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1.
Front Biosci (Landmark Ed) ; 27(5): 157, 2022 05 13.
Article in English | MEDLINE | ID: covidwho-1876486

ABSTRACT

Coronavirus disease 2019 (COVID-19), which broke out at the end of 2019, is a global pandemic and seriously threatens human health. Vaccination is the most effective way to prevent and control COVID-19. At present, more than 13 COVID-19 vaccines have been urgently authorized for use, but the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has brought unprecedented challenges to the protective efficiency of these COVID-19 vaccines. In particular, the recent emergence of Delta and Omicron variants, which are rapidly spreading worldwide, may bring many challenges to the medical systems. Interestingly, previous studies have shown that the Bacillus Calmette-Guerin (BCG) vaccine used to prevent tuberculosis can induce non-specific trained immunity, protecting against infectious diseases caused by respiratory viruses. Therefore, there is a hypothesis that BCG plays an essential role in reducing the incidence, severity, hospitalization, and mortality of COVID-19 and enhancing the protection efficiency of the COVID-19 vaccine. To confirm this hypothesis, 56 clinical trials have been conducted globally to assess BCG's protective effectiveness against COVID-19 infection. Herein, this review discussed the trained immunity induced by BCG and its underlying mechanisms and summarised BCG's latest research progress in preventing COVID-19, especially the ongoing clinical trials. We hope this review will provide new strategies for fighting against COVID-19.


Subject(s)
BCG Vaccine , COVID-19 , BCG Vaccine/therapeutic use , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Humans , SARS-CoV-2
2.
Cutis ; 109(3): 148-149, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1870121

ABSTRACT

The devastating effects of the COVID-19 pandemic have prompted rapid development and distribution of multiple vaccines. A 2-dose messenger RNA (mRNA) vaccine developed by Moderna (Moderna COVID-19 Vaccine) was approved in December 2020 for the prevention of COVID-19. We describe a case of BCG vaccination scar reactivation in a 48-year-old man after he received the first dose of the Moderna COVID-19 Vaccine.


Subject(s)
COVID-19 , Cicatrix , /adverse effects , BCG Vaccine , COVID-19/prevention & control , Cicatrix/etiology , Humans , Male , Middle Aged , Pandemics , Vaccination/adverse effects
4.
Int Immunopharmacol ; 108: 108870, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1851322

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19), and its variants have brought unprecedented impacts to the global public health system, politics, economy, and other fields. Although more than ten COVID-19 specific vaccines have been approved for emergency use, COVID-19 prevention and control still face many challenges. Bacille Calmette-Guérin (BCG) is the only authorized vaccine used to fight against tuberculosis (TB), it has been hypothesized that BCG may prevent and control COVID-19 based on BCG-induced nonspecific immune responses. Herein, we summarized: 1) The nonspecific protection effects of BCG, such as prophylactic protection effects of BCG on nonmycobacterial infections, immunotherapy effects of BCG vaccine, and enhancement effect of BCG vaccine on unrelated vaccines; 2) Recent evidence of BCG's efficacy against SARS-COV-2 infection from ecological studies, analytical analyses, clinical trials, and animal studies; 3) Three possible mechanisms of BCG vaccine and their effects on COVID-19 control including heterologous immunity, trained immunity, and anti-inflammatory effect. We hope that this review will encourage more scientists to investigate further BCG induced non-specific immune responses and explore their mechanisms, which could be a potential tool for addressing the COVID-19 pandemic and COVID-19-like "Black Swan" events to reduce the impacts of infectious disease outbreaks on public health, politics, and economy.


Subject(s)
COVID-19 , Animals , BCG Vaccine , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Pandemics/prevention & control , SARS-CoV-2 , Vaccination
5.
JCI Insight ; 7(11)2022 Jun 08.
Article in English | MEDLINE | ID: covidwho-1807763

ABSTRACT

SARS-CoV-2 has been confirmed in over 450 million confirmed cases since 2019. Although several vaccines have been certified by the WHO and people are being vaccinated on a global scale, it has been reported that multiple SARS-CoV-2 variants can escape neutralization by antibodies, resulting in vaccine breakthrough infections. Bacillus Calmette-Guérin (BCG) is known to induce heterologous protection based on trained immune responses. Here, we investigated whether BCG-induced trained immunity protected against SARS-CoV-2 in the K18-hACE2 mouse model. Our data demonstrate that i.v. BCG (BCG-i.v.) vaccination induces robust trained innate immune responses and provides protection against WT SARS-CoV-2, as well as the B.1.617.1 and B.1.617.2 variants. Further studies suggest that myeloid cell differentiation and activation of the glycolysis pathway are associated with BCG-induced training immunity in K18-hACE2 mice. Overall, our study provides the experimental evidence that establishes a causal relationship between BCG-i.v. vaccination and protection against SARS-CoV-2 challenge.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , BCG Vaccine , COVID-19/prevention & control , Humans , Melphalan , Mice , gamma-Globulins
6.
Trends Mol Med ; 28(6): 497-512, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1799777

ABSTRACT

The innate immune system is able to build memory-like features in response to certain infections or vaccines, resulting in enhanced responsiveness upon (re)challenge with the same or an unrelated pathogen, a phenomenon termed 'trained immunity'. Compared with antigen-dependent adaptive immune responses triggered by classical vaccines against specific pathogens, trained immunity-related vaccines induce enhanced innate immune responses against unrelated pathogens and provide 'heterologous protection'. Here, we discuss the heterologous effects of vaccines against infections and detail the latest insights into the cellular and molecular mechanisms mediating trained immunity. Additionally, novel vaccine strategies are suggested for fighting new pandemics in the future by taking advantage of the heterologous memory features of trained immunity.


Subject(s)
Immunologic Memory , Vaccines , Adaptive Immunity , BCG Vaccine , Humans , Immune System , Immunity, Innate , Pandemics
7.
Front Immunol ; 13: 841868, 2022.
Article in English | MEDLINE | ID: covidwho-1785344

ABSTRACT

The Bacillus Calmette-Guérin (BCG) vaccine, which is widely used to protect children against tuberculosis, can also improve immune response against viral infections. This unicentric, randomized-controlled clinical trial assessed the efficacy and safety of revaccination with BCG Moscow in reducing the positivity and symptoms of COVID-19 in health care workers (HCWs) during the COVID-19 pandemic. HCWs who had negative COVID-19 IgM and IgG and who dedicated at least eight hours per week in facilities that attended to individuals suspected of having COVID-19 were included in the study and were followed for 7, 15, 30, 60, and 180 days by telemedicine. The HCWs were randomly allocated to a revaccinated with BCG group, which received the BCG vaccine, or an unvaccinated group. Revaccination with BCG Moscow was found to be safe, and its efficacy ranged from 30.0% (95.0%CI -78.0 to 72.0%) to 31.0% (95.0%CI -74.0 to 74.0%). Mycobacterium bovis BCG Moscow did not induce NK cell activation at 15-20 days post-revaccination. As hypothesized, revaccination with BCG Moscow was associated with a lower incidence of COVID-19 positivity, though the results did not reach statistical significance. Further studies should be carried out to assess whether revaccination with BCG is able to protect HCWs against COVID-19. The protocol of this clinical trial was registered on August 5th, 2020, at REBEC (Registro Brasileiro de Ensaios Clínicos, RBR-4kjqtg - ensaiosclinicos.gov.br/rg/RBR-4kjqtg/1) and the WHO (# U1111-1256-3892). The clinical trial protocol was approved by the Comissão Nacional de ética de pesquisa- CONEP (CAAE 31783720.0.0000.5078).


Subject(s)
COVID-19 , Mycobacterium bovis , BCG Vaccine , COVID-19/prevention & control , Child , Health Personnel , Humans , Immunization, Secondary/methods , Moscow , Pandemics/prevention & control
8.
Tuberculosis (Edinb) ; 134: 102186, 2022 05.
Article in English | MEDLINE | ID: covidwho-1783793

ABSTRACT

COVID-19 has affected the progress made in the prevention and treatment of tuberculosis (TB); hence, the mortality of tuberculosis has risen. Different strategies-based novel TB vaccine candidates have been developed. This study identifies strategies to overcome the limitations of Bacille Calmette-Guérin (BCG) in preventing latent infection and reactivation of TB. The latency antigen Rv0572c was selected based on the mechanism of interaction between Mycobacterium tuberculosis and its host. The rRv0572c protein was used to stimulate whole blood samples derived from patients with clinically diagnosed active TB (ATBs) or latent TB infections (LTBIs) and healthy control (HCs) donors, confirming that this protein can be recognized by T cells in patients with TB, especially LTBIs. C57BL/6 mice were used to investigate the immunogenicity of the rRv0572c protein emulsified in the liposome adjuvant dimethyldioctadecylammonium [DDA], monophosphoryl lipid A [MPLA], trehalose-6, 6'-dibehenate [TDB] (DMT). The results demonstrated that rRv0572c/DMT could boost BCG-primed mice to induce antigen-specific CD4+ T cell production and generate functional T cells dominated by antigen-specific CD8+ T cells. The rRv0572c/DMT vaccine could also trigger limited Th2 humoral immune responses. These findings suggest that rRv0572c/DMT is a potential subunit vaccine candidate that can be used as a booster vaccine for BCG.


Subject(s)
COVID-19 , Latent Tuberculosis , Mycobacterium tuberculosis , Tuberculosis Vaccines , Tuberculosis , Adjuvants, Immunologic , Animals , Antigens, Bacterial , BCG Vaccine , CD8-Positive T-Lymphocytes , Humans , Liposomes , Mice , Mice, Inbred C57BL , Tuberculosis/prevention & control , Vaccines, Subunit
9.
EBioMedicine ; 79: 103993, 2022 May.
Article in English | MEDLINE | ID: covidwho-1783294

ABSTRACT

The Mycobacterium bovis BCG vaccine was first used in 1921, but has not controlled the global spread of tuberculosis (TB). There are still no new licensed tuberculosis vaccines, although there much active research and a vaccine development pipeline, with vaccines designed to prevent infection, prevent disease, or accelerate TB treatment. These vaccines are of different types, and designed to replace BCG, or to boost immunity following BCG vaccination. This viewpoint discusses why, when it has been possible to develop new vaccines for SARS-CoV-2 so quickly, it is taking so long to develop new tuberculosis vaccines.


Subject(s)
COVID-19 , Mycobacterium bovis , Mycobacterium tuberculosis , Tuberculosis Vaccines , BCG Vaccine/therapeutic use , COVID-19/prevention & control , COVID-19 Vaccines , Humans , SARS-CoV-2 , Tuberculosis Vaccines/therapeutic use , Vaccination
11.
Cell Rep ; 38(10): 110502, 2022 03 08.
Article in English | MEDLINE | ID: covidwho-1757194

ABSTRACT

Since the vast majority of species solely rely on innate immunity for host defense, it stands to reason that a critical evolutionary trait like immunological memory evolved in this primitive branch of our immune system. There is ample evidence that vaccines such as bacillus Calmette-Guérin (BCG) induce protective innate immune memory responses (trained immunity) against heterologous pathogens. Here we show that while BCG vaccination significantly reduces morbidity and mortality against influenza A virus (IAV), it fails to provide protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In contrast to IAV, SARS-CoV-2 infection leads to unique pulmonary vasculature damage facilitating viral dissemination to other organs, including the bone marrow (BM), a central site for BCG-mediated trained immunity. Finally, monocytes from BCG-vaccinated individuals mount an efficient cytokine response to IAV infection, while this response is minimal following SARS-CoV-2. Collectively, our data suggest that the protective capacity of BCG vaccination is contingent on viral pathogenesis and tissue tropism.


Subject(s)
COVID-19 , Influenza A virus , BCG Vaccine , COVID-19/prevention & control , Humans , Immunity, Innate , SARS-CoV-2 , Vaccination
12.
Hum Vaccin Immunother ; 17(12): 5284-5295, 2021 12 02.
Article in English | MEDLINE | ID: covidwho-1746993

ABSTRACT

Bacillus Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB). However, BCG has variable efficacy and cannot completely prevent TB infection and transmission. Therefore, the worldwide prevalence of TB calls for urgent development of a more effective TB vaccine. In the absence of other approved vaccines, it is also necessary to improve the efficacy of BCG itself. Intravenous (IV) BCG administration and BCG revaccination strategies have recently shown promising results for clinical usage. Therefore, it is necessary for us to revisit the BCG vaccination strategies and summarize the current research updates related to BCG vaccination. This literature review provides an updated overview and perspectives of the immunization strategies against TB using BCG, which may inspire the following research on TB vaccine development.


Subject(s)
Mycobacterium bovis , Mycobacterium tuberculosis , Tuberculosis Vaccines , Tuberculosis , BCG Vaccine , Humans , Immunization, Secondary , Tuberculosis/epidemiology , Tuberculosis/prevention & control , Vaccination
13.
Int J Mol Sci ; 23(5)2022 Feb 28.
Article in English | MEDLINE | ID: covidwho-1736946

ABSTRACT

Mycobacterium tuberculosis (Mtb) represents a major burden to global health, and refined vaccines are needed. Replication-deficient lymphocytic choriomeningitis virus (rLCMV)-based vaccine vectors against cytomegalovirus have proven safe for human use and elicited robust T cell responses in a large proportion of vaccine recipients. Here, we developed an rLCMV vaccine expressing the Mtb antigens TB10.4 and Ag85B. In mice, rLCMV elicited high frequencies of polyfunctional Mtb-specific CD8 and CD4 T cell responses. CD8 but not CD4 T cells were efficiently boosted upon vector re-vaccination. High-frequency responses were also observed in neonatally vaccinated mice, and co-administration of rLCMV with Expanded Program of Immunization (EPI) vaccines did not result in substantial reciprocal interference. Importantly, rLCMV immunization significantly reduced the lung Mtb burden upon aerosol challenge, resulting in improved lung ventilation. Protection was associated with increased CD8 T cell recruitment but reduced CD4 T cell infiltration upon Mtb challenge. When combining rLCMV with BCG vaccination in a heterologous prime-boost regimen, responses to the rLCMV-encoded Mtb antigens were further augmented, but protection was not significantly different from rLCMV or BCG vaccination alone. This work suggests that rLCMV may show utility for neonatal and/or adult vaccination efforts against pulmonary tuberculosis.


Subject(s)
Mycobacterium tuberculosis , Animals , Antigens, Bacterial , BCG Vaccine , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Lymphocytic choriomeningitis virus/genetics , Mice , Mycobacterium tuberculosis/genetics
15.
Surv Ophthalmol ; 67(2): 307-320, 2022.
Article in English | MEDLINE | ID: covidwho-1705413

ABSTRACT

Vaccines such as bacille Calmette-Guérin (BCG) are known for their heterologous effects mediated through a number of mechanisms, including trained immunity constituted by monocyte-macrophage based innate immunity. Other events such as direct hematogenous spread and induction of autoimmunity are also described. There has been a resurgent interest in harnessing some of the benefits of trained immunity in the management of COVID-19, even as several specific vaccines have been approved. We summarize the current knowledge of ocular effects of BCG. Potential effect of granulomatous inflammation on angiotensin converting enzyme activity and accentuation of cytokine storm that may result in undesirable ocular and systemic effects are also discussed.


Subject(s)
BCG Vaccine , COVID-19 , BCG Vaccine/pharmacology , Eye , Humans , Immunity, Innate , SARS-CoV-2
16.
Monaldi Arch Chest Dis ; 91(4)2021 Aug 09.
Article in English | MEDLINE | ID: covidwho-1700991

ABSTRACT

COVID-19 is a pandemic caused by SARS-CoV-2 virus which is a very worrisome public health emergency. In this study, we compared the mortality rate and recovery rate in countries with and without BCG vaccination policy. The data of mortality of COVID-19 was extracted from worldometer (https://www.worldometers.info/coronavirus/) on 26th July 2020. The data of countries where BCG vaccination is being done for all individuals is taken from BCG world atlas (http://www.bcgatlas.org/index.php), updated in 2017. BCG vaccination policy recommended countries are intervention group versus countries without BCG vaccination policies which are regarded as control group. Pooled analysis of countries with and without BCG vaccination policy revealed mortality rate of 1.31% (95%CI - 1.31% to 1.32%; I2 = 100%, p<0.01) and 3.25% (95%CI - 3.23% to 3.26%; I2 = 100%, p<0.01), respectively. The recovery rates in two country groups were found to be 72.60% (95%CI - 72.57% to 72.63%) and 55.94% (95%CI - 55.90% to 55.98%), respectively. 52 individuals need to be BCG vaccinated to prevent one death (NNT = 52). In BCG vaccination program countries, there is statistically and clinically significant less mortality (p<0.001) as compared to countries without BCG policy. Our findings corroborate the hypothesis that BCG vaccination may provide protection from COVID-19. High quality evidence from randomised controlled trials are required to establish causality between BCG vaccination and protection from severe COVID-19.


Subject(s)
BCG Vaccine , COVID-19 , Humans , Pandemics , SARS-CoV-2 , Vaccination
17.
JCI Insight ; 7(3)2022 02 08.
Article in English | MEDLINE | ID: covidwho-1705325

ABSTRACT

BackgroundAdenovirus-vectored (Ad-vectored) vaccines are typically administered via i.m. injection to humans and are incapable of inducing respiratory mucosal immunity. However, aerosol delivery of Ad-vectored vaccines remains poorly characterized, and its ability to induce mucosal immunity in humans is unknown. This phase Ib trial evaluated the safety and immunogenicity of human serotype-5 Ad-vectored tuberculosis (TB) vaccine (AdHu5Ag85A) delivered to humans via inhaled aerosol or i.m. injection.MethodsThirty-one healthy, previously BCG-vaccinated adults were enrolled. AdHu5Ag85A was administered by single-dose aerosol using Aeroneb Solo Nebulizer or by i.m. injection. The study consisted of the low-dose (LD) aerosol, high-dose (HD) aerosol, and i.m. groups. The adverse events were assessed at various times after vaccination. Immunogenicity data were collected from the peripheral blood and bronchoalveolar lavage samples at baseline, as well as at select time points after vaccination.ResultsThe nebulized aerosol droplets were < 5.39 µm in size. Both LD and HD of AdHu5Ag85A administered by aerosol inhalation and i.m. injection were safe and well tolerated. Both aerosol doses, particularly LD, but not i.m., vaccination markedly induced airway tissue-resident memory CD4+ and CD8+ T cells of polyfunctionality. While as expected, i.m. vaccination induced Ag85A-specific T cell responses in the blood, the LD aerosol vaccination also elicited such T cells in the blood. Furthermore, the LD aerosol vaccination induced persisting transcriptional changes in alveolar macrophages.ConclusionInhaled aerosol delivery of Ad-vectored vaccine is a safe and superior way to elicit respiratory mucosal immunity. This study warrants further development of aerosol vaccine strategies against respiratory pathogens, including TB and COVID-19.Trial registrationClinicalTrial.gov, NCT02337270.FundingThe Canadian Institutes for Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada funded this work.


Subject(s)
Aerosols/pharmacology , COVID-19/prevention & control , SARS-CoV-2/drug effects , Tuberculosis Vaccines/immunology , Tuberculosis/prevention & control , Administration, Inhalation , Adolescent , Adult , Aerosols/administration & dosage , Antibodies, Neutralizing/blood , BCG Vaccine/immunology , COVID-19/immunology , Female , Humans , Immunity, Mucosal/drug effects , Immunity, Mucosal/immunology , Male , Middle Aged , Mycobacterium tuberculosis/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Tuberculosis/immunology , Vaccination/methods , Young Adult
18.
Vaccine ; 40(13): 1987-1995, 2022 03 18.
Article in English | MEDLINE | ID: covidwho-1689017

ABSTRACT

National immunisation programmes require an adequate supply of vaccines to function properly but many countries, globally and in Europe, have reported vaccine shortages. A comprehensive view of vaccine shortages and stockouts in the EU/EEA is missing in the published literature. This study was conducted in the framework of the European Joint Action on Vaccination (EU-JAV). Twenty-eight countries, including 20 EU-JAV consortium member states and an additional 8 EU/EEA countries, were invited to participate in a survey aimed at collecting information on vaccine shortages and stock-outs experienced from 2016 to 2019, their main causes, actions taken, and other aspects of vaccine supply. Twenty-one countries completed the survey (response rate 75%), of which 19 reported at least one shortage/stock-out event. Overall, 115 events were reported, 28 of which led to a change in the national immunisation programme. The most frequently involved vaccines were DT- and dT-containing combination vaccines, hepatitis B, hepatitis A, and BCG vaccines. The median duration of shortages/stock-outs was five months (range <1 month-39 months). Interruption in supply and global shortage were the most frequently indicated causes. Only about half of countries reported having an immunization supply chain improvement plan. Similarly, only about half of countries had recommendations or procedures in place to address shortages/stockouts. The survey also identified the occurrence of shortages/stockouts of other biological products (e.g. diphtheria antitoxin in 12 countries). Public health strategies to assure a stable and adequate vaccine supply for immunization programmes require coordinated actions from all stakeholders, harmonized definitions, strengthening of reporting and monitoring systems, the presence of an immunization supply chain improvement plan in all countries, and procedures or recommendations in place regarding the use of alternative vaccines or vaccination schedules in case of shortages/stockouts.


Subject(s)
Public Health , Vaccination , BCG Vaccine , Europe , Immunization Programs/methods
20.
Prog Urol ; 32(5): 326-331, 2022 Apr.
Article in French | MEDLINE | ID: covidwho-1683554

ABSTRACT

INTRODUCTION: Mitomycin C is the gold standard intravesical adjuvant therapy for intermediate-risk non-muscle-invasive bladder cancer (NMIBC). Tensions in the supply of mitomycin have emerged in France since late 2019. The ANSM in agreement with the AFU proposed to use epirubicin, already available in other European countries in this indication. The objective of our study was to report the initial French experience with the use of epirubicin in adjuvant treatment of NMIBC. MATERIALS AND METHODS: We undertook a French multicenter retrospective descriptive study to collect, from the centers of the members of the CC-AFU bladder, the clinico-pathological data of the patients, the indications, the modalities of use (dose, indication, circuit in the pharmacy) and the tolerance data of epirubicin. The impact of the COVID-19 epidemic on treatment interruptions was also identified. Of the 20 centers contacted, 5 (25%) had implemented the epirubicin administration protocol developed by the CC-AFU bladder subcommittee. A total of 61 patients were treated with endovesical instillations of epirubicin between November 2019 and November 2020 for NMIBC at a single dose of 50mg. RESULTS: A total of 61 patients (mean age 67 years, 64-77 years) were treated with epirubicin, of which 45 (73.8%) were male. The patients had intermediate-risk NMIBC in 88.5%, the rest had high-risk disease. Induction therapy without or with maintenance was planned for 48 (78.7%) and 13 patients (21.3%), respectively. The preparation and administration of epirubicin was similar to that of mitomycin: central pharmacy preparation for same-day dispensing with immediate outpatient instillation. Unlike mitomycin, urinary alkalinization was not required. Of the 498 total instillations scheduled, 345 were performed (69.3%). The COVID-19 epidemic significantly impacted epirubicin delivery: one patient could not start treatment (1.6%), 8 patients (13.1%) had to discontinue it permanently; the rest of the patients underwent delayed instillations (18%). Other causes of discontinuation included infectious complications (9.8%). No major toxicities were reported. CONCLUSION: The implementation of an adjuvant epirubicin treatment protocol presented a good feasibility with low toxicity, without modifying the organization of the patients' care pathway. In the context of unpredictable mitomycin shortage, epirubicin represents a good therapeutic alternative in the endovesical adjuvant treatment of intermediate-risk NMIBC. LEVEL OF PROOF: 3.


Subject(s)
COVID-19 , Urinary Bladder Neoplasms , Adjuvants, Immunologic , Administration, Intravesical , Aged , Antibiotics, Antineoplastic , BCG Vaccine/therapeutic use , COVID-19/drug therapy , Clinical Protocols , Epirubicin/therapeutic use , Female , Humans , Male , Mitomycin , Neoplasm Invasiveness , Retrospective Studies , Urinary Bladder Neoplasms/pathology
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