Immediate Bacille Calmette-Guérin Vaccination to Neonates Requiring Perinatal Treatment at the Maternity Ward in Guinea-Bissau: A Randomized Controlled Trial.

BACKGROUND: Randomized controlled trials (RCTs) indicate that bacille Calmette-Guérin (BCG) vaccination provides broad beneficial "nonspecific" protection against infections. We investigated the effect on in-hospital mortality of providing BCG immediately upon admission to a neonatal intensive care unit (NICU), rather than BCG-at-discharge. The pretrial NICU mortality was 13% and we hypothesized that BCG would reduce mortality by 40%. METHODS: Parallel-group, open-label RCT was initiated in 2013 in Guinea-Bissau. Neonatal intensive care unit-admitted neonates were randomized 1:1 to BCG + oral polio vaccine (OPV) immediately (intervention) versus BCG + OPV at hospital discharge (control; usual practice). The trial was discontinued due to decreasing in-hospital mortality and major NICU restructuring. We assessed overall and disease-specific mortality by randomization allocation in cox proportional hazards models providing mortality rate ratios (MRRs). RESULTS: We recruited 3353 neonates, and the overall mortality was 3.1% (52 of 1676) for BCG-vaccinated neonates versus 3.3% (55 of 1677) for controls (MRR = 0.94; 0.64-1.36). For noninfectious causes of death, the MRR was 1.20 (0.70-2.07), and there tended to be fewer deaths from infections in the BCG group (N = 14) than among controls (N = 21) (MRR = 0.65; 0.33-1.28). CONCLUSIONS: Providing BCG + OPV to frail neonates was safe and might protect against fatal infection in the immediate newborn period. Deaths due to prematurity and perinatal complications were unaffected by BCG.

The role of surgical management of BCG vaccine-induced regional suppurative lymphadenitis in children: a 7 years' experience from one medical center.

BACKGROUND: The management strategy of Bacille Calmette-Guérin (BCG) vaccine-induced regional suppurative lymphadenitis in children is still controversial and more clinical studies are needed. We therefore present a surgical case series to explore the role of surgical management for this dilemma. METHODS: From January 2013 to June 2020, data from 65 patients diagnosed with BCG vaccine-induced regional suppurative lymphadenitis were retrospectively reviewed. Clinical characteristics, ultrasonographic findings, surgical procedures, perioperative management, and outcome were analyzed. The association between postoperative seroma and symptom duration, skin involvement, and postoperative hospital stay were compared using Yates's corrected Chi-square test and Student's t-test for statistical analysis. The follow-up period ranged from three to six months. RESULTS: Of the 65 cases, the median age at presentation was 3.4 months. All patients were full-term with normal range of birth weight and received a BCG vaccination in the first 24 h of life. All patients underwent surgical excision of the abscess with the involved lymph node(s). Postoperative seroma formation was found in 20 patients and fine needle aspiration was needed. There was no significant association between postoperative seroma formation with symptom duration, skin involvement, and postoperative hospital stay. No oral anti-tubercular agents were given postoperatively. The mean length of postoperative hospital stay was 6.02 ± 1.62 days. Sixty-four cases (98.46%) received only one procedure and recovered. One patient required a second procedure due to postoperative sinus. CONCLUSIONS: The present study showed that surgical excision of the abscess with involved lymph node(s) is one of the choices for BCG vaccine-induced suppurative lymphadenitis, but special attention should be paid to controlling the surgical indications. Intraoperative meticulous manipulation and postoperative care are crucial to achieve a good outcome.

Epidemiology of Kawasaki disease before and after universal Bacille Calmette-Guérin vaccination program was discontinued.

AIM: Bacille Calmette-Guérin (BCG) vaccine (BCG) has been suggested to induce the primary immunity needed for the subsequent Kawasaki disease (KD). We studied the epidemiology of KD before and after the universal BCG vaccination ended in Finland in September 2006. METHODS: Kawasaki disease cases were retrieved from national health registries from 1996 to 2016 for annual incidence rates. We then compared 612 433 children born in the BCG vaccination era, from 1 January 1996 to 30 August 2006, to 604 163 born after BCG era, from 1 September 2006 to 31 December 2016. RESULTS: The annual incidence rates did not change after the BCG vaccination stopped. We found 370 first visits for KD by children born in the BCG era and 341 after universal BCG vaccination ended. The mean age at diagnosis increased from 2.6 years to 3.0 years (95% CI-0.64 to -0.012, P = .04) and the proportion of children with Kawasaki disease under 5 years decreased from 87% to 81% (95% CI 1%-12%, P = .02). CONCLUSION: Discontinuing the universal BCG vaccination programme did not change the incidence rates of KD. The increased age at diagnosis could suggest that the pathogenesis of KD may be associated with the immunological pathways primed by BCG immunisation.

Rapid Protective Effects of Early BCG on Neonatal Mortality Among Low Birth Weight Boys: Observations From Randomized Trials.

Background: Three randomized trials (RCTs) in low-weight (<2.5 kg) infants have shown that Bacille Calmette-Guérin (BCG) vaccine nonspecifically reduces all-cause mortality in the neonatal period. Methods: Using data from 3 RCTs of early BCG (n = 6583) we examined potential sex differences in the timing of the mortality reduction in the neonatal period, presenting metaestimates of the main outcome mortality rate ratios (MRR) for BCG-vaccinated and controls. Results: Among controls, boys had a particularly high mortality during the first week after randomization: male-female MRR 2.71 (95% CI, 1.70-4.50). During the first week, BCG had a marked beneficial effect for boys, reducing mortality 3-fold (MRR [BCG/no BCG] = 0.36 [0.20-0.67]). In weeks 2-4 the effect waned for boys (MRR = 0.91 [0.51-1.69]). In girls, the pattern was opposite with a limited effect in the first week (MRR = 0.85 [0.46-1.54]), but a significant reduction in weeks 2-4 (MRR = 0.56 [0.31-1.00]). This was consistent in all 3 trials. Verbal autopsies linked early benefit to fewer sepsis-related deaths among BCG-vaccinated boys. Discussion: The marked reduction in mortality in the days after BCG vaccination in boys emphasizes the importance of providing BCG soon after birth. Trial registration numbers: ClinicalTrials.gov (NCT00146302) and ClinicalTrials.gov (NCT00625482).

Retrospective cohort study exploring the impact of universal Tuberculosis (TB) vaccination cessation on the epidemiology of paediatric TB in Ireland, 2011-2021.

BACKGROUND: Since 2010, Ireland's Tuberculosis (TB) crude incidence rate (CIR) remains below 10 per 100,000 population defining it as a low TB incidence country. Ireland maintained a universal BCG vaccination programme until its discontinuation in 2015 due to lack of vaccine supply. This study explores the impact of discontinuing a national universal BCG vaccination programme on the epidemiology of paediatric TB cases. METHODS: We retrospectively analysed TB notifications aged 0-6 years old reported to the Irish National TB Surveillance System between 2011 and 2021. Key epidemiological characteristics and temporal trends in TB age specific incidence rates (ASIRs) were compared between 0 and 6 year old cases born during a period of universal BCG vaccination (2007-2015) and 0-6 year old cases born after BCG vaccination ceased (2015-2021). RESULTS: No significant temporal trend was detected in the overall 0-6 year old ASIR by notification year during 2011-2021 (IRR:0.95; 0.86-1.1). However, the temporal trend for cases born during universal vaccination showed a significant decline (0.74; CIR: 0.62-0.89) while cases born after BCG vaccination ceased had a non-significant increase (1.2; CIR: 0.73-1.86). A significantly declining temporal trend was detected among cases born in Ireland during universal vaccination (IRR:0.73; 0.62-0.86), but no significant trend was detected in the cases born outside Ireland during universal vaccination (IRR:0.83; 0.53-1.31). No significant trend was detected in cases born after vaccination ceased in either cases born in Ireland (IRR:1.0; 0.60-1.65) or those born outside Ireland (IRR:0.64; 0.29-1.40). CONCLUSIONS: Universal BCG cessation has not yet directly impacted on TB cases among 0-6 year olds in Ireland. However, interruption of the previously declining temporal trend in this cohort during universal vaccination may be an early warning of a future increase. Paediatric TB cases remain an important cohort for timely surveillance to monitor trends in this primarily unvaccinated cohort to evaluate the long-term effects.

Effects of Neonatal BCG-Japan Versus BCG-Russia Vaccination on Overall Mortality and Morbidity: Randomized Controlled Trial From Guinea-Bissau (BCGSTRAIN II).

Background: Vaccination with the Danish strain of bacille Calmette-Guérin (BCG) has been associated with pronounced reductions in all-cause neonatal mortality and morbidity. Developing a skin reaction postvaccination is associated with markedly reduced mortality risk. It is unknown whether the beneficial nonspecific effects are maintained across different BCG strains. Methods: This was an open-label randomized controlled trial in Guinea-Bissau, comparing BCG-Japan (n = 8754) versus BCG-Russia (n = 8752) for all-cause hospital admission risk by 6 weeks of age (primary outcome) and 6 months of age. Additional secondary outcomes were in-hospital case-fatality risk (CFR), all-cause mortality, and BCG skin reaction prevalence. Participants were followed through telephone calls at 6 weeks and 6 months, with a subgroup also visited at home. We assessed admission and mortality risk in Cox models providing incidence rate ratios (IRRs) and mortality rate ratios. CFR and skin reactions were assessed by binomial regression providing risk ratios. Analyses were done overall and stratified by sex. Results: BCG strain was not associated with admission risk, the BCG-Japan/BCG-Russia IRR being 0.92 (95% confidence interval [CI], .81-1.05) by 6 weeks and 0.92 (95% CI, .82-1.02) by 6 months. By 6 months of age, there were significantly fewer BCG-Japan infants with no skin reaction (1%) than for BCG-Russia (2%), the risk ratio being 0.36 (95% CI, .16-.81). BCG-Japan skin reactions were also larger. Conclusions: Both vaccines induced a skin reaction in almost all participants. The BCG strains had comparable effects on morbidity and mortality, but BCG-Japan was associated with more and larger skin reactions that are indicators of lower mortality risk. Clinical Trials Registration: NCT03400878.

A retrospective audit of neonatal BCG vaccination in Grampian, Scotland.

Bacillus Calmette-Guerin (BCG) vaccine confers protection against tuberculosis (TB) and works most effectively when given to infants. Scotland runs a risk-based program in which BCG vaccine is offered to infants whose parent or grandparent was born in a high incidence country for TB. BCG vaccination records for all infants born in Grampian from 1st January 2019 to 31st December 2021 were reviewed from Nov 2022 to Feb 2023. Three electronic databases were examined, i.e. BadgerNet, Scottish Immunisation Recall System and TrakCare. Data were analyzed using Microsoft Excel 2013. Out of a total of 16,078 live births in the 3-year study period, 2060 met the criteria for offering BCG vaccination. The uptake level was 93% in 2019, 89% in 2020 (in the midst of the COVID-19 pandemic) and 93% in 2021. Audit results demonstrated higher uptake than the 85% key performance indicator target within the 2018 Scottish TB Framework and improvement in vaccination rates as compared to earlier rates of 86% in 2012 and 90% in 2013 in Grampian. Strengthening electronic systems and enhancing awareness regarding TB and the BCG vaccine can further progress BCG vaccination uptake.

Glucose metabolism and its role in the maturation and migration of human CD1c+ dendritic cells following exposure to BCG.

Introduction: Tuberculosis (TB) still kills over 1 million people annually. The only approved vaccine, BCG, prevents disseminated disease in children but shows low efficacy at preventing pulmonary TB. Myeloid dendritic cells (mDCs) are promising targets for vaccines and immunotherapies to combat infectious diseases due to their essential role in linking innate and adaptive immune responses. DCs undergo metabolic reprogramming following exposure to TLR agonists, which is thought to be a prerequisite for a successful host response to infection. We hypothesized that metabolic rewiring also plays a vital role in the maturation and migration of DCs stimulated with BCG. Consequently, we investigated the role of glycolysis in the activation of primary human myeloid CD1c+ DCs in response to BCG. Methods/results: We show that CD1c+ mDC mature and acquire a more energetic phenotype upon challenge with BCG. Pharmacological inhibition of glycolysis with 2-deoxy-D-glucose (2-DG) decreased cytokine secretion and altered cell surface expression of both CD40 and CCR7 on BCG-challenged, compared to untreated, mDCs. Furthermore, inhibition of glycolysis had differential effects on infected and uninfected bystander mDCs in BCG-challenged cultures. For example, CCR7 expression was increased by 2-DG treatment following challenge with BCG and this increase in expression was seen only in BCG-infected mDCs. Moreover, although 2-DG treatment inhibited CCR7-mediated migration of bystander CD1C+ DCs in a transwell assay, migration of BCG-infected cells proceeded independently of glycolysis. Discussion: Our results provide the first evidence that glycolysis plays divergent roles in the maturation and migration of human CD1c+ mDC exposed to BCG, segregating with infection status. Further investigation of cellular metabolism in DC subsets will be required to determine whether glycolysis can be targeted to elicit better protective immunity against Mtb.

Preoperative sarcopenia and systemic immune-inflammation index can predict response to intravesical Bacillus Calmette-Guerin instillation in patients with non-muscle invasive bladder cancer.

Background: To explore the prognostic significance of sarcopenia and systemic immune-inflammation index (SII) for response to intravesical Bacillus Calmette-Guerin (BCG) in patients with intermediate-, and high-risk non-muscle invasive bladder cancer (NMIBC). Methods: We retrospectively analyzed 183 consecutive patients treated in Qilu hospital of Shandong University for a first diagnosis of intermediate and high risk NMIBC. Using computed tomography scans at the third lumbar vertebra level, we calculated skeletal muscle index (SMI). Sarcopenia was defined as SMI <43 cm2/m2 for males with BMI < 25 kg/m2, <53 cm2/m2 for males with BMI ≥ 25 kg/m2, and <41 cm2/m2 for females. The response to intravesical BCG immunotherapy and relapse-free survival (RFS) were analyzed. Results: Compared with BCG responders, BCG non-responders were associated with sarcopenia (P < 0.001), carcinoma in situ (P < 0.001), T1 stage (P < 0.001), multiple tumor (P < 0.001), tumor diameter >=3cm (P < 0.001), and have a significant increase of neutrophil-to-lymphocyte ratio (NLR) (P < 0.001), platelet to lymphocyte ratio (PLR) (P = 0.004), SII (P < 0.001). The area under the ROC curve (AUC) of the BMI, NLR, PLR, and SII for response to intravesical BCG immunotherapy were 0.425, 0.693, 0.631, and 0.702 respectively. Logistic regression analysis demonstrated that sarcopenia and SII were predictors of response to intravesical BCG immunotherapy. The Kaplan-Meier survival analysis showed that the RFS of patients with BCG response, lower SII and no sarcopenia was significantly increased compared with that of patients with BCG non-response, higher SII and sarcopenia, respectively. Subgroup analysis demonstrated that the RFS of patients with high SII and sarcopenia was significantly decreased compared with those with low SII and no sarcopenia in Ta stage subgroup, T1 stage subgroup, non-Cis subgroup, multiple tumor subgroup, single tumor subgroup, tumor diameter≥3cm subgroup and tumor diameter<3cm subgroup, respectively (P < 0.05). However, there was no significant difference in RFS for patients in CIS subgroup (P > 0.05). Multivariate Cox analysis shown that sarcopenia (p=0.005) and high SII (p = 0.003) were significantly associated with poor RFS. Conclusions: Both sarcopenia and high SII are useful predictors of response to intravesical BCG in intermediate- and high-risk NMIBC patients. Patients with intermediate- and high-risk NMIBC that had sarcopenia or high SII at diagnosis were associated with poor RFS, and the combination of sarcopenia and SII may be a better predictor of RFS.

Tuberculosis vaccine BCG: the magical effect of the old vaccine in the fight against the COVID-19 pandemic.

Bacillus Calmette-Guérin (BCG) is a live attenuated M. bovis vaccine that was developed about 100 years ago by Albert Calmette and Camille Guérin. Many countries have been using the vaccine for decades against tuberculosis (TB). The World Health Organization (WHO) recommends a single dose of BCG for infants in TB endemic as well as leprosy high risk countries, and globally almost 130 million infants are vaccinated yearly. The role of BCG is well known in reducing neonatal and childhood death rates. Epidemiological and retrospective cross-sectional studies demonstrated that the BCG vaccination protects the children against respiratory tract infections and lowers the risk of malaria in children. In addition, BCG enhances IFN-γ and IL-10 levels, thus providing immunity against respiratory tract infection even in elderly people. The BCG is also known to provide nonspecific innate immunity against viruses and parasites, through an innate immune mechanism termed 'trained immunity' and is defined as the immunological recall of the innate immune system by epigenetic reprogramming. Based on these studies it is suggested that the BCG has the potential to act as a protective agent against COVID-19. Further proven safety records of BCG in humans, its adjuvant activity and low-cost manufacturing make it an attractive option to stop the pandemic and reduce the COVID-19 related mortality. In this review we discuss the heterologous effects of BCG, induction of trained immunity and its implication in development of a potential vaccine against COVID-19 pandemic.

Retesting the hypothesis that early Diphtheria-Tetanus-Pertussis vaccination increases female mortality: An observational study within a randomised trial.

BACKGROUND: There are worrying indications that diphtheria-tetanus-pertussis (DTP) vaccine has negative non-specific effects for females. We previously found, in a trial of early-Bacillus Calmette-Guérin (BCG) to low weight (LW) neonates, that receiving early-DTP (before 2 months of age), was associated with increased female mortality compared with no-DTP/delayed-DTP. Within a subsequent LW trial, we aimed to retest this observation. METHODS: Between 2010 and 2014, in Guinea-Bissau, 2,398 infants were randomised 1:1 to early-BCG (intervention) or delayed-BCG (standard practice for LW neonates) and visited at 2, 6 and 12 months of age to assess nutritional and vaccination status. DTP is recommended at 6 weeks of age. We examined the effect of having "early-DTP" versus "no-DTP" at the time of the 2-month visit on all-cause mortality between the 2- and 6-month visits in Cox models stratified by sex and adjusted for BCG-group and 2-month-weight-for-age (z-scores) providing adjusted mortality rate ratios (aMRRs). We analysed to which extent conditions varied between the present and the previous LW trials and how that might have affected the overall result of comparing the early-DTP and the no-DTP groups. RESULTS: At the time of the 2-month visit, 75% (1,795/2,398) had received DTP. Those vaccinated had better anthropometric indices than no-DTP infants at birth and by 2 months of age. Between the 2- and 6-month visits, 29 deaths occurred. The early-DTP/no-DTP aMRR was 1.09 (95% CI: 0.44-2.69); 1.19 (0.45-3.15) for females and 0.77 (0.14-4.19) for males. Compared to the previous study, the present study cohort had 56% (30-72%) lower overall mortality, fewer no-DTP infants, higher BCG vaccination coverage and several more oral polio vaccine campaigns. CONCLUSION: We did not find that early-DTP was associated with increased female mortality as found in a previous study; differences in results may partly be due to a decline in overall mortality and changes in vaccination practices.

CyTOF analysis identifies unusual immune cells in urine of BCG-treated bladder cancer patients.

High grade non-muscle-invasive bladder tumours are treated with transurethral resection followed by recurrent intravesical instillations of Bacillus Calmette Guérin (BCG). Although most bladder cancer patients respond well to BCG, there is no clinical parameter predictive of treatment response, and when treatment fails, the prognosis is very poor. Further, a high percentage of NMIBC patients treated with BCG suffer unwanted effects that force them to stop treatment. Thus, early identification of patients in which BCG treatment will fail is really important. Here, to identify early stage non-invasive biomarkers of non-responder patients and patients at risk of abandoning the treatment, we longitudinally analysed the phenotype of cells released into the urine of bladder cancer patients 3-7 days after BCG instillations. Mass cytometry (CyTOF) analyses revealed a large proportion of granulocytes and monocytes, mostly expressing activation markers. A novel population of CD15+CD66b+CD14+CD16+ cells was highly abundant in several samples; expression of these markers was confirmed using flow cytometry and qPCR. A stronger inflammatory response was associated with increased cell numbers in the urine; this was not due to hematuria because the cell proportions were distinct from those in the blood. This pilot study represents the first CyTOF analysis of cells recruited to urine during BCG treatment, allowing identification of informative markers associated with treatment response for sub-selection of markers to confirm using conventional techniques. Further studies should jointly evaluate cells and soluble factors in urine in larger cohorts of patients to characterise the arms of the immune response activated in responders and to identify patients at risk of complications from BCG treatment.

Secondary Prevention in Radiologically Isolated Syndromes and Prodromal Stages of Multiple Sclerosis.

Following the extraordinary progress in the treatment of multiple sclerosis (MS), two major unmet needs remain: understanding the etiology of the disease and, hence, designing definitive cures (this perspective is neither at hand, nor it can be taken for granted that the etiologic targets will be readily treatable); the prevention of an overt and disabling disease, which seems to be a more realistic and pragmatic perspective, as the integration of genetic data with endophenotypes, MRI, and other biomarkers ameliorates our ability to identify early neuroinflammation. Radiologically isolated syndrome (RIS; diagnosed when the unanticipated MRI finding of brain spatial dissemination of focal white matter lesions highly suggestive of MS occurs in subjects without symptoms of MS, and with normal neurological examinations) and the recently focused "prodromal MS" are conditions at risk of conversion toward overt disease. Here, we explore the possibility of secondary prevention approaches in these early stages of neuroinflammation. RIS and prodromal MS are rare conditions, which suggest the importance of Study Groups and Disease Registry to implement informative clinical trials. We summarize ongoing preventive approaches in the early stages of the demyelinating process, especially in RIS conditions. Moreover, we highlight the importance of the biomarkers and the predictors of evolution to overt disease, which may be useful to select the individuals at risk of conversion to clinically isolated syndrome (CIS) and/or clinically definite MS. Finally, we illustrate the importance of the endophenotypes to test the frontline immunomodulatory approach for preventive strategies. Future investigations, especially in relatives of patients, based on MRI techniques and biological studies (better with integrated approaches) may provide opportunities to understand the MS early causal cascade and may help to identify a "therapeutic window" to potentially reverse early disease processes.

Durable Expansion of TCR-δ Meta-Clonotypes After BCG Revaccination in Humans.

Mycobacterium bovis bacille Calmette-Guérin (BCG) has been used for 100 years and prevents disseminated tuberculosis and death in young children. However, it shows only partial efficacy against pulmonary tuberculosis (TB) in adults, so new vaccines are urgently needed. The protective efficacy of BCG depends on T cells, which are typically activated by pathogen-derived protein antigens that bind to highly polymorphic major histocompatibility complex (MHC) molecules. Some T cells recognize non-protein antigens via antigen presenting systems that are independent of genetic background, leading to their designation as donor-unrestricted T (DURT) cells. Whether live whole cell vaccines, like BCG, can induce durable expansions of DURT cells in humans is not known. We used combinatorial tetramer staining, multi-parameter flow cytometry, and immunosequencing to comprehensively characterize the effect of BCG on activation and expansion of DURT cell subsets. We examined peripheral blood mononuclear cells (PBMC) derived from a Phase I study of South African adults in which samples were archived at baseline, 3 weeks, and 52 weeks post-BCG revaccination. We did not observe a change in the frequency of total mucosal-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, germline encoded mycolyl-reactive (GEM) T cells, or γδ T cells at 52 weeks post-BCG. However, immunosequencing revealed a set of TCR-δ clonotypes that were expanded at 52 weeks post-BCG revaccination. These expanded clones expressed the Vδ2 gene segment and could be further defined on the basis of biochemical similarity into several 'meta-clonotypes' that likely recognize similar epitopes. Our data reveal that BCG vaccination leads to durable expansion of DURT cell clonotypes despite a limited effect on total circulating frequencies in the blood and have implications for defining the immunogenicity of candidate whole cell TB vaccines.

Association Between Antibiotic Treatment and the Efficacy of Intravesical BCG Therapy in Patients With High-Risk Non-Muscle Invasive Bladder Cancer.

OBJECTIVE: To investigate the association between antibiotic therapy and the efficacy of intravesical BCG therapy in patients with high-risk non-muscle invasive bladder cancer (NMIBC). METHODS: This study involved the retrospective review of medical records of patients who underwent transurethral resection of bladder tumors for high-risk NMIBC followed by intravesical BCG therapy between 2008 and 2017. Patients were categorized as none, short- (2-6 days), and long-course use (≥7 days) based on the duration of antibiotic treatment concurrent with or initiated ≤30 days before BCG therapy. Oncologic outcomes, including recurrence-free survival and progression-free survival, were analyzed. RESULTS: Of the 276 patients enrolled in the study, 162 (58.7%) had pathologic T1 disease and 206 (80.2%) had high-grade disease. Concurrently with or prior to BCG therapy, 114 patients had (41.3%) received short-course antibiotic therapy, and 96 (34.8%) patients had received long-course antibiotics. The 5-year recurrence-free survival (62.2% vs 26.9%; log rank, p <0.001) and progression-free survival (79.6% vs. 53.3%; log rank, p=0.001) rates were significantly higher in patients who did not receive antibiotic therapy than in those treated with long-course antibiotics. Multivariable analysis revealed that antibiotic treatment for more than 7 days was independently associated with increased risks of recurrence (hazard ratio [HR], 2.45; 95% confidence interval [CI], 1.49-4.05; p < 0.001) and progression (HR, 3.68; 95% CI, 1.65-8.22 p = 0.001). CONCLUSION: Long-course antibiotic treatment concurrently with or prior to intravesical BCG adversely influenced disease recurrence and progression outcomes in patients with high-risk NMIBC. Careful use of antibiotics may be required to enhance the efficacy of intravesical BCG therapy. Further mechanistic and prospective studies are warranted.

Is the tuberculosis vaccine BCG an alternative weapon for developing countries to defeat COVID-19?

BACKGROUD: Coronavirus disease (COVID-19) is a new respiratory infectious disease, and there is no vaccine currently. Previous studies have found that BCG vaccination can provide extensive protection against respiratory infectious diseases. METHODS: Herein, we obtained the latest data from the World Health Organization (WHO) as of August 12, 2020, and determined the relationship between three parameters (including the BCG vaccination coverage, human development index (HDI), and transmission classifications) and the incidence rate and mortality of COVID-19. RESULTS: The results showed that the morbidity and mortality of COVID-19 in countries with BCG vaccination recommendation were significantly lower than these in countries without BCG vaccination recommendation, and countries with lower HDI have lower morbidity and mortality. In addition, we also found that the mode of virus transmission is also related to the morbidity and mortality of COVID-19. CONCLUSIONS: Although our data supports the hypothesis that BCG vaccination is beneficial in reducing the morbidity and mortality of COVID-19, the data supporting this result may be inaccurate due to many confounders such as PCR testing rate, population characteristics, and protection strategies, the reliability of this result still needs to be verified by clinical trials.

A Survey Among Italian Physicians During COVID-19 Outbreak. Could Bacillus Calmette-Guérin Vaccine Be Effective Against SARS-CoV2?

Background: Epidemiological studies show that BCG-vaccinated population seems to be more likely protected from COVID-19 infection, but WHO gave a stark warning on use of BCG vaccine without confirmed COVID-19 trials. The aim of the study is to evaluate whether TB vaccination, performed several years earlier, could confer protection against COVID-19. Methods: After the Ethical Committee authorization, professional orders were used to contact physicians with an online survey. Specialty, COVID-19 infection and previous BCG vaccination were recorded. Statistical data analysis was performed. Results: 1906 physicians answered the questionnaire, (M = 1068; F = 838; mean age 50.7 ± 13.3 years; range 24-87), more than half (1062; 55.7%) experienced BCG vaccination. Professional activity was recorded, and only 49 subjects (2.6%) of them were infected by SARS-CoV2. Among the group of infected people, asymptomatic form occurred in 12 subjects (24.5%); a pauci-symptomatic form in 24 subjects (49.0%); and a severe form (pneumonia and/or respiratory distress) in 13 (26.5%). Considering only the clinically relevant form of COVID-19, period prevalence was 2.2% (23/1062) in the vaccinated group and 1.7% (14/844) in the unvaccinated group (OR: 1.31, 95% C.I.: 0.68-2.63, p = 0.427). Conclusion: Our experience does not confirm the possible protective role of BCG vaccination, performed years earlier, against COVID-19. Although recent epidemiological studies point out in BCG-vaccinated population a lower prevalence of SARS-CoV2 infection, in our cohort of physicians no significant difference was found in terms of prevalence of COVID-19 infection. Our data underline the necessity to follow the WHO warning about the indiscriminate use of BCG vaccine, until clear evidence of protection by BCG vaccination against COVID-19 is fully demonstrated.

Cheap and Commonplace: Making the Case for BCG and γδ T Cells in COVID-19.

Antigen-specific vaccines developed for the COVID-19 pandemic demonstrate a remarkable achievement and are currently being used in high income countries with much success. However, new SARS-CoV-2 variants are threatening this success via mutations that lessen the efficacy of antigen-specific antibodies. One simple approach to assisting with this issue is focusing on strategies that build on the non-specific protection afforded by the innate immune response. The BCG vaccine has been shown to provide broad protection beyond tuberculosis disease, including against respiratory viruses, and ongoing studies are investigating its efficacy as a tool against SARS-CoV-2. Gamma delta (γδ) T cells, particularly the Vδ2 subtype, undergo rapid expansion after BCG vaccination due to MHC-independent mechanisms. Consequently, γδ T cells can produce diverse defenses against virally infected cells, including direct cytotoxicity, death receptor ligands, and pro-inflammatory cytokines. They can also assist in stimulating the adaptive immune system. BCG is affordable, commonplace and non-specific, and therefore could be a useful tool to initiate innate protection against new SARS-CoV-2 variants. However, considerations must also be made to BCG vaccine supply and the prioritization of countries where it is most needed to combat tuberculosis first and foremost.

Characterizing the BCG Induced Macrophage and Neutrophil Mechanisms for Defense Against Mycobacterium tuberculosis.

The live attenuated Mycobacterium bovis strain, Bacille Calmette Guérin (BCG) is a potent innate immune stimulator. In the C57BL/6 mouse model of tuberculosis, BCG vaccination leads to a significant reduction of Mycobacterium tuberculosis burden after aerogenic infection. Our studies indicated that BCG induced protection against pulmonary tuberculosis was independent of T cells and present as early as 7 days after vaccination. This protection showed longevity, as it did not wane when conventional T cell and TNF-α deficient mice were infected 30 days post-vaccination. As BCG induced mycobacterial killing after 7 days, this study investigated the contributions of the innate immune system after BCG vaccination to better understand mechanisms required for mycobacterial killing. Subcutaneous BCG inoculation resulted in significant CD11b+F4/80+ monocyte subset recruitment into the lungs within 7 days. Further studies revealed that killing of mycobacteria was dependent on the viability of BCG, because irradiated BCG did not have the same effect. Although others have identified BCG as a facilitator of trained innate immunity, we found that BCG reduced the mycobacterial burden in the absence of mechanisms required for trained innate immunity, highlighting a role for macrophages and neutrophils for vaccine induced killing of M. tuberculosis.