Macrophages directly kill bladder cancer cells through TNF signaling as an early response to BCG therapy.

The Bacillus Calmette-Guérin (BCG) vaccine is the oldest cancer immunotherapeutic agent in use. Despite its effectiveness, its initial mechanisms of action remain largely unknown. Here, we elucidate the earliest cellular mechanisms involved in BCG-induced tumor clearance. We developed a fast preclinical in vivo assay to visualize in real time and at single-cell resolution the initial interactions among bladder cancer cells, BCG and innate immunity using the zebrafish xenograft model. We show that BCG induced the recruitment and polarization of macrophages towards a pro-inflammatory phenotype, accompanied by induction of the inflammatory cytokines tnfa, il1b and il6 in the tumor microenvironment. Macrophages directly induced apoptosis of human cancer cells through zebrafish TNF signaling. Macrophages were crucial for this response as their depletion completely abrogated the BCG-induced phenotype. Contrary to the general concept that macrophage anti-tumoral activities mostly rely on stimulating an effective adaptive response, we demonstrate that macrophages alone can induce tumor apoptosis and clearance. Thus, our results revealed an additional step to the BCG-induced tumor immunity model, while providing proof-of-concept experiments demonstrating the potential of this unique model to test innate immunomodulators.

Evidence of innate training in bovine γδ T cells following subcutaneous BCG administration.

The Bacillus Calmette Guerin (BCG) vaccine has been shown to induce non-specific protection against diseases other than tuberculosis in vaccinated individuals, attributed to the induction of trained immunity. We have previously demonstrated that BCG administration induces innate immune training in mixed peripheral blood mononuclear cells and monocytes in calves. Gamma Delta (γδ) T cells are non-conventional T cells that exhibit innate and adaptive immune system features. They are in higher proportion in the peripheral blood of cattle than humans or rodents and play an essential role in bovine immune response to pathogens. In the current study, we determined if BCG administration induced innate immune training in bovine γδ T cells. A group of 16 pre-weaned Holstein calves (2-4 d age) were enrolled in the study and randomly assigned to vaccine and control groups (n=8/group). The vaccine group received two doses of 106 colony forming units (CFU) BCG Danish strain subcutaneously, separated by 2 weeks. The control group remained unvaccinated. Gamma delta T cells were purified from peripheral blood using magnetic cell sorting three weeks after receiving the 1st BCG dose. We observed functional changes in the γδ T cells from BCG-treated calves shown by increased IL-6 and TNF-α cytokine production in response to in vitro stimulation with Escherichia coli LPS and PAM3CSK4. ATAC-Seq analysis of 78,278 regions of open chromatin (peaks) revealed that γδ T cells from BCG-treated calves had an altered epigenetic status compared to cells from the control calves. Differentially accessible peaks (DAP) found near the promoters of innate immunity-related genes like Siglec14, Irf4, Ifna2, Lrrfip1, and Tnfrsf10d were 1 to 4-fold more accessible in cells from BCG-treated calves. MOTIF enrichment analysis of the sequences within DAPs, which explores transcription factor binding motifs (TFBM) upstream of regulatory elements, revealed TFBM for Eomes and IRF-5 were among the most enriched transcription factors. GO enrichment analysis of genes proximal to the DAPs showed enrichment of pathways such as regulation of IL-2 production, T-cell receptor signaling pathway, and other immune regulatory pathways. In conclusion, our study shows that subcutaneous BCG administration in pre-weaned calves can induce innate immune memory in the form of trained immunity in γδ T cells. This memory is associated with increased chromatin accessibility of innate immune response-related genes, thereby inducing a functional trained immune response evidenced by increased IL-6 and TNF-α cytokine production.

Developments in conservative treatment for BCG-unresponsive non-muscle invasive bladder cancer.

INTRODUCTION: To reduce the risk of disease recurrence and progression of intermediate and high-risk Non-Muscle Invasive Bladder Cancers (NMIBCs), intravesical adjuvant treatment with Bacillus Calmette-Guerin (BCG) represents the standard of care, although up to 50% of patients will eventually recur and up to 20% of them will progress to Muscle Invasive Bladder Cancer (MIBC). Radical Cystectomy (RC) is the treatment of choice in this setting; however, this represents a major and morbid surgery, thus meaning that not all NMIBCs patient could undergo or may refuse this procedure or may refuse. The search for effective bladder sparing strategies in NMIBCs BCG-unresponsive patients is a hot topic in the urologic field. AREAS COVERED: We aimed to review the most important bladder-preserving strategies for BCG unresponsive disease, from those used in the past, even though rarely used nowadays (intravesical chemotherapy with single agents), to current available therapies (e.g. intravesical instillation with Gemcitabine-Docetaxel), and to future upcoming treatments (Oportuzumab Monatox). EXPERT OPINION: At present, bladder-preserving treatments in BCG-unresponsive patients are represented by the use of intravesical instillations, systemic immunotherapies, both with good short-term and modest mid-term efficacy, and numerous clinical trials ongoing, with encouraging initial results, in which patients could be recruited.

Signal mining and gender differences analysis of adverse events in NMIBC treatment with gemcitabine and BCG bladder instillation based on the FAERS database.

OBJECTIVE: To explore safety differences and perform a gender-based analysis of adverse events related to gemcitabine and Bacillus Calmette-Guérin (BCG) vaccine using the U.S. FDA Adverse Event Reporting System (FAERS) database. METHODS: Using the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) methods, adverse events associated with gemcitabine and BCG were mined from FAERS database reports spanning from Q1 2004 to Q3 2023. RESULTS: The study extracted 37,855 reports with gemcitabine and 5,455 reports with BCG as the primary suspected drugs. Adverse events were more prevalent in males (male-to-female ratio: gemcitabine 1.10, BCG 4.25). Differences in high-frequency adverse events among the top 20 signals were detected for both drugs. Both drugs affected similar organ systems, including potential pulmonary, ocular, and renal toxicity, with gemcitabine showing a broader range of adverse events. Gender analysis revealed fewer adverse reactions to gemcitabine in females, while males had fewer adverse reactions to BCG. CONCLUSION: Differences in high-frequency adverse events between gemcitabine and BCG, including some not listed on drug labels, were observed. Both drugs affect similar organ systems, with gemcitabine showing a broader range of adverse events. Gender differences in adverse events were notable.

BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial.

OBJECTIVES: Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19. DESIGN: Phase III double blind randomised controlled trial. SETTING: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic. PARTICIPANTS: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG. INTERVENTION: Randomised 1:1 using a web-based procedure to receive a single 0.1mL intradermal dose of BCG-Denmark (BCG group, n=1999) or saline (placebo group, n=1989). MAIN OUTCOME MEASURES: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12-months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion). RESULTS: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6% to 24.5%) compared with the placebo group (19.6%; 95%CI 17.6% to 21.5%); adjusted difference +3.0 percentage points (95%CI 0.2% to 5.8%; p=0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95%CI 9.5% to 12.4%) compared with 9.6% in the placebo group (95%CI 8.3% to 11.1%); adjusted difference +1.3 percentage points (95%CI -0.7% to 3.3%, p=0.2). Breakthrough COVID-19 (post COVID-19 vaccination), and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95%CI 0.60 to 4.02, p=0.4) and two deaths due to COVID-19, both in the placebo group. CONCLUSIONS: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among health care workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.

Invasive Mycobacterium bovis Infection Outside the Genitourinary Tract Following Bacille Calmette-Guerin Therapy for Non-muscle Invasive Bladder Cancer.

Bladder cancer significantly impacts global health, particularly non-muscle-invasive bladder cancer (NMIBC), which is typically treated with transurethral resection of bladder tumor (TURBT) and intravesical Bacillus Calmette-Guérin (BCG) therapy. While there is evidence that BCG can effectively prevent tumor recurrence and progression, it can cause adverse effects, including disseminated infection, necessitating the exclusion of active tuberculosis and the assessment of immunosuppressive conditions before treatment. We present two cases of disseminated BCG infection. The first involves an 85-year-old male who developed an abscess in his right thigh post-BCG therapy, successfully treated with isoniazid (INH), ethambutol, and rifampin. The second case is a 63-year-old male who, three years post-BCG therapy and abdominal aortic aneurysm repair, developed a right psoas abscess and a mycotic aneurysm. He was also treated with ethambutol, INH, and rifampin, in addition to surgical intervention. Effective management of BCG-related infections requires early identification of Mycobacterium bovis, a multidisciplinary approach, thorough pre-treatment evaluations, and aggressive treatment strategies, including anti-tubercular drugs and surgical intervention as necessary.

The clinical significance and anti-tumor role of PRKG1 in bladder cancer.

Introduction: cGMP-dependent protein kinase 1 (PRKG1) has shown to be associated with some tumorigenesis, while the role of PRKG1 in bladder cancer is unclear. Methods: To investigate the biological and clinical significance of PRKG1 in bladder cancer, we detected the expression of PRKG1 and explored the function of PRKG1 in bladder cancer cells. The PRKG1 transcripts data was downloaded from The Cancer Genome Atlas (TCGA) database, and immunohistochemistry staining was conducted on formalin-fixed paraffin-embedded (FFPE) sample tissues. Relationship between clinical characteristics of patients and expression of PRKG1 was analyzed in FFPE samples, TCGA database, and GSE19423 dataset. PRKG1 was over-expressed, and cell proliferation, migration, invasion, apoptosis, and spheroidizing ability were then detected. Chemosensitivity to cisplatin was detected with cell viability, and half-maximal drug inhibitory concentration (IC50) was calculated. In addition, the relation between PRKG1 expression and the infiltration level of tumor immune cells in tumor microenvironment were analyzed. Results: The results showed expression of PRKG1 was lower in bladder cancer, compared with normal tissues both at protein and transcript levels. Lower PRKG1 expression was related to higher tumor grade, T stage, and muscle invasion, also predicted worse overall survival and recurrence free survival in patients treated with Bacillus Calmette-Guerin (BCG) intravesical immunotherapy. Analysis of tumor immune cells infiltration showed lower PRKG1 was associated with non-inflamed tumor microenvironment. Conclusion: The present study firstly identified the anti-tumor role and tumor immune regulatory role of PRKG1, also found loss of PRKG1 could be used as a prognosis factor. The present study provided a potential biomarker and therapy target to bladder cancer.

Sex-specific epigenetic signatures of circulating urate and its increase after BCG vaccination.

Background: Urate concentration and the physiological regulation of urate homeostasis exhibit clear sex differences. DNA methylation has been shown to explain a substantial proportion of serum urate variance, mediate the genetic effect on urate concentration, and co-regulate with cardiometabolic traits. However, whether urate concentration is associated with DNA methylation in a sex-dependent manner is unknown. Additionally, it is worth investigating if urate changes after perturbations, such as vaccination, are associated with DNA methylation in a sex-specific manner. Methods: We investigated the association between DNA methylation and serum urate concentrations in a Dutch cohort of 325 healthy individuals. Urate concentration and DNA methylation were measured before and after Bacillus Calmette-Guérin (BCG) vaccination, used as a perturbation associated with increased gout flares. The association analysis included united, interaction, and sex-stratified analysis. Validation of the identified CpG sites was conducted using three independent cohorts. Results: 215 CpG sites were associated with serum urate in males, while 5 CpG sites were associated with serum urate in females, indicating sex-specific associations. Circulating urate concentrations significantly increased after BCG vaccination, and baseline DNA methylation was associated with differences in urate concentration before and after vaccination in a sex-specific manner. The CpG sites associated with urate concentration in males were enriched in neuro-protection pathways, whereas in females, the urate change-associated CpG sites were related to lipid and glucose metabolism. Conclusion: Our study enhances the understanding of how epigenetic factors contribute to regulating serum urate levels in a sex-specific manner. These insights have significant implications for the diagnosis, prevention, and treatment of various urate-related diseases and highlight the importance of personalized and sex-specific approaches in medicine.

Association Between Residual Urine Volume and Recurrence Among Patients at High Risk of Non-Muscle-Invasive Bladder Carcinoma With Versus Without Bacillus Calmette-Guérin Treatment.

Non-muscle-invasive bladder carcinoma often occurs in older adults, who often also have urinary dysfunction. The residual urine volume is an important indicator of urinary dysfunction. However, the impact of the residual urine volume on intravesical recurrence remains unclear. In the present study, we analyzed the data of 372 patients at high or very high risk of cancer progression according to the Japanese Urological Association classification who had undergone transurethral resection of a bladder tumor. In univariate analysis, postoperative absence of intravesical Bacillus Calmette-Guérin (BCG) induction was an independent risk factor for intravesical recurrence (hazard ratio 1.94, absence versus presence, p = 0.0019). The incidence of intravesical recurrence did not significantly differ between the mild, intermediate, and severe residual urine groups in the total cohort. Among the BCG-treated cohort, the three groups showed similar trends. Among the non-BCG-treated cohort, although the patients with more than 100 ml of residual urine tended to have more intravesical recurrence than patients with a smaller residual urine volume, this difference did not reach statistical significance. BCG treatment is recommended for patients at high risk of bladder carcinoma. Patients with a large residual urine volume without BCG treatment may be at high risk of intravesical recurrence.

BCG vaccination is associated with longitudinal changes in systemic eicosanoid levels in elderly individuals: A secondary outcome analysis.

We investigated how BCG vaccination affects the levels of certain eicosanoids, namely Leukotriene B4, 15-epimer of LXA4, prostaglandin F2, Lipoxin A4, Prostaglandin E2 and Resolvin D1 in the plasma of healthy elderly individuals (aged 60-80) before vaccination, one month post-vaccination (M1), and six months post-vaccination (M6). This study is part of the clinical trial "BCG Vaccine Study: Reducing COVID-19 Impact on the Elderly in Indian Hotspots," registered in the clinical trial registry (NCT04475302). While some primary outcomes have been previously reported, this analysis delves into the immunological outcomes. Our findings indicate that BCG vaccination leads to reduced plasma levels of 15-epi-LXA4, LXA4, PGE2, and Resolvin D1 at both M1 and M6. In contrast, there is a notable increase in circulating levels of LTB4 at these time points following BCG vaccination. This underscores the immunomodulatory effects of BCG vaccination and hints at its potential to modulate immune responses by dampening inflammatory reactions.

Assessing the impact of COVID-19 on routine immunization in Sierra Leone.

BACKGROUND: The COVID-19 pandemic had a profound impact on healthcare systems and services, including routine immunization (RI). To date, there is limited information on the effects of the COVID-19 pandemic on RI in West African countries such as Sierra Leone, which had already experienced public health emergencies that disrupted its healthcare system. Here, we describe the impact of the COVID-19 pandemic on the RI of key antigens in Sierra Leone. METHODS: We used vaccination data from the District Health Information System for BCG, measles-rubella 1 and 2, and pentavalent 1 and 3 antigens. We compared 2019, 2020, 2021, and 2022 annual coverage rates for the selected antigens at the national and district levels. We used the Pearson chi-square test to assess the difference between annual coverage rates between 2019 and 2020, 2020-2021, and 2021-2022. RESULTS: National coverage rates for all antigens declined in 2019-2020, notably measles-rubella 1 and pentavalent 3 (-5.4% and - 4.9%). Between 2020 and 2021, there was an overall increase in coverage (+ 0.2% to + 2.5%), except for measles-rubella 2 (-1.8%). Measles-rubella antigens rebounded in 2021-2022, while others decreased between - 0.5 and - 1.9% in coverage. Overall, all district-level coverage rates in 2022 were lower than those in 2019. Most districts decreased between 2019 and 2022, though a few had a continuous increase; some had an increase/recovery between 2020 and 2021; some districts had recovered 2019 levels by 2022. CONCLUSION: The COVID-19 pandemic impacted Sierra Leone's national BCG, measles-rubella, and pentavalent antigen immunization, which were not fully restored in 2022. Most districts experienced notable coverage declines during the pandemic, though a few reached or surpassed 2019 rates in 2022. Examining pandemic impact can benefit from a focus beyond the national level to identify vulnerable regions. Sierra Leone's post-pandemic RI reestablishment needs targeted strategies and continual investments for equitable access and coverage, as well as to prevent vaccine-preventable diseases.

Vesical Endometriosis in a male patient on treatment for papillary urothelial carcinoma.

Endometriosis denotes the abnormal growth of tissue resembling endometrium in ectopic sites and has largely been studied in women of reproductive age. It is an extremely rare phenomenon in men. We came across an exceptional clinical scenario of histologically proven bladder endometriosis in a 66-year-old man in relook bladder biopsy following completion of adjuvant intravesical Bacillus Calmette-Guerin induction course for G3pTa bladder cancer. We have pencilled down pathophysiology and commonly seen predisposing factors for "endometriosis in male patients" from available case reports and applied those findings to hypothesise the disease profile of our patient in this case report.

Dosage and organic acid residue of MOG35-55 peptide influences immunopathology and development of BCG induced experimental autoimmune encephalomyelitis (EAE).

Experimental autoimmune encephalomyelitis (EAE) serves as a model for studying multiple sclerosis, with immunization strategies utilizing MOG35-55 peptide, emulsified in adjuvant enriched with mycobacterium tuberculosis (Mtb). This study examined the effects of Bacillus Calmette-Guérin (BCG) as an adjuvant, alongside the impact of MOG35-55 peptide doses and their residual counter ions on EAE development. We found that BCG can be effectively used to induce EAE with similar incidence and severity as heat-killed H37Ra, contingent upon the appropriate MOG35-55 peptide dose. Different immunization doses of MOG35-55 peptide significantly affect EAE development, with higher doses leading to a paradoxical reduction in disease activity, probably due to peripheral tolerance mechanisms. Furthermore, doses of MOG35-55 peptides with acetate showed a more pronounced effect on disease development compared to those containing trifluoroacetic acid (TFA), suggesting the potential influence of residual counter ions on EAE activity. We highlighted the feasibility of applying BCG to the establishment of EAE for the first time. Our findings emphasized the importance of MOG peptide dosage and composition in modulating EAE development, offering insights into the mechanisms of autoimmunity and tolerance. This could have implications for autoimmune disease research and the design of therapeutic strategies.

Seasonal variation in BCG-induced trained immunity.

The Bacille Calmette-Guerin (BCG) vaccine is a well-established inducer of innate immune memory (also termed trained immunity), causing increased cytokine production upon heterologous secondary stimulation. Innate immune responses are known to be influenced by season, but whether seasons impact induction of trained immunity is not known. To explore the influence of season on innate immune memory induced by the BCG vaccine, we vaccinated healthy volunteers with BCG either during winter or spring. Three months later, we measured the ex vivo cytokine responses against heterologous stimuli, analyzed gene expressions and epigenetic signatures of the immune cells, and compared these with the baseline before vaccination. BCG vaccination during winter induced a stronger increase in the production of pro-inflammatory cytokines by peripheral blood mononuclear cells (PBMCs) upon stimulation with different bacterial and fungal stimuli, compared to BCG vaccination in spring. In contrast, winter BCG vaccination resulted in lower IFNγ release in PBMCs compared to spring BCG vaccination. Furthermore, NK cells of the winter-vaccinated people had a greater pro-inflammatory cytokine and IFNγ production capacity upon heterologous stimulation. BCG had only minor effects on the transcriptome of monocytes 3 months later. In contrast, we identified season-dependent epigenetic changes in monocytes and NK cells induced by vaccination, partly explaining the higher immune cell reactivity in the winter BCG vaccination group. These results suggest that BCG vaccination during winter is more prone to induce a robust trained immunity response by activating and reprogramming the immune cells, especially NK cells. (Dutch clinical trial registry no. NL58219.091.16).

Enhanced efficacy of BCG vaccine formulated in adjuvant is dependent on IL-17A expression.

A new, more effective vaccine against tuberculosis (TB) is urgently needed to curtail the current TB problem. The only licensed vaccine, BCG, has been shown to have highly variable protective efficacy in several clinical trials ranging from zero to 80 % against TB disease. We have previously reported that BCG formulated in dimethyl dioctadecyl-ammonium bromide (DDA) with D-(+)-Trehalose 6,6'-Dibehenate (TDB) adjuvant (BCG + Adj) is significantly more protective than BCG alone following murine aerosol Mycobacterium tuberculosis infection. Here we investigate the immunological basis for this improved efficacy by examining expression of different immune markers and cytokines in the lungs of vaccinated mice after M. tuberculosis aerosol challenge. We found significantly greater numbers of pulmonary IL-17A-expressing CD4+ T cells in mice immunized with BCG+Adj as compared to nonvaccinated and BCG-immunized mice at one-month post-challenge and that the enhanced protection was abrogated in IL-17A-deficient mice. Furthermore, we found significantly higher levels of IL-17A, IL-12p40 and IL-33 expression in the lungs of BCG + Adj immunized animals relative to nonvaccinated mice after M. tuberculosis challenge. These results demonstrate that the DDA/TDB adjuvant increases expression of IL-17A in response to the BCG vaccine and that these augmented IL-17A levels enhance control of M. tuberculosis infection.

N-803 Plus BCG Treatment for BCG-Naïve or -Unresponsive Non-Muscle Invasive Bladder Cancer: A Plain Language Review.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of two studies that looked at the safety and effectiveness of a potential new treatment, N-803 (Anktiva), in combination with a standard treatment bacillus Calmette-Guerin (BCG) for people with non-muscle invasive bladder cancer (NMIBC).One study was a Phase 1b study that tested increasing doses of N-803 in combination with the same dose of BCG in people with NMIBC who had never received BCG previously (BCG-naive). The other study is a Phase 2/3 study of N-803 and BCG in people with NMIBC whose cancer wasn't eliminated by BCG alone (BCGunresponsive). WHAT HAPPENED IN THE STUDIES?: In the Phase 1b study, the nine participants were split into three groups of 3 participants who received a dose of 100, 200, or 400 µg N-803 along with a standard 50 mg dose of BCG. In the Phase 2/3 study, one group (cohort A) of participants with carcinoma in situ (CIS) disease and another group (cohort B) with papillary disease were treated with 400 µg N-803 plus 50 mg BCG. There was also a cohort C that received only 400 µg N-803. Treatments were delivered directly into the bladder once a week for 6 weeks in a row. WHAT WERE THE KEY TAKEAWAYS?: N-803 plus BCG eliminated NMIBC in all nine BCG-naive participants and the effects were long-lasting, with participants remaining NMIBC-free for a range of 8.3 to 9.2 years.As reported in 2022, cancer was eliminated in 58 of 82 (71%) participants with BCG-unresponsive CIS disease and the effect was also long-lasting. Importantly, approximately 90% of the successfully treated participants avoided surgical removal of the bladder. In cohort B participants with papillary disease, 40 of 72 (55.4%) were cancer-free 12 months after treatment. N-803 used alone was only effective in 2 of 10 participants. In both studies, the combination of N-803 and BCG was found to be associated with very few adverse events.Based on results from the Phase 2/3 study, the U.S. Food and Drug Association (FDA) approved the use of N-803 plus BCG for the treatment of BCG-unresponsive bladder CIS with or without Ta/T1 papillary disease.Clinical Trial Registration: NCT02138734 (Phase 1b study), NCT03022825 (Phase 2/3 study).

Addition of the IL-15 superagonist N-803 to BCG therapy produces a high rate of success in eliminating non-muscle invasive bladder cancer in both BCG-naive and BCG-unresponsive patients, with long-lasting effects that allow patients to avoid surgical removal of the bladder.

Partial long-term clinical improvement after a BCG challenge in systemic lupus erythematosus-prone mice.

Systemic Lupus Erythematosus (SLE) is an autoimmune disorder that causes a breakdown of immune tolerance. Current treatments mainly involve general immunosuppression, increasing the risk of infections. On the other hand, Bacillus Calmette-Guérin (BCG) has been investigated as a potential therapy for autoimmune diseases in recent years, prompting an ongoing investigation. This study aimed to evaluate the effect of BCG vaccination on early and late clinical presentation of SLE in a murine disease model. MRL/MPJ-Faslpr mice were immunized with BCG or treated with PBS as a control. The progress of the disease was evaluated at 27 days post-immunization (dpi) (early) and 56 dpi (late). Clinical parameters and proteinuria were monitored. Blood samples were collected for measurement of antinuclear antibodies (ANAs), anti-double-stranded DNA (anti-dsDNA), and cytokine determination was performed using ELISA. Samples collected from mice were analyzed by flow cytometry and histopathology. We observed a clinical improvement in BCG-treated mice, reduced proteinuria in the latter stages of the disease, and decreased TNF-α. However, BCG did not elicit significant changes in ANAs, anti-dsDNA, histopathological scores, or immune cell infiltration. BCG was only partially beneficial in an SLE mouse model, and further research is needed to determine whether the immunity induced by this vaccine can counteract lupus's autoimmune response.

Neonatal BCG Vaccination for Prevention of Allergy in Infants: The MIS BAIR Randomised Controlled Trial.

BACKGROUND: The beneficial off-target effects of Bacille Calmette-Guérin (BCG) vaccination potentially include protection against allergy. OBJECTIVE: In the MIS BAIR trial, we aimed to determine whether neonatal BCG vaccination reduces atopic sensitisation and clinical food allergy in infants. METHODS: In this randomised controlled trial, 1272 neonates were allocated to BCG-Denmark vaccine (0.05 mL intradermal dose) or no BCG at birth. Randomisation was stratified by recruitment site, mode of delivery and plurality of birth. The primary outcome was the incidence of atopic sensitisation determined by skin prick test at 1 year of age. Food allergy was determined by 3-monthly online questionnaires and oral food challenges. Data were analysed by intention-to-treat using binary regression. CLINICALTRIALS: gov (NCT01906853). RESULTS: Atopic sensitisation during the first year of life was 22.9% among infants in the BCG group and 18.9% in the control group (adjusted risk difference (aRD) 3.8% (95% CI -1.5 to 9.1) after multiple imputation). Clinical food allergy was similar between infants in the BCG and control groups (9.8% vs. 9.6%; aRD 0.2, 95% CI -3.4 to 3.8). An interaction was observed between the primary outcome and maternal history of BCG vaccination. No interaction was observed for the additional prespecified potential effect modifiers tested (sex, delivery mode, family history of any allergy, season of birth, hepatitis B vaccination at randomisation, BCG scar and age at BCG administration). CONCLUSIONS AND CLINICAL RELEVANCE: Neonatal BCG-Denmark vaccination does not protect against atopic sensitisation or clinical food allergy in the first year of life.

Accelerated Bacille Calmette-Guérin reactions: More than meets the eye.

An accelerated local injection site reaction following Bacille Calmette-Guérin (BCG) vaccination has been associated with underlying active tuberculosis (TB) in high TB-prevalence settings. The clinical significance of this accelerated BCG reaction in individuals without TB symptoms, particularly in low TB-prevalence countries, is unclear. Using safety surveillance data and baseline interferon-gamma release assays (IGRA) within an international randomised trial of BCG vaccination in healthcare workers (the BRACE trial), we aimed to determine the incidence, and investigate for clinical implications, of an accelerated BCG reaction in asymptomatic adults in low and high TB-prevalence settings. An accelerated BCG reaction occurred in 755/1984 (38 %) of BCG-vaccinees. Although more frequently painful, tender, erythematous and/or swollen within the first fourteen days of vaccination, compared with non-accelerated reactions, the majority of injection site reactions were mild and did not meet criteria for an adverse event. Prior mycobacterial exposure, through prior BCG vaccination (OR 2.46, 95%CI 1.93-3.13, p < 0.001) or latent TB infection (OR 4.17, 95%CI 1.16-14.93, p = 0.03), and female sex (OR 1.27, 95%CI 1.03-1.57, p = 0.02), were key determinants for the occurrence of an accelerated BCG reaction. The development of an accelerated local reaction to BCG vaccination in an individual without prior history of BCG vaccination, should prompt consideration of further investigations for potential underlying TB infection.

Mycobacterium bovis BCG reverses deleterious effects of H. pylori components towards gastric barrier cells in vitro.

Mycobacterium bovis (M. bovis) Bacillus Calmette-Guerin (BCG) strain used in immunotherapy of bladder cancer (onco-BCG) due to its acid tolerance can be a candidate for prevention or reversion of deleterious effects towards gastric cell barrier initiated by gastric pathogen Helicobacter pylori (Hp) with high resistance to commonly used antibiotics. Colonization of gastric mucosa by Hp promotes oxidative stress, apoptosis resulting in the gastric barrier damage. The aim of this study was to examine the ability of onco-BCG bacilli to control the Hp driven gastric damage using the model of Cavia porcellus primary gastric epithelial cells or fibroblasts in vitro. These cells were treated with Hp surface antigens (glycine acid extract-GE or lipopolysaccharide-LPS) alone or with onco-BCG bacilli and evaluated for cell apoptosis and proliferation in conjunction with the level of soluble lipid peroxidation marker (s4HNE). The cell migration was determined by "wound healing assay", while cytokine response of cells, including interleukin (IL)-33, IL-1ß, IL-8 and tumor necrosis factor alpha (TNF-α), by the ELISA. The apoptosis of cells pulsed in vitro with Hp surface components present in GE or with LPS was reduced after exposure of cells to mycobacteria. Similarly, the cell regeneration which was diminished by Hp LPS has been improved in response to mycobacteria. This study reveals that vaccine mycobacteria may reduce gastric barrier damage induced by Hp infection.