BCG for Immunotherapy BP 40mg powder for reconstitution for instillation vials

BackgroundTuberculosis vaccine trials using disease as the primary endpoint are large, time consuming, and expensive. An earlier immunological measure of the protection against disease would accelerate tuberculosis vaccine development. We aimed to assess whether the effectiveness of the Bacillus Calmette-Guérin (BCG) vaccine for prevention of Mycobacterium tuberculosis infection was consistent with that for prevention of tuberculosis disease.MethodsWe conducted an individual participant data (IPD) meta-analysis on experimental and observational longitudinal studies before April 6, 2018, identified through systematic reviews, known to us through expert knowledge in the field, reporting on BCG vaccination status, M tuberculosis infection test (QuantiFERON IFN-γ release assay [IGRA] and tuberculin skin test [TST]), and tuberculosis incidence. Cohort studies were included only for countries with a mandatory neonatal BCG vaccination policy. Exclusion criteria were previous or current tuberculosis disease, HIV infection, tuberculosis preventive treatment usage, and for household contacts, a positive baseline IGRA or TST test and young children aged 0-2 years; for randomised controlled trials, TST results within 2 years after random assignation were excluded. We contacted the investigators of the identified studies to provide IPD. We compared the protective efficacy of the BCG vaccine against M tuberculosis infection with that against tuberculosis disease using mixed-effects, multivariable proportional hazards modelling, by study type, M tuberculosis infection test (IGRA and TST), cutoff for defining test positivity, age, sex, and latitude.FindingsWe identified 79 studies eligible for full screening and of these, IPD datasets from 14 studies were included in our analysis: 11 household contact studies (29 147 participants), two adolescent cohort studies (11 368 participants), and one randomised controlled trial (2963 participants). Among 28 188 participants we found no protection by the BCG vaccine against TST conversion regardless of cutoff in any type of study. Among 1491 household contacts, but not among 5644 adolescents, the BCG vaccine protected against QuantiFERON conversion at the primary cutoff of 0·7 IU/mL or more with the adjusted hazard ratio (0·65, 95% CI 0·51-0·82) being consistent with that for protection against disease (0·68, 0·18-2·59). Protection against QuantiFERON conversion at cutoff of 0·35 IU/mL or more (0·64, 0·51-0·81) was similar.InterpretationProtection from the BCG vaccination against M tuberculosis infection, measured as QuantiFERON conversion, is inconsistent across different groups. Among groups with recent household exposure, QuantiFERON conversion is consistent with protection against disease and could be evaluated as a proxy for disease in tuberculosis vaccine trials. We found that TST lacks value for prevention in phase 2b proof-of-concept trials.FundingBill & Melinda Gates Foundation.

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Bacillus Calmette-Guérin (BCG) vaccination remains a cornerstone in global efforts to combat tuberculosis (TB), a persistent public health threat worldwide. The purpose of this systematic review is to find out how well BCG revaccination protects against TB. This systematic review synthesized recent studies investigating the efficacy of BCG vaccination in preventing TB infection and disease. A total of 15 relevant publications were identified through a comprehensive search across multiple databases, including Cochrane Library, PubMed, Medline, and Scopus. The inclusion criteria encompassed studies involving humans, written in English, and categorized as case-control, cohort, meta-analysis, or full-text. Studies were selected based on their relevance to BCG revaccination and protection against TB, and a standardized data extraction form was used to gather pertinent information from each study. Quality assessment was conducted using established tools to evaluate the rigor, study design, and risk of bias in each included study. The findings revealed significant insights into BCG's effectiveness across different populations and age groups. Several studies demonstrated a substantial reduction in latent TB infection (LTBI) and incidence rates of TB following BCG vaccination. However, the protective efficacy of BCG revaccination varied across studies and populations, with some indicating modest protection against TB disease development, particularly in high-risk populations like healthcare workers. Furthermore, investigations into the immunological mechanisms underlying BCG's protective efficacy provided valuable insights into cytokine/chemokine profiles and immunomodulatory properties.

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BackgroundThe predictive accuracy of the preoperative neutrophil-to-lymphocyte ratio (NLR) on the prognosis of patients with non-muscle-invasive bladder cancer (NMIBC) with intravesical Bacillus Calmette-Guérin immunotherapy (BCG) after transurethral resection of the bladder tumor (TURBT) remains unknown. Therefore, the current study performed a systematic review and meta-analysis to examine the relationship between preoperative NLR and the prognosis of patients with NMIBC with intravesical BCG immunotherapy.MethodsFor this systematic review and meta-analysis, articles were retrieved from PubMed, Cochrane Library, Web of Science, and Embase databases from their inception to 14 May 2024. The role of NLR in predicting recurrence and progression in NMIBC was determined using pooled hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsSeven articles were included in this meta-analysis, involving 4,187 patients. An elevated NLR was significantly associated with recurrence (HR = 2.67, 95% CI = 1.34-5.32, P P = 0.004) in patients with NMIBC with intravesical BCG immunotherapy.ConclusionThis meta-analysis demonstrated that elevated preoperative NLR levels were significantly associated with recurrence and disease progression in patients with NMIBC who underwent intravesical BCG immunotherapy after TURBT.Systematic review registrationhttps://inplasy.com/inplasy-2024-7-0058/, identifier 202470058.

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Background: The Bacillus Calmette-Guérin (BCG) vaccine — the only licensed anti-tuberculosis vaccine — is administered at birth in over 150 countries. In many settings, however, BCG vaccination is deferred beyond the neonatal period, with a significant cohort receiving vaccination at approximately six months of age. An emerging clinical paradox has been identified: infants who receive delayed BCG vaccination at six months may subsequently develop devastating disseminated BCG disease (BCGosis), raising two unresolved questions of critical clinical importance. First, whether pre-existing subclinical Mycobacterium tuberculosis latent infection (LTBI) acquired during the unprotected window period acts as an immunological cofactor precipitating dissemination of the live attenuated BCG strain upon vaccination. Second, whether the tuberculin skin test (TST/PPD) — the most widely available diagnostic tool — provides sufficient sensitivity and specificity at six months of age to serve as a pre-vaccination safety screen. Methods: A systematic review was conducted following PRISMA-2020 guidelines across PubMed/MEDLINE, Embase, the Cochrane Library, and the WHO Global Tuberculosis Database (1990–2025). Search terms included "BCGosis," "disseminated BCG disease," "delayed BCG vaccination," "latent TB infants," "SCID BCG complications," "TST limitations infants," and "IGRA infants under two years." Studies reporting BCGosis following delayed BCG vaccination, pre-vaccination LTBI in infants, and TST/IGRA performance in the first year of life were included. Results: The pooled evidence from 32 high-quality studies across 17 countries confirms that BCGosis occurs almost exclusively in infants with undiagnosed inborn errors of immunity (IEI), especially severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), and Mendelian susceptibility to mycobacterial disease (MSMD). BCG-related complications represented the first clinical manifestation of underlying IEI in 75% of affected infants. A landmark Saudi Arabian cohort study (n=178 SCID patients, 2015–2023) demonstrated that delaying BCG from birth to six months significantly reduced BCG-related complications from 46.1% to 2.6% (p<0.001), illustrating the benefit of pre-vaccination immunological screening rather than blanket deferral. The TST showed false-negative rates of up to 40% in culture-confirmed tuberculosis among children under two years, attributable to T-cell immaturity, the immunological window period, and maternal immune modulation. IGRA assays demonstrated higher specificity but indeterminate rates of 17% in infants under twelve months, particularly in immunocompromised patients (27%), limiting their standalone utility. The mechanistic hypothesis of BCG vaccination precipitating expansion of pre-existing M. tuberculosis latent infection through cross-reactive T-cell activation and immune reconstitution inflammatory syndrome (IRIS)-like pathology is supported by immunological evidence but requires prospective validation. Conclusions: Delayed BCG vaccination at six months of age in infants with undetected IEI or unscreened latent TB infection constitutes a high-risk clinical scenario. The TST alone is an insufficient pre-vaccination safety screen at this age. Newborn screening for SCID using T-cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC), supplemented by comprehensive family history assessment, is essential before administering BCG to any infant beyond the neonatal period. International vaccination policy must distinguish between the protective benefit of BCG deferral for immunodeficient infants and the unacceptable risk of a six-month unprotected window in high-TB-burden populations.

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health burden despite widespread Bacillus Calmette-Guérin vaccination, which provides inconsistent protection against adult pulmonary TB. This systematic review, conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, synthesizes recent advances in TB vaccine development, encompassing conventional live-attenuated and protein subunit vaccines as well as computationally designed multi-epitope vaccines (MEVs). A comprehensive literature search of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar for studies published between January 2020 and December 2024 identified 847 records, of which 63 met inclusion criteria for qualitative synthesis. Clinical-stage development remains dominated by conventional platforms, with M72/AS01E demonstrating 54% efficacy in a Phase 2b trial and advancing to Phase 3 evaluation, representing the most promising next-generation candidate to date. In parallel, immunoinformatics and reverse vaccinology (RV) approaches have enabled rational MEV design, including constructs such as PP13138R and PP19128R, which exhibit strong antigenicity and immunogenicity in silico and in vitro. Novel hypothetical protein antigens, including Rv3899c, Rv1509, Rv0574c, and Rv0790c, have also emerged as potential targets. However, no computationally designed MEV has yet progressed to clinical evaluation, highlighting a significant translational gap between predictive modeling and experimental validation. TB vaccine research is increasingly transitioning toward rational, computationally guided strategies, but integration of computational discovery with rigorous preclinical and clinical validation remains essential to accelerate the development of effective next-generation TB vaccines.

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BackgroundAlthough intravesical Bacillus Calmette-Guerin (BCG) immunotherapy usually exhibits a favorable safety profile, it can lead to the development of BCG infections, both localized and disseminated. Understanding of BCG infections following intravesical BCG immunotherapy is limited because of the lack of consensus definitions of BCG infections and limited post-instillation follow-up. We aim to perform a systematic review of the literature of BCG infections following intravesical BCG immunotherapy to elucidate the epidemiology, risk factors, and outcomes of BCG infections.MethodsSystematic review of peer-reviewed published articles that describe the treatment of one or more persons with intravesical BCG and the occurrence of BCG infections among these patients. No temporal, geographic, or demographic limitations will be applied. Animal studies will be excluded. Gray literature, editorials, and comments will be excluded. Information sources will include the following databases: MEDLINE, Embase, and Web of Science. A search concept representing BCG and intravesical administration will be applied after validation against a set of pre-selected articles. Screening and data extraction will be performed in duplicate by two independent reviewers. Disagreements will be resolved by a third independent reviewer. The methodological quality of studies will be assessed using the Mixed Methods Appraisal Tool. A narrative synthesis of the extracted data will be provided in line with the guidance from the Centre for Reviews and Dissemination. The quality of evidence for all outcomes will be judged using the Grading of Recommendations Assessment, Development, and Evaluation working group methodology.DiscussionThe data generated by this review will assist clinicians in managing BCG-infected patients and inform future research efforts.Systematic review registrationIn accordance with international guidelines, our systematic review protocol was submitted for registration with the International Prospective Register of Systematic Reviews (PROSPERO) on February 26, 2024.

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