Bacillus Calmette-Guérin Strains Research Articles

Compared Efficacy of Adjuvant Intravesical BCG-TICE vs. BCG-RIVM for High-Risk Non-Muscle Invasive Bladder Cancer (NMIBC): A Propensity Score Matched Analysis.

Simple SummaryIntravesical immunotherapy with bacillus Calmette–Guerin (BCG) is the standard therapy for high-risk non-muscle invasive bladder cancer. Different BCG strains are currently available and the superiority of any BCG strain over another could not be demonstrated yet. We compared the efficacy of two BCG strains: RIVM and TICE, respectively. In this propensity-score matched cohort study, we showed no particular survival benefit of TICE vs RIVM in the case of high-risk disease. Nevertheless, stratifying our data for re-staging procedures and for those who received BCG maintenance, we identified BCG TICE to improve RFS independently. Herein, we corroborated the importance of performing a routine secondary resection followed by an adequate maintenance course of BCG. Future larger prospective randomized head-to-head trials are needed to further elucidate this important topic, especially in this era of BCG shortage.Background: Intravesical immunotherapy with bacillus Calmette–Guerin (BCG) is the standard therapy for high-risk non-muscle invasive bladder cancer (NMIBC). The superiority of any BCG strain over another could not be demonstrated yet. Methods: Patients with NMIBCs underwent adjuvant induction ± maintenance schedule of intravesical immunotherapy with either BCG TICE or RIVM at two high-volume tertiary institutions. Only BCG-naïve patients and those treated with the same strain over the course of follow-up were included. One-to-one (1:1) propensity score matching (PSM) between the two cohorts was utilized to adjust for baseline demographic and tumor characteristics imbalances. Kaplan–Meier estimates and multivariable Cox regression models according to high-risk NMIBC prognostic factors were implemented to address survival differences between the strains. Sub-group analysis modeling of the influence of routine secondary resection (re-TUR) in the setting of the sole maintenance adjuvant schedule for the two strains was further performed. Results: 852 Ta-T1 NMIBCs (n = 719, 84.4% on TICE; n = 133, 15.6% on RIVM) with a median of 53 (24–77) months of follow-up were reviewed. After PSM, no differences at 5-years RFS, PFS, and CSS at both Kaplan–Meier and Cox regression analyses were detected for the whole cohort. In the sub-group setting of full adherence to European/American Urology Guidelines (EAU/NCCN), BCG TICE demonstrated longer 5-years RFS compared to RIVM (68% vs. 43%, p = 0.008; HR: 0.45 95% CI 0.25–0.81). Conclusion: When routinely performing re-TUR followed by a maintenance BCG schedule, TICE was superior to RIVM for RFS outcomes. However, no significant differences were detected for PFS and CSS, respectively.

The Comparison of Efficacy between the Connaught and Tice Strains of Bacillus Calmette-guérin in Patients with Non-muscle-invasive Bladder Cancer in Taiwan

Purpose: The purpose of the study is to compare the efficacy of Bacillus Calmette-Guérin (BCG) strains, Connaught (ImmuCyst®), and TICE (OncoTICE®) in patients with nonmuscle invasive bladder cancer (nMIBC). Materials and Methods: Patients with nMIBC who underwent transurethral resection between March 1997 and December 2017 were enrolled. TICE was used due to the Connaught strain shortage since 2012; hence, direct comparison of the two strains could not be performed. An intravesical instillation (IVI) regimen of mitomycin-C, doxorubicin, and cisplatin (MDP) was used as the reference for comparison. The MDP group was separated into two cohorts (MDP-1 and MDP-2) that matched the same time period of Connaught and TICE treatment. Patients who did not complete the IVI course before disease recurrence or progression or were not followed up for at least 24 months were excluded. Results: A total of 730 patients were included in the analysis. There were 67 (9.2%), 38 (5.2%), and 625 (85.6%) patients who received the Connaught, TICE, and MDP treatment, respectively. During a median follow-up duration of 59 months, the recurrence rates of the Connaught, MDP-1, TICE, and MDP-2 groups were 10.5%, 22.8%, 28.9%, and 23.0%, respectively. Both BCG groups had higher tumor grades and more instances of carcinoma in situthan their corresponding MDP cohorts. The Connaught and TICE strains had similar effects in preventing tumor recurrence (Connaught vs. MDP, P= 0.876; TICE vs. MDP, P= 0.556). In the multivariable Cox proportional hazard model that included all patients, the Connaught and TICE groups had a similar risk (hazard ratio = 0.784 and 0.850) of recurrence compared to the MDP protocol. Although progression events were more frequently noticed in the Connaught group, the small number of events limited the analysis. Conclusion: The BCG strains, Connaught and TICE, had similar efficacy in reducing bladder tumor recurrence in nMIBC patients. Both strains resulted in similar bladder recurrence-free survival rates to chemotherapeutic agents.

Decrease of IL-5 Production by Naive T Cells Cocultured with IL-18-Producing BCG-Pulsed Dendritic Cells from Patients Allergic to House Dust Mite.

The only currently available anti-tuberculosis vaccine, Bacillus Calmette–Guérin (BCG), has been reported to also protect against unrelated diseases, including inflammatory diseases such as allergic asthma. Recombinant BCG strains that produce IL-18 have been shown to enhance Th1 responses over non-recombinant BCG and to reduce IL-5 production and bronchoalveolar eosinophilia in mice. However, their ability to decrease the immune polarization of human Th2 cells is not known. Here, we show that BCG and recombinant BCG producing human IL-18 (rBCG-hIL-18) induced the maturation of Der p 1-stimulated monocyte-derived dendritic cells (MD-DCs) from healthy controls and from patients allergic to house dust mites. After incubation with mycobacteria and Der p 1, MD-DCs produced significantly more IL-23 and IP-10 but had no effect on IL-12p70 or IL-10 production compared to Der p 1-pulsed MD-DCs in the absence of mycobacteria. In the presence of Der p 1, BCG- and rBCG-hIL-18-pulsed MD-DCs cocultured with naive, but not with memory T cells from allergic patients, resulted in a decrease in IL-5 production compared to non-pulsed MD-DCs cultured in the presence of Der p 1. BCG, and especially rBCG-hIL-18, may thus be potential therapeutic tools to reduce exacerbated Th2 responses in patients with allergic asthma.

In silico comparisons of lipid-related genes between Mycobacterium tuberculosis and BCG vaccine strains.

Despite highly variable efficacy, BCG (Bacillus Calmette-Guérin) is the only vaccine available to prevent the tuberculosis (TB). Genomic heterogeneity between attenuated BCG strains and virulent Mycobacterium tuberculosis might help to explain this vaccine’s impaired capacity to induce long-term protection. Here, we investigate the lipid-related genes absent in attenuated BCG strains in order to correlate changes in both lipid metabolism and cell-wall lipid content to vaccine impairment. Whole genome sequences of M. tuberculosis H37Rv and the six most used BCG strains worldwide were aligned and the absent regions functionally categorized. Genomes of the BCG strains showed a total of 14 non-homologous lipid-related genes, including those belonging to mce3 operon, as well as the gene echaA1, which encodes an enoyl-CoA hydratase, and the genes encoding phospholipases PlcA, PlcB and PlcC. Taken together, the depletion of these M. tuberculosis H37Rv genomic regions were associated with marked alterations in lipid-related genes of BCG strains. Such alterations may indicate a dormant-like state and can be determining factors to the vaccine’s inability to induce long-term protection. These lipids can be further evaluated as an adjuvant to boost the current BCG-based vaccine.

Association of Bacillus Calmette Guerin Vaccine Strains with COVID-19 Morbidity and Mortality - Evaluation of Global Data.

Background:Literature suggests that the presence of the current Bacillus Calmette Guerin (BCG) policy appears to mitigate COVID-19 disease burden but no information exists on the nature of the BCG strain and disease burden.Objectives:To study the association between type of BCG strain, BCG coverage (%), and COVID-19 disease burden.Methodology:An audit of global data on strains and disease burden was done. Country-specific data for COVID-19 cases and deaths, BCG-related data, and income level were obtained from the online databases, and the association was analyzed using linear regression.Results:Data of 139 countries were studied and 117 (84%) had a current BCG policy. Data on BCG strains were available for 51 countries and 18/51 (35%) used the Danish strain. While the choice of strain did not impact COVID-19-related disease burden, the presence of a current BCG policy was significantly associated with lower COVID-19 mortality.Conclusion:The presence of current BCG policy is associated with decreased COVID-19-related disease burden, but the type of strain used by a country in its vaccination program does not impact disease burden.

P094 - Intravesical bacillus Calmette - Guérin (BCG) in treating non-muscle invasive bladder cancer (NMIBC)- Analysis of adverse effects and effectiveness between two strains of BCG (Danish 1331 and Moscow)

P094 - Intravesical bacillus Calmette - Guérin (BCG) in treating non-muscle invasive bladder cancer (NMIBC)- Analysis of adverse effects and effectiveness between two strains of BCG (Danish 1331 and Moscow)

Mucosal delivery of ESX-1–expressing BCG strains provides superior immunity against tuberculosis in murine type 2 diabetes

Tuberculosis (TB) claims 1.5 million lives per year. This situation is largely due to the low efficacy of the only licensed TB vaccine, Bacillus Calmette-Guérin (BCG) against pulmonary TB. The metabolic disease type 2 diabetes (T2D) is a risk factor for TB and the mechanisms underlying increased TB susceptibility in T2D are not well understood. Furthermore, it is unknown if new TB vaccines will provide protection in the context of T2D. Here we used a diet-induced murine model of T2D to investigate the underlying mechanisms of TB/T2D comorbidity and to evaluate the protective capacity of two experimental TB vaccines in comparison to conventional BCG. Our data reveal a distinct immune dysfunction that is associated with diminished recognition of mycobacterial antigens in T2D. More importantly, we provide compelling evidence that mucosal delivery of recombinant BCG strains expressing the Mycobacterium tuberculosis (Mtb) ESX-1 secretion system (BCG::RD1 and BCG::RD1 ESAT-6 ∆92-95) are safe and confer superior immunity against aerosol Mtb infection in the context of T2D. Our findings suggest that the remarkable anti-TB immunity by these recombinant BCG strains is achieved via augmenting the numbers and functional capacity of antigen presenting cells in the lungs of diabetic mice.

BCG scarring and improved child survival: a combined analysis of studies of BCG scarring.

Bacillus Calmette-Guérin (BCG) vaccine against tuberculosis (TB) is recommended at birth in TB-endemic areas. Currently, BCG vaccination programmes use "BCG vaccination coverage by 12months of age" as the performance indicator. Previous studies suggest that BCG-vaccinated children, who develop a scar, have better overall survival compared with BCG-vaccinated children, who do not develop a scar. We summarized the available studies of BCG scarring and child survival. A structured literature search for studies with original data and analysis of BCG scarring and mortality were performed. Combined analyses on the effect of BCG scarring on overall mortality. We identified six studies covering seven cohorts, all from Guinea-Bissau, West Africa, with evaluation of BCG scarring amongst BCG-vaccinated children and follow-up for mortality. Determinants of BCG scarring were BCG strain, intradermal injection route, size of injection wheal, and co-administered vaccines and micronutrients. In a combined analysis, having a BCG scar vs. no BCG scar was associated with a mortality rate ratio (MRR) of 0.61 (95% CI: 0.51-0.74). The proportion with a BCG scar varied from 52 to 93%; the estimated effect of a BCG scar was not associated with the scar prevalence. The effect was strongest in the first (MRR=0.48 (0.37-0.62)) and second (MRR=0.63 (0.44-0.92)) year of life, and in children BCG-vaccinated in the neonatal period (MRR=0.45 (0.36-0.55)). The effect was not explained by protection against TB. Confounding and genetic factors are unlikely to explain the strong association between BCG scarring and subsequent survival. Including "BCG scar prevalence" as a BCG vaccination programme performance indicator should be considered. The effect of revaccinating scar-negative children should be studied.

Treatment options and results of adjuvant treatment in nonmuscle-invasive bladder cancer (NMIBC) during the Bacillus Calmette-Guérin shortage.

Given the worldwide shortage of Bacillus Calmette-Guérin (BCG), we review the efficacy of alternative BCG application schedules, doses or strains and intravesical chemotherapy in patients with nonmuscle-invasive bladder cancer (NMIBC). Modifying BCG schedules by reducing the dose is preferable to reducing the frequency of BCG that increases recurrence rates and should be avoided if possible. Changing the BCG substrain represents a reasonable option, as current evidence does not suggest different oncological outcomes with specific BCG substrains. Mitomycin C (MMC) alone is inferior to BCG with maintenance, but promising results have been demonstrated when used with chemohyperthermia and electromotive drug administration. Several other intravesical chemotherapies including Gemcitabine and Epirubicin should be used when both BCG and MMC are in short supply. In case of BCG shortage, much will depend on the severity and length of the BCG shortage, but our review supports several solutions: First, we recommend contacting the local pharmacist or BCG supplier to consider alternative BCG strains or sterile splitting of BCG doses. In the complete absence of BCG, consideration should be given to MMC with chemohyperthermia or electromotive drug administration where available or other intravesical chemotherapy. High-risk patients should be considered for cystectomy.

Clinical and molecular insights into BCG immunotherapy for melanoma.

The incidence of cutaneous melanoma and the mortality rate of advanced melanoma patients continue to rise globally. Despite the recent success of immunotherapy including ipilimumab and pembrolizumab checkpoint inhibitors, a large proportion of patients are refractory to such treatment modalities. The application of mycobacteria such as Bacillus Calmette-Guérin (BCG) in the treatment of various malignancies, including cutaneous melanoma, has been clearly demonstrated after almost a century of observations and experimentation. Intralesional BCG (IL-BCG) immunotherapy is a highly efficient and cost-effective treatment option for inoperable stage III in-transit melanoma, as recommended in the National Comprehensive Cancer Network Guidelines. IL-BCG has shown great efficacy in the regression of directly injected metastatic melanoma lesions, as well as distal noninjected nodules in immunocompetent patients. Clinical and preclinical studies have shown that BCG serves as a strong immune modulator, inducing the recruitment of various immune cells that contribute to antitumour immunity. However, the specific mechanism of BCG-mediated tumour immunity remains poorly understood. Comparative genome analyses have revealed that different BCG strains exhibit distinct immunological activity and virulence, which might impact the therapeutic response and clinical outcome of patients. In this review, we discuss the immunostimulatory potential of different BCG substrains and highlight clinical studies utilizing BCG immunotherapy for the treatment of cutaneous melanoma. Furthermore, the review focuses on the cellular and molecular mechanisms of the BCG-induced immune responses of both the innate and adaptive arms of the immune system. Furthermore, the review discussed the administration of BCG as a monotherapy or in combination with other immunotherapeutic or chemotherapeutic agents.

Recombinant BCG Expressing HTI Prime and Recombinant ChAdOx1 Boost Is Safe and Elicits HIV-1-Specific T-Cell Responses in BALB/c Mice.

Despite the availability of anti-retroviral therapy, HIV-1 infection remains a massive burden on healthcare systems. Bacillus Calmette-Guérin (BCG), the only licensed vaccine against tuberculosis, confers protection against meningitis and miliary tuberculosis in infants. Recombinant BCG has been used as a vaccine vehicle to express both HIV-1 and Simian Immunodeficiemcy Virus (SIV) immunogens. In this study, we constructed an integrative E. coli-mycobacterial shuttle plasmid, p2auxo.HTI.int, expressing the HIVACAT T-cell immunogen (HTI). The plasmid was transformed into a lysine auxotrophic Mycobacterium bovis BCG strain (BCGΔLys) to generate the vaccine BCG.HTI2auxo.int. The DNA sequence coding for the HTI immunogen and HTI protein expression were confirmed, and working vaccine stocks were genetically and phenotypically characterized. We demonstrated that the vaccine was stable in vitro for 35 bacterial generations, and that when delivered in combination with chimpanzee adenovirus (ChAd)Ox1.HTI in adult BALB/c mice, it was well tolerated and induced HIV-1-specific T-cell responses. Specifically, priming with BCG.HTI2auxo.int doubled the magnitude of the T-cell response in comparison with ChAdOx1.HTI alone while maintaining its breadth. The use of integrative expression vectors and novel HIV-1 immunogens can aid in improving mycobacterial vaccine stability as well as specific immunogenicity. This vaccine candidate may be a useful tool in the development of an effective vaccine platform for priming protective responses against HIV-1/TB and other prevalent pediatric pathogens.

The Humoral Immune Response to BCG Vaccination.

Bacillus Calmette Guérin (BCG) is the only currently available vaccine against tuberculosis (TB), but it confers incomplete and variable protection against pulmonary TB in humans and bovine TB (bTB) in cattle. Insights into the immune response induced by BCG offer an underexploited opportunity to gain knowledge that may inform the design of a more efficacious vaccine, which is urgently needed to control these major global epidemics. Humoral immunity in TB and bTB has been neglected, but recent studies supporting a role for antibodies in protection against TB has driven a growing interest in determining their relevance to vaccine development. In this manuscript we review what is known about the humoral immune response to BCG vaccination and re-vaccination across species, including evidence for the induction of specific B cells and antibodies; and how these may relate to protection from TB or bTB. We discuss potential explanations for often conflicting findings and consider how factors such as BCG strain, manufacturing methodology and route of administration influence the humoral response. As novel vaccination strategies include BCG prime-boost regimens, the literature regarding off-target immunomodulatory effects of BCG vaccination on non-specific humoral immunity is also reviewed. Overall, reported outcomes to date are inconsistent, but indicate that humoral responses are heterogeneous and may play different roles in different species, populations, or individual hosts. Further study is warranted to determine whether a new TB vaccine could benefit from the targeting of humoral as well as cell-mediated immunity.

A systematic review of preventive and therapeutic options for symptoms of cystitis in patients with bladder cancer receiving intravesical bacillus Calmette-Guérin immunotherapy.

Local adverse effects are the most common clinical issues in patients with bladder cancer receiving intravesical BCG immunotherapy. The aim of this systematic review was to present available options for prevention and treatment of cystitis symptoms related to bacillus Calmette-Guérin (BCG) intravesical instillations. A literature search within the Medline database was conducted in June 2018 with the following search terms: adverse events, Bacillus Calmette-Guerin, BCG, bladder cancer, cystitis, dose, dwell time, dysuria, frequency, intravesical instillations, haematuria, pain, side effects, toxicity and urgency. Eighteen relevant original articles were identified, including 15 randomized controlled trials. Potentially effective options to prevent symptoms of cystitis are BCG dose reduction, intravesical hyaluronic acid instillations and oral prulifloxacin or ofloxacin administration. For the treatment of BCG-related cystitis, available options include oral pentosan polysulphate or a combination of intravesical hyaluronic acid and chondroitin sulphate. The included studies were characterized by high heterogeneity in terms of BCG strains, schedules and endpoints. Studies on treatment of BCG-related cystitis included only small number of patients. Studies on directed medical interventions did not consider the influence on the BCG efficacy. Among few proposed preventive or therapeutic options for symptoms of cystitis related to BCG, none was proven to be both definitively effective and oncologically safe.

Bacillus Calmette-Guérin treatment of bladder cancer: a systematic review and commentary on recent publications.

Bacillus Calmette-Guérin (BCG) is the standard immune therapy for nonmuscle invasive bladder cancer. A systematic review of published articles regarding BCG treatment of bladder cancer was conducted and a commentary of these is provided to gain a perspective of the current major developments in the field. Several BCG strains are utilized worldwide. As the understanding of genetic and phenotypic differences in these strains is elucidated, inquiries into the potential clinical effects of these various strains have been studied. Data suggest that some strains could be more effective than others but further study is needed. Although response to BCG is heterogenous, current clinical practice does not incorporate use of biomarkers to delegate treatment selection. Thus, biomarker prediction is an important area of research in this area. Novel urine and tissue markers show promise in this endeavor. Notable publications also include mechanistic studies showing a role for T cells, natural killer cells, mast cells, and granulocytes in BCG's antitumor efficacy. Significant developments have occurred in understanding BCG's response and mechanism of action, which remains incompletely understood. Future work includes efforts to create recombinant BCG strains to decrease side effects, repeated instillations, and increase overall efficacy.

Moreau Strain Bacillus Calmette-Guérin Low Versus Standard Dose in the Treatment of High-Grade T1 Bladder Cancer: A Retrospective Observational Cohort Study

To evaluate recurrence, progression, and cancer-specific mortality of high-grade T1 non-muscle-invasive bladder cancer by assessing receipt of a low dose of the underexplored bacillus Calmette-Guérin (BCG) Moreau strain in a retrospective observational cohort study. From January 2006 to December 2015, a total of 219 consecutive patients with high-grade T1 non-muscle-invasive bladder cancer received half-dose (40 mg; n=109) or standard-dose (80 mg; n= 110) BCG Moreau strain after transurethral resection of the bladder. BCG therapy was initiated 2 or 3 weeks after transurethral resection of the bladder using the following protocol: 6 weekly doses, 12 monthly, 4 once every 3 months, and 2 once every 6 months, with a total of 24 doses. Comparing the half-dose and standard-dose treatment groups, in a median follow-up of 74.6 months, recurrence (n= 51, 46.8% vs. n= 60, 54.5%, P= .28), progression (n= 18, 16.5% vs. n= 16, 14.5%, P= .69), and disease-specific mortality (n= 9, 8.3% vs. n= 5, 4.5%, P= .26) were not significantly different on Kaplan-Meier curves and log-rank test, respectively. Charlson comorbidity index was an independent predictor of death from disease (hazard ratio= 1.341; 95% confidence interval, 1.033-1.740; P= .0274); no predictor of recurrence or progression was identified. Treatment intolerance occurred in 1 (0.9%) versus 6 (5.4%) patients (P= .12), respectively. No hospital admission or systemic BCG toxicity was reported. To our knowledge, this is the largest low-dose Moreau BCG strain study in high-grade T1 scenario. A half dose of BCG Moreau strain might be safe and effective in terms of tumor control, progression, or cancer-specific mortality with a low complication rate, which is central to the worldwide scenario of BCG shortage, and can help regulatory agencies approve efficient daughter BCG strains.

Intravesical bacillus Calmette-Guérin for bladder cancer: are all the strains equal?

Intravesical immunotherapy with bacillus Calmette-Guérin (BCG) is the standard of care for high-risk and intermediate-risk non-muscle-invasive bladder cancer (NMIBC). Several BCG strains are available. Despite originating all from subcultures of the same Mycobacterium, strains are genetically different which may lead to differences in treatment efficacy and adverse events. Identification of a more efficient strain and assessing its optimal administration schedule may improve oncological outcomes in NMIBC, specifically because of the worldwide shortage in BCG availability. This review focused on the antitumor effect of different BCG strains with a particular emphasis on the evidence underlying BCG dose and treatment schedules.

Two Randomized Trials of the Effect of the Russian Strain of Bacillus Calmette-Guérin Alone or With Oral Polio Vaccine on Neonatal Mortality in Infants Weighing

In randomized trials in Guinea-Bissau, the Danish strain of Bacillus Calmette-Guérin (BCG) reduces neonatal mortality, primarily by reducing deaths from pneumonia and sepsis. Because World Health Organization-prequalified BCG-Denmark was not available in India, we conducted 2 randomized trials to test whether BCG-Russia alone or with oral polio vaccine (OPV) has similar effects to BCG-Denmark. We randomized neonates weighing <2000 g to a control group that was not vaccinated before 28 days of age or to receive either BCG-Russia alone (first trial) or BCG-Russia with OPV (second trial) soon after birth. We performed intention-to-treat analysis using Cox hazards models with age as the underlying time and adjusted for weight, sex and inborn versus outborn status. Administration of BCG-Russia alone had no effect on neonatal mortality (to 28 days of age): 15.6% of 1537 infants died in the BCG-Russia group and 16.1% of 1535 died in the control group; the adjusted hazard ratio was 0.95 [95% confidence interval (CI): 0.80-1.13]. Administration of BCG-Russia with OPV also had no effect on neonatal mortality: 18.0% of 1103 infants died in the BCG-OPV group and 17.6% of 1104 died in the control group; the adjusted hazard ratio was 1.01 (95% CI: 0.83-1.23). The adjusted hazard ratio for the 2 trials combined was 0.98 (95% CI: 0.85-1.11). BCG-Russia with or without OPV had no effect on neonatal mortality. It is important to determine which strains of BCG have the greatest specific effects (on tuberculosis) and nonspecific effects (on infections other than tuberculosis) in high-mortality regions.

A novel evaluation of genetic polymorphism in BCG adenitis.

Hassanzad M, Farnia P, Darougar S, Velayati AA. A novel evaluation of genetic polymorphism in BCG adenitis. Turk J Pediatr 2019; 61: 466-470. Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine which has been used to prevent tuberculosis, according to the World Health Organization (WHO) recommendation in parts of the world with an incidence of tuberculosis infection more than 1%. The incidence of BCG adverse reactions differs between regions with regional lymphadenitis as the most common presentation. The aim of this study was to detect the impact of polymorphisms causing BCG lymphadenitis in children receiving BCG vaccination at birth. Eight healthy infants with BCG adenitis from 4 to 12 months old were enrolled. All these patients underwent a thorough physical examination, abdominopelvic ultrasound evaluation to detect distant lymphadenopathies and immunodeficiency screening tests for any possible underlying immunodeficiency disorders. Then genotyping for known mutations was performed using restriction fragments length polymorphism (PCR-RFLP) assays. Sequencing was performed for IL-12 Rβ1, IFN-ϒ receptor 1, IL-10, TNF-α and P2X7. The mean age of onset of the adenitis was 6.5 months. TNF-857, IL-12Rβ1 705, IL-10 1082, and IFN-ϒ- 56 single nucleotide polymorphisms (SNPs) were common in the children studied. The most frequent polymorphism found in the patients with BCG adenitis except one, was the P2X7 -762 polymorphism. To conclude, these polymorphisms are more common in some ethnic populations but not others and make the genetic basis of immunity to BCG strains and the occurrence of post-BCG lymphadenitis in otherwise healthy children.

Evaluation of Immune Responses to a DNA Vaccine Encoding Ag85a-Cfp10 Antigen of Mycobacterium tuberculosis in an Animal Model

Background: Manystudies indicate that the Bacillus Calmette-Guerin (BCG) vaccine has low protective efficacy, especially in endemic areas. There are several factors in this assessment, such as genetic diversity of BCG strains, pre-exposure to environmental mycobacteria, and variations in host immune responses. Currently, more than 200 new vaccine candidates have been proposed, such as recombinant BCG, DNA, and subunit vaccines. However, none of them are superior to BCG. Nevertheless, several approaches are considered to reduce the cases of tuberculosis infection. Objectives: The aim of the present study was to evaluate the capability of the Ag85a-cfp10 fusion protein as a new chimeric protein in stimulating immune responses. Methods: A DNA vaccine encoding Ag85a-cfp10 fusion protein was constructed in the previous study. The expression of Ag85a-cfp10 fusion protein in host cells was confirmed by the RT-PCR method. Six pathogen-free female mice were injected intramuscularly at a total concentration of 100 µg/mL three times at two-week intervals. The BCG and the control groups received BCG and PBS vaccines, respectively. One month after the final immunization, mice were killed and their splenocytes were cultured in RPMI medium supplemented with 1 antibiotics and 10 serum. Four cytokines including IL-4, IL-12, TGF-β, and IFN- were measured in the culture supernatant using the ELISA test. Results: RT-PCR analysis showed that Ag85a-cfp10 recombinant vector is able to replicate in eukaryotic cells and produce mRNA. The vaccinated groups were compared to the control group, showing induction of high levels of cytokine production. Conclusions: Some reports depicted that DNA vaccines are able to induce humoral and cellular immune responses both in animal models and humans. Therefore, in the current study, the immune response was induced in mice, which were inoculated with recombinant expression plasmid, pcDNA3.1 (+)-Ag85a-cfp10. We showed that this recombinant vector can stimulate mycobacterial specific modulating cytokines. Nonetheless, analysis appeared that this vaccine is unable to stimulate cell mediated immunity, however, still further studies are needed in future. © 2018, Author(s).

What to do during Bacillus Calmette-Guérin shortage? Valid strategies based on evidence.

Over the last decade, the world has experienced health-threatening supply shortages of Bacillus Calmette-Guérin (BCG) immunotherapy for nonmuscle-invasive bladder cancer (NMIBC). We summarize the current literature to assist in treatment decisions in light of suboptimal supply. Currently available data do not support a superiority of one BCG strain over the other. Intravesical chemotherapy seems to provide similar results in term of disease progression but not recurrence in intermediate-risk patients. One trial has shown that a 3-year maintenance course of BCG in high-risk NMIBC has no advantage in term of progression or overall survival in comparison with 1-year maintenance. Synergo radiofrequency-induced hyperthermia is a reliable alternative in intermediate or high-risk NMIBC with at least similar recurrence rates compared with BCG. Patients with intermediate-risk NMIBC can be offered multiple instillations of intravesical chemotherapy for up to 12 months. In high-risk patients and in case of BCG shortage, BCG instillations can be terminated when the patient has completed 1 year of maintenance. Mitomycin C is an alternative in lowest risk high-risk (G3Ta) NMIBC, whereas patients with pT1/carcinoma in situ can be offered Synergo with mitomycin C when radical cystectomy is not feasible. Immediate radical cystectomy should always be considered in highest risk NMIBC after weighing up benefit to risk.