-334550-xb0alubj
pos: NNP
token:
  https://www.indiatoday.in/india/story/wuhan-s-l-strainmay-be-behind-gujarat-s-high-death-rate-experts-1671346-2020-04-26

lemma:
  https://www.indiatoday.in/india/story/wuhan-s-l-strainmay-be-behind-gujarat-s-high-death-rate-experts-1671346-2020-04-26


# ent

id: cord-305264-0uhabgsr
type: LAW
entity:
  STATA 13 1 StataCorp College Station TX USA The Providence Community Health Centers Review Committee


id: cord-000153-134qz0aw
type: PROTEIN
entity:
  MKP 1 Stealth Select RNAi ratio 1 1 1 200 nM Invitrogen USA Stealth RNAi Negative Control Duplex 200


id: cord-294302-hboc3xcz
type: CELL_TYPE
entity:
  natural killers NK and dendritic cells activator 50 51 52 In 1985 Cioffi and colleagues reported that C parvum protects splenectomized Sprague Dawley rats


id: cord-271734-1cfhjuxi
type: PROTEIN
entity:
  anti guinea pig cell monoclonal antibodies 37 40 MSgp7 pan T marker antibodies CT6 putative T suppressor cell marker antibodies


id: cord-002058-rppsmirp
type: PROTEIN
entity:
  M bovis BCG chaperone protein DnaK DnaK 60 kDa chaperonin 1 Cpn60 1 glyceraldehyde 3 phosphate dehydrogenase GAPDH


id: cord-002058-rppsmirp
type: PROTEIN
entity:
  Helicobacter pylori Cpn60 1 60 kDa chaperonin 1 DC dendritic cell DC SIGN CD209 dendritic cell specific intercellular adhesion molecule 3


id: cord-005882-iodfgzjf
type: WORK_OF_ART
entity:
  Creating Incentives For Pharmaceutical Research on Neglected Diseases World Health Organization Global Atlas


id: cord-285306-leu2hygk
type: ORG
entity:
  Heterologous Protection of Neonatal BCG Vaccination Against Hospitalization Due to Respiratory Infection


id: cord-014712-5u4e00q6
type: ORG
entity:
  International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee


id: cord-014712-5u4e00q6
type: PERCENT
entity:
  2 1 Department of Pediatrics Division of Allergy Immunology Sakarya University Medical Faculty Adapazarı Türkiye 2 Department


id: cord-014712-5u4e00q6
type: ORG
entity:
  Goran Ristic Srdjan Pasic Bojana Slavkovic Division of Clinical Immunology Mother and Child Health Care Institute of Serbia


id: cord-014712-5u4e00q6
type: CHEMICAL
entity:
  N 6 chronic granulomatous disease CGD N 3 Xlinked lymphoproliferative disease XLP N 3 Whim syndrome N 1 hyper IgM


id: cord-334550-xb0alubj
type: CHEMICAL
entity:
  3067 SARS CoV 2 genomes reveals a clonal geo distribution and a rich genetic variations of hotspots mutations bioRxiv Vanilloid receptor 1 agonists capsaicin


id: cord-283603-d6ult65u
type: ORG
entity:
  BCG Induced Cross Protection and Development of Trained Immunity Implication for Vaccine Design Safety


id: cord-260826-1n96pz86
type: ORG
entity:
  the Chinese Center for Disease Control and Prevention Case Fatality Rate and Characteristics of Patients Dying in Relation to


id: cord-265472-b1s4stvz
type: CELL_LINE
entity:
  C3H HeJ mouse model Alopecia universalis in an adult after routine tetanus toxoid vaccine Telogen effluvium following bivalent human papillomavirus vaccine administration a report of two cases Acute onset madarosis following MMR vaccination Long term outcome of otherwise healthy individuals with incidentally discovered borderline thrombocytopenia Immune thrombocytopenic purpura ITP


id: cord-340532-fpmd9nzf
type: PRODUCT
entity:
  John s Hopkins Coronavirus Resource Center World Bank International Monetary Fund United Nations Human Freedom Report


id: cord-328262-hw8swbt5
type: GGP
entity:
  Rev Immunol DOI 10 1038 s41577 020 0337 y sha 22e2b04516fb11694e588124e849615311b27e5b doc_id 328262


id: cord-325966-0g7a9s5z
type: ORG
entity:
  Association of Treatment With Hydroxychloroquine or Azithromycin With In Hospital Mortality in Patients


id: cord-325966-0g7a9s5z
type: WORK_OF_ART
entity:
  A Trial of Lopinavir Ritonavir in Adults Hospitalized with Severe Covid 19 Efficacy and Safety of Ivermectin


id: cord-325966-0g7a9s5z
type: ORG
entity:
  Ebola Virus Infection Review of the Pharmacokinetic and Pharmacodynamic Properties of Drugs Considered for Testing in Human Efficacy Trials


# url

id: cord-340532-fpmd9nzf
domain: www.who.int
url:
  http://www.who.int/docs/defaultsource/coronaviruse/situation-reports/20200417-sitrep-88-covid-191b6cccd94f8b4f219377bff55719a6ed.pdf?sfvrsn=ebe78315_6


id: cord-340532-fpmd9nzf
domain: www.cato.org
url:
  http://www.cato.org/sites/cato.org/files/human-freedom-index-files/human-freedom-index-2018-revised.pdf


id: cord-300729-35meen0h
domain: datahelpdesk.worldbank.org
url:
  http://datahelpdesk.worldbank.org/knowledgebase/articles/906519-worldbank-country-and-lending-groups


id: cord-334550-xb0alubj
domain: www.indiatoday.in
url:
  http://www.indiatoday.in/india/story/wuhan-s-l-strainmay-be-behind-gujarat-s-high-death-rate-experts-1671346-2020-04-26


# bib

id: cord-000153-134qz0aw
title: A novel anti-mycobacterial function of mitogen-activated protein kinase phosphatase-1
author: Cheung, Benny KW
date: 2009-12-17
txt: ./txt/cord-000153-134qz0aw.txt
cache: ./cache/cord-000153-134qz0aw.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804704/
doi: 10.1186/1471-2172-10-64
summary:
  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 ).

abstract:
  BACKGROUND: Mycobacterium tuberculosis (MTB) is a major cause of morbidity and mortality in the world. To combat against this pathogen, immune cells release cytokines including tumor necrosis factor-α (TNF-α), which is pivotal in the development of protective granulomas. 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 phosphatase-1 (MKP-1) is known to regulate MAPK activities, we examined whether MKP-1 plays a role in BCG-induced MAPK activation and cytokine expression. RESULTS: Primary human blood monocytes were treated with BCG and assayed for MKP-1 expression. Our results demonstrated that following exposure to BCG, there was an increase in the expression of MKP-1. Additionally, the induction of MKP-1 was regulated by p38 MAPK and extracellular signal-regulated kinase 1 and 2 (ERK1/2). Surprisingly, when MKP-1 expression was blocked by its specific siRNA, there was a significant decrease in the levels of phospho-MAPK (p38 MAPK and ERK1/2) and TNF-α inducible by BCG. CONCLUSIONS: Since TNF-α is pivotal in granuloma formation, the results indicated an unexpected positive function of MKP-1 against mycobacterial infection as opposed to its usual phosphatase activity.


id: cord-002058-rppsmirp
title: Identification of four novel DC-SIGN ligands on Mycobacterium bovis BCG
author: Carroll, Maria V.
date: 2010-09-01
txt: ./txt/cord-002058-rppsmirp.txt
cache: ./cache/cord-002058-rppsmirp.txt
extension: .txt
mime: text/plain
url: https://link.springer.com/content/pdf/10.1007%2Fs13238-010-0101-3.pdf
doi: 10.1007/s13238-010-0101-3
summary:
  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.

abstract:
  Dendritic-cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN; CD209) has an important role in mediating adherence of Mycobacteria species, including M. tuberculosis and M. bovis BCG to human dendritic cells and macrophages, in which these bacteria can survive intracellularly. DC-SIGN is a C-type lectin, and interactions with mycobacterial cells are believed to occur via mannosylated structures on the mycobacterial surface. Recent studies suggest more varied modes of binding to multiple mycobacterial ligands. Here we identify, by affinity chromatography and mass-spectrometry, four novel ligands of M. bovis BCG that bind to DC-SIGN. The novel ligands are chaperone protein DnaK, 60 kDa chaperonin-1 (Cpn60.1), glyceraldehyde-3 phosphate dehydrogenase (GAPDH) and lipoprotein lprG. Other published work strongly suggests that these are on the cell surface. Of these ligands, lprG appears to bind DC-SIGN via typical proteinglycan interactions, but DnaK and Cpn60.1 binding do not show evidence of carbohydrate-dependent interactions. LprG was also identified as a ligand for DC-SIGNR (L-SIGN; CD299) and the M. tuberculosis orthologue of lprG has been found previously to interact with human toll-like receptor 2. Collectively, these findings offer new targets for combating mycobacterial adhesion and within-host survival, and reinforce the role of DCSIGN as an important host ligand in mycobacterial infection.


id: cord-003504-wjab4y0g
author: Copland, Alastair
date: 2019-03-06
txt: ./txt/cord-003504-wjab4y0g.txt
cache: ./cache/cord-003504-wjab4y0g.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403281/
doi: 10.1038/s41598-019-40145-0
summary:
  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

title:
  Bacillus Calmette-Guérin Induces PD-L1 Expression on Antigen-Presenting Cells via Autocrine and Paracrine Interleukin-STAT3 Circuits

abstract:
  Bacillus Calmette-Guérin (BCG) is the only licensed vaccine for tuberculosis (TB), and is also used as an immunotherapy for bladder cancer and other malignancies due to its immunostimulatory properties. Mycobacteria spp., however, are well known for their numerous immune evasion mechanisms that limit the true potential of their therapeutic use. One such major mechanism is the induction of programmed death ligand-1 (PD-L1), which mitigates adaptive immune responses. Here, we sought to unravel the molecular pathways behind PD-L1 up-regulation on antigen-presenting cells (APCs) by BCG. We found that infection of APCs with BCG induced PD-L1 up-regulation, but that this did not depend on direct infection, suggesting a soluble mediator for this effect. BCG induced potent quantities of IL-6 and IL-10, and the downstream transcription factor STAT3 was hyper-phosphorylated. Intracellular analyses revealed that levels of PD-L1 molecules were associated with the STAT3 phosphorylation state, suggesting a causal link. Neutralisation of the IL-6 or IL-10 cytokine receptors dampened STAT3 phosphorylation and BCG-mediated up-regulation of PD-L1 on APCs. Pharmacological inhibition of STAT3 achieved the same effect, confirming an autocrine-paracrine cytokine loop as a mechanism for BCG-mediated up-regulation of PD-L1. Finally, an in vivo immunisation model showed that BCG vaccination under PD-L1 blockade could enhance antigen-specific memory CD4 T-cell responses. These novel findings could lead to refinement of BCG as both a vaccine for infectious disease and as a cancer immunotherapy.


id: cord-005882-iodfgzjf
title: Annulling a dangerous liaison: vaccination strategies against AIDS and tuberculosis
author: Kaufmann, Stefan H E
date: 2005-04-05
txt: ./txt/cord-005882-iodfgzjf.txt
cache: ./cache/cord-005882-iodfgzjf.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095892/
doi: 10.1038/nm1221
summary:
  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.

abstract:
  Human immunodeficiency virus (HIV) and Mycobacterium tuberculosis annually cause 3 million and 2 million deaths, respectively. Last year, 600,000 individuals, doubly infected with HIV and M. tuberculosis, died. Since World War I, approximately 150 million people have succumbed to these two infections—more total deaths than in all wars in the last 2,000 years. Although the perceived threats of new infections such as SARS, new variant Creutzfeldt-Jakob disease and anthrax are real, these outbreaks have caused less than 1,000 deaths globally, a death toll AIDS and tuberculosis exact every 2 h. In 2003, 40 million people were infected with HIV, 2 billion with M. tuberculosis, and 15 million with both. Last year, 5 million and 50 million were newly infected with HIV or M. tuberculosis, respectively, with 2 million new double infections. Better control measures are urgently needed.


id: cord-014712-5u4e00q6
title: Selected Abstracts from the 100th J Project Meeting, Antalya, Turkey, March 12-14, 2014
author: nan
date: 2014-08-02
txt: ./txt/cord-014712-5u4e00q6.txt
cache: ./cache/cord-014712-5u4e00q6.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086544/
doi: 10.1007/s10875-014-0065-9
abstract: nan
summary:
  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.


id: cord-018737-1h84yi2i
author: Kumar, Sudeep
date: 2019-01-10
txt: ./txt/cord-018737-1h84yi2i.txt
cache: ./cache/cord-018737-1h84yi2i.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7123696/
doi: 10.1007/978-3-030-01881-8_2
summary:
  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

title:
  Live-Attenuated Bacterial Vectors for Delivery of Mucosal Vaccines, DNA Vaccines, and Cancer Immunotherapy

abstract:
  Vaccines save millions of lives each year from various life-threatening infectious diseases, and there are more than 20 vaccines currently licensed for human use worldwide. Moreover, in recent decades immunotherapy has become the mainstream therapy, which highlights the tremendous potential of immune response mediators, including vaccines for prevention and treatment of various forms of cancer. However, despite the tremendous advances in microbiology and immunology, there are several vaccine preventable diseases which still lack effective vaccines. Classically, weakened forms (attenuated) of pathogenic microbes were used as vaccines. Although the attenuated microbes induce effective immune response, a significant risk of reversion to pathogenic forms remains. While in the twenty-first century, with the advent of genetic engineering, microbes can be tailored with desired properties. In this review, I have focused on the use of genetically modified bacteria for the delivery of vaccine antigens. More specifically, the live-attenuated bacteria, derived from pathogenic bacteria, possess many features that make them highly suitable vectors for the delivery of vaccine antigens. Bacteria can theoretically express any heterologous gene or can deliver mammalian expression vectors harboring vaccine antigens (DNA vaccines). These properties of live-attenuated microbes are being harnessed to make vaccines against several infectious and noninfectious diseases. In this regard, I have described the desired features of live-attenuated bacterial vectors and the mechanisms of immune responses manifested by live-attenuated bacterial vectors. Interestingly anaerobic bacteria are naturally attracted to tumors, which make them suitable vehicles to deliver tumor-associated antigens thus I have discussed important studies investigating the role of bacterial vectors in immunotherapy. Finally, I have provided important discussion on novel approaches for improvement and tailoring of live-attenuated bacterial vectors for the generation of desired immune responses.


id: cord-024716-1waejlwb
title: Does the Bacillus Calmette–Guérin vaccine provide protection from COVID-19?
author: Roy, Soumya
date: 2020-04-30
txt: ./txt/cord-024716-1waejlwb.txt
cache: ./cache/cord-024716-1waejlwb.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217267/
doi: 10.25259/ijms_37_2020
summary:
  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.

abstract:
  OBJECTIVE: The novel coronavirus pandemic is ravaging throughout the world. It has infected more than 1.2 million people and killed more than 64,000. Frantic research is underway to find prevention and cure. Of late, Bacillus Calmette–Guérin (BCG) has been speculated as a possible protection from COVID-19. We sought to investigate the evidence behind the claim. MATERIAL AND METHODS: Data were collected regarding the total number of COVID-19 cases per million and total number of COVID-19 deaths per million in various countries. The BCG vaccination policies of these countries were also obtained. RESULTS: It was seen that the countries with no universal BCG policy had a mean 1272.9 (median 795) cases per million and 80.7 deaths (median 18) per million population. On the contrary, the countries with a universal BCG vaccination policy had a mean 131.2 (median 40) cases per million and 4 deaths (median 1) per population. The difference is highly significant (P < 0.001). CONCLUSION: The data strongly support the hypothesis that BCG may offer protection from COVID-19. 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 cross- protection against the novel coronavirus.


id: cord-208177-m8q6dyfx
author: Chaisemartin, Cl''ement de
date: 2020-06-08
txt: ./txt/cord-208177-m8q6dyfx.txt
cache: ./cache/cord-208177-m8q6dyfx.txt
extension: .txt
mime: text/plain
url: https://arxiv.org/pdf/2006.05504v2.pdf
doi: nan
summary:
  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.

title:
  BCG vaccination in infancy does not protect against COVID-19. Evidence from a natural experiment in Sweden

abstract:
  The Bacille Calmette-Gu'erin (BCG) tuberculosis vaccine has immunity benefits against respiratory infections. Accordingly, it has been hypothesized that it may have a protective effect against COVID-19. Recent research found that countries with universal Bacillus Calmette-Gu'erin (BCG) childhood vaccination policies tend to be less affected by the COVID-19 pandemic. However, such ecological studies are biased by numerous confounders. 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. Numbers of COVID-19 cases and hospitalizations were recorded for birth cohorts born just before and just after that change, representing 1,026,304 and 1,018,544 individuals, respectively. We used regression discontinuity to assess the effect of BCG vaccination on Covid-19 related outcomes. This method used on such a large population allows for a high precision that would be hard to achieve using a classical randomized controlled trial. The odds ratio for Covid-19 cases and Covid-19 related hospitalizations were 0.9997 (CI95: [0.8002-1.1992]) and 1.1931 (CI95: [0.7558-1.6304]), respectively. We can thus reject with 95% confidence that universal BCG vaccination reduces the number of cases by more than 20% and the number of hospitalizations by more than 24%. While the effect of a recent vaccination must be evaluated, we provide strong evidence that receiving the BCG vaccine at birth does not have a protective effect against COVID-19.


id: cord-252855-xtsnlu1f
title: Lactoferrin: Balancing Ups and Downs of Inflammation Due to Microbial Infections
author: Drago-Serrano, Maria Elisa
date: 2017-03-01
txt: ./txt/cord-252855-xtsnlu1f.txt
cache: ./cache/cord-252855-xtsnlu1f.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/28257033/
doi: 10.3390/ijms18030501
summary:
  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] .

abstract:
  Lactoferrin (Lf) is a glycoprotein of the primary innate immune-defense system of mammals present in milk and other mucosal secretions. This protein of the transferrin family has broad antimicrobial properties by depriving pathogens from iron, or disrupting their plasma membranes through its highly cationic charge. Noteworthy, Lf also exhibits immunomodulatory activities performing up- and down-regulation of innate and adaptive immune cells, contributing to the homeostasis in mucosal surfaces exposed to myriad of microbial agents, such as the gastrointestinal and respiratory tracts. Although the inflammatory process is essential for the control of invasive infectious agents, the development of an exacerbated or chronic inflammation results in tissue damage with life-threatening consequences. 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. Thus, this new knowledge of Lf immunomodulation paves the way to more effective design of treatments that include native or synthetic Lf derivatives, which may be useful to reduce immune-mediated tissue damage in infectious diseases.


id: cord-256642-payjduek
title: Measles infection causing Bacillus Calmette-Guérin reactivation: a case report
author: Muthuvelu, Sobana
date: 2019-07-24
txt: ./txt/cord-256642-payjduek.txt
cache: ./cache/cord-256642-payjduek.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/31340782/
doi: 10.1186/s12887-019-1635-z
summary:
  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.

abstract:
  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). We report the unusual finding of BCG reactivation in an infant with laboratory-confirmed measles. CASE PRESENTATION: A previously healthy 7-month old infant presented initially with fever, cough and coryza, and subsequently developed Koplik’s spots followed by a typical morbilliform skin rash. There was significant contact history with a household relative who had recently been diagnosed with measles. On examination, a 2.5 cm area of erythema and induration was seen at the previous BCG inoculation site, in addition to the widespread maculopapular rash. No other clinical features of KD were present. Measles virus was isolated from the throat swab and measles antibodies (IgM) were present in the serum. The patient recovered completely with oral vitamin A and supportive therapy, and had normal echocardiography examination on follow up. 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.


id: cord-258742-li71b9e0
title: Covid-19 Epidemiological Factor Analysis: Identifying Principal Factors with Machine Learning
author: Dolgikh, S.
date: 2020-06-05
txt: ./txt/cord-258742-li71b9e0.txt
cache: ./cache/cord-258742-li71b9e0.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.06.01.20119560
doi: 10.1101/2020.06.01.20119560
summary:
  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.

abstract:
  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 consistent conclusion of the analysis with the available data is that apart from the policy and management quality, being the dominant factor, the most influential factors among the considered were current or recent universal BCG immunization and the prevalence of smoking.


id: cord-258877-6hy37qxa
title: Covid-19 vs BCG Universal Immunization: Statistical Significance at Six Months of Exposure
author: Dolgikh, S.
date: 2020-09-08
txt: ./txt/cord-258877-6hy37qxa.txt
cache: ./cache/cord-258877-6hy37qxa.txt
extension: .txt
mime: text/plain
url: http://medrxiv.org/cgi/content/short/2020.09.06.20189423v1?rss=1
doi: 10.1101/2020.09.06.20189423
summary:
  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.

abstract:
  With a time-adjusted dataset of Covid-19 statistical data by reporting jurisdiction at the time point of six months after the local epidemics landfall we perform a statistical analysis of the significance of the correlation hypothesis between universal BCG immunization and milder Covid-19 scenarios proposed in the earlier studies. With the data accumulated to date the statistical significance of the BCG immunization correlation hypothesis is evaluated both qualitatively and quantitatively with the conclusion that it has achieved a significant level of confidence. The conclusions of this research can be used in public policy as well as the rationale to investigate the nature and working of a potential broad immunity mechanism associated with an early-age BCG exposure.


id: cord-260826-1n96pz86
title: Differential COVID-19-attributable mortality and BCG vaccine use in countries
author: Shet, Anita
date: 2020-04-06
txt: ./txt/cord-260826-1n96pz86.txt
cache: ./cache/cord-260826-1n96pz86.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.04.01.20049478
doi: 10.1101/2020.04.01.20049478
summary:
  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).

abstract:
  While mortality attributable to COVID-19 has devastated global health systems and economies, striking regional differences have been observed. The Bacille Calmette Guerin (BCG) vaccine has previously been shown to have non-specific protective effects on infections, as well as long-term efficacy against tuberculosis. 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. The timing of country entry into the pandemic epidemiological trajectory was aligned by plotting time since the 100th reported case. Countries with economies classified as lower-middle-income, upper-middle-income and high-income countries (LMIC, UMIC, HIC) had median crude COVID-19 log-mortality of 0.4 (Interquartile Range (IQR) 0.1, 0.4), 0.7 (IQR 0.2, 2.2) and 5.5 (IQR 1.6, 13.9), respectively. COVID-19-attributable mortality among BCG-using countries was 5.8 times lower [95% CI 1.8-19.0] than in non BCG-using countries. 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.


id: cord-263455-dquztf5l
author: Schoenmakers, Anne
date: 2020-10-15
txt: ./txt/cord-263455-dquztf5l.txt
cache: ./cache/cord-263455-dquztf5l.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.2147/rrtm.s190300
doi: 10.2147/rrtm.s190300
summary:
  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)

title:
  The State of Affairs in Post-Exposure Leprosy Prevention: A Descriptive Meta-Analysis on Immuno- and Chemo-Prophylaxis

abstract:
  OBJECTIVE: Annually, over 200,000 people are diagnosed with leprosy, also called Hansen’s disease. This number has been relatively stable over the past years. Progress has been made in the fields of chemoprophylaxis and immunoprophylaxis to prevent leprosy, with a primary focus on close contacts of patients. In this descriptive meta-analysis, we summarize the evidence and identify knowledge gaps regarding post-exposure prophylaxis against leprosy. METHODS: A systematic literature search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was conducted by searching the medical scientific databases Cochrane, Embase, Pubmed/MEDLINE, Research Gate, Scopus and Web of Science on Jan. 22, 2020, using a combination of synonyms for index terms in four languages: “leprosy” and “population” or “contacts” and “prevention” or “prophylaxis.” Subsequently, Infolep.org and Google Scholar were searched and the "snowball method" was used to retrieve other potentially relevant literature. The found articles were screened for eligibility using predetermined inclusion and exclusion criteria. RESULTS: After deduplication, 1,515 articles were screened, and 125 articles were included in this descriptive meta-analysis. Immunoprophylaxis by bacillus Calmette-Guérin (BCG) vaccination is known to provide protection against leprosy. The protection it offers is higher in household contacts of leprosy patients compared with the general population and is seen to decline over time. Contact follow-up screening is important in the first period after BCG administration, as a substantial number of new leprosy patients presents three months post-vaccination. Evidence for the benefit of re-vaccination is conflicting. The World Health Organization (WHO) included BCG in its Guidelines for the Diagnosis, Treatment and Prevention of Leprosy by stating that BCG at birth should be maintained in at least all leprosy high-burden regions. Literature shows that several vaccination interventions with other immunoprophylactic agents demonstrate similar or slightly less efficacy in leprosy risk reduction compared with BCG. However, most of these studies do not exclusively focus on post-exposure prophylaxis. Two vaccines are considered future candidates for leprosy prophylaxis: Mycobacterium indicus pranii (MiP) and LepVax. For chemoprophylaxis, trials were performed with dapsone/acedapsone, rifampicin, and ROM, a combination of rifampicin, ofloxacin, and minocycline. Single-dose rifampicin is favored as post-exposure prophylaxis, abbreviated as SDR-PEP. It demonstrated a protective effect of 57% in the first two years after administration to contacts of leprosy patients. It is inexpensive, and adverse events are rare. The risk of SDR-PEP inducing rifampicin resistance is considered negligible, but continuous monitoring in accordance with WHO policies should be encouraged. The integration of contact screening and SDR-PEP administration into different leprosy control programs was found to be feasible and well accepted. Since 2018, SDR-PEP is included in the WHO Guidelines for the Diagnosis, Treatment and Prevention of Leprosy. CONCLUSION: Progress has been made in the areas of chemoprophylaxis and immunoprophylaxis to prevent leprosy in contacts of patients. Investing in vaccine studies, like LepVax and MiP, and increasing harmonization between tuberculosis (TB) and leprosy research groups is important. SDR-PEP is promising as a chemoprophylactic agent, and further implementation should be promoted. 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. Additionally, both leprosy prophylactic drug registration nationally and prophylactic drug availability globally at low or no cost are important for the implementation and further upscaling of preventive measures against leprosy, such as SDR-PEP and new vaccines.


id: cord-265472-b1s4stvz
title: Vaccines, adjuvants and autoimmunity
author: Guimarães, Luísa Eça
date: 2015-10-31
txt: ./txt/cord-265472-b1s4stvz.txt
cache: ./cache/cord-265472-b1s4stvz.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S1043661815001711
doi: 10.1016/j.phrs.2015.08.003
summary:
  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)

abstract:
  Abstract Vaccines and autoimmunity are linked fields. Vaccine efficacy is based on whether host immune response against an antigen can elicit a memory T-cell response over time. Although the described side effects thus far have been mostly transient and acute, vaccines are able to elicit the immune system towards an autoimmune reaction. The diagnosis of a definite autoimmune disease and the occurrence of fatal outcome post-vaccination have been less frequently reported. Since vaccines are given to previously healthy hosts, who may have never developed the disease had they not been immunized, adverse events should be carefully accessed and evaluated even if they represent a limited number of occurrences. In this review of the literature, there is evidence of vaccine-induced autoimmunity and adjuvant-induced autoimmunity in both experimental models as well as human patients. Adjuvants and infectious agents may exert their immune-enhancing effects through various functional activities, encompassed by the adjuvant effect. These mechanisms are shared by different conditions triggered by adjuvants leading to the autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). 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. Despite this, efforts to unveil the connection between the triggering of the immune system by adjuvants and the development of autoimmune conditions should be undertaken. Vaccinomics is a field that may bring to light novel customized, personalized treatment approaches in the future.


id: cord-266549-g8060w8v
author: Gkentzi, Despoina
date: 2020-06-05
txt: ./txt/cord-266549-g8060w8v.txt
cache: ./cache/cord-266549-g8060w8v.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1097/inf.0000000000002713
doi: 10.1097/inf.0000000000002713
abstract: nan
summary:
  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.

title:
  Challenges for the Pediatricians During the Coronavirus Disease 2019 Pandemic Start From the Neonatal Period


id: cord-270675-37kus7mz
author: Aziz, Asma Binte
date: 2020-07-09
txt: ./txt/cord-270675-37kus7mz.txt
cache: ./cache/cord-270675-37kus7mz.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S2590053620300744?v=s5
doi: 10.1016/j.bsheal.2020.07.001
summary:
  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.

title:
  Debate on Bacille Calmette-Guérin vaccination against COVID-19: Is it worth performing clinical trials?

abstract:
  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. This study thus aims to evaluate whether it is worth performing clinical trials to examine the effects of the BCG vaccine on COVID-19. We herein emphasize the need to conduct phase III randomized controlled trials with an adequate sample size and quality to investigate the effects of the BCG vaccine on COVID-19. In the event that BCG vaccination provides non-specific protection against COVID-19, administering it could be helpful in controlling the transmission of COVID-19 and other infectious diseases during future pandemics.


id: cord-271734-1cfhjuxi
author: Vergkizi, Souzan
date: 2020-10-16
txt: ./txt/cord-271734-1cfhjuxi.txt
cache: ./cache/cord-271734-1cfhjuxi.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0264410X20312846
doi: 10.1016/j.vaccine.2020.10.009
summary:
  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.

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

abstract:
  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.


id: cord-276351-cv5th7hd
author: Moorlag, Simone J.C.F.M.
date: 2020-08-05
txt: ./txt/cord-276351-cv5th7hd.txt
cache: ./cache/cord-276351-cv5th7hd.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.xcrm.2020.100073
doi: 10.1016/j.xcrm.2020.100073
summary:
  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.

title:
  Safety and COVID-19 symptoms in individuals recently vaccinated with BCG: a retrospective cohort study

abstract:
  Summary Bacille Calmette-Guérin (BCG) induces long-term boosting of innate immunity, termed trained immunity, and decreases susceptibility to respiratory tract infections. 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. BCG vaccination is not associated with increased incidence of symptoms during the COVID-19 outbreak in the Netherlands. Our data suggest that BCG vaccination might be associated with a decrease in the incidence of sickness during the COVID-19 pandemic (AOR 0.58, P < 0.05), and lower incidence of extreme fatigue. 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.


id: cord-276495-q22jnkn2
title: Trained innate immunity, COVID-19 therapeutic dilemma, and fake science
author: Belizário, José Ernesto
date: 2020-07-06
txt: ./txt/cord-276495-q22jnkn2.txt
cache: ./cache/cord-276495-q22jnkn2.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32667492/
doi: 10.6061/clinics/2020/e2124
abstract: nan
summary:
  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) .


id: cord-278417-ty4wbtkv
title: Timelines of COVID-19 Vaccines
author: Chugh, Tulsi
date: 2020-07-21
txt: ./txt/cord-278417-ty4wbtkv.txt
cache: ./cache/cord-278417-ty4wbtkv.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32839724/
doi: 10.1016/j.cmrp.2020.07.009
abstract: nan
summary:
  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?


id: cord-279620-ckh4uke6
title: The Imperative of Early Treatment for Children With COVID-19 Infection
author: Elenga, Narcisse
date: 2020-04-30
txt: ./txt/cord-279620-ckh4uke6.txt
cache: ./cache/cord-279620-ckh4uke6.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32358228/
doi: 10.1007/s13312-020-1871-1
abstract: nan
summary:
  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] .


id: cord-281354-sa27k8o3
author: Takahashi, Harutaka
date: 2020-08-26
txt: ./txt/cord-281354-sa27k8o3.txt
cache: ./cache/cord-281354-sa27k8o3.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0306987720325305?v=s5
doi: 10.1016/j.mehy.2020.110214
summary:
  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).

title:
  Role of Latent Tuberculosis Infections in Reduced COVID-19 Mortality: Evidence from an Instrumental Variable Method Analysis

abstract:
  Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, there has been significant interest in the potential protective effect of the Bacillus Calmette-Guerin (BCG) vaccine against COVID-19 mortality. This effect has been attributed to innate immune responses induced by BCG vaccination. 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. Thus, both LTBI and BCG induce lifelong immunity and may provide immunological protection against COVID-19. In this study, the relationship between LTBI and reduced COVID-19 mortality was analyzed using the instrumental variable method. The results showed with robust statistical support that LTBI was also associated with reduced COVID-19 mortality.


id: cord-283603-d6ult65u
title: Lessons from Bacillus Calmette-Guérin: Harnessing Trained Immunity for Vaccine Development
author: Pasco, Samuel T.
date: 2020-09-16
txt: ./txt/cord-283603-d6ult65u.txt
cache: ./cache/cord-283603-d6ult65u.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32948003/
doi: 10.3390/cells9092109
summary:
  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] .

abstract:
  Vaccine design traditionally focuses on inducing adaptive immune responses against a sole target pathogen. Considering that many microbes evade innate immune mechanisms to initiate infection, and in light of the discovery of epigenetically mediated innate immune training, the paradigm of vaccine design has the potential to change. 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. This review will explore BCG-induced trained immunity, including the required pathways to establish this phenotype. Additionally, potential methods to improve or expand BCG trained immunity effects through alternative vaccine delivery and formulation methods will be discussed. Finally, advances in new anti-Mtb vaccines, other antimicrobial uses for BCG, and “innate memory-based vaccines” will be examined.


id: cord-285306-leu2hygk
author: Gallagher, J.
date: 2020-06-05
txt: ./txt/cord-285306-leu2hygk.txt
cache: ./cache/cord-285306-leu2hygk.txt
extension: .txt
mime: text/plain
url: http://medrxiv.org/cgi/content/short/2020.06.03.20121624v1?rss=1
doi: 10.1101/2020.06.03.20121624
summary:
  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.

title:
  Association of Bacille Calmette-Guerin (BCG), Adult Pneumococcal and Adult Seasonal Influenza Vaccines with Covid-19 Adjusted Mortality Rates in Level 4 European countries

abstract:
  Introduction Non-specific effects of vaccines have gained increasing interest during the Covid-19 pandemic. In particular, population use of BCG vaccine has been associated with improved outcomes. This study sought to determine the association of population use of BCG, adult pneumococcal and adult seasonal influenza vaccination with Covid-19 mortality when adjusted for a number of confounding variables. Methods: Using publicly available data, mortality adjusted for the timeframe of crisis, population size and population characteristics was calculated. The primary analysis was the relationship between each of the day 15 and day 30 standardised mortality rates and BCG, adult pneumococcal and influenza vaccination scores using unadjusted measures and with adjustment for population structure and case fatality rates. Secondary analyses were measures of case increases and mortality increases from day 15 to day 30 for each of the relative vaccination scores. 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. In the best fit model, BCG vaccination score was associated with a 64% reduction in log(10) mortality per 10 million population (OR 0.362 reduction [95% CI 0.188 to 0.698]), following adjustment for population size, median age, density, urbanization, elderly dependency ratio, days to lockdown, yearly migration and case fatality rate. Conclusion BCG vaccine was associated with reduced mortality rates in level 4 countries while adult pneumococcal and adult seasonal influenza vaccines were not when adjusted for a number of confounding variables. A number of trials are ongoing to determine if BCG is protective against severe Covid-19 infection.


id: cord-288618-01hxgcds
title: Rapid characterization of the propagation of COVID-19 in different countries
author: Vargas, P.
date: 2020-06-11
txt: ./txt/cord-288618-01hxgcds.txt
cache: ./cache/cord-288618-01hxgcds.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.06.09.20126631
doi: 10.1101/2020.06.09.20126631
summary:
  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.

abstract:
  BACKGROUND COVID-19 has spread rapidly, and there are still many characteristics of this new disease to be unveiled. We propose a simple method to calculate a figure of merit FC to provide an early characterization of the disease status in country C. METHODS We use mathematical tools to adjust a Gaussian function to the daily increase of infected patients. Maximum value and full width half maximum of the Gaussian are characteristics of the development of the development of the pandemic in each country. These parameters are supplemented by the testing volume and the mortality rate to produce just one characterizing parameter: FC. In addition, the stability of the Gaussian fits was calculated within an entire week towards the end of the study period. Seventeen different countries were fully considered, while others are considered when discussing particular properties. Data employed is publically available. FINDINGS Fitted Gaussian functions render effective information about the development of COVID-19. The number of critical days vary between 11 (South Korea) and 52 (Mexico). FC varies between 1 (Australia) and 899 (Mexico). The epidemic appears stabilized in some countries and unstable in others. Some large countries are experiencing fast development of the propagation of the disease with high FC. A correlation between low (high) values of the mortality rate (and to some extent FC) and the presence (absence) of BCG vaccination is exposed. 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. Testing plays a clear role to control the spread of the disease. Mortality rate spans more than one order of magnitude and is somewhat related to permanent massive BCG vaccination. The figure of merit, FC, introduced here spans more than 2 orders of magnitude which makes it a useful indicator to quickly find out the status of the pandemics in each territory. Geography plays a role: low population density and isolated countries can be efficient in controlling the spread of the disease.


id: cord-289008-c4cu3vrp
author: Wallis, Christopher J.D.
date: 2020-05-03
txt: ./txt/cord-289008-c4cu3vrp.txt
cache: ./cache/cord-289008-c4cu3vrp.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0302283820303316?v=s5
doi: 10.1016/j.eururo.2020.04.063
summary:
  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] .

title:
  Risks from Deferring Treatment for Genitourinary Cancers: A Collaborative Review to Aid Triage and Management During the COVID-19 Pandemic

abstract:
  CONTEXT: The coronavirus disease 2019 (COVID-19) pandemic is leading to delays in the treatment of many urologic cancers. OBJECTIVE: To provide a contemporary picture of the risks from delayed treatment for urologic cancers to assist with triage. EVIDENCE ACQUISITION: A collaborative review using literature published as of April 2, 2020. EVIDENCE SYNTHESIS: Patients with low-grade non–muscle-invasive bladder cancer are unlikely to suffer from a 3–6-month delay. 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. Prioritization of these patients for surgery or management with radiochemotherapy is encouraged. Active surveillance should be used for low-risk prostate cancer (PCa). Treatment of most patients with intermediate- and high-risk PCa can be deferred 3–6 mo without change in outcomes. The same may be true for cancers with the highest risk of progression. With radiotherapy, neoadjuvant androgen deprivation therapy (ADT) is the standard of care. For surgery, although the added value of neoadjuvant ADT is questionable, it may be considered if a patient is interested in such an approach. Intervention may be safely deferred for T1/T2 renal masses, while locally advanced renal tumors (≥T3) should be treated expeditiously. Patients with metastatic renal cancer may consider vascular endothelial growth factor targeted therapy over immunotherapy. Risks for delay in the treatment of upper tract urothelial cancer depend on grade and stage. For patients with high-grade disease, delays of 12 wk in nephroureterectomy are not associated with adverse survival outcomes. Expert guidance recommends expedient local treatment of testis cancer. In penile cancer, adverse outcomes have been observed with delays of ≥3 mo before inguinal lymphadenectomy. Limitations include a paucity of data and methodologic variations for many cancers. CONCLUSIONS: Patients and clinicians should consider the oncologic risk of delayed cancer intervention versus the risks of COVID-19 to the patient, treating health care professionals, and the health care system. PATIENT SUMMARY: The coronavirus disease 2019 pandemic has led to delays in the treatment of patients with urologic malignancies. Based on a review of the literature, patients with high-grade urothelial carcinoma, advanced kidney cancer, testicular cancer, and penile cancer should be prioritized for treatment during these challenging times.


id: cord-289742-1usxeo9a
title: Immunometabolic control of trained immunity
author: Riksen, Niels P.
date: 2020-09-02
txt: ./txt/cord-289742-1usxeo9a.txt
cache: ./cache/cord-289742-1usxeo9a.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.mam.2020.100897
doi: 10.1016/j.mam.2020.100897
summary:
  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.

abstract:
  Innate immune cells can adopt long-term inflammatory phenotypes following brief encounters with exogenous (microbial) or endogenous stimuli. This phenomenon is named trained immunity and can improve host defense against (recurrent) infections. In contrast, trained immunity can also be maladaptive in the context of chronic inflammatory disorders, such as atherosclerosis. Key to future therapeutic exploitation of this mechanism is thorough knowledge of the mechanisms driving trained immunity, which can be used as pharmacological targets. These mechanisms include profound changes in intracellular metabolism, which are closely intertwined with epigenetic reprogramming at the level of histone modifications. Glycolysis, glutamine replenishment of the tricarboxylic acid cycle with accumulation of fumarate, and the mevalonate pathway have all been identified as critical pathways for trained immunity in monocytes and macrophages. In this review, we provide a state-of-the-art overview of how these metabolic pathways interact with epigenetic programs to develop trained immunity.


id: cord-291719-1ku6cmwj
author: Hajjo, Rima
date: 2020-10-06
txt: ./txt/cord-291719-1ku6cmwj.txt
cache: ./cache/cord-291719-1ku6cmwj.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33025261/
doi: 10.1007/s11095-020-02930-9
summary:
  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) .

title:
  A Systems Biology Workflow for Drug and Vaccine Repurposing: Identifying Small-Molecule BCG Mimics to Reduce or Prevent COVID-19 Mortality

abstract:
  PURPOSE: Coronavirus disease 2019 (COVID-19) is expected to continue to cause worldwide fatalities until the World population develops ‘herd immunity’, or until a vaccine is developed and used as a prevention. Meanwhile, there is an urgent need to identify alternative means of antiviral defense. Bacillus Calmette–Guérin (BCG) vaccine that has been recognized for its off-target beneficial effects on the immune system can be exploited to boast immunity and protect from emerging novel viruses. 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. We have identified small-molecule BCG mimics, including antiviral drugs such as raltegravir and lopinavir as high confidence hits. Strikingly, our top hits emetine and lopinavir were independently validated by recent experimental findings that these compounds inhibit the growth of SARS-CoV-2 in vitro. CONCLUSIONS: Our results provide systems biology support for using BCG and small-molecule BCG mimics as putative vaccine and drug candidates against emergent viruses including SARS-CoV-2. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11095-020-02930-9) contains supplementary material, which is available to authorized users.


id: cord-291722-xnfdjriz
title: Protective effects of vaccinations and endemic infections on COVID-19: A Hypothesis
author: Meenakshisundaram, Ramachandran
date: 2020-05-26
txt: ./txt/cord-291722-xnfdjriz.txt
cache: ./cache/cord-291722-xnfdjriz.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0306987720308902?v=s5
doi: 10.1016/j.mehy.2020.109849
abstract: nan
summary:
  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


id: cord-292128-8o20mcur
author: Fritschi, Nora
date: 2020-08-20
txt: ./txt/cord-292128-8o20mcur.txt
cache: ./cache/cord-292128-8o20mcur.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S1526054220301202
doi: 10.1016/j.prrv.2020.08.004
summary:
  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

title:
  Bacille Calmette Guérin (BCG) and new TB vaccines: specific, cross-mycobacterial and off-target effects

abstract:
  The Bacille Calmette Guérin (BCG) vaccine was developed over a century ago and has become one of the most used vaccines without undergoing a modern vaccine development life cycle. Despite this, the vaccine has protected many millions from severe and disseminated forms of tuberculosis (TB). In addition, BCG has cross-mycobacterial effects against non-tuberculous mycobacteria and off-target (also called non-specific or heterologous) effects against other infections and diseases. More recently, BCG’s effects on innate immunity suggest it might improve the immune response against viral respiratory infections including SARS-CoV-2. New TB vaccines, developed over the last 30 years, show promise, particularly in prevention of progression to disease from TB infection in young adults. The role of BCG in the context of new TB vaccines remains uncertain as most participants included in trials have been previously BCG immunised. BCG replacement vaccines are in efficacy trials and these may also have off-target effects.


id: cord-292372-kn27ghlv
author: de Chaisemartin, Clément
date: 2020-08-23
txt: ./txt/cord-292372-kn27ghlv.txt
cache: ./cache/cord-292372-kn27ghlv.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1093/cid/ciaa1223
doi: 10.1093/cid/ciaa1223
summary:
  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.

title:
  BCG vaccination in infancy does not protect against COVID-19. Evidence from a natural experiment in Sweden

abstract:
  BACKGROUND: The Bacille Calmette-Guérin (BCG) tuberculosis vaccine has immunity benefits against respiratory infections. Accordingly, it has been hypothesized to have a protective effect against COVID-19. Recent research found that countries with universal BCG childhood vaccination policies tend to be less affected by the COVID-19 pandemic. However, such ecological studies are biased by numerous confounders. 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. METHODS: Numbers of COVID-19 cases and hospitalizations were recorded for birth cohorts born just before and just after 1975, representing 1,026,304 and 1,018,544 individuals, respectively. We used regression discontinuity to assess the effect of BCG vaccination on Covid-19 related outcomes. This method used on such a large population allows for a high precision that would be hard to achieve using a randomized controlled trial. RESULTS: The odds ratio for Covid-19 cases and Covid-19 related hospitalizations were 1·0005 (CI95: [0·8130-1·1881]) and 1·2046 (CI95: [0·7532-1·6560]), allowing us to reject fairly modest effects of universal BCG vaccination. We can reject with 95% confidence that universal BCG vaccination reduces the number of cases by 19% and the number of hospitalizations by 25%. CONCLUSIONS: While the effect of a recent vaccination must be evaluated, we provide strong evidence that receiving the BCG vaccine at birth does not have a protective effect against COVID-19 among middle-aged individuals.


id: cord-294302-hboc3xcz
title: COVID-19 vaccine and boosted immunity: nothing ad interim to do?
author: Roncati, Luca
date: 2020-10-09
txt: ./txt/cord-294302-hboc3xcz.txt
cache: ./cache/cord-294302-hboc3xcz.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.vaccine.2020.10.013
doi: 10.1016/j.vaccine.2020.10.013
summary:
  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

abstract:
  SUMMARY Today, Coronavirus Disease 2019 (COVID-19) is a global public health emergency and vaccination measures to counter its diffusion are deemed necessary. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of the disease, unleashes a T-helper 2 immune response in those patients requiring intensive care. 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.


id: cord-298867-hzshnq7b
title: Impact of Duration of Cessation of Mass BCG Vaccination Programs on Covid -19 Mortality
author: Raham, T. F.
date: 2020-08-23
txt: ./txt/cord-298867-hzshnq7b.txt
cache: ./cache/cord-298867-hzshnq7b.txt
extension: .txt
mime: text/plain
url: http://medrxiv.org/cgi/content/short/2020.08.20.20178889v1?rss=1
doi: 10.1101/2020.08.20.20178889
summary:
  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.

abstract:
  Back ground: BCG have heterogeneous immunity to certain pathogens other than Mycobacterium tuberculosis effect. 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 . These studies was criticized because of low evidence of such studies and possible confounding factors. For that reason this study was designed to look for impact of duration of cessation of BCG programs on Covid-19 mortality looking for the hypotheses by different design and looking forward to support previous studies. Methods: Total number of studied group is 14 countries which has stopped BCG vaccination programs. 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. Obsolescence of duration of cessation of mass BCG vaccination programs has strongly negatively associated with Covid-19 mortality in countries which stopped BCG vaccination programs. Conclusion: The longer the cessation duration of BCG programs, the higher the Covid-19 mortality is, and vice versa.


id: cord-298945-0sm0r4v8
author: Kuratani, N.
date: 2020-05-16
txt: ./txt/cord-298945-0sm0r4v8.txt
cache: ./cache/cord-298945-0sm0r4v8.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.05.13.20100156
doi: 10.1101/2020.05.13.20100156
summary:
  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.

title:
  Association of national Bacille Calmette-Guerin vaccination policy with COVID-19 epidemiology: an ecological study in 78 countries

abstract:
  A possible association between national Bacille Calmette-Guerin (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. Data collection was conducted from April 25 to May 5, 2020. I compared countries that have a current universal BCG vaccination policy (BCG countries), with countries that currently lack such a policy (non-BCG 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 intervals 0.323 - 0.614, P =1x10-5). In BCG countries, the case increase rate was attenuated marginally by 25.4% (95% CI 3.0 to 42.7, P=0.029) as compared with those of the non-BCG countries. Although the protective mechanism of BCG vaccination against COVID-19 remains unknown, further laboratory and clinical research should be warranted.


id: cord-299676-6wt9rn1a
author: Gursel, Mayda
date: 2020-04-27
txt: ./txt/cord-299676-6wt9rn1a.txt
cache: ./cache/cord-299676-6wt9rn1a.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32339299/
doi: 10.1111/all.14345
abstract: nan
summary:
  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

title:
  Is global BCG vaccination‐induced trained immunity relevant to the progression of SARS‐CoV‐2 pandemic?


id: cord-300338-duhyb754
title: BCG Vaccination and Mortality of COVID-19 across 173 Countries: An Ecological Study
author: Urashima, Mitsuyoshi
date: 2020-08-03
txt: ./txt/cord-300338-duhyb754.txt
cache: ./cache/cord-300338-duhyb754.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3390/ijerph17155589
doi: 10.3390/ijerph17155589
summary:
  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.

abstract:
  Ecological studies have suggested fewer COVID-19 morbidities and mortalities in Bacillus Calmette–Guérin (BCG)-vaccinated countries than BCG-non-vaccinated countries. However, these studies obtained data during the early phase of the pandemic and did not adjust for potential confounders, including PCR-test numbers per population (PCR-tests). Currently—more than four months after declaration of the pandemic—the BCG-hypothesis needs reexamining. An ecological study was conducted by obtaining data of 61 factors in 173 countries, including BCG vaccine coverage (%), using morbidity and mortality as outcomes, obtained from open resources. ‘Urban population (%)’ and ‘insufficient physical activity (%)’ in each country was positively associated with morbidity, but not mortality, after adjustment for PCR-tests. On the other hand, recent BCG vaccine coverage (%) was negatively associated with mortality, but not morbidity, even with adjustment for percentage of the population ≥ 60 years of age, morbidity, PCR-tests and other factors. The results of this study generated a hypothesis that a national BCG vaccination program seems to be associated with reduced mortality of COVID-19, although this needs to be further examined and proved by randomized clinical trials.


id: cord-300729-35meen0h
author: Miller, Aaron
date: 2020-03-28
txt: ./txt/cord-300729-35meen0h.txt
cache: ./cache/cord-300729-35meen0h.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.03.24.20042937
doi: 10.1101/2020.03.24.20042937
summary:
  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.

title:
  Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study

abstract:
  COVID-19 has spread to most countries in the world. Puzzlingly, the impact of the disease is different in different countries. These differences are attributed to differences in cultural norms, mitigation efforts, and health infrastructure. Here we propose that national differences in COVID-19 impact could be partially explained by the different national policies respect to Bacillus Calmette-Guerin (BCG) childhood vaccination. BCG vaccination has been reported to offer broad protection to respiratory infections. We compared large number of countries BCG vaccination policies with the morbidity and mortality for COVID-19. We found that countries without universal policies of BCG vaccination (Italy, Nederland, USA) have been more severely affected compared to countries with universal and long-standing BCG policies. Countries that have a late start of universal BCG policy (Iran, 1984) had high mortality, consistent with the idea that BCG protects the vaccinated elderly population. We also found 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 potential new tool in the fight against COVID-19.


id: cord-304108-kn9v8qmz
title: Factors determining COVID‐19 pneumonia severity in a country with routine BCG vaccination
author: Aksu, Kurtuluş
date: 2020-08-19
txt: ./txt/cord-304108-kn9v8qmz.txt
cache: ./cache/cord-304108-kn9v8qmz.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1111/cei.13507
doi: 10.1111/cei.13507
summary:
  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.

abstract:
  BACKGROUND: The impact of countries' Bacillus Calmette‐Guérin (BCG) vaccination policies on the course of coronavirus disease (COVID‐19) outbreak is a curiosity. In this study, the relationship between BCG vaccination status and severity of COVID‐19 pneumonia and the factors affecting disease severity were investigated. METHODS: A retrospective cross‐sectional study was conducted between March‐June 2020 in patients diagnosed with COVID‐19 pneumonia, confirmed by severe acute respiratory syndrome coronavirus‐2 polymerase chain reaction positivity in a nasopharyngeal sample and pulmonary infiltrates in computed chest tomography, in a state hospital in Istanbul, Turkey. Sociodemographic features, body mass index, smoking status, concomitant diseases, income rates, and BCG vaccination status of subjects were analyzed. RESULTS: Study population consisted of 123 adults with COVID‐19 pneumonia (mean age, 49.7 years [standard deviation, 13.3 years]; 82 (66.7%) male). 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. According to multivariate analysis increasing age (odds ratio [OR], 1.119; 95% confidence interval [CI], 1.062 – 1.178; p<.001) and low income (OR, 3.209; 95% CI, 1.008 – 10.222; p =.049) are associated with severe disease in COVID‐19 pneumonia. CONCLUSION: This study reveals that BCG vaccination is not associated with disease severity in COVID‐19 pneumonia. Age and low income are the main determinants of severe COVID‐19 pneumonia.


id: cord-305264-0uhabgsr
author: Weng, C-H.
date: 2020-07-09
txt: ./txt/cord-305264-0uhabgsr.txt
cache: ./cache/cord-305264-0uhabgsr.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32641191/
doi: 10.1017/s0950268820001569
summary:
  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.

title:
  Bacillus Calmette–Guérin vaccination and clinical characteristics and outcomes of COVID-19 in Rhode Island, United States: a cohort study

abstract:
  Coronavirus disease 2019 (COVID-19) has resulted in a global pandemic, and there is limited data on effective therapies. Bacillus Calmette–Guérin (BCG) vaccine, a live-attenuated strain derived from an isolate of Mycobacterium bovis and originally designed to prevent tuberculosis, has shown some efficacy against infection with unrelated pathogens. 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. Median age was 39.5 years (interquartile range, 27.0–50.0), 30% were male and 87.5% were Latino/Hispanics. Eighty-two (68.3%) patients had BCG vaccination. Individuals with BCG vaccination were less likely to require hospital admission during the disease course (3.7% vs. 15.8%, P = 0.019). This association remained unchanged after adjusting for demographics and comorbidities (P = 0.017) using multivariate regression analysis. The finding from our study suggests the potential of BCG in preventing more severe COVID-19.


id: cord-309888-93rdcwrh
title: COVID-19 research: promising tracks leading to uro-oncology
author: Tamás, Fazekas
date: 2020-05-11
txt: ./txt/cord-309888-93rdcwrh.txt
cache: ./cache/cord-309888-93rdcwrh.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1007/s11255-020-02490-2
doi: 10.1007/s11255-020-02490-2
abstract: nan
summary:
  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?


id: cord-314121-ez62fx9p
author: de Chaisemartin, C.
date: 2020-06-23
txt: ./txt/cord-314121-ez62fx9p.txt
cache: ./cache/cord-314121-ez62fx9p.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.06.22.20137802
doi: 10.1101/2020.06.22.20137802
summary:
  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.

title:
  BCG vaccination in infancy does not protect against COVID-19. Evidence from a natural experiment in Sweden.

abstract:
  Background The Bacille Calmette-Guerin (BCG) tuberculosis vaccine has immunity benefits against respiratory infections. Accordingly, it has been hypothesized that it may have a protective effect against COVID-19. Recent research found that countries with universal BCG childhood vaccination policies tend to be less affected by the COVID-19 pandemic. However, such ecological studies are biased by numerous confounders. 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. Methods Numbers of COVID-19 cases and hospitalizations were recorded for birth cohorts born just before and just after that change, representing 1,026,304 and 1,018,544 individuals, respectively. We used regression discontinuity to assess the effect of BCG vaccination on Covid-19 related outcomes. This method used on such a large population allows for a high precision that would be hard to achieve using a classical randomized controlled trial. Results The odds ratio for Covid-19 cases and Covid-19 related hospitalizations were 0.9997 (CI95: [0.8002-1.1992]) and 1.1931 (CI95: [0.7558-1.6304]), respectively. We can thus reject with 95% confidence that universal BCG vaccination reduces the number of cases by more than 20% and the number of hospitalizations by more than 24% Conclusions While the effect of a recent vaccination must be evaluated, we provide strong evidence that receiving the BCG vaccine at birth does not have a protective effect against COVID-19.


id: cord-315101-7mim3yl6
title: New disease old vaccine: Is recombinant BCG vaccine an answer for COVID-19?
author: Kumar Gupta, Pramod
date: 2020-07-28
txt: ./txt/cord-315101-7mim3yl6.txt
cache: ./cache/cord-315101-7mim3yl6.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0008874920303476?v=s5
doi: 10.1016/j.cellimm.2020.104187
summary:
  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

abstract:
  Mycobacterium bovis BCG, a live attenuated tuberculosis vaccine offers protection against disseminated TB in children. BCG exhibits heterologous protective effects against unrelated infections and reduces infant mortality due to non-mycobacterial infections. 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. Further proven safety records of BCG in humans, its adjuvant activity and low cost manufacturing makes it a frontrunner in the vaccine development to stop this pandemic. 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.


id: cord-318542-785hnh19
title: Systematic Review: Safety of Intravesical Therapy for Bladder Cancer in the Era of COVID-19
author: Leeson, Cale E.
date: 2020-08-18
txt: ./txt/cord-318542-785hnh19.txt
cache: ./cache/cord-318542-785hnh19.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32838196/
doi: 10.1007/s42399-020-00461-3
summary:
  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.

abstract:
  A novel coronavirus has emerged in late 2019 capable of causing a severe respiratory disease known as COVID-19. Its pathogenesis appears to be the initiation of an immune response and resulting cytokine storm that damages the healthy lung tissue of the host. Some epidemiological studies found bacillus Calmette-Guérin (BCG) vaccine can help to decrease morbidity and mortality of the viral infection. We aim to review and summarize what is known about COVID-19 and the current implications of intravesical BCG with regard to the disease.


id: cord-323141-6z750avb
author: Kuroda, Naoto
date: 2020-12-05
txt: ./txt/cord-323141-6z750avb.txt
cache: ./cache/cord-323141-6z750avb.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1097/inf.0000000000002724
doi: 10.1097/inf.0000000000002724
abstract: nan
summary:
  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.

title:
  Demand for BCG Vaccine Due to Unproven Claims of its Role in Preventing COVID-19 Is Causing Shortages of Vaccines for Infants in Japan


id: cord-325966-0g7a9s5z
title: Fighting COVID-19: a quick review of diagnoses, therapies, and vaccines
author: Shih, Hsin-I.
date: 2020-05-30
txt: ./txt/cord-325966-0g7a9s5z.txt
cache: ./cache/cord-325966-0g7a9s5z.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.bj.2020.05.021
doi: 10.1016/j.bj.2020.05.021
summary:
  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.

abstract:
  The COVID-19 pandemic caused by a novel coronavirus, SARS-CoV-2, has infected more than 4.9 million individuals and resulted in over 300,000 deaths globally. The rapid spread of the virus and the precipitously increasing numbers of cases necessitate the urgent development of accurate diagnostic methods, effective treatments, and vaccines. Here, we review the progress of developing diagnostic methods, therapies, and vaccines for SARS-CoV-2 with a focus on current clinical trials and their challenges. For diagnosis, nucleic acid amplification tests remain the mainstay diagnostics for laboratory confirmation of SARS-CoV-2 infection, while serological antibody tests are used to aid contact tracing, epidemiological, and vaccine evaluation studies. Viral isolation is not recommended for routine diagnostic procedures due to safety concerns. Currently, no single effective drug or specific vaccine is available against SARS-CoV-2. 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. Other supportive care measures for critical patients are still necessary. Advances in genetic sequencing and other technological developments have sped up the establishment of a variety of vaccine platforms. Accordingly, numerous vaccines are under development. Vaccine candidates against SARS-CoV-2 are mainly based upon the viral spike protein due to its vital role in viral infectivity, and most of these candidates have recently moved into clinical trials. Before the efficacy of such vaccines in humans is demonstrated, strong international coordination and collaboration among studies, pharmaceutical companies, regulators, and governments are needed to limit further damage due the emerging SARS-CoV-2 virus.


id: cord-328262-hw8swbt5
title: BCG-induced trained immunity: can it offer protection against COVID-19?
author: O’Neill, Luke A. J.
date: 2020-05-11
txt: ./txt/cord-328262-hw8swbt5.txt
cache: ./cache/cord-328262-hw8swbt5.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41577-020-0337-y
doi: 10.1038/s41577-020-0337-y
summary:
  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

abstract:
  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.


id: cord-328623-ud8vz3zu
title: Malaria Endemicity Influence on COVID -19 Mortality: New Evidence Added to BCG and TB Prevalence
author: Raham, T. F.
date: 2020-09-11
txt: ./txt/cord-328623-ud8vz3zu.txt
cache: ./cache/cord-328623-ud8vz3zu.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.09.09.20191684
doi: 10.1101/2020.09.09.20191684
summary:
  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.

abstract:
  Background: Regarding SARS-CoV-2 it is well known that a substantial percentage of adult population cannot get infected if exposed to this novel coronavirus. Several studies give primary indication of the possible role of preexisting immunity whether cross immunity or not. Possible role of latent TB and BCG have been already suggested to create innate cross heterogeneous immunity. Possible role of malaria is suggested in this paper possibly by same mechanism of protection. Material and methods:80 malarious countries are enrolled in this study. Hierarchical multiple regression type of analyses is used for data analyses. TB prevalence/ 100,000 population standardized to BCG coverage rates is taken as direct factor in the test. Malaria incidence /1000 population is considered as intermediate factor and the outcome is COVID-19 mortality/ 1 million (M) population. 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. Conclusions: Malaria and standardized TB prevalence are statistical significant factors predicting COVID-19 mortality in negative associations.


id: cord-330203-7xen4nlm
author: Joy, Melvin
date: 2020-09-05
txt: ./txt/cord-330203-7xen4nlm.txt
cache: ./cache/cord-330203-7xen4nlm.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S2213398420301949
doi: 10.1016/j.cegh.2020.08.015
summary:
  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.

title:
  Is BCG associated with reduced incidence of COVID-19? A meta-regression of global data from 160 countries

abstract:
  BACKGROUND: Global research is running towards to find a vaccine to stop the threat of the COVID-19. The Bacillus Calmette–Guérin (BCG) vaccine that prevents severe forms of tuberculosis is getting more attention in this scenario. The objective of our study was to determine the association between BCG vaccine coverage and incidence of COVID-19 at a national-level across the Globe. METHODS: The data of 160 countries were included in the study. Meta-regression was done to estimate the difference in the incidence of COVID-19 cases between countries with BCG vaccination coverage. BCG coverage was categorized as ≤70%, >70% and no vaccination. The analyses were carried out by adjusting for factors such as population density, income group, latitude, and percentage of the total population under age groups 15–64 and above 65 years of each country. 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. Those that had >70% coverage reported 10.1 (95% CI: −11.4 to −8.7) less infections per 10,000 population compared to those with no BCG countries. CONCLUSION: Our analysis suggests that BCG is associated with reduced COVID-19 infections if the BCG vaccine coverage is over 70%. The region-wise analyses also suggested similar findings, except the Middle East and North African region.


id: cord-331477-2x9szmjc
title: Protecting dental manpower from COVID‐19 infection
author: Warnakulasuriya, Saman
date: 2020-06-01
txt: ./txt/cord-331477-2x9szmjc.txt
cache: ./cache/cord-331477-2x9szmjc.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1111/odi.13410
doi: 10.1111/odi.13410
summary:
  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

abstract:
  World Health Organization declared on 11 March, COVID 19 as a pandemic infection that has spread rapidly across the globe. Covid-19 currently has no known treatment or a vaccine. 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. Since January 2020, and by the end of April this year, more than 150 medical doctors in Italy and over 100 National Health Service workers in the UK have died in the COVID-19 crisis. While the transmission of COVID 19 via human ex-haled droplets and direct contact is clear, the potential for aerosol transmission is a significant risk particularly for dental practices. The objective of this brief review is to highlight ways how dental manpower could protect from the spread of disease.


id: cord-334550-xb0alubj
title: The Enigma of Low COVID-19 Fatality Rate in India
author: Samaddar, Arghadip
date: 2020-07-28
txt: ./txt/cord-334550-xb0alubj.txt
cache: ./cache/cord-334550-xb0alubj.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32849833/
doi: 10.3389/fgene.2020.00854
summary:
  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.

abstract:
  Coronavirus disease 2019 (COVID-19), an acute onset pneumonia caused by a novel Betacoronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has rapidly evolved into a pandemic. Though its origin has been linked to the Wuhan City of China’s Hubei Province in December 2019, recent reports claim that the original animal-to-human transmission of the virus probably happened sometime between September and October 2019 in Guangdong Province, rather than Hubei. As of July 3, 2020, India has reported a case positivity rate of 6.5% and a fatality rate of 2.8%, which are among the lowest in the world. Also, the severity of the disease is much less among Indians as evidenced by the low rate of ICU admission (15.3%) and the need for mechanical ventilation (4.16%). As per the World Health Organization (WHO) situation report 165 on July 3, 2020, India has one of the lowest deaths per 100,000 population (1.32 deaths against a global average of 6.04). Several factors related to the pathogen, host and environment might have some role in reducing the susceptibility of Indians to COVID-19. 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. This perspective -highlights the potential factors that might be responsible for the observed low COVID-19 fatality rate in Indian population. It puts forward several hypotheses which can be a ground for future studies determining individual and population susceptibility to COVID-19 and thus, may offer a new dimension to our current understanding of the disease.


id: cord-338498-3238fz73
author: Kleen, Thomas-Oliver
date: 2020-09-04
txt: ./txt/cord-338498-3238fz73.txt
cache: ./cache/cord-338498-3238fz73.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.02059
doi: 10.3389/fimmu.2020.02059
summary:
  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) .

title:
  Mitigating Coronavirus Induced Dysfunctional Immunity for At-Risk Populations in COVID-19: Trained Immunity, BCG and “New Old Friends”

abstract:
  The novel, highly contagious coronavirus SARS-CoV-2 spreads rapidly throughout the world, leading to a deadly pandemic of a predominantly respiratory illness called COVID-19. Safe and effective anti-SARS-CoV-2 vaccines are urgently needed. However, emerging immunological observations show hallmarks of significant immunopathological characteristics and dysfunctional immune responses in patients with COVID-19. Combined with existing knowledge about immune responses to other closely related and highly pathogenic coronaviruses, this could forebode significant challenges for vaccine development, including the risk of vaccine failure. Animal data from earlier coronavirus vaccine efforts indicate that elderly people, most at risk from severe COVID-19 disease, could be especially at risk from immunopathologic responses to novel coronavirus vaccines. 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.”


id: cord-340532-fpmd9nzf
author: Ventura, L.
date: 2020-05-26
txt: ./txt/cord-340532-fpmd9nzf.txt
cache: ./cache/cord-340532-fpmd9nzf.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.05.20.20107755
doi: 10.1101/2020.05.20.20107755
summary:
  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.

title:
  BCG vaccination and socioeconomic variables vs Covid-19 global features: clearing up a controversial issue

abstract:
  Background: The Covid-19 pandemic is characterized by extreme variability in the outcome distribution and mortality rates across different countries. Some recent studies suggested an inverse correlation with BCG vaccination at population level, while others denied this hypothesis. In order to address this controversial issue, we performed a strict epidemiological study collecting data available on a global scale, considering additional variables such as cultural-political factors and adherence to other vaccination coverages. Methods: Data on 121 countries, accounting for about 99% of Covid-19 cases and deaths globally, were from John's Hopkins Coronavirus Resource Center, World Bank, International Monetary Fund, United Nations, Human Freedom Report, and BCG Atlas. Statistical models used were Ordinary Least Squares, Tobit and Fractional Probit, implemented on Stata/MP16 software. Results: Based on our results, countries where BCG vaccination is or has been mandated in the last decades have seen a drastic reduction in Covid-19 diffusion (-80% on average) and mortality (-50% on average), even controlling for relative wealth of countries and their governmental health expenditure. A significant contribution to this reduction (respectively -50% and -13% on average) was also associated to the outbreak onset during summer, suggesting a possible influence of seasonality. Other variables turned out to be associated, though to a lesser extent. 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.


id: cord-342847-sjcanw19
title: Novel genome polymorphisms in BCG vaccine strains and impact on efficacy
author: Leung, Andrea S
date: 2008-09-15
txt: ./txt/cord-342847-sjcanw19.txt
cache: ./cache/cord-342847-sjcanw19.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/1471-2164-9-413
doi: 10.1186/1471-2164-9-413
summary:
  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.

abstract:
  Bacille Calmette-Guérin (BCG) is an attenuated strain of Mycobacterium bovis currently used as a vaccine against tuberculosis. Global distribution and propagation of BCG has contributed to the in vitro evolution of the vaccine strain and is thought to partially account for the different outcomes of BCG vaccine trials. Previous efforts by several molecular techniques effectively identified large sequence polymorphisms among BCG daughter strains, but lacked the resolution to identify smaller changes. In this study, we have used a NimbleGen tiling array for whole genome comparison of 13 BCG strains. 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. Moreover, we have uncovered various polymorphisms in the phoP-phoR locus. 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. These findings have important implications for the development of a new generation of vaccines.


id: cord-344553-uya1j94u
author: Bodova, K.
date: 2020-05-06
txt: ./txt/cord-344553-uya1j94u.txt
cache: ./cache/cord-344553-uya1j94u.txt
extension: .txt
mime: text/plain
url: http://medrxiv.org/cgi/content/short/2020.05.01.20087809v1?rss=1
doi: 10.1101/2020.05.01.20087809
summary:
  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.

title:
  Time-adjusted Analysis Shows Weak Associations Between BCG Vaccination Policy and COVID-19 Disease Progression

abstract:
  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. We observe weak correlation between BCG vaccination status and indicators related to disease reproduction characteristics. We did not find any associations with case fatality rates (CFR), but the differences in CFR estimates are at present likely dominated by differences in testing and case reporting between countries.


id: cord-345114-b06uz0sj
author: Klinger, Danielle
date: 2020-07-11
txt: ./txt/cord-345114-b06uz0sj.txt
cache: ./cache/cord-345114-b06uz0sj.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32664505/
doi: 10.3390/vaccines8030378
summary:
  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).

title:
  Significantly Improved COVID-19 Outcomes in Countries with Higher BCG Vaccination Coverage: A Multivariable Analysis

abstract:
  The COVID-19 pandemic that started in China has spread within 3 months to the entire globe. We tested the hypothesis that the vaccination against tuberculosis by Bacille Calmette–Guérin vaccine (BCG) correlates with a better outcome for COVID-19 patients. Our analysis covers 55 countries complying with predetermined thresholds on the population size and number of deaths per million (DPM). We found a strong negative correlation between the years of BCG administration and the DPM along with the progress of the pandemic, corroborated by permutation tests. The results from multivariable regression tests with 23 economic, demographic, health-related, and pandemic restriction-related quantitative properties, substantiate the dominant contribution of BCG years to the COVID-19 outcomes. 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). Furthermore, a strong correlation and statistical significance are associated with the degree of BCG coverage for the most recent 15 years, but no association was observed in these years for other broadly used vaccination protocols for measles and rubella. We propose that BCG immunization coverage, especially among the most recently vaccinated population, contribute to attenuation of the spread and severity of the COVID-19 pandemic.


id: cord-350103-liwvhuzj
title: The role of the urologist, BCG vaccine administration, and SARS‐CoV‐2: An overview
author: Brooks, Nathan A.
date: 2020-06-22
txt: ./txt/cord-350103-liwvhuzj.txt
cache: ./cache/cord-350103-liwvhuzj.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1002/bco2.21
doi: 10.1002/bco2.21
summary:
  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.

abstract:
  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. MATERIALS AND METHODS: We reviewed the available literature regarding COVID‐19 and BCG vaccination. 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. RESULTS: Epidemiologic evidence suggests that the crude case fatality rates are lower for countries with BCG vaccination compared to those without such programs. Four prospective, randomized clinical trials for BCG vaccination were identified including NCT04348370 (BADAS), NCT04327206 (BRACE), NCT04328441 (BCG‐CORONA), and NCT04350931. BCG administration may contribute to innate and adaptive immune priming with several opportunities for translational research. CONCLUSIONS: The urologist’s expertise with BCG and the infrastructure of urologic clinics may afford several opportunities for collaboration and leadership to evaluate and understand the potential role of BCG in the current COVID‐19 pandemic.


id: cord-351002-msjurww1
title: Does BCG protect against SARS-CoV-2 infection ?: elements of proof.
author: Ouanes, Y.
date: 2020-05-06
txt: ./txt/cord-351002-msjurww1.txt
cache: ./cache/cord-351002-msjurww1.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.05.01.20087437
doi: 10.1101/2020.05.01.20087437
summary:
  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.

abstract:
  Background : There are several factors explaining the difference in the spread of SARS-CoV-2 infection including the BCG vaccination. This fact is supported by the concept of beneficial non specific effect of this live vaccine associated to its interaction with the immune system. Our study aims to identify the correlation between the universal BCG vaccination policy and the mortality attributed to COVID-19. Methods : We conducted an epidemiological study in which we collected COVID-19 pandemic data of April 11th, 2020 from the web site worldometers.info . The exclusion criteria for our study were a number of inhabitants less than one million, low-income countries according to the World Bank classification, a total number of infection cases less than 500 and countries that have performed less than one hundred tests per million inhabitants. 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). We found that the year of introduction of vaccination influenced significantly the mortality. Countries that started immunization policy before 1960 had more favorable results (p=0.049). 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). Conclusions : Countries that have a BCG vaccination policy have a lower mortality attributed to SARS-CoV-2 infection. The populations of countries that applied this immunization before 1960 are more protected even if this universal policy has been interrupted.


id: cord-354972-nc496v6s
title: Prospects for SARS-CoV-2 diagnostics, therapeutics and vaccines in Africa
author: Margolin, Emmanuel
date: 2020-09-10
txt: ./txt/cord-354972-nc496v6s.txt
cache: ./cache/cord-354972-nc496v6s.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32913297/
doi: 10.1038/s41579-020-00441-3
summary:
  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).

abstract:
  The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a global pandemic, prompting unprecedented efforts to contain the virus. Many developed countries have implemented widespread testing and have rapidly mobilized research programmes to develop vaccines and therapeutics. However, these approaches may be impractical in Africa, where the infrastructure for testing is poorly developed and owing to the limited manufacturing capacity to produce pharmaceuticals. Furthermore, a large burden of HIV-1 and tuberculosis in Africa could exacerbate the severity of infection and may affect vaccine immunogenicity. This Review discusses global efforts to develop diagnostics, therapeutics and vaccines, with these considerations in mind. We also highlight vaccine and diagnostic production platforms that are being developed in Africa and that could be translated into clinical development through appropriate partnerships for manufacture.


id: cord-355384-qa7grviy
author: NaserEddin, Adeeb
date: 2020-10-27
txt: ./txt/cord-355384-qa7grviy.txt
cache: ./cache/cord-355384-qa7grviy.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1007/s10875-020-00892-6
doi: 10.1007/s10875-020-00892-6
summary:
  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) .

title:
  Bacillus Calmette–Guerin (BCG) Vaccine-associated Complications in Immunodeficient Patients Following Stem Cell Transplantation

abstract:
  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). We aim to investigate risk factors of post-HSCT BCG-related complications in PID patients. METHODS: A retrospective analysis of pediatric PID patients who had received the BCG vaccine and underwent HSCT at Hadassah-Hebrew University Medical Center, between 2007 and 2019. RESULTS: We found 15/36 (41.67%) patients who developed post-HSCT BCG-related complications. The most significant risk factor for developing BCG-related complications was T cell deficiency (47.6% of the non-complicated vs 83.3% of the BCGitis and 100% of the BCGosis groups had T cell lymphopenia, p = 0.013). None of the chronic granulomatous patients developed BCG-related manifestation post-transplant. Among T cell–deficient patients, lower NK (127 vs 698 cells/μl, p = 0.04) cell counts and NK-SCID were risk factors for ongoing post-HSCT BCGosis, as was pretransplant disseminated BCGosis (33.3% of patients with BCGosis vs none of the non-BCGosis patients, p = 0.04). Immune reconstitution inflammatory syndrome (IRIS) was observed in 3/5 patients with Omenn syndrome. Prophylactic antimycobacterial treatment was not proven effective. CONCLUSION: BCG vaccination can cause significant morbidity and mortality in the post-transplant T cell–deficient patient, especially in the presence of pre-transplant disease. Taking a detailed medical history prior to administering, the BCG vaccine is crucial for prevention of this complication.


id: cord-355926-24z5lhet
title: BCG Vaccination Policy and Protection Against COVID-19
author: Meena, Jitendra
date: 2020-06-09
txt: ./txt/cord-355926-24z5lhet.txt
cache: ./cache/cord-355926-24z5lhet.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1007/s12098-020-03371-3
doi: 10.1007/s12098-020-03371-3
abstract: nan
summary:
  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.


