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Sample records for bacillus calmette-guerin bcg

  1. Original Article Failure of Bacillus Calmette Guerin (BCG) Therapy ...

    African Journals Online (AJOL)

    Administrator

    a second tumor recurrence or progression according to the tumor aggressiveness and the patient's preference. Keywords : Superficial bladder cancer, Bacillus Calmette Guerin (BCG), tumor .... from the remaining bladder in high-risk pa- tients. Statistical analysis was performed with. Student's t-test and Chi-square test and.

  2. Bacillus Calmette-Guerin (BCG) Vaccine

    Science.gov (United States)

    TheraCys® BCG ... TICE® BCG ... WHY is this medicine prescribed?BCG vaccine provides immunity or protection against tuberculosis (TB). The vaccine may be given to persons at high risk of developing TB. ...

  3. Original Article Failure of Bacillus Calmette Guerin (BCG) Therapy ...

    African Journals Online (AJOL)

    Administrator

    -up, 6 (3.8%) stopped BCG due to side-effects and were subsequently treated with intravesical chemotherapy, while another 5 (3.1%) died during BCG therapy ... patients with impaired renal function. Hematuria was the most common clinical.

  4. Discriminators of mouse bladder response to intravesical Bacillus Calmette-Guerin (BCG

    Directory of Open Access Journals (Sweden)

    Centola Michael

    2007-05-01

    Full Text Available Abstract Background Intravesical Bacillus Calmette-Guerin (BCG is an effective treatment for bladder superficial carcinoma and it is being tested in interstitial cystitis patients, but its precise mechanism of action remains poorly understood. It is not clear whether BCG induces the release of a unique set of cytokines apart from its pro-inflammatory effects. Therefore, we quantified bladder inflammatory responses and alterations in urinary cytokine protein induced by intravesical BCG and compared the results to non-specific pro-inflammatory stimuli (LPS and TNF-α. We went further to determine whether BCG treatment alters cytokine gene expression in the urinary bladder. Methods C57BL/6 female mice received four weekly instillations of BCG, LPS, or TNF-α. Morphometric analyses were conducted in bladders isolated from all groups and urine was collected for multiplex analysis of 18 cytokines. In addition, chromatin immune precipitation combined with real-time polymerase chain reaction assay (CHIP/Q-PCR was used to test whether intravesical BCG would alter bladder cytokine gene expression. Results Acute BCG instillation induced edema which was progressively replaced by an inflammatory infiltrate, composed primarily of neutrophils, in response to weekly administrations. Our morphological analysis suggests that these polymorphonuclear neutrophils are of prime importance for the bladder responses to BCG. Overall, the inflammation induced by BCG was higher than LPS or TNF-α treatment but the major difference observed was the unique granuloma formation in response to BCG. Among the cytokines measured, this study highlighted the importance of IL-1β, IL-2, IL-3, IL-4, IL-6, IL-10, IL-17, GM-CSF, KC, and Rantes as discriminators between generalized inflammation and BCG-specific inflammatory responses. CHIP/Q-PCR indicates that acute BCG instillation induced an up-regulation of IL-17A, IL-17B, and IL-17RA, whereas chronic BCG induced IL-17B, IL-17RA, and

  5. Effects of Bacillus Calmette-Guerin (BCG) vaccination at birth on T and B lymphocyte subsets: Results from a clinical randomized trial

    NARCIS (Netherlands)

    Birk, N.M.; Nissen, T.N.; Kjaergaard, J.; Hartling, H.J.; Thostesen, L.M.; Kofoed, P.E.; Stensballe, L.G.; Andersen, A.; Pryds, O.; Netea, M.G.; Benn, C.S.; Nielsen, S.D.; Jeppesen, D.L.

    2017-01-01

    The Bacillus Calmette-Guerin vaccine (BCG) has been associated with beneficial non-specific effects (NSEs) on infant health. Within a randomized trial on the effect of neonatal BCG on overall health, we investigated the possible immunological impact of neonatal BCG vaccination on lymphocyte subsets,

  6. CYTOKINE PRODUCTION BY THE HUMAN BLADDER-CARCINOMA CELL-LINE T24 IN THE PRESENCE OF BACILLUS-CALMETTE-GUERIN (BCG)

    NARCIS (Netherlands)

    de Reijke, T. M.; Vos, P. C.; de Boer, E. C.; Bevers, R. F.; de Muinck Keizer, W. H.; Kurth, K. H.; Schamhart, D. H.

    1993-01-01

    The study was initiated as an in vitro approach to the situation existing during intravesical bacillus Calmette-Guerin (BCG) instillation in patients with superficial bladder cancer. Cytokine secretion of a human bladder carcinoma cell line T 24 treated with BCG was investigated. A 24-h treatment of

  7. [The long controversy over anti-tuberculosis vaccination in Canada: the Calmette-Guerin bacillus (BCG), 1925-1975].

    Science.gov (United States)

    Malissard, P

    1998-01-01

    The focus of this article is the history of Canada's reception of Bacillus Calmette-Guerin (BCG), an anti-tuberculosis vaccine which has almost constantly been plagued with controversy. The article examines this vaccine NRCC sponsored introduction in 1925, which led to the creation of the Associate Committee on Tuberculosis Research, a committee almost unique for its acrimonious debates. It also analyzes the interests at stakes in the ultimate rejection of the BCG by the federal Department of Agriculture veterinary services and, with the exception of Quebec and Newfoundland, by almost all public health authorities in Canada. Based on sources never taped before, this paper sheds a light on the multiple ramifications of a little known episode of the Canadian public health history.

  8. Disseminated Bacillus Calmette-Guerin infections after intravesical therapy

    Directory of Open Access Journals (Sweden)

    I Gerogianni

    2014-01-01

    Full Text Available Intravesical instillation of Bacillus Calmette-Guerin (BCG is the treatment of choice for superficial bladder carcinoma. Disseminated BCG infection presenting as granulomatous hepatitis or pneumonitis is a very rare complication of this treatment. Here we report a case series of seven patients previously treated with BCG presenting with pneumonitis. In two of the cases, identification of Mycobacterium bovis was achieved with molecular methods.

  9. Molecular networks discriminating mouse bladder responses to intravesical bacillus Calmette-Guerin (BCG, LPS, and TNF-α

    Directory of Open Access Journals (Sweden)

    Dozmorov Igor

    2008-02-01

    Full Text Available Abstract Background Despite being a mainstay for treating superficial bladder carcinoma and a promising agent for interstitial cystitis, the precise mechanism of Bacillus Calmette-Guerin (BCG remains poorly understood. It is particularly unclear whether BCG is capable of altering gene expression in the bladder target organ beyond its well-recognized pro-inflammatory effects and how this relates to its therapeutic efficacy. The objective of this study was to determine differentially expressed genes in the mouse bladder following chronic intravesical BCG therapy and to compare the results to non-specific pro inflammatory stimuli (LPS and TNF-α. For this purpose, C57BL/6 female mice received four weekly instillations of BCG, LPS, or TNF-α. Seven days after the last instillation, the urothelium along with the submucosa was removed from detrusor muscle and the RNA was extracted from both layers for cDNA array experiments. Microarray results were normalized by a robust regression analysis and only genes with an expression above a conditional threshold of 0.001 (3SD above background were selected for analysis. Next, genes presenting a 3-fold ratio in regard to the control group were entered in Ingenuity Pathway Analysis (IPA for a comparative analysis in order to determine genes specifically regulated by BCG, TNF-α, and LPS. In addition, the transcriptome was precipitated with an antibody against RNA polymerase II and real-time polymerase chain reaction assay (Q-PCR was used to confirm some of the BCG-specific transcripts. Results Molecular networks of treatment-specific genes generated several hypotheses regarding the mode of action of BCG. BCG-specific genes involved small GTPases and BCG-specific networks overlapped with the following canonical signaling pathways: axonal guidance, B cell receptor, aryl hydrocarbon receptor, IL-6, PPAR, Wnt/β-catenin, and cAMP. In addition, a specific detrusor network expressed a high degree of overlap with the

  10. The Moreau Strain of Bacillus Calmette-Guerin (BCG) for High-Risk Non-Muscle Invasive Bladder Cancer: An Alternative during Worldwide BCG Shortage?

    Science.gov (United States)

    Hofbauer, Sebastian L; Shariat, Shahrokh F; Chade, Daher C; Sarkis, Alvaro S; Ribeiro-Filho, Leopoldo A; Nahas, Willian C; Klatte, Tobias

    2016-01-01

    Bacillus Calmette-Guerin (BCG) is the standard of care for adjuvant intravesical instillation therapy for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) after complete transurethral resection. Increasing evidence suggests that there are marked differences in outcomes according to BCG substrains. BCG-Moreau was recently introduced to the European market to cover the issue of BCG shortage, but there are little data regarding the oncologic efficacy. We retrospectively analyzed 295 consecutive patients, who received adjuvant intravesical instillation therapy with BCG-Moreau for intermediate- and high-risk NMIBC between October 2007 and April 2013 at a single institution. The end points of this study were time to first recurrence and progression to muscle-invasive disease. Median age was 66 years (interquartile range 59-74, mean 65.9 years). According to the EAU risk group, 76 patients presented with intermediate-risk and 219 patients with high-risk NMIBC. The 5-year recurrence-free survival and progression-free survival rate was 64.8% (95% CI 52.8-74.4) and 81.4% (95% CI 65.2-90.2), respectively. BCG-Moreau is an effective substrain for adjuvant instillation therapies of NMIBC, and outcomes appear to be comparable to series using other substrains. During worldwide shortage of BCG-TICE, Connaught and RIVM, BCG-Moreau may serve as an equally effective alternative. © 2015 S. Karger AG, Basel.

  11. Failure of bacillus calmette guerin (bcg) therapy for the treatment of ...

    African Journals Online (AJOL)

    BCG) instillation following complete transurethral resection of superficial transitional cell carcinoma (TCC) of the urinary bladder at the Urology Department, Al-Azhar University, Cairo, Egypt. Patients and Methods: A prospective analysis of 160 ...

  12. CD4 and CD8 counts of Bacillus Calmette Guerin (BCG) vaccinated ...

    African Journals Online (AJOL)

    This study examines the cellular immune factors responsible for combating infections by assessing CD4 and CD8 counts of neonates (pre and post BCG vaccination). A total of 373 blood samples were collected from neonates that visited the immunization clinics at Irrua Specialist Teaching Hospital (ISTH), Irrua and Federal ...

  13. Current clinical practice gaps in the treatment of intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) with emphasis on the use of bacillus Calmette-Guerin (BCG): results of an international individual patient data survey (IPDS)

    NARCIS (Netherlands)

    Witjes, J.A.; Palou, J.; Soloway, M.; Lamm, D.; Kamat, A.M.; Brausi, M.; Persad, R.; Buckley, R.; Colombel, M.; Bohle, A.

    2013-01-01

    OBJECTIVES: To examine the management of intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC), particularly with regard to the use of bacillus Calmette-Guerin (BCG) therapy, in North America and Europe. To compare NMIBC management practices to European Association of Urology (EAU)

  14. Treatment Options Available for Bacillus Calmette-Guerin Failure in Non-muscle-invasive Bladder Cancer

    NARCIS (Netherlands)

    Yates, D.R.; Brausi, M.A.; Catto, J.W.; Dalbagni, G.; Roupret, M.; Shariat, S.F.; Sylvester, R.J.; Witjes, J.A.; Zlotta, A.R.; Palou-Redorta, J.

    2012-01-01

    CONTEXT: Intravesical bacillus Calmette-Guerin (BCG) is a standard conservative treatment for patients with high-risk non-muscle-invasive bladder cancer (NMIBC). Many patients will experience recurrence or progression following BCG and are termed BCG failures. OBJECTIVE: To summarise the current

  15. [Fever, Hepatic Dysfunction and Interstitial Pneumonia Caused by Intravesical Bacillus Calmette-Guerin (BCG) Instillation after Urethral Bougie : A Case Report].

    Science.gov (United States)

    Nitta, Satoshi; Sakka, Shotaro; Endo, Tsuyoshi; Komine, Manabu; Tsutsumi, Masakazu; Nishiyama, Hiroyuki

    2017-10-01

    A 60-year-old man had a past history of urothelial carcinoma of the left renal pelvis treated with laparoscopic left total nephroureterectomy in October 2004. He underwent transurethral resection of the bladder tumor (TUR-Bt) twice for recurrence of urothelial carcinoma in the bladder in April 2014 and February 2015, and subsequently received intravesical Bacillus Calmette-Guerin (BCG) instillation at weekly intervalsfor prevention of recurrence. In November 2016, a year and a half after BCG induction, he received BCG therapy after urethral bougie to dilate the urethral stricture. After BCG therapy, he exhibited a continuously high fever. Immediate antituberculosis drug therapy in consideration of BCG sepsis failed to improve the symptoms, and all cultures from urine and blood were negative for mycobacterium tuberculosis. Serum liver enzyme was markedly elevated and chest CT showed diffuse interstitial shadows in both lower lungs. Thus, we considered that these symptoms were caused by a hypersensitivity reaction to BCG and started pulse steroid therapy. After pulse steroid therapy, body temperature, and hepatic function became normal and interstitial pneumonia subsided.

  16. INCREASED URINARY ALBUMIN INDICATING UROTHELIAL LEAKAGE FOLLOWING INTRAVESICAL BACILLUS-CALMETTE-GUERIN THERAPY FOR SUPERFICIAL BLADDER-CANCER

    NARCIS (Netherlands)

    de Boer, E. C.; de Reijke, T. M.; Schamhart, D. H.; Vos, P. C.; Kurth, K. H.

    1993-01-01

    This study on the increase in albumin in the urine of patients with superficial bladder cancer after intravesical bacillus Calmette-Guerin (BCG) treatment was initiated on the basis of two facts. First, extravasation of serum albumin could be expected as a result of the BCG-induced delayed-type

  17. Choice of an optimal diluent for intravesical bacillus Calmette-Guerin administration.

    Science.gov (United States)

    Hudson, M A; Catalona, W J; Ritchey, J K; Aslanzadeh, J; Brown, E J; Ratliff, T L

    1989-12-01

    The physical conditions, including diluent pH, salt concentration and duration of bacillus Calmette-Guerin attachment, were determined in in vitro binding assays for soluble and matrix fibronectin. Since soluble fibronectin may block attachment of bacillus Calmette-Guerin to matrix fibronectin in the bladder, the optimal conditions were determined under which matrix fibronectin-bacillus Calmette-Guerin binding was maximal and soluble fibronectin-bacillus Calmette-Guerin binding was minimal. These conditions, which were confirmed in vivo in the murine bladder model, included use of normal saline, pH 7 as diluent for bacillus Calmette-Guerin organisms, with retention of the bacillus Calmette-Guerin suspension for 2 hours.

  18. Oral vaccination of white-tailed deer (Odocoileus virginianus with Mycobacterium bovis Bacillus Calmette-Guerin (BCG.

    Directory of Open Access Journals (Sweden)

    Mitchell V Palmer

    Full Text Available Wildlife reservoirs of Mycobacterium bovis represent serious obstacles to the eradication of tuberculosis from livestock, particularly cattle. In Michigan, USA tuberculous white-tailed deer transmit M. bovis to other deer and cattle. One approach in dealing with this wildlife reservoir is to vaccinate deer, thus interfering with the intraspecies and interspecies transmission cycles. Thirty-three white-tailed deer were assigned to one of two groups; oral vaccination with 1 × 10(8 colony-forming units of M. bovis BCG Danish (n = 17; and non-vaccinated (n = 16. One hundred eleven days after vaccination deer were infected intratonsilarly with 300 colony-forming units of virulent M. bovis. At examination, 150 days after challenge, BCG vaccinated deer had fewer gross and microscopic lesions, fewer tissues from which M. bovis could be isolated, and fewer late stage granulomas with extensive liquefactive necrosis. Fewer lesions, especially those of a highly necrotic nature should decrease the potential for dissemination of M. bovis within the host and transmission to other susceptible hosts.

  19. Disseminated bacillus calmette guerin disease in a twin infant with severe combined immunodeficiency disease

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    Hema Mittal

    2014-01-01

    Full Text Available Fatal-disseminated Bacillus Calmette Guerin (BCG disease is well known in infants with severe combined immunodeficiency after BCG vaccination. We report a 7 month male infant delivered as a product of in vitro fertilization and twin gestation that presented with fever, cough and multiple nodular skin lesions. A biopsy of skin lesions revealed the presence of acid fast bacilli. Mycobacterium bovis infection was confirmed by polymerase chain reaction (PCR and molecular studies. Immunological profile confirmed the diagnosis of severe combined immunodeficiency. Only few reports of similar case exist in the literature.

  20. Granulomatous epididymo-orchitis, a rare complication of intravesical bacillus Calmette-Guerin therapy for urothelial cancer

    DEFF Research Database (Denmark)

    Harving, S.S.; Asmussen, L.; Roosen, Jens Ulrik

    2009-01-01

    Only a few cases of tuberculous epididymo-orchitis after bacillus Calmette-Guerin (BCG) therapy have been published. This report presents a case of granulomatous epididymo-orchitis after intravesical BCG therapy in a patient presenting with pain and unilateral swelling of the scrotal content....... This complication should always be considered when a patient presents with these symptoms after BCG therapy. Isoniazid may be used as a first choice of treatment Udgivelsesdato: 2009...

  1. THE EFFECTS OF INTRAVESICAL PRETREATMENT WITH PENTOSAN POLYSULFATE ON THE BACILLUS-CALMETTE-GUERIN INDUCED IMMUNE-REACTION OF THE GUINEA-PIG

    NARCIS (Netherlands)

    de Reijke, T. M.; de Boer, L. C.; Steerenberg, P. A.; Vos, P. C.; Kurth, K. H.; Schamhart, D. H.

    1994-01-01

    Immunotherapy with intravesical instillation of bacillus Calmette-Guerin (BCG) is an effective treatment for superficial bladder carcinoma. In the present study the BCG-induced immunological reaction in the guinea pig (PPD skin test, bladder wall infiltrates and number of cells in the iliac lymph

  2. Cytokine gene expression in a mouse model: The first instillations with viable bacillus Calmette-Guerin determine the succeeding Th1 response

    NARCIS (Netherlands)

    de Boer, Elizabeth C.; Rooijakkers, Sietske J.; Schamhart, Denis H.; Kurth, Karl-Heinz

    2003-01-01

    Purpose: Bacillus Calmette-Guerin (BCG) therapy for superficial bladder cancer is immune dependent and activation of a Th1 immune response is probably required for clinical efficacy. Given the empirical approach to improving BCG therapy we investigated in a mouse model the consequences of

  3. Multiphase contrast-enhanced magnetic resonance imaging features of Bacillus Calmette-Guerin-induced granulomatous prostatitis in five patients

    Energy Technology Data Exchange (ETDEWEB)

    Kawada, Hiroshi; Kanematsu, Masayuki; Goshima, Satoshi; Kondo, Hiroshi; Watanabe, Haruo; Noda, Yoshifumi; Tanahashi, Yukichi; Kawai, Nobuyuki; Hoshi, Hiroaki [Gifu University Hospital, Gifu (Japan)

    2015-04-15

    To evaluate the multiphase contrast-enhanced magnetic resonance (MR) imaging features of Bacillus Calmette-Guerin (BCG)-induced granulomatous prostatitis (GP). Magnetic resonance images obtained from five patients with histopathologically proven BCG-induced GP were retrospectively analyzed for tumor location, size, signal intensity on T2-weighted images (T2WI) and diffusion-weighted images (DWI), apparent diffusion coefficient (ADC) value, and appearance on gadolinium-enhanced multiphase images. MR imaging findings were compared with histopathological findings. Bacillus Calmette-Guerin-induced GP (size range, 9-40 mm; mean, 21.2 mm) were identified in the peripheral zone in all patients. The T2WI showed lower signal intensity compared with the normal peripheral zone. The DWIs demonstrated high signal intensity and low ADC values (range, 0.44-0.68 x 10(-3) mm2/sec; mean, 0.56 x 10(-3) mm2/sec), which corresponded to GP. Gadolinium-enhanced multiphase MR imaging performed in five patients showed early and prolonged ring enhancement in all cases of GP. Granulomatous tissues with central caseation necrosis were identified histologically, which corresponded to ring enhancement and a central low intensity area on gadolinium-enhanced MR imaging. The findings on T2WI, DWI, and gadolinium-enhanced images became gradually obscured with time. Bacillus Calmette-Guerin-induced GP demonstrates early and prolonged ring enhancement on gadolinium-enhanced MR imaging which might be a key finding to differentiate it from prostate cancer.

  4. Bacille Calmette-Guerin (BCG) vaccination at birth and antibody responses to childhood vaccines. A randomised clinical trial

    NARCIS (Netherlands)

    Nissen, T.N.; Birk, N.M.; Smits, G.; Jeppesen, D.L.; Stensballe, L.G.; Netea, M.G.; Klis, F. van der; Benn, C.S.; Pryds, O.

    2017-01-01

    INTRODUCTION: BCG vaccination has been associated with beneficial non-specific effects on child health. Some immunological studies have reported heterologous effects of vaccines on antibody responses to heterologous vaccines. Within a randomised clinical trial of Bacille Calmette-Guerin (BCG)

  5. Primary tuberculosis of glans penis after intravesical Bacillus Calmette Guerin immunotherapy

    Directory of Open Access Journals (Sweden)

    V K Sharma

    2011-01-01

    Full Text Available A 55-year-old male with carcinoma in situ of urinary bladder was treated with weekly intravesical injections of Bacillus Calmette Guerin (BCG vaccine. Three days after the sixth injection, he developed low grade fever and multiple grouped punched out, 2-3 mm ulcers around meatus and corona glandis. In addition, multiple, firm, indurated, nontender papules and few deeper nodules were present on the proximal part of glans penis, along with bilateral enlarged, matted and nontender inguinal lymph nodes. There was no history suggestive of sexually transmitted diseases and high risk behavior. Chest X-ray was within normal limits, and Mantoux, Venereal Disease Research Laboratory (VDRL and HIV antibody tests were negative. The biopsy from the penile ulcer revealed epithelioid cell granuloma with Langhans giant cells. Fine needle aspiration cytology from the lymph node also revealed epithelioid cell granuloma and acid fast bacilli on Ziehl Neelsen′s stain. The tissue biopsy grew Mycobacterium tuberculosis. The BCG immunotherapy was stopped and patient was treated with four drug antitubercular therapy with isoniazid, rifampicin, ethambutol, and pyrazinamide in standard daily doses along with pyridoxine. The edema resolved and the ulcers started healing within 2 weeks, and at 6 weeks after starting antitubercular therapy almost complete healing occurred. To the best of our knowledge, we describe the first case of an Indian patient with BCG induced primary tuberculosis of penis after immunotherapy for carcinoma urinary bladder and review the previously described cases to increase awareness of this condition in dermatologists and venereologists.

  6. Bacillus Calmette-Guerin, polysaccharide nucleic acid in the treatment of cutaneous and oral lichen planus.

    Science.gov (United States)

    Nasr, Mohamad M; Ebrahim, Howyda M; Khattab, Fathia M; Marei, Ayman M

    2018-02-06

    The aim of this study was to evaluate the safety and efficacy of Bacillus Calmette-Guerin, polysaccharide nucleic acid (BCG-PSN) therapy in the treatment of oral and cutaneous LP. Twenty-four LP patients were included in this study and classified randomly into; Oral LP group (OLP), 11 patients and Cutaneous LP group (CLP), 13 patients. All patients received intradermal injections of BCG-PSN, twice weekly for three weeks. Patients with complete response were followed up for 3 months. The assessment in OLP was based on the reduction in the treated area, (Reticulation/Erythema/Ulceration) REU scoring system and numerical rating scale (NRS). CLP evaluated by the response to treatment as (complete, partial and no response) and visual analogue scale (VAS). There were highly significant differences in the diminution of lesion areas (p < .006), NRS scores (p < .001), REU score (p < .011), and VAS (p < .001) after treatment. The majority of patients achieved complete response after 3-week management. The BCG-PNS is safe and effective in the treatment of oral and cutaneous LP. © 2018 Wiley Periodicals, Inc.

  7. Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials

    NARCIS (Netherlands)

    Sylvester, Richard J.; van der Meijden, Adrian P. M.; Witjes, J. Alfred; Kurth, Karlheinz

    2005-01-01

    We determined the short-term and long-term efficacy of bacillus Calmette-Guerin (BCG) and chemotherapy in the treatment of patients with carcinoma in situ (CIS). A meta-analysis was performed on published results of randomized clinical trials comparing intravesical BCG to intravesical chemotherapy.

  8. Molecular confirmation of Bacillus Calmette Guerin vaccine related adverse events among Saudi Arabian children.

    Directory of Open Access Journals (Sweden)

    Sahal Al-Hajoj

    Full Text Available Bacillus Calmette Guerin (BCG is the only available vaccine for tuberculosis (TB. Low grade complications in healthy recipients and disseminated vaccine associated complications among immuno-suppressed individuals were noticed globally after administration. Recently a series of clinically suspected BCG associated suppurative and non-suppurative lymphadenitis cases were reported from different regions of Saudi Arabia. However a molecular confirmative analysis was lacking to prove these claims.During 2009-2010, 42 Mycobacterium bovis BCG suspected clinical isolates from children diagnosed with suppurative lymphadenitis from different provinces of the country were collected and subjected to 24 loci based MIRU-VNTR typing, spoligotyping and first line anti-TB drugs susceptibility testing.Of the total 42 cases, 41 (97.6% were Saudi nationals and particularly male (64.3%. Majority of the cases were aged below 6 months (83.3% with a median of age 4 months. All the enrolled subjects showed left axillary mass which suppurated in a median of 4 months after vaccination. Among the study subjects, 1 (2.4% case was reactive to HIV antigen and 2 (4.8% case had severe combined immunodeficiency. Genotyping results showed that, 41 (97.6% isolates were identical to the vaccine strain Danish 1331 and one to Tokyo 172-1. Phylogenetic analysis revealed all the Danish 1331 isolates in a single cluster.Elevated proportion of suppurative lymphadenitis caused by M. bovis BCG reported in the country recently is majorly related to the vaccine strain Danish 1331. However lack of nationwide data on real magnitude of BCG related adverse events warrants population centric, long term future studies.

  9. Reduction of Mycobacterium tuberculosis infection in Bacillus Calmette Guerin immunized people is due to training of innate immunity.

    Science.gov (United States)

    Eisenhut, Michael

    2015-03-01

    The currently used vaccine for prevention of tuberculosis is Bacillus Calmette Guerin, which has been associated with a protective effect of 51% against tuberculosis. New vaccination strategies based on an enhancement of adaptive T-cell based immunity have been unsuccessful in increasing the efficiency of BCG immunisation. The proposed hypothesis is that a reduction of Mycobacterium (M.) tuberculosis infection in Bacillus Calmette Guerin immunized people is due to training of innate immunity. Evidence to support the hypothesis is a systematic review, which showed that BCG protects against M. tuberculosis infection as evident from negative interferon gamma release assay results in BCG immunised exposed people. BCG has been shown to enhance innate immunity in monocytes via nucleotide binding oligomerisation domain 2 receptor activation by muramyldipeptide. An alternative hypothesis may be that T-suppressor cells induced by BCG immunisation may be the reason for the absence of an interferon gamma response mimicking absence of infection in immunized people. In order to test the primary hypothesis an ultra-low dose mouse model of M. tuberculosis infection could be used. Innate immunity could be enhanced by administration of murabutide and groups with and without murabutide enhanced BCG immunisation and with and without elimination of T-suppressor cells compared. The contribution of training of innate immunity in reduction of infection could hereby be demonstrated by treatment of mice prior to immunisation with an inhibitor of epigenetic programming. Confirmation of the hypothesis could provide the foundation of a new approach to an improved vaccine against M. tuberculosis infection. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Generalized Granuloma Annulare in Infancy Following Bacillus Calmette-Guerin Vaccination

    OpenAIRE

    Lee, Sang Woo; Cheong, Seung Hyun; Byun, Ji Yeon; Choi, You Won; Choi, Hae Young; Myung, Ki Bum

    2011-01-01

    Generalized granuloma annulare (GGA) is a rare benign granulomatous dermatosis characterized by disseminated necrobiotic dermal papules. Histologically, it presents as a lymphohistiocytic granuloma associated with varying degrees of connective tissue degeneration. It usually occurs in adults and rarely affects infants. Herein, we report an interesting case of GGA which occurred in a 3 month-old girl in association with Bacillus Calmette-Guerin vaccination.

  11. Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials.

    NARCIS (Netherlands)

    Sylvester, R.J.; Meijden, A.P. van der; Witjes, J.A.; Kurth, K.H.

    2005-01-01

    PURPOSE: We determined the short-term and long-term efficacy of bacillus Calmette-Guerin (BCG) and chemotherapy in the treatment of patients with carcinoma in situ (CIS). MATERIALS AND METHODS: A meta-analysis was performed on published results of randomized clinical trials comparing intravesical

  12. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer.

    NARCIS (Netherlands)

    Malmstrom, P.U.; Sylvester, R.J.; Crawford, D.E.; Friedrich, M.; Krege, S.; Rintala, E.; Solsona, E.; Stasi, S.M. Di; Witjes, J.A.

    2009-01-01

    BACKGROUND: Patients with non-muscle-invasive bladder cancer with an intermediate or high risk need adjuvant intravesical therapy after surgery. Based largely on meta-analyses of previously published results, guidelines recommend using either bacillus Calmette-Guerin (BCG) or mitomycin C (MMC) in

  13. Prognostic factors and risk groups in T1G3 non-muscle-invasive bladder cancer patients initially treated with Bacillus Calmette-Guerin: results of a retrospective multicenter study of 2451 patients

    NARCIS (Netherlands)

    Gontero, P.; Sylvester, R.; Pisano, F.; Joniau, S.; Eeckt, K. Vander; Serretta, V.; Larre, S.; Stasi, S. Di; Rhijn, B. Van; Witjes, J.A.; Grotenhuis, A.J.; Kiemeney, L.A.L.M.; Colombo, R.; Briganti, A.; Babjuk, M.; Malmstrom, P.U.; Oderda, M.; Irani, J.; Malats, N.; Baniel, J.; Mano, R.; Cai, T.; Cha, E.K.; Ardelt, P.; Varkarakis, J.; Bartoletti, R.; Spahn, M.; Johansson, R.; Frea, B.; Soukup, V.; Xylinas, E.; Dalbagni, G.; Karnes, R.J.; Shariat, S.F.; Palou, J.

    2015-01-01

    BACKGROUND: The impact of prognostic factors in T1G3 non-muscle-invasive bladder cancer (BCa) patients is critical for proper treatment decision making. OBJECTIVE: To assess prognostic factors in patients who received bacillus Calmette-Guerin (BCG) as initial intravesical treatment of T1G3 tumors

  14. Bacillus Calmette Guerin induces fibroblast activation both directly and through macrophages in a mouse bladder cancer model.

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    Catalina Lodillinsky

    Full Text Available BACKGROUND: Bacillus Calmette-Guerin (BCG is the most effective treatment for non-muscle invasive bladder cancer. However, a failure in the initial response or relapse within the first five years of treatment has been observed in 20% of patients. We have previously observed that in vivo administration of an inhibitor of nitric oxide improved the response to BCG of bladder tumor bearing mice. It was described that this effect was due to a replacement of tumor tissue by collagen depots. The aim of the present work was to clarify the mechanism involved in this process. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated that BCG induces NIH-3T3 fibroblast proliferation by activating the MAPK and PI3K signaling pathways and also differentiation determined by alpha-smooth muscle actin (alpha-SMA expression. In vivo, intratumoral inoculation of BCG also increased alpha-SMA and collagen expression. Oral administration of L-NAME enhanced the pro-fibrotic effect of BCG. Peritoneal macrophages obtained from MB49 tumor-bearing mice treated in vivo with combined treatment of BCG with L-NAME also enhanced fibroblast proliferation. We observed that FGF-2 is one of the factors released by BCG-activated macrophages that is able to induce fibroblast proliferation. The involvement of FGF-2 was evidenced using an anti-FGF2 antibody. At the same time, this macrophage population improved wound healing rate in normal mice and FGF-2 expression was also increased in these wounds. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that fibroblasts are targeted by BCG both directly and through activated macrophages in an immunotherapy context of a bladder murine model. We also described, for the first time, that FGF-2 is involved in a dialog between fibroblasts and macrophages induced after BCG treatment. The fact that L-NAME administration improves the BCG effect on fibroblasts, NO inhibition, might represent a new approach to add to the conventional BCG therapy.

  15. Interferon-γ Added During Bacillus Calmette-Guerin Induced Dendritic Cell Maturation Stimulates Potent Th1 Immune Responses

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    Pestano Linda A

    2003-10-01

    Full Text Available Abstract Dendritic cells (DC are increasingly prepared in vitro for use in immunotherapy trials. Mature DC express high levels of surface molecules needed for T cell activation and are superior at antigen-presentation than immature DC. Bacillus Calmette-Guerin (BCG is one of several products known to induce DC maturation, and interferon (IFN-γ has been shown to enhance the activity of DC stimulated with certain maturation factors. In this study, we investigated the use of IFN-γ in combination with the powerful maturation agent, BCG. The treatment of immature DC with IFN-γ plus BCG led to the upregulation of CD54, CD80, and CD86 in comparison with BCG treatment alone. In MLR or recall immune responses, the addition of IFN-γ at the time of BCG-treatment did not increase the number of antigen-specific T cells but enhanced the development of IFN-γ-producing Th1 cells. In primary immune responses, on the other hand, BCG and IFN-γ co-treated DC stimulated higher proportions of specific T cells as well as IFN-γ secretion by these T cells. Thus the use of IFN-γ during BCG-induced DC maturation differentially affects the nature of recall versus naïve antigen-specific T-cell responses. IFN-γ co-treatment with BCG was found to induce IL-12 and, in some instances, inhibit IL-10 secretion by DC. These findings greatly enhance the potential of BCG-matured dendritic cells for use in cancer immunotherapy.

  16. Fecal volatile organic compound profiles from white-tailed deer (Odocoileus virginianus) as indicators of Mycobacterium bovis exposure or Mycobacterium bovis bacille Calmette-Guerin (BCG) vaccination

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    White-tailed deer (Odocoileus virginianus) serve as a reservoir for bovine tuberculosis, caused by Mycobacterium bovis, and can be a source of infection in cattle. Vaccination with M. bovis bacille Calmette-Guerin (BCG) is being considered for management of bovine tuberculosis in deer. Presently, no...

  17. Role of Aspirin in Patients with Bladder Cancer Receiving Intravesical Bacillus Calmette-Guerin: A Prospective, Observational Study

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    Rupesh Gupta

    2017-10-01

    Full Text Available Introduction: High-Risk Non-Muscle Invasive Bladder Cancers (HR NMIBC are prone to recur and progress even with intravesical Bacillus Calmette-Guerin (BCG therapy. Aim: To investigate the role of aspirin in prevention of early recurrence and progression in patients with HR NMIBC receiving intravesical BCG. Materials and Methods: This was a prospective, single centre, observational study that included patients with HR NMIBC {Ta, T1 or Carcinoma in situ (CIS} from February 2015 to January 2017. Patients were screened for eligibility based on clinical, radiological and risk factor profile assessment, history of treatment with aspirin and medical records. Eligible patients were grouped into Group 1 and Group 2 based on aspirin (for minimum of three months or non-aspirin consumption respectively. Both groups received similar induction, maintenance and intravesical BCG therapy; according to Southwest Oncology Group (SWOG protocol. Follow up cystoscopy was done every three months for up to two years. Results: A total of 152 patients were screened and 103 patients were included in the study (Group 1, n=15; Group 2, n=88. Binary progression analysis revealed that focality was the only significant predictor variable for the recurrence (OR, 5.064; p=0.001. Aspirin intake was not related to stage (p=0.595, grade (p=0.558, recurrence (p=0.508 and progression (p=0.621 of the tumour. Kaplan-Meier analysis showed that 12-month recurrence (64.2% versus 64.7%, p=0.566 and progression free survival rate (66.7% versus 57.3%, p=0.640 were same in both groups. Conclusion: Results showed that aspirin does not affect the recurrence and progression of HR NMIBC in patients receiving BCG therapy.

  18. Various ultrasonographic manifestations of Bacille Calmette-Guerin (BCG) lymphadenitis in infants after BCG vaccination

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    Yoon, Choon Sik; Kim, Myung Joon; Lee, Kwang Hun; Kwon, Woo Cheol; Cho, Nariya; Lee, Sung Il; Park, Kae Young; Kim, Dong Jin

    1999-01-01

    To evaluate the various ultrasonographic manifestations of BCG lymphadenitis complicated by BCG vaccination in infants. Among a total of 59 patients of BCG lymphadenitis, we retrospectively evaluated the ultrasonographic findings of five patients (seven involved areas), who were operated and confirmed by histopathology. Three cases were male and two were female and the age range is from 3 months to 9 months (mean: 5.5 months). Among five cases two had only a single lesion and three had multiple lesions, and two of those had multiple lesions at 2 separate locations. All five cases had ipsilateral supraclavicular lesions with same BCG vaccination site and two also had ipsilaeteral axillary lesions. Ultrasonography showed enlarged lymph nodes and heterogeneous hypoechoic changes suggesting internal necrosis or suppurative changes in three cases, but 1 had cystic necrotic change with fluid-fluid level and another had conglomerated mass with intermingled hyper and hypoechoic areas, which were initially suspected to be a tumorous conditions but revealed conglomerated lymph nodes on follow-up ultrasonography and MRI. BCG lymphadenitis is usually located adjacent to a BCG vaccination site, but ultrasonography can show single or multiple lymph node enlargement and various manifestations from homogeneous lymphadenitis to cystic abscess changes and even a mass-like appearance, demonstrating that the evaluation of ultrasonography should be done very carefully.

  19. Determining optimal maintenance schedules for adjuvant intravesical bacillus Calmette-Guerin immunotherapy in non-muscle-invasive bladder cancer: a systematic review and network meta-analysis.

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    Huang, Zixiong; Liu, Huixin; Wang, Yizeng; Zhang, Chunfang; Xu, Tao

    2017-08-01

    To figure out optimal bacillus Calmette-Guerin (BCG) maintenance schedules for non-muscle-invasive bladder cancer (NMIBC) patients by comparing different schedules in a systematic review using conventional and network meta-analysis. Literature was searched in the databases of Medline, Embase, Cochrane library, Clinicaltrials.gov, Wanfang, CNKI and SinoMed in April 2016 and 9 randomized clinical trials comparing intravesical BCG maintenance therapy with BCG induction-only therapy or comparing different BCG maintenance schedules (induction-only, 1 year, 1.5 year, 2 year, 3 year maintenance) in NMIBC patients were included. Conventional and network meta-analyses within a Bayesian framework were performed to calculate odds ratios of tumor recurrence, progression and side effects (cystitis, hematuria, general malaise and fever). The surface under the cumulative ranking curve (SUCRA) mean ranking was used to obtain schedule hierarchy. Data from 1951 patients showed that longer-term maintenance BCG therapy does not significantly decrease tumor recurrence and progression rate of NMIBC compared to shorter-term maintenance BCG therapy. However, longer-maintenance therapy does not increase side effect incidence compared to induction-only therapy. According to SUCRA results, induction-only therapy has the highest probability of recurrence and progression but least probability of side effects. Longer BCG maintenance therapy (such as 3 years) is not superior to shorter maintenance therapy (such as 1 year). But maintenance therapy overall is better than induction-only BCG therapy while not increasing side effects. Though further evidence and clinical practice with balanced confounding factors (risk stratification and BCG strain) are wished for, the current study suggests the common use of 1 year intravesical BCG instillation for NMIBC patients.

  20. Comparison of effect of kangaroo mother care, breastfeeding and swaddling on Bacillus Calmette-Guerin vaccination pain score in healthy term neonates by a clinical trial.

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    Fallah, Razieh; Naserzadeh, Naeimah; Ferdosian, Farzad; Binesh, Fariba

    2017-05-01

    The purpose of this research was to compare the analgesic effect of kangaroo mother care (KMC), breastfeeding and swaddling in Bacillus Calmette-Guerin (BCG) vaccination in term neonates. In a randomized 120 healthy term neonates who received routine BCG vaccination in the first day of their life are distributed into three groups. In group 1, neonates breastfed two minutes before, during and one minute after BCG vaccination. In group 2, neonates received KMC 10 minutes before, during and one minute after vaccination and in group 3, they were swaddled 10 minutes before, during and one minute after vaccination. Primary outcomes included pain score during, one minute and two minutes after BCG vaccination and obtaining pain score of less than three during vaccination . Pain scores during, one minute and two minutes after vaccination in group 1 were lower than in groups 2 and 3. Group 1 had higher success rate in painless vaccination and had lower crying duration in comparison to another groups (p vaccination pain in healthy term neonates.

  1. Protective effect of Bacillus Calmette-Guerin (BCG) vaccination in children with extra-pulmonary tuberculosis, but not the pulmonary disease. A case-control study in Rosario, Argentina.

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    Bonifachich, Elena; Chort, Monica; Astigarraga, Ana; Diaz, Nora; Brunet, Beatriz; Pezzotto, Stella Maris; Bottasso, Oscar

    2006-04-05

    A hospital-based case-control study was carried out at the Vilela Children's Hospital in Rosario, Argentina, to measure the protection conferred by BCG vaccination against tuberculosis (TB). The study included 148 newly diagnosed cases of TB (75 males and 73 females, mean age 3.34+/-2.97 years, S.D.), 134 of them with pulmonary TB and 14 cases with extra-pulmonary disease. Controls (425 males and 357 females, 3.39+/-2.98 years) were selected randomly among children who attended to the Hospital showing, neither respiratory diseases nor any other infectious illnesses. Information on BCG vaccination history was assessed from scars or immunisation records. All participants were negative to human immunodeficiency virus and belonged to the lower and upper-lower socioeconomic status, being similar in place of residence and ethnic characteristics. Rate of vaccinated children was 92.6% of cases and 94.5% of controls (3.4 and 3.9% of them without scars, respectively). Regarding the total cases, the protective association between BCG and TB was statistically insignificant, as was for the pulmonary form. Among cases with extra-pulmonary disease, vaccine effectiveness attained significance [79% (95% CI=26-94)], no matter their age, sex or nutritional status. BCG vaccination exerted a beneficial role in extra-pulmonary TB, even in children not seriously undernourished.

  2. Assessment of angiogenic factor, vascular endothelial growth factor, serum and urine level changes in superficial bladder tumor immunotherapy by intravesical Bacillus Calmette-Guerin

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    Kerigh Behzad

    2010-01-01

    Full Text Available Background and Aim: Bladder tumor is one of the most common genitourinary tumors. Management of non-muscle invasive (NMI bladder tumors is primarily by transurethral resection (TURBT followed by intravesical immunotherapy or chemotherapy. Bacillus Calmette-Guerin (BCG is the most effective adjuvant therapy in NMI bladder tumor. Since angiogenesis is an essential factor in solid tumor progression and vascular endothelial growth factor (VEGF is an important factor in angiogenesis, the aim of this study is the assessment of angiogenic factor, VEGF, serum and urine level changes in superficial bladder tumor immunotherapy by intravesical BCG. Materials and Methods: A total of 23 patients with bladder transitional cell carcinoma (TCC in stage Ta/T1 or carcinoma insitu (CIS, low or high grade, which passed a 2-4 week period from TURBT participated in this study. Blood and urine samples were obtained at first and sixth sessions before instillation of BCG. Enzyme-linked immunosorbent assay (ELISA method was used to obtain VEGF level in samples. Results: Urine and serum VEGF levels did not change significantly before and after BCG therapy. Changes in VEGF level were significantly different neither in low grade against high grade tumors nor in stage T1 against stage Ta tumors. A significant difference in VEGF level was seen between low grade and high grade tumors in serum after BCG therapy (P=0.007; but not in urine samples. Conclusion: Although intravesical BCG possesses anti-angiogenic activity, it seems that it exerts its effect through pathways other than VEGF, especially in low grade tumors.

  3. Adverse Reactions Due to the Bacillus Calmette-Guerin Vaccine: Twenty Tunisian Cases.

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    Sellami, Khadija; Amouri, Meriem; Kmiha, Sana; Bahloul, Emna; Aloulou, Hajer; Sfaihi, Lamia; Guirat, R; Mseddi, Madiha; Kamoun, T; Hachicha, Mongia; Turki, Hamida

    2018-01-01

    Bacillus Calmette-Guérin (BCG) vaccine is a widely used vaccine. Management of local BCG complications differs between clinicians, and the optimal approach remains unclear. We aim to describe the epidemiological, clinical and therapeutic aspects of the BCG vaccine side effects in Sfax. This was a retrospective study of all the cases of BCG vaccine adverse reactions recorded in the Dermatology and Paediatrics Departments of Hedi Chaker University Hospital of Sfax over a period of 10 years (2005-2015). Twenty cases of BCG adverse reactions were notified during the study period. Actually, 80% of the patients presented local adverse reactions. The outcome was good in all the followed patients. The rate of disseminated BCG disease was 20%. Biological tests of immunity showed a primary immunodeficiency in three cases, whereas the outcome was fatal in two cases. BCG vaccine adverse reactions range from mild to severe. However, the management of benign local reactions remains unclear. Disseminated BCG disease must alert clinicians to the possibility of a primary immunodeficiency.

  4. Adverse reactions due to the bacillus Calmette-Guerin vaccine: Twenty Tunisian cases

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    Khadija Sellami

    2018-01-01

    Full Text Available Background: Bacillus Calmette-Guérin (BCG vaccine is a widely used vaccine. Management of local BCG complications differs between clinicians, and the optimal approach remains unclear. Aims: We aim to describe the epidemiological, clinical and therapeutic aspects of the BCG vaccine side effects in Sfax. Patients and Methods: This was a retrospective study of all the cases of BCG vaccine adverse reactions recorded in the Dermatology and Paediatrics Departments of Hedi Chaker University Hospital of Sfax over a period of 10 years (2005–2015. Results: Twenty cases of BCG adverse reactions were notified during the study period. Actually, 80% of the patients presented local adverse reactions. The outcome was good in all the followed patients. The rate of disseminated BCG disease was 20%. Biological tests of immunity showed a primary immunodeficiency in three cases, whereas the outcome was fatal in two cases. Conclusion: BCG vaccine adverse reactions range from mild to severe. However, the management of benign local reactions remains unclear. Disseminated BCG disease must alert clinicians to the possibility of a primary immunodeficiency.

  5. Clinical features and outcome of eleven patients with disseminated Bacille Calmette-Guerin (BCG) infection

    International Nuclear Information System (INIS)

    Al-Arishi, Haider M.; Frayha, Husn H.; Qari, Hussni Y.; Al-Rayes, H.; Tufenkeji, Haysam T.; Harfi, H.

    1996-01-01

    Disseminated BCG infection is a very rare complication of BCG vaccination. This study presents 11 patients with such complication. The underlying disease in eight of the 11 patients was primary immunodeficiency. Seven of these had severe combined immune deficiency (SCID) and one had isolated T-cell defect. Of the three remaining patients, one was healthy, one was diagnosed with mucocutaneous candidiasis and the third was diagnosed with leukocytoclastic vasculitis. Cutaneous nodular lesion, persistent fever, hepatosplenomegaly and pulmonary symptoms were common presenting features. All but one patient received antituberculous treatment. Four of 11 patients died because of extensive BCG disease. Three of these had SCID and one had T-cell deficiency. Patients with SCID who survived had bone marrow transplantation in addition to antituberculous chemotherapy. We conclude that a family history of immunodeficiency should be sought and if suggestive, BCG vaccine should be deferred until the immune status of the baby is clarified. In addition, early diagnosis is important for successful outcome. Bone marrow transplant on an emergency basis is the treatment of choice in patients with SCID and disseminated BCG infection, as immune reconstitution is essential to control infection in these patients. (author)

  6. Effect of Age on Outcome of High-Risk Non-Muscle-Invasive Bladder Cancer Patients Treated with Second Transurethral Resection and Maintenance Bacillus Calmette-Guerin Therapy

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    Sümer Baltacı

    2016-09-01

    Full Text Available Objective To determine the effect of age on recurrence and progression rates in a population of high-risk non-muscle invasive bladder cancer (NMIBC patients treated with a second transurethral resection (TUR and at least 1 year of maintenance Bacillus Calmette-Guerin (BCG therapy. Materials and Methods In this multicenter study, we reviewed the data of patients treated for high-risk NMIBC between 2005 and 2012. Patients without a muscle-invasive cancer on second TUR and received induction BCG and at least one year of maintenance BCG therapy and at least 12 months of follow-up after completion of maintenance BCG were included. Effect of age was analyzed both dichotomously (<70 or ≥70 years as well as by 10-year increments. Chi-square test, Student’s T-test and analysis of variance (ANOVA were used for comparison of the groups. Univariate and multivariate logistic regression analyses were performed to identify predictors of recurrence and progression. Results Overall, 242 eligible patients were included. Baseline parameters were similar. With a mean follow-up of 29.4±22.2 months, neither 3-year recurrence-free survival nor 3-year progression-free survival differed between the age groups when examined either dichotomously or by 10-year increments. Conclusion In high-risk NMIBC patients treated with a second TUR and received maintenance BCG therapy, age was not associated with increased rates of neither recurrence nor progression. Until a randomized prospective clinical trial assess the appropriate adjuvant intravesical therapy in the elderly, elderly patients should probably be treated in the same manner as younger patients.

  7. Bacillus Calmette-Guerin in the management of superficial bladder cancer

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    Rakesh Kapoor

    2008-01-01

    Full Text Available Intravesical Bacillus Calmette-Guιrin (BCG is the mainstay of superficial bladder cancer treatment. We performed a literature search through Medline/Pubmed using key words ′Bacillus Calmette-Guιrin′, ′intravesical′, ′bladder neoplasm′ and ′immunotherapy′ for published data in the English language from 1970 to 2007 to review the current status of intravesical therapy and practice recommendations. The exact mechanism of action of intravesical BCG is yet to be elucidated. However, it appears that it is mediated by the local immune response, mainly through T-helper cell response. It reduces the recurrence rate by an average of 40% and progression by more than 20% in papillary tumors over the patients without BCG therapy. However, progression prevention is seen only in series which have used maintenance therapy at least for one year. It is effective in CIS of bladder with a response rate of more than 40% and prevention of progression in one-fourth patients. Most acceptable dose, induction treatment and maintenance therapy protocols are discussed. However, these are yet to be confirmed in large randomized trials. Intravesical BCG is well tolerated in most of the patients with mild to moderate side-effects in induction therapy; however, most patients do not complete maintenance therapy due to side-effects which is the most common concern at the present time.

  8. Therapy of Venezuelan patients with severe mucocutaneous or early lesions of diffuse cutaneous leishmaniasis with a vaccine containing pasteurized Leishmania promastigotes and bacillus Calmette-Guerin: preliminary report

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    Jacinto Convit

    2004-02-01

    Full Text Available Severe mucocutaneous (MCL and diffuse (DCL forms of American cutaneous leishmaniasis (ACL are infrequent in Venezuela. Chemotherapy produces only transitory remission in DCL, and occasional treatment failures are observed in MCL. We have evaluated therapy with an experimental vaccine in patients with severe leishmaniasis. Four patients with MCL and 3 with early DCL were treated with monthly intradermal injections of a vaccine containing promastigotes of Leishmania (Viannia braziliensis killed by pasteurization and viable Bacillus Calmette- Guerin. Clinical and immunological responses were evaluated. Integrity of protein constituents in extracts of pasteurized promastigotes was evaluated by gel electrophoresis. Complete remission of lesions occurred after 5-9 injections in patients with MCL or 7-10 injections in patients with early DCL. DCL patients developed positive skin reactions, average size 18.7 mm. All have been free of active lesions for at least 10 months. Adverse effects of the vaccine were limited to local reactivity to BCG at the injection sites and fever in 2 patients. Extracts of pasteurized and fresh promastigotes did not reveal differences in the integrity of protein components detectable by gel electrophoresis. Immunotherapy with this modified vaccine offers an effective, safe option for the treatment of patients who do not respond to immunotherapy with vaccine containing autoclaved parasites or to chemotherapy .

  9. Systemic granulomatous reaction secondary to treatment of bladder cancer with Bacillus Calmette-Guerin

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    Caterina Giovanna Valentini

    2012-01-01

    Full Text Available

    Intravesical instillation of Bacillus Calmette-Guérin is the elective treatment for transitional cell and in situ bladder carcinoma. Severe complications occur very seldom, but must be known and promptly recognized. We describe the case of a 48-year-old man, treated with chemo-immunotherapy ten years before for a follicular lymphoma, who developed a systemic granulomatous reaction after his twelfth intravescical BCG instillation for bladder cancer.

  10. Systemic granulomatous reaction secondary to treatment of bladder cancer with Bacillus Calmette-Guerin

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    Caterina Giovanna Valentini

    2012-06-01

    Full Text Available Intravesical instillation of Bacillus Calmette-Guérin is the elective treatment for transitional cell and in situ bladder carcinoma. Severe complications occur very seldom, but must be known and promptly recognized. We describe the case of a 48-year-old man, treated with chemo-immunotherapy ten years before for a follicular lymphoma, who developed a systemic granulomatous reaction after his twelfth intravescical BCG instillation for bladder cancer.

  11. Dose, duration and strain of bacillus Calmette-Guerin in the treatment of nonmuscle invasive bladder cancer: Meta-analysis of randomized clinical trials.

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    Quan, Yongjun; Jeong, Chang Wook; Kwak, Cheol; Kim, Hyeon Hoe; Kim, Hyung Suk; Ku, Ja Hyeon

    2017-10-01

    Intravesical bacillus Calmette-Guerin (BCG) instillation is widely used as an adjuvant therapy after transurethral resection of bladder tumor (TURBT) in patients with intermediate- and high-risk nonmuscle invasive bladder cancer (NMIBC). However, the effective dose, duration, and strain of BCG have not yet been clearly determined. We aimed to elucidate the relationship between dose, duration, and strain of BCG and clinical outcomes in NMIBC patients treated with TURBT. We conducted a literature search in Embase, Scopus, and PubMed databases for all relevant articles published up to October 2016 in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. The relative risks of clinical outcomes, including recurrence, progression, cancer-specific mortality, and all-cause mortality according to dose (standard vs low), duration (induction vs maintenance), and strain of BCG were presented as the pooled risk ratio (RR) and 95% confidence interval (CI). Nineteen studies meeting the inclusion criteria were finally selected in this meta-analysis. The risk of recurrence was significantly highly observed in case of low-dose BCG (RR, 1.17; 95% CI 1.06-1.30) and induction BCG (RR, 1.33; 95% CI 1.17-1.50) only group without heterogeneity among the included studies. Although there were no significant differences between dose or duration and other clinical outcomes. On direct comparison in each study comparing BCG strains, the Tice stain showed a relatively high probability of recurrence compared with the Connaught (RR, 1.29; 95% CI 1.01-1.64) and RIVM (RR, 2.04, 95% CI 1.28-3.25) strains. Funnel plot testing revealed no significant publication bias. The use of standard dose and maintenance BCG instillation may be effective to reduce recurrence rate after TURBT for NMIBC. Further large scale, well-designed, and prospective studies, with stratification of the patients into risk group at randomization, will be required to determine the optimal

  12. Suppression of 2,4-dinitrochlorobenzene-induced atopic dermatitis by extract of Bacillus Calmette-Guerin.

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    Sun, Mingli; Wang, Shuang; Zhao, Lin; Zhao, Haishan; Yao, Weifan; Jin, Wanbao; Wei, Minjie

    2014-02-01

    Bacillus Calmette-Guerin extract (BCGE) has been proven to be clinically effective for anaphylactic disease, infectious diseases and cancer. In this study, we investigated the effect of the intramuscular application of BCGE on 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD). We established an AD model in BALB/c mice by repeated local exposure of DNCB to the ear and dorsal skin. Following intramuscular application of BCGE, the ear thickness, mast cell infiltration, serum total immunoglobulin E (IgE) and histamine level were measured. In addition, levels of interleukin (IL)-4, IL-13, interferon (IFN)-γ and tumor necrosis factor (TNF)-α in the ears were assayed. BCGE reduced AD symptoms based on ear thickness, dermatitis score, histopathological analysis and serum IgE levels. In addition, BCGE inhibited mast cell infiltration into the ear and elevation of serum histamine, increased IFN-γ level and suppressed IL-4, IL-13 and TNF-α levels in the ears. Furthermore, BCGE attenuated the NF-κBp65 expression in the nuclear extract of the ear tissue. Taken together, our results demonstrated that intramuscular application of BCGE exerts beneficial effects on the symptoms of AD suggesting that BCGE may be a candidate for the treatment of AD.

  13. Anti-angiogenic effects of the superantigen staphylococcal enterotoxin B and Bacillus Calmette-Guerin immunotherapy in the non-muscle invasive bladder cancer

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    Leonardo Oliveira Reis

    2011-01-01

    Resumo: O tratamento do câncer de bexiga urotelial não músculo invasivo (CBNMI) com Bacilo Calmette-Guerin (BCG) tem efeito comprovado na redução de recidiva tumoral, embora ocorram efeitos colaterais de intensidades variadas, desde sintomas irritativos leves até reação sistêmica grave e o impacto na progressão tumoral seja controverso. Neste cenário a enterotoxina B do Staphylococcus aureus (EBS) destaca-se como alternativa promissora na terapêutica do CBNMI. Assim, os objetivos principais d...

  14. Bacillus calmette-guerin infection in NADPH oxidase deficiency: defective mycobacterial sequestration and granuloma formation.

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    Christine Deffert

    2014-09-01

    Full Text Available Patients with chronic granulomatous disease (CGD lack generation of reactive oxygen species (ROS through the phagocyte NADPH oxidase NOX2. CGD is an immune deficiency that leads to frequent infections with certain pathogens; this is well documented for S. aureus and A. fumigatus, but less clear for mycobacteria. We therefore performed an extensive literature search which yielded 297 cases of CGD patients with mycobacterial infections; M. bovis BCG was most commonly described (74%. The relationship between NOX2 deficiency and BCG infection however has never been studied in a mouse model. We therefore investigated BCG infection in three different mouse models of CGD: Ncf1 mutants in two different genetic backgrounds and Cybb knock-out mice. In addition, we investigated a macrophage-specific rescue (transgenic expression of Ncf1 under the control of the CD68 promoter. Wild-type mice did not develop severe disease upon BCG injection. In contrast, all three types of CGD mice were highly susceptible to BCG, as witnessed by a severe weight loss, development of hemorrhagic pneumonia, and a high mortality (∼ 50%. Rescue of NOX2 activity in macrophages restored BCG resistance, similar as seen in wild-type mice. Granulomas from mycobacteria-infected wild-type mice generated ROS, while granulomas from CGD mice did not. Bacterial load in CGD mice was only moderately increased, suggesting that it was not crucial for the observed phenotype. CGD mice responded with massively enhanced cytokine release (TNF-α, IFN-γ, IL-17 and IL-12 early after BCG infection, which might account for severity of the disease. Finally, in wild-type mice, macrophages formed clusters and restricted mycobacteria to granulomas, while macrophages and mycobacteria were diffusely distributed in lung tissue from CGD mice. Our results demonstrate that lack of the NADPH oxidase leads to a markedly increased severity of BCG infection through mechanisms including increased cytokine

  15. Maintenance versus non-maintenance intravesical Bacillus Calmette-Guerin instillation for non-muscle invasive bladder cancer: A systematic review and meta-analysis of randomized clinical trials.

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    Chen, Siteng; Zhang, Ning; Shao, Jialiang; Wang, Xiang

    2018-02-28

    It is not clear whether maintenance Bacillus Calmette-Guerin (BCG) is necessary for intermediate- or high-risk non-muscle-invasive bladder cancer (NMIBC). This systematic review and meta-analysis aimed to illustrate the effects of maintenance BCG for intermediate- or high-risk NMIBC. A comprehensive literature search of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov databases and International Clinical Trials Register (ICTRP) Search was conducted to identify relevant randomized controlled trials (RCTs) that have assessed the efficacy of maintenance or non-maintenance BCG therapy for patients with NMIBC. The maintenance group first received induction BCG instillations, and subsequently received BCG intravesical instillations regularly for at least 1 year, while the control group only received induction BCG instillations. Systematic review and meta-analysis were performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis Criteria. Ten RCTs were eligible in this systematic review. The meta-analysis showed that induction BCG followed by maintenance BCG instillation after transurethral resection (TUR) could reduce the risk ratios of tumor recurrence by 21% (RR = 0.79; 95% CI 0.70-0.89; P maintenance BCG. It could also reduce the risk ratios of tumor progression (RR = 0.81; 95% CI 0.68-0.97; P = 0.02). However, these pooled results should be considered with caution since the quality of evidences for outcomes ranged low. Subgroup analysis implied that different durations of maintenance BCG instillations might be one of the sources of potential clinical heterogeneity of included studies. Begg's funnel plot and Egger's test did not reveal any evidence of publication bias in this meta-analysis. Induction BCG followed by maintenance BCG instillation after TUR, compared with induction BCG along, can reduce the risk ratios of tumor recurrence and tumor progression, and prolong RFS. However, these results with a lower level of

  16. Intravesical rAd-IFNα/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study.

    Science.gov (United States)

    Shore, Neal D; Boorjian, Stephen A; Canter, Daniel J; Ogan, Kenneth; Karsh, Lawrence I; Downs, Tracy M; Gomella, Leonard G; Kamat, Ashish M; Lotan, Yair; Svatek, Robert S; Bivalacqua, Trinity J; Grubb, Robert L; Krupski, Tracey L; Lerner, Seth P; Woods, Michael E; Inman, Brant A; Milowsky, Matthew I; Boyd, Alan; Treasure, F Peter; Gregory, Gillian; Sawutz, David G; Yla-Herttuala, Seppo; Parker, Nigel R; Dinney, Colin P N

    2017-10-20

    Purpose Many patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd-IFNα/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study ( ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd-IFNα/Syn3 (randomly assigned 1:1 to 1 × 10 11 viral particles (vp)/mL or 3 × 10 11 vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd-IFNα/Syn3 (1 × 10 11 vp/mL, n = 21; 3 × 10 11 vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd-IFNα/Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%). Conclusion rAd-IFNα/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to

  17. The efficacy of BCG TICE and BCG Connaught in a cohort of 2,099 patients with T1G3 non-muscle-invasive bladder cancer

    NARCIS (Netherlands)

    Witjes, J.A.; Dalbagni, G.; Karnes, R.J.; Shariat, S.; Joniau, S.; Palou, J.; Serretta, V.; Larre, S.; Stasi, S. Di; Colombo, R.; Babjuk, M.; Malmstrom, P.U.; Malats, N.; Irani, J.; Baniel, J.; Cai, T.; Cha, E.; Ardelt, P.; Varkarakis, J.; Bartoletti, R.; Spahn, M.; Pisano, F.; Gontero, P.; Sylvester, R.

    2016-01-01

    BACKGROUND: Potential differences in efficacy of different bacillus Calmette-Guerin (BCG) strains are of importance for daily practice, especially in the era of BCG shortage. OBJECTIVE: To retrospectively compare the outcome with BCG Connaught and BCG TICE in a large study cohort of pT1 high-grade

  18. Suppurative supraclavicular bacille calmette-guerine lymphadenitis - A case report, awareness and management options

    Directory of Open Access Journals (Sweden)

    U S Udgaonkar

    2015-01-01

    Full Text Available Diagnosis of Bacille calmette-guerine (BCG adenitis is clinical. Conventional laboratory tests do not differentiate BCG adenitis from tuberculous adenitis. We report a case of a 3-month-old healthy baby presenting with suppurative BCG adenitis. FNAC revealed AFB on ZN-Staining, later confirmed to be Mycobacterium bovis by multiplex PCR. The treatment of suppurative BCG adenitis is needle aspiration. Anti-tubercular treatment is unwarranted.

  19. BCG-induced interleukin-6 upregulation and BCG internalization in well and poorly differentiated human bladder cancer cell lines

    NARCIS (Netherlands)

    Bevers, R. F.; de Boer, E. C.; Kurth, K. H.; Schamhart, D. H.

    1998-01-01

    Intravesical bacillus Calmette-Guerin (BCG) is a successful therapy for superficial bladder cancer. However, the working mechanism of BCG after intravesical instillation is not completely understood. A functional role of urothelial (tumor) cells in the initiation of the BCG-induced immune reaction

  20. Autophagy Controls BCG-Induced Trained Immunity and the Response to Intravesical BCG Therapy for Bladder Cancer

    NARCIS (Netherlands)

    Buffen, Kathrin; Oosting, Marije; Quintin, Jessica; Ng, Aylwin; Kleinnijenhuis, Johanneke; Magadi Gopalaiah, Vinod Kumar; van de Vosse, Esther; Wijmenga, Cisca; van Crevel, Reinout; Oosterwijk, Egbert; Grotenhuis, Anne J.; Vermeulen, Sita H.; Kiemeney, Lambertus A.; van de Veerdonk, Frank L.; Chamilos, Georgios; Xavier, Ramnik J.; van der Meer, Jos W. M.; Netea, Mihai G.; Joosten, Leo A. B.

    2014-01-01

    The anti-tuberculosis-vaccine Bacillus Calmette-Guerin (BCG) is the most widely used vaccine in the world. In addition to its effects against tuberculosis, BCG vaccination also induces non-specific beneficial effects against certain forms of malignancy and against infections with unrelated

  1. The contribution of non-conventional T cells and NK cells in the mycobacterial-specific IFNγ response in Bacille Calmette-Guerin (BCG-immunized infants.

    Directory of Open Access Journals (Sweden)

    Christel Zufferey

    Full Text Available BACKGROUND: The Mycobacterium bovis Bacille Calmette-Guérin (BCG vaccine is given to >120 million infants each year worldwide. Most studies investigating the immune response to BCG have focused on adaptive immunity. However the importance of TCR-gamma/delta (γδ T cells and NK cells in the mycobacterial-specific immune response is of increasing interest. METHODS: Participants in four age-groups were BCG-immunized. Ten weeks later, in vitro BCG-stimulated blood was analyzed for NK and T cell markers, and intracellular IFNgamma (IFNγ by flow cytometry. Total functional IFNγ response was calculated using integrated median fluorescence intensity (iMFI. RESULTS: In infants and children, CD4 and CD4-CD8- (double-negative (DN T cells were the main IFNγ-expressing cells representing 43-56% and 27-37% of total CD3+ IFNγ+ T cells respectively. The iMFI was higher in DN T cells compared to CD4 T cells in all age groups, with the greatest differences seen in infants immunized at birth (p=0.002 or 2 months of age (p<0.0001. When NK cells were included in the analysis, they accounted for the majority of total IFNγ-expressing cells and, together with DN Vδ2 γδ T cells, had the highest iMFI in infants immunized at birth or 2 months of age. CONCLUSION: In addition to CD4 T cells, NK cells and DN T cells, including Vδ2 γδ T cells, are the key populations producing IFNγ in response to BCG immunization in infants and children. This suggests that innate immunity and unconventional T cells play a greater role in the mycobacterial immune response than previously recognized and should be considered in the design and assessment of novel tuberculosis vaccines.

  2. Nitric oxide and KLF4 protein epigenetically modify class II transactivator to repress major histocompatibility complex II expression during Mycobacterium bovis bacillus Calmette-Guerin infection.

    Science.gov (United States)

    Ghorpade, Devram Sampat; Holla, Sahana; Sinha, Akhauri Yash; Alagesan, Senthil Kumar; Balaji, Kithiganahalli Narayanaswamy

    2013-07-12

    Pathogenic mycobacteria employ several immune evasion strategies such as inhibition of class II transactivator (CIITA) and MHC-II expression, to survive and persist in host macrophages. However, precise roles for specific signaling components executing down-regulation of CIITA/MHC-II have not been adequately addressed. Here, we demonstrate that Mycobacterium bovis bacillus Calmette-Guérin (BCG)-mediated TLR2 signaling-induced iNOS/NO expression is obligatory for the suppression of IFN-γ-induced CIITA/MHC-II functions. Significantly, NOTCH/PKC/MAPK-triggered signaling cross-talk was found critical for iNOS/NO production. NO responsive recruitment of a bifunctional transcription factor, KLF4, to the promoter of CIITA during M. bovis BCG infection of macrophages was essential to orchestrate the epigenetic modifications mediated by histone methyltransferase EZH2 or miR-150 and thus calibrate CIITA/MHC-II expression. NO-dependent KLF4 regulated the processing and presentation of ovalbumin by infected macrophages to reactive T cells. Altogether, our study delineates a novel role for iNOS/NO/KLF4 in dictating the mycobacterial capacity to inhibit CIITA/MHC-II-mediated antigen presentation by infected macrophages and thereby elude immune surveillance.

  3. Bacille-Calmette-Guerin vaccination and the development of allergic disease in children: a randomized, prospective, single-blind study

    NARCIS (Netherlands)

    Steenhuis, T. J.; van Aalderen, W. M. C.; Bloksma, N.; Nijkamp, F. P.; van der Laag, J.; van Loveren, H.; Rijkers, G. T.; Kuis, W.; Hoekstra, M. O.

    2008-01-01

    Background The increase in the prevalence of allergic diseases in countries with a so-called western lifestyle may be due to a decrease in exposure to infectious agents in early life. Objective To establish the effect of Bacille-Calmette-Guerin (BCG) vaccination in 6-week-old high-risk infants in a

  4. BCG (Bacille Calmette-Guerin) Vaccine

    Science.gov (United States)

    ... Studies Consortium Research Projects Publications TB Trials Consortium Study Descriptions Background Behavioral & Social Science Research Infection Control TB in Specific Populations African-American Community Stop TB in the African-American ...

  5. Immunometabolic Pathways in BCG-Induced Trained Immunity

    NARCIS (Netherlands)

    Arts, R.J.; Carvalho, A.; Rocca, C. La; Palma, C.; Rodrigues, F.; Silvestre, R.; Kleinnijenhuis, J.; Lachmandas, E.; Goncalves, L.G.; Belinha, A.; Cunha, C.; Oosting, M.; Joosten, L.A.; Matarese, G.; Crevel, R. van; Netea, M.G.

    2016-01-01

    The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity.

  6. The Type of Growth Medium Affects the Presence of a Mycobacterial Capsule and Is Associated With Differences in Protective Efficacy of BCG Vaccination Against Mycobacterium tuberculosis

    OpenAIRE

    Prados-Rosales, Rafael; Carreño, Leandro J.; Weinrick, Brian; Batista-Gonzalez, Ana; Glatman-Freedman, Aarona; Xu, Jiayong; Chan, John; Jacobs, William R.; Porcelli, Steven A.; Casadevall, Arturo

    2016-01-01

    Background. Bacillus Calmette-Guerin (BCG) vaccine is widely used for the prevention of tuberculosis, despite limited efficacy. Most immunological studies of BCG or Mycobacterium tuberculosis strains grow bacteria in the presence of detergent, which also strips the mycobacterial capsule. The impact of the capsule on vaccine efficacy has not been explored.

  7. Heterologous Immunological Effects of Early BCG Vaccination in Low-Birth-Weight Infants in Guinea-Bissau: A Randomized-controlled Trial

    NARCIS (Netherlands)

    Jensen, K.J.; Larsen, N.; Biering-Sorensen, S.; Andersen, A.; Eriksen, H.B.; Monteiro, I.; Hougaard, D.; Aaby, P.; Netea, M.G.; Flanagan, K.L.; Benn, C.S.

    2015-01-01

    BACKGROUND: Bacillus Calmette-Guerin (BCG) seems to have beneficial nonspecific effects; early BCG vaccination of low-birth-weight (LBW) newborns reduces neonatal mortality by >40% due to prevention of primarily septicemia and pneumonia. METHODS: Within a randomized trial in LBW infants in

  8. Treatment of non muscle invasive bladder tumor related to the problem of bacillus Calmette-Guerin availability. Consensus of a Spanish expert's panel. Spanish Association of Urology.

    Science.gov (United States)

    Fernández-Gómez, J M; Carballido-Rodríguez, J; Cozar-Olmo, J M; Palou-Redorta, J; Solsona-Narbón, E; Unda-Urzaiz, J M

    2013-01-01

    Since June 2012, the has been a worldwide lack of available of the Connaught strain. In December 2012, a group of experts met in the Spanish Association of Urology to analyze this situation and propose alternatives. To present the work performed by said committee and the resulting recommendations. An update has been made of the principal existing evidence in the treatment of middle and high risk tumors. Special mention has been made regarding the those related with the use of BCG and their possible alternative due to the different availability of BCG. In tumors with high risk of progression, immediate cystectomy should be considered when BCG is not available, with dose reduction or alternating with chemotherapy as methods to economize on the use of BCG when availability is reduced. In tumors having middle risk of progression, chemotherapy can be used, although when it is associated to a high risk of relapse, BCG would be indicated if available with the mentioned savings guidelines. BCG requires maintenance to maintain its effectiveness, it being necessary to optimize the application of endovesical chemotherapy and to use systems that increase its penetration into the bladder wall (EMDA) if they are available. Due to the scarcity of BCG, it has been necessary to agree on a series of recommendations that have been published on the web page of the Spanish Association of Urology. Copyright © 2013 AEU. Published by Elsevier Espana. All rights reserved.

  9. Investigations on Deer to Deer and Deer to Cattle Transmission of the Vaccine Mycobacterium bovis bacillus Calmette-Guerin (BCG)

    Science.gov (United States)

    Mycobacterium bovis is the causative agent of tuberculosis in animals and causes tuberculosis in humans clinically indistinguishable from disease caused by M. tuberculosis. Some countries have found it impossible to eradicate or control bovine tuberculosis due to the presence of a wildlife reservoir...

  10. Oral vaccination of white-tailed deer (Odocoileus virginianus) with Mycobacterium bovis Bacillus Calmette-Guerin (BCG)

    Science.gov (United States)

    Wildlife reservoirs of Mycobacterium bovis represent serious obstacles to the eradication of tuberculosis from livestock, particularly cattle. In Michigan, USA tuberculous white-tailed deer transmit M. bovis to other deer and cattle. One approach in dealing with this wildlife reservoir is to vaccina...

  11. Early versus late BCG vaccination in HIV-1-exposed infants in Uganda: study protocol for a randomized controlled trial

    NARCIS (Netherlands)

    Nankabirwa, V.; Tumwine, J.K.; Namugga, O.; Tylleskar, T.; Ndeezi, G.; Robberstad, B.; Netea, M.G.; Sommerfelt, H.

    2017-01-01

    BACKGROUND: Bacillus Calmette-Guerin (BCG) vaccination may have nonspecific effects, i.e., effects on childhood morbidity and mortality that go beyond its effect on the risk of childhood tuberculosis (TB). Though the available scientific literature is mostly from observational studies, and is

  12. Disseminated BCG infection in a patient with severe combined immunodeficiency

    International Nuclear Information System (INIS)

    Han, Tae Il; Kim, In One; Kim, Woo Sun; Yeon, Kyung Mo

    2000-01-01

    Disseminated mycobacterial infection after bacillus Calmette-Guerin (BCG) accination is a very rare disorder, occurring mostly in patients with immunologic eficiency. We report a case of disseminated BCG infection in a 16-month-old girl with severe combined immunodeficiency. Plain radiographs showed multiple osteolytic lesions in the femora, tibiae, humerus, and phalanges. Abdominal sonography and CT scanning revealed multiple nodules in the spleen, and portocaval lymphadenopathy

  13. Disseminated BCG infection in a patient with severe combined immunodeficiency

    Energy Technology Data Exchange (ETDEWEB)

    Han, Tae Il [Eulji University School of Medicine, Taejon (Korea, Republic of); Kim, In One; Kim, Woo Sun; Yeon, Kyung Mo [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2000-06-01

    Disseminated mycobacterial infection after bacillus Calmette-Guerin (BCG) accination is a very rare disorder, occurring mostly in patients with immunologic eficiency. We report a case of disseminated BCG infection in a 16-month-old girl with severe combined immunodeficiency. Plain radiographs showed multiple osteolytic lesions in the femora, tibiae, humerus, and phalanges. Abdominal sonography and CT scanning revealed multiple nodules in the spleen, and portocaval lymphadenopathy.

  14. Reiter’s syndrome occurred following intravesical BCG immunotherapy: Case presentation

    Directory of Open Access Journals (Sweden)

    Fatih Elbir

    2015-06-01

    Full Text Available Intravesical instillation of Bacillus Calmette Guerin (BCG is used in the treatment of patients with superficial bladder carcinoma with efficacy and safety. Although clinically very effective this method is associated with a variety of side effects. In these side effects, Reiter’s Syndrome is occurred most rare. We report here the case of Reiter’s Syndrome following BCG instillation with a different clinical manifestation.

  15. The value of perioperative mitomycin C instillation in improving subsequent bacillus calmette-guerin instillation efficacy in intermediate and high-risk patients with non-muscle invasıve bladder cancer: a prospective randomized study

    Directory of Open Access Journals (Sweden)

    Ömer Gülpinar

    2012-08-01

    Full Text Available PURPOSE: We evaluated the efficacy of perioperative mitomycin C (MMC instillation to improve subsequent bacillus Calmette-Guérin (BCG instillation efficacy in intermediate and high risk patients with non-muscle invasive bladder cancer (NMIBC. MATERIALS AND METHODS: From November 2004 to May 2006, 51 patients with intermediate or high risk NMIBC were enrolled in this prospective randomized trial. In group A, patients were treated with perioperative MMC (40 mg MMC in 40 mL saline was administered within 6 hours of surgery followed by delayed (at least 15 days from surgery BCG instillations (once a week for 6 weeks, 5 x 108 colony-forming units in 50 mL saline. Patients in group B were treated with delayed BCG instillations alone. The primary end points were recurrence-free interval and recurrence rate. RESULTS: There were 25 and 26 patients in groups A and B, respectively. Median follow-up was 41.3 months (range 8 to 64 in group A and 40.9 months (range 6 to 68 in group B. Recurrence rate was 36% (9 of 25 and 19.3% (5 of 26 in group A and B, respectively (p = 0.052. Median time to the first recurrence was 8 months in group A and 7 months in group B (p = 0.12. CONCLUSIONS: The present study showed no statistically significant difference in terms of recurrence rate and median time to first recurrence between intermediate or high-risk patients with NMIBC who were treated with early single dose instillation of MMC plus delayed BCG and those who were treated with only BCG.

  16. BCG lowers plasma cholesterol levels and delays atherosclerotic lesion progression in mice

    NARCIS (Netherlands)

    Dam, A.D. van; Bekkering, S.; Crasborn, M.; Beek, L. van der; Berg, S.M. van den; Vrieling, F.; Joosten, S.A.; Harmelen, V. van; Winther, M.P. de; Lutjohann, D.; Lutgens, E.; Boon, M.R.; Riksen, N.P.; Rensen, P.C.; Berbee, J.F.

    2016-01-01

    BACKGROUND AND AIMS: Bacille-Calmette-Guerin (BCG), prepared from attenuated live Mycobacterium bovis, modulates atherosclerosis development as currently explained by immunomodulatory mechanisms. However, whether BCG is pro- or anti-atherogenic remains inconclusive as the effect of BCG on

  17. Paediatric - An HIV-infected infant with Bacille Calmette-Guerin ...

    African Journals Online (AJOL)

    Paediatric - An HIV-infected infant with Bacille Calmette-Guerin disease, recurrent and multidrug-resistant tuberculosis complicated by acute cor pulmonale and hepatitis while on antiretroviral therapy.

  18. Modification of death rate of irradiated mice by B.C.G

    International Nuclear Information System (INIS)

    Allain, P.; Chaleil, D.; Maingot, D.; Larra, F.

    1976-01-01

    Freeze-dried Bacillus Calmette Guerin (BCG) of Institut Pasteur was given by intravenous route to mice at 1,2 and 4mg/kg before and after γ irradiation of animals by 1000 rad. B.C.G. 1 mg/kg injected the day or the day after irradiation has a protective effect (mortality reduced from 77% for controls to 58% and 50% for treated mice). B.C.G. given before irradiation in single or double doses increased mortality [fr

  19. BCG plus levamisole following irradiation of advanced squamous bronchial carcinoma. [Hard X Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Pines, A.

    1980-08-01

    Fifty patients with inoperable squamous cell carcinoma of the bronchus were treated with radical radiotherapy. Afterwards, 16 patients received levamisole on 2 days per week and bacillus calmette guerin (B.C.G.) skin innoculations every two weeks;another 16 received the same dosage of levamisole but B.C.G. every 4 weeks; 18 patients were controls. Survival was better in the first group of patients only during the first two years of study (P = 0.02) but not later: metastases were fewer. Both B.C.G. and levamisole gave little discomfort when the dose was adjusted for each patient.

  20. Persistence of Mycobacterium bovis bacillus Calmette-Guerin (BCG) Danish in White-tailed deer (Odocoileus virginianus) vaccinated with a lipid-formulated oral vaccine

    Science.gov (United States)

    Mycobacterium bovis, the causative agent of tuberculosis in animals has a broad host range, including humans. Historically, public health concerns prompted programs to eradicate tuberculosis from cattle in many nations. Eradication efforts decreased the prevalence of bovine tuberculosis; nevertheles...

  1. Persistence of Mycobacterium bovis Bacillus Calmette-Guerin (BCG) in White-tailed Deer (Odocoileus virginianus) After Oral or Parenteral Vaccination

    Science.gov (United States)

    Mycobacterium bovis is the cause of tuberculosis in cattle and a serious zoonotic pathogen, most commonly contracted through consumption of unpasteurized dairy products. To control this zoonosis, many countries have developed bovine tuberculosis eradication programs. Although relatively successful, ...

  2. Granulomas do pênis: uma complicação rara da terapia intravesical com Bacilo Calmette-Guérin Granulomas of the penis: a rare complication of intravesical therapy with Bacillus Calmette-Guerin

    Directory of Open Access Journals (Sweden)

    Sara Isabel Alcântara Lestre

    2011-08-01

    Full Text Available A imunoterapia com o Bacilo Calmette-Guérin é amplamente usada no tratamento e profilaxia da neoplasia urotelial superficial. As complicações associadas ao tratamento são comuns. Os autores relatam um caso de inflamação granulomatosa do pênis, associada à terapia intravesical com Bacilo Calmette-Guérin, com múltiplos nódulos eritematosos indolores localizados na glande. É também efetuada uma revisão da literatura. A balanopostite granulomatosa é uma complicação rara associada à imunoterapia com Bacilo Calmette-Guérin, com uma apresentação clinicamente heterogênea que pode dificultar o diagnóstico. O seu reconhecimento clínico é essencial para o início precoce de tuberculostáticos e interrupção de Bacilo Calmette-GuérinImmunotherapy with Bacillus Calmette-Guérin is widely used for treatment and prophylaxis of superficial urothelial cancer. Complications associated with Bacillus Calmette-Guérin treatment are common. The authors describe a case of granulomatous inflammation of the penis associated with intravesical Bacillus Calmette-Guérin therapy, presenting with multiple erythematous and painless nodules located on the glans. A review of the literature is also performed. Granulomatous balanoposthitis is a rare complication of Bacillus Calmette-Guérin immunotherapy, with heterogeneous clinical presentation, which can make the diagnosis difficult. Its clinical recognition is essential for early start of therapy with antitubercular agents and interruption of Bacillus Calmette-Guérin

  3. Bacille Calmette-Guerin can induce cellular apoptosis of urothelial cancer directly through toll-like receptor 7 activation

    Directory of Open Access Journals (Sweden)

    Dah-Shyong Yu

    2015-08-01

    Full Text Available Immunotherapy using bacille Calmette-Guerin (BCG instillation is the mainstay treatment modality for superficial urothelial cancer (UC through toll-like receptor (TLR activation of cognitive immune response. We investigated the roles of TLR7 in the activation of apoptosis in UC cells after BCG treatment. The in vitro cytotoxicity effect of BCG on UC cells was measured by a modified 3-(4,5-dimethylthiazo-2-yl-2,5-diphenyl tetrazolium assay. Expressions of TLR7 mRNA and protein in native UC cells prior to and after BCG treatment were analyzed using real-time quantitative polymerase chain reaction and western blot methods. Phagocytotic processes after BCG treatment in UC cells were observed microscopically using a specific immunostain, subsequent cellular apoptosis-related signals induced by TLR7 were analyzed by western blot. Low-grade UC cells, TSGH8301, showed significant cellular death (4.23-fold higher than the high-grade UC cells T24 and J82 when treated with BCG and the BCG cytotoxicity was displayed in a dose–time-dependent manner. TSGH8301 cells had the highest content of TLR7 mRNA, 7.2- and 4.5-fold higher than that of T24 and J82 cells, respectively. TLR7 protein expression was also significantly increased in TSGH8301 cells. Phagocytosis-related markers, including beclin 1, ATG2, and LC3, were increased when TSGH8301 cells were treated by BCG. Interleukin-1 receptor-associated kinases 2 and 4 were also increased markedly in TSGH8301 cells. On the contrary, cellular apoptosis of TSGH8301 cells decreased by 34% when TLR7 activation was suppressed by the TLR antagonist IRS661 after BCG treatment. Our findings suggest that well differentiated TCC cells have higher expression of TLR7 and BCG can drive cellular death of TCC cells directly via TLR7 activation and related apoptotic pathway.

  4. Different effects of BCG strains - A natural experiment evaluating the impact of the Danish and the Russian BCG strains on morbidity and scar formation in Guinea-Bissau

    DEFF Research Database (Denmark)

    Frankel, H; Byberg, S; Andersen, Morten Bjerregaard

    2016-01-01

    BACKGROUND: Different Bacillus Calmette-Guerin (BCG) vaccine strains may have different non-specific effects. We assessed the effect of two BCG strains (Danish and Russian) on childhood morbidity and BCG scarification in Guinea-Bissau. METHODS: During 2011-2013, infants in the Bandim Health Project......'s urban study area received the Danish or Russian BCG in a natural experiment. Health center consultations were registered at point of care and scar status and size at age 4½ months. We assessed the effect of strain on consultation rates between vaccination and age 45days in Cox proportional hazards...... models. Scar prevalence and size were compared using binomial regression and ranksum tests. RESULTS: Among 1206 children, 18% received Danish BCG (n=215) and 82% Russian BCG (n=991). The adjusted hazard ratio (aHR) for consultations was 0.94 (95% CI 0.60-1.46) for Danish BCG compared with Russian BCG...

  5. Intravesical BCG immunotherapy: Sepsis and multiorgan failure developed after traumatic catheterization

    Directory of Open Access Journals (Sweden)

    Tufan Cicek

    2014-02-01

    Full Text Available Intravesical Bacillus Calmette-Guerin (BCG instillation is a prophylactic therapy using for treating bladder cancer to prevent tumour progression and recurrence. Both local and systemic complications can arise after the installation. Although local complications are common , this therapy is generally well tolerated. Systemic complications are rarely than local complications but can be fatal. We report a case who died from severe complications such as sepsis, pneumonia, renal failure and granulomatous hepatitis after receiving the first maintanence installation of intravesical BCG immunotherapy for bladder transitional cell carcinoma.

  6. Sternal osteomyelitis after bacillus Calmette-Guérin vaccination

    Directory of Open Access Journals (Sweden)

    Rolandas Selvestravičius

    2016-09-01

    Full Text Available Presented here is the case of a nine-month-old boy with the osteomyelitis of the upper area sternum caused by bacillus Calmette-Guerin (BCG, the Danish 1331 strain vaccine against tuberculosis. Upon examination, a swelling of approximately 2×3 cm diameter was observed in the upper sternal area. The mass was hard, fixed and sensitive to palpation with no local skin hyperaemia. Chest X-rays revealed a round mass anterior to the sternum, suggesting a diagnosis of osteomyelitis. A consequent sternal biopsy was performed and Mycobacterium bovis BCG was identified by a positive growth culture.

  7. Visible and subvisible particles in the BCG immunotherapeutic product Immucyst®.

    Science.gov (United States)

    Kirkitadze, Marina; Remi, Elena; Bhandal, Kamajit; Carpick, Bruce

    2016-01-01

    Bacille Calmette-Guerin, BCG, is a live attenuated bovine tubercle bacillus used for the treatment of non-muscle invasive bladder cancer. In this study, an Electrical Sensing Zone (ESZ) method was developed to measure the particle count and the size of BCG immunotherapeutic (BCG IT), or ImmuCyst® product using a Coulter Counter Multisizer 4® instrument. The focus of this study was to establish a baseline for reconstituted lyophilized BCG IT product using visible and sub-visible particle concentration and size distribution as reportable values. ESZ method was used to assess manufacturing process consistency using 20 production scale lots of BCG IT product. The results demonstrated that ESZ can be used to accumulate product and process knowledge of BCG IT.

  8. Late-onset granulomatous prostatitis following intravesical bacille Calmette-Guerin therapy: case report

    Directory of Open Access Journals (Sweden)

    Octavio Castillo Cádiz

    2016-06-01

    Full Text Available Resumen El bacilo de Calmette-Guerin es el tratamiento intravesical más efectivo para disminuir la recurrencia de los carcinomas uroteliales no-músculo-invasivos. La aplicación de este tratamiento en ocasiones puede presentar efectos secundarios y, excepcionalmente, complicaciones graves. La prostatitis granulomatosa es un hallazgo histológico frecuente pero una entidad rara desde el punto de vista clínico. Se presenta el caso de un paciente de 75 años, diabético tipo 2, que fue diagnosticado de carcinoma in situ vesical, para lo cual inició tratamiento con bacilo de Calmette-Guerin intravesical. El paciente consultó cinco años después por presentar cuadro de nicturia, frecuencia miccional aumentada, urgencia miccional grave y dolor perineal intenso y recurrente asociado a una curva de antígeno prostático específico con marcada elevación. Se le realizó biopsia prostática que mostró una prostatitis crónica granulomatosa de grado moderado a grave relacionada a bacilo de Calmette-Guerin. El paciente recibió esquema antituberculoso completo con buena respuesta clínica.

  9. No adverse events after simultaneous administration of 50 000 IU vitamin A and Bacille Calmette-Guerin vaccination to normal-birth-weight newborns in Guinea-Bissau.

    Science.gov (United States)

    Nante, J E; Diness, B R; Ravn, H; Roth, A; Aaby, P; Benn, C S

    2008-07-01

    To determine whether the combined intervention of 50 000 IU vitamin A administered together with Bacille Calmette-Guerin (BCG) vaccination at birth was associated with adverse events, in particular bulging fontanels and adverse reactions to BCG. From an ongoing trial, 2145 infants randomized to 50 000 IU vitamin A or placebo with BCG vaccination were recruited. Adverse events were monitored in two different ways: (A) daily clinical examinations by a medical doctor during the first 3 days post supplementation; (B) weekly interviews by a trained assistant during the first month post supplementation. In part A, 1271 infants were enrolled, in part B 2078. Vitamin A supplementation (VAS) was associated with a relative risk (RR) of bulging fontanels of 1.16 (95% confidence interval (CI)=0.82-1.65). The rate of health care contacts and various symptoms during the first month were comparable between the groups. VAS was associated with larger peak local reactions to BCG vaccination in boys, but not in girls (P-value for test of interaction between VAS and sex=0.02). 50 000 IU vitamin A with BCG was not associated with adverse events. The observed sex-differential effect of VAS on local reaction to BCG is in line with other observations of sex-differential effects of VAS.

  10. Innate-like gammadelta T cell responses to mycobacterium Bacille Calmette-Guerin using the public V gamma 2 repertoire in Macaca fascicularis.

    Science.gov (United States)

    Cairo, Cristiana; Hebbeler, Andrew M; Propp, Nadia; Bryant, Joseph L; Colizzi, Vittorio; Pauza, C David

    2007-07-01

    The V gamma 2 V delta 2 T cell subset responds to Bacille Calmette-Guerin (BCG) immunization in macaques and may be a component of protective immunity against tuberculosis. We characterized the effects of BCG on the V gamma 2 V delta 2 T cell receptor repertoire by comparing the starting population of V gamma 2 chains in cynomolgus macaques with the repertoire found after priming or booster immunization with BCG. The starting repertoire was dominated by public V gamma 2 chain sequences that were found repeatedly among unrelated animals. Primary exposure to BCG triggered expansion of cells expressing public V gamma 2 chains and booster immunization was often associated with contraction of these same subsets. Thus, BCG-reactive V gamma 2 chains were present at high frequency in the repertoire of mycobacteria-naïve macaques and they comprised the major response to primary or booster immunization. Normal selection processes that created the naïve V gamma 2 repertoire in macaques, also encoded the capacity for rapid responses to mycobacteria. The unusual composition of a normal V gamma 2 repertoire helps to explain the powerful gammadelta T cell responses to BCG immunization.

  11. BCG status in children with tuberculosis: A multicenter study in ...

    African Journals Online (AJOL)

    Background: Bacille Calmette.Guerin (BCG) vaccine has been in use since 1921, yet childhood TB is still very prevalent in Nigeria. Since BCG efficacy depends in part on appropriate vaccine utilization, this study was designed to investigate the current practice of BCG administration through determination of BCG status.

  12. Dactilitis and oligoarthritis after BCG immunotherapy in a patient affected by bladder cancer

    Directory of Open Access Journals (Sweden)

    N. Elkhaldi

    2011-09-01

    Full Text Available The treatment of bladder cancer with Bacillus of Calmette-Guerin (BCG immunotherapy can induce the appearance of a reactive disorder. The Authors describe a 55-year-old male patient with bladder cancer treated with endovesical instillation of BCG immunotherapy, followed after the fifth application by asymmetric oligoarthritis and dactilitis. The observed positivity of both HLA-B27 and HLA-B51 antigens reinforces the hypothesis of a reactive form, possibly through "molecular mimicry" mechanism. The discontinuation of BCG instillation along which a therapeutic attempt with NSAD failed to improve the rheumatic manifestation, which completely remitted after a four-month course of oral steroids. No relapses of joint and tendon involvement was observed during the following five-month period. The clinico- pathogenetic implications suggested by this case are discussed.

  13. Recognition and Treatment of BCG Failure in Bladder Cancer

    Directory of Open Access Journals (Sweden)

    Andrew J. Lightfoot

    2011-01-01

    Full Text Available Patients with high-grade Ta, T1, or carcinoma in situ non–muscle-invasive bladder cancer (NMIBC are at high risk for recurrence and, more importantly, progression. Thus, both the American Urological Association and European Association of Urology recommend initial intravesical treatment with bacillus Calmette-Guerin(BCG followed by maintenance therapy for a minimum of 1 year. The complete response rate to BCG therapy in patients with high-risk NMIBC can be as high as ∼80%; however, most patients with high-risk disease suffer from recurrence. BCG failure can be further characterized into BCG refractory, BCG resistant, BCG relapsing, and BCG intolerant. Current recommendations include one further course of BCG or cystectomy. In patients who continue to fail conservative treatment and who refuse surgical therapy or are not surgical candidates, treatment options become even more complicated. In this setting, treatment options are limited and include repeat BCG treatment, an alternate immunotherapy regimen, chemotherapy, or device-assisted therapy. To date, however, further research is necessary for all secondary treatment options in order to determine which might be the most efficacious. All conservative treatments should be considered investigational. Currently, cystectomy remains the standard of care for high-risk patients who have failed BCG therapy.

  14. BCG-osis after BCG vaccination in immunocompromised children: Case series and review

    Directory of Open Access Journals (Sweden)

    Soheila Shahmohammadi

    2014-02-01

    Full Text Available Bacillus Calmette Guerin (BCG developed by Albert Calmette and Camille Guerin in France between 1908 and 1921 contained a live attenuated strain of Mycobacterium bovis and was administered worldwide to prevent tuberculosis. BCG vaccination is also administered at birth to all the newborns in Iran. Disseminated BCG infection after BCG vaccination is rare. Here in, we report 2 new cases of disseminated BCGinfection and review 15 additional cases identified from our previous retrospective study during a 5-year period from 2005-2010. All of these reported patients were vaccinated. Impaired immunity was detected in 10 cases (59% including severe combined immunodeficiency, chronic granulomatous disease, Mendelian susceptibility to mycobacterial disease, combined variable immunodeficiency, and HIV infection. Response to therapy was poor among those patients with immune deficiencies, but the overall mortality rate was 32.3%. Disseminated BCG infection is a rare but devastating complication of vaccination. Immune-compromised children are at high risk of developing BCG related complications including regional BCG-itis or disseminated disease; BCG-osis.

  15. BCG vaccination scar associated with better childhood survival in Guinea-Bissau

    DEFF Research Database (Denmark)

    Roth, Adam Anders Edvin; Gustafson, Per; Nhaga, Alexandro

    2005-01-01

    Recent studies have suggested that Bacille Calmette-Guerin (BCG) vaccination may have a non-specific beneficial effect on infant survival and that a BCG scar may be associated with lower child mortality. No study has previously examined the influence of BCG vaccination on cause of death....

  16. Protection Induced by Simultaneous Subcutaneous and Endobronchial Vaccination with BCG/BCG and BCG/Adenovirus Expressing Antigen 85A against Mycobacterium bovis in Cattle.

    Science.gov (United States)

    Dean, Gillian S; Clifford, Derek; Whelan, Adam O; Tchilian, Elma Z; Beverley, Peter C L; Salguero, Francisco J; Xing, Zhou; Vordermeier, Hans M; Villarreal-Ramos, Bernardo

    2015-01-01

    The incidence of bovine tuberculosis (bTB) in the GB has been increasing since the 1980s. Immunisation, alongside current control measures, has been proposed as a sustainable measure to control bTB. Immunisation with Mycobacterium bovis bacillus Calmette-Guerin (BCG) has been shown to protect against bTB. Furthermore, much experimental data indicates that pulmonary local immunity is important for protection against respiratory infections including Mycobacterium tuberculosis and that pulmonary immunisation is highly effective. Here, we evaluated protection against M. bovis, the main causative agent of bTB, conferred by BCG delivered subcutaneously, endobronchially or by the new strategy of simultaneous immunisation by both routes. We also tested simultaneous subcutaneous immunisation with BCG and endobronchial delivery of a recombinant type 5 adenovirus expressing mycobacterial antigen 85A. There was significantly reduced visible pathology in animals receiving the simultaneous BCG/BCG or BCG/Ad85 treatment compared to naïve controls. Furthermore, there were significantly fewer advanced microscopic granulomata in animals receiving BCG/Ad85A compared to naive controls. Thus, combining local and systemic immunisation limits the development of pathology, which in turn could decrease bTB transmission.

  17. Protection Induced by Simultaneous Subcutaneous and Endobronchial Vaccination with BCG/BCG and BCG/Adenovirus Expressing Antigen 85A against Mycobacterium bovis in Cattle.

    Directory of Open Access Journals (Sweden)

    Gillian S Dean

    Full Text Available The incidence of bovine tuberculosis (bTB in the GB has been increasing since the 1980s. Immunisation, alongside current control measures, has been proposed as a sustainable measure to control bTB. Immunisation with Mycobacterium bovis bacillus Calmette-Guerin (BCG has been shown to protect against bTB. Furthermore, much experimental data indicates that pulmonary local immunity is important for protection against respiratory infections including Mycobacterium tuberculosis and that pulmonary immunisation is highly effective. Here, we evaluated protection against M. bovis, the main causative agent of bTB, conferred by BCG delivered subcutaneously, endobronchially or by the new strategy of simultaneous immunisation by both routes. We also tested simultaneous subcutaneous immunisation with BCG and endobronchial delivery of a recombinant type 5 adenovirus expressing mycobacterial antigen 85A. There was significantly reduced visible pathology in animals receiving the simultaneous BCG/BCG or BCG/Ad85 treatment compared to naïve controls. Furthermore, there were significantly fewer advanced microscopic granulomata in animals receiving BCG/Ad85A compared to naive controls. Thus, combining local and systemic immunisation limits the development of pathology, which in turn could decrease bTB transmission.

  18. Different effects of BCG strains - A natural experiment evaluating the impact of the Danish and the Russian BCG strains on morbidity and scar formation in Guinea-Bissau.

    Science.gov (United States)

    Frankel, H; Byberg, S; Bjerregaard-Andersen, M; Martins, C L; Aaby, P; Benn, C S; Fisker, A B

    2016-08-31

    Different Bacillus Calmette-Guerin (BCG) vaccine strains may have different non-specific effects. We assessed the effect of two BCG strains (Danish and Russian) on childhood morbidity and BCG scarification in Guinea-Bissau. During 2011-2013, infants in the Bandim Health Project's urban study area received the Danish or Russian BCG in a natural experiment. Health center consultations were registered at point of care and scar status and size at age 4½ months. We assessed the effect of strain on consultation rates between vaccination and age 45days in Cox proportional hazards models. Scar prevalence and size were compared using binomial regression and ranksum tests. Among 1206 children, 18% received Danish BCG (n=215) and 82% Russian BCG (n=991). The adjusted hazard ratio (aHR) for consultations was 0.94 (95% CI 0.60-1.46) for Danish BCG compared with Russian BCG. Girls vaccinated with Danish BCG tended to have lower consultation rates compared with girls vaccinated with Russian BCG (aHR 0.56 (0.25-1.24)), whereas the effect was opposite for boys (aHR 1.24 (0.74-2.11)), p=0.09. Children vaccinated with Danish BCG were more likely to develop a scar (97%) than children vaccinated with Russian BCG (87%), the relative risk (RR) being 1.11 (1.06-1.16). The effect was stronger in girls, and BCG scar size was larger among infants vaccinated with the Danish strain. BCG strain influences scar prevalence and scar size, and may have sex differential effects on morbidity. BCG strains are currently used interchangeably, but BCG scarring has been linked to subsequent survival. Hence, more research into the health effects of different BCG strains is warranted. Small adjustments of BCG production could potentially lower childhood morbidity and mortality at low cost. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Variation of growth in the production of the BCG vaccine and the association with the immune response. An observational study within a randomised trial

    NARCIS (Netherlands)

    Biering-Sorensen, S.; Jensen, K.J.; Aamand, S.H.; Blok, B.; Andersen, A.; Monteiro, I.; Netea, M.G.; Aaby, P.; Benn, C.S.; Haslov, K.R.

    2015-01-01

    INTRODUCTION: Bacille Calmette-Guerin (BCG) vaccine has beneficial non-specific effects on overall survival. After BCG vaccination, positive PPD response and scar formation are associated with increased survival. During a trial randomising low-birth-weight neonates to BCG at birth or the usual

  20. Mycobacterium bovis bacille Calmette-Guerin vaccination of cattle: activation of bovine CD4+ and gamma delta TCR+ cells and modulation by 1,25-dihydroxyvitamin D3.

    Science.gov (United States)

    Waters, W R; Nonnecke, B J; Foote, M R; Maue, A C; Rahner, T E; Palmer, M V; Whipple, D L; Horst, R L; Estes, D M

    2003-01-01

    1,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3)) is a potent modulator of immune responses and may be beneficial in the treatment of tuberculosis. Recent evidence suggest that 1,25(OH)(2)D(3) may affect T-dependent responses in cattle; however, mechanisms by which this vitamin modulates activation of bovine T cells are unclear. Determine the effects of 1,25(OH)(2)D(3) on the expression of CD25, CD44, and CD62L by bovine T cell subsets proliferating in response to antigen stimulation. Antigen-specific recall responses of Mycobacterium bovis bacille Calmette-Guerin (BCG) vaccinated cattle were used as a model system to evaluate effects of 1,25(OH)(2)D(3) on the proliferation and activation of bovine T cell subsets. CD4(+) and gamma delta TCR(+) cells were the predominant T cell subsets responding to soluble crude M. bovis-derived antigens (i.e., purified protein derivative and a BCG whole cell sonicate) by proliferation and activation-induced alterations in phenotype. These subsets exhibited increased CD25 and CD44 mean fluorescence intensity (mfi) and decreased CD62L mfi upon antigen stimulation. Addition of 1,25(OH)(2)D(3) inhibited proliferation of CD4(+) cells and decreased the expression of CD44 on responding (i.e., proliferating) CD4(+) and gamma delta TCR(+) cells. These findings suggest that the production of 1,25(OH)(2)D(3) by macrophages within tuberculous lesions would inhibit proliferation and CD44 expression by co-localized CD4(+) and gamma delta TCR(+) cells.

  1. Non-tuberculous mycobacteria have diverse effects on BCG efficacy against Mycobacterium tuberculosis☆

    Science.gov (United States)

    Poyntz, Hazel C.; Stylianou, Elena; Griffiths, Kristin L.; Marsay, Leanne; Checkley, Anna M.; McShane, Helen

    2014-01-01

    Summary The efficacy of Bacillus Calmette-Guerin (BCG) vaccination in protection against pulmonary tuberculosis (TB) is highly variable between populations. One possible explanation for this variability is increased exposure of certain populations to non-tuberculous mycobacteria (NTM). This study used a murine model to determine the effect that exposure to NTM after BCG vaccination had on the efficacy of BCG against aerosol Mycobacterium tuberculosis challenge. The effects of administering live Mycobacterium avium (MA) by an oral route and killed MA by a systemic route on BCG-induced protection were evaluated. CD4+ and CD8+ T cell responses were profiled to define the immunological mechanisms underlying any effect on BCG efficacy. BCG efficacy was enhanced by exposure to killed MA administered by a systemic route; T helper 1 and T helper 17 responses were associated with increased protection. BCG efficacy was reduced by exposure to live MA administered by the oral route; T helper 2 cells were associated with reduced protection. These findings demonstrate that exposure to NTM can induce opposite effects on BCG efficacy depending on route of exposure and viability of NTM. A reproducible model of NTM exposure would be valuable in the evaluation of novel TB vaccine candidates. PMID:24572168

  2. Development of a BCG challenge model for the testing of vaccine candidates against tuberculosis in cattle.

    Science.gov (United States)

    Villarreal-Ramos, Bernardo; Berg, Stefan; Chamberlain, Laura; McShane, Helen; Hewinson, R Glyn; Clifford, Derek; Vordermeier, Martin

    2014-09-29

    Vaccination is being considered as part of a sustainable strategy for the control of bovine tuberculosis (BTB) in the UK. The live attenuated Mycobacterium bovis bacillus Calmette-Guerin (BCG) has been used experimentally to vaccinate cattle against BTB. However, BCG confers partial protection against BTB and therefore, there is a need to develop improved vaccines. BTB vaccine efficacy experiments require the use of biosafety level 3 facilities which are expensive to maintain, generally oversubscribed and represent a bottle neck for the testing of vaccine candidates. One indicator of the induction of protective responses would be the ability of the host's immune response to control/kill mycobacteria. In this work we have evaluated an intranodal BCG challenge for the selection of vaccine candidates at biosafety level 2 which are capable of inducing mycobactericidal responses. To our knowledge, this is the first such report. Whilst BCG only confers partial protection, it is still the standard against which other vaccines are judged. Therefore we tested the BCG intranodal challenge in BCG (Danish strain) vaccinated cattle and showed that vaccinated cattle had lower BCG cfu counts than naïve cattle at 14 and 21 days after intranodal challenge with BCG (Tokyo strain). This model could help prioritize competing TB vaccine candidates and exploration of primary and secondary immune responses to mycobacteria. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

  3. Viral Booster Vaccines Improve Mycobacterium bovis BCG-Induced Protection Against Bovine Tuberculosis

    Science.gov (United States)

    Previous work in small animal laboratory models of tuberculosis have shown that vaccination strategies based on heterologous prime-boost protocols using Mycobacterium bovis bacille Calmette-Guerin (BCG) to prime and Modified Vaccinia Ankara strain (MVA85A) or recombinant attenuated adenoviruses (Ad8...

  4. Immunometabolic Pathways in BCG-Induced Trained Immunity.

    Science.gov (United States)

    Arts, Rob J W; Carvalho, Agostinho; La Rocca, Claudia; Palma, Carla; Rodrigues, Fernando; Silvestre, Ricardo; Kleinnijenhuis, Johanneke; Lachmandas, Ekta; Gonçalves, Luís G; Belinha, Ana; Cunha, Cristina; Oosting, Marije; Joosten, Leo A B; Matarese, Giuseppe; van Crevel, Reinout; Netea, Mihai G

    2016-12-06

    The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity. Here, we show that BCG induction of trained immunity in monocytes is accompanied by a strong increase in glycolysis and, to a lesser extent, glutamine metabolism, both in an in-vitro model and after vaccination of mice and humans. Pharmacological and genetic modulation of rate-limiting glycolysis enzymes inhibits trained immunity, changes that are reflected by the effects on the histone marks (H3K4me3 and H3K9me3) underlying BCG-induced trained immunity. These data demonstrate that a shift of the glucose metabolism toward glycolysis is crucial for the induction of the histone modifications and functional changes underlying BCG-induced trained immunity. The identification of these pathways may be a first step toward vaccines that combine immunological and metabolic stimulation. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  5. The Type of Growth Medium Affects the Presence of a Mycobacterial Capsule and Is Associated With Differences in Protective Efficacy of BCG Vaccination Against Mycobacterium tuberculosis.

    Science.gov (United States)

    Prados-Rosales, Rafael; Carreño, Leandro J; Weinrick, Brian; Batista-Gonzalez, Ana; Glatman-Freedman, Aarona; Xu, Jiayong; Chan, John; Jacobs, William R; Porcelli, Steven A; Casadevall, Arturo

    2016-08-01

    Bacillus Calmette-Guerin (BCG) vaccine is widely used for the prevention of tuberculosis, despite limited efficacy. Most immunological studies of BCG or Mycobacterium tuberculosis strains grow bacteria in the presence of detergent, which also strips the mycobacterial capsule. The impact of the capsule on vaccine efficacy has not been explored. We tested the influence of detergent in cultures of BCG and M. tuberculosis strains on the outcome of vaccination experiments on mice and transcriptional responses on M. tuberculosis  Vaccination of mice with encapsulated BCG promoted a more potent immune response relative to vaccination with unencapsulated BCG, including higher polysaccharide-specific capsule antibody titers, higher interferon γ and interleukin 17 splenic responses, and more multifunctional CD4(+) T cells. These differences correlated with variability in the bacterial burden in lung and spleen of mice infected with encapsulated or unencapsulated M. tuberculosis The combination of vaccination and challenge with encapsulated strains resulted in the greatest protection efficacy. The transcriptome of encapsulated M. tuberculosis was similar to that of starvation, hypoxia, stationary phase, or nonreplicating persistence. The presence of detergent in growth media and a capsule on BCG were associated with differences in the outcome of vaccination, implying that these are important variables in immunological studies. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  6. Vacuna contra la tuberculosis BCG: Eficacia y efectos adversos

    Directory of Open Access Journals (Sweden)

    Quezada-Andrade, Steven

    2015-12-01

    Full Text Available TB is the second leading cause of death from an infectious agent, disease caused by Mycobacterium tuberculosis. It allowed the creation of a vaccine officially launched in 1924 and known as Bacillus Calmette-Guerin (BCG used since then. However, there has been extensive research on its effectiveness and other related factors have shown an imbalance. Several countries recommend the use of this vaccine in infants, but in the case of Ecuador has failed to suggest its application, although there are no data regarding the efficacy of the vaccine in that country. Other studies show that the knowledge of people about the disease is destitute, thus allowing this could spread more quickly because the infected person does not know the type of symptoms that generates Tuberculosis. This article aims to identify the current status of the efficiency and safety of BCG through review and analysis of collected items related to the use of the vaccine and its effectiveness in the research population.

  7. Preparation and stability of agarose microcapsules containing BCG.

    Science.gov (United States)

    Esquisabel, A; Hernandez, R M; Igartua, M; Gascón, A R; Calvo, B; Pedraz, J L

    2002-01-01

    An emulsification/internal gelation method of preparing small-sized agarose microcapsules containing Bacillus Calmette-Guerin (BCG) is reported. Agarose microcapsules have been prepared by the emulsification of the hydrogel within a vegetable oil followed by its gelation due to the cooling of the system. Four different oils (sesame, sweet almonds, camomile and jojoba) were assayed. The rheological analysis of the oils showed a Newtonian behaviour, with viscosity values of 37.7, 51.2, 59.3 and 67.1 mPa s for jojoba, camomile, sesame and sweet almonds oil, respectively. The particle size of the microcapsules obtained ranged from 23.1 microm for the microcapsules prepared with sweet almonds oil to 42.6 microm for those prepared with jojoba. The microcapsule particle size was found to be dependent on the viscosity of the oil used in the emulsification step. The encapsulated BCG was identified by the Difco TB stain set K, followed by observation under optical microscopy. Once prepared, microcapsules were freeze-dried using 5% trehalose as cryoprotectant and the stability of the microcapsules was assayed during 12 months storage at room temperature, observing that agarose microcapsules were stable after 12 months storage, since there was no evidence of alteration in the freeze-dried appearance, resuspension rate, observation under microscope, or particle size.

  8. Effect of BCG vaccine on peritoneal endometriotic implants in a rat model of endometriosis.

    Science.gov (United States)

    Itil, Ismail Mete; Cirpan, Teksin; Akercan, Fuat; Gamaa, Akram; Kazandi, Mert; Kazandi, Ali Can; Yildiz, Pinar Solmaz; Askar, Niyazi

    2006-02-01

    To investigate the effect of Bacillus Calmette-Guerin (BCG) vaccine on peritoneal implantation of endometrial tissue in rats. Forty sexually mature virgin Wistar albino rats weighing 190-200 g were randomly assigned (double blind) to two groups. The rats in the first group were vaccinated with 0.1 mL BCG and those in the second group were injected with 0.1 mL saline into the tail, intracutaneously. All the rats underwent median laparotomy after 4 weeks of vaccination or injection. The right uterine horn was excised, and the two samples of endometrial tissue dissected from myometrium were implanted on each side of peritoneum at the 2 cm lateral line of the median laparotomy incision. The implanted peritoneal segments were excised after 8 weeks of laparotomy. The tissue samples were accepted, histologically, as endometriosis when both glands and stroma of endometrial tissue were seen in sections. Thirty-six implants from the study group and 34 implants from the control group were obtained. Ten and 23 implants were accepted as endometriosis in the study and control group, respectively. The number of endometriotic foci were significantly lower in the study group than in the control group (P = 0.01). Stimulation of the cellular immune response with BCG vaccine could exert an inhibitory effect on ectopic endometriotic implants.

  9. Bacillus Calmette-Guérin Vaccination Using a Microneedle Patch

    Science.gov (United States)

    Hiraishi, Yasuhiro; Nandakumar, Subhadra; Choi, Seong-O; Lee, Jeong Woo; Kim, Yeu-Chun; Posey, James E.; Sable, Suraj B.; Prausnitz, Mark R.

    2011-01-01

    Tuberculosis (TB) caused by Mycobacterium tuberculosis continues to be a leading cause of mortality among bacterial diseases, and the bacillus Calmette-Guerin (BCG) is the only licensed vaccine for human use against this disease. TB prevention and control would benefit from an improved method of BCG vaccination that simplifies logistics and eliminates dangers posed by hypodermic needles without compromising immunogenicity. Here, we report the design and engineering of a BCG-coated microneedle vaccine patch for a simple and improved intradermal delivery of the vaccine. The microneedle vaccine patch induced a robust cell-mediated immune response in both the lungs and spleen of guinea pigs. The response was comparable to the traditional hypodermic needle based intradermal BCG vaccination and was characterized by a strong antigen specific lymphocyte proliferation and IFN-γ levels with high frequencies of CD4+IFN-γ+, CD4+TNF-α+ and CD4+IFN-γ+TNF-α+ T cells. The BCG-coated microneedle vaccine patch was highly immunogenic in guinea pigs and supports further exploration of this new technology as a simpler, safer, and compliant vaccination that could facilitate increased coverage, especially in developing countries that lack adequate healthcare infrastructure. PMID:21277407

  10. SEQUENTIAL INTRAVESICAL IMMUNOCHEMOTHERAPY FOR ...

    African Journals Online (AJOL)

    chemotherapy using bacillus Calmette-Guerin (BCG) and epirubicin in superficial bladder tumors. In addition, the question of whether to start with BCG or epirubicin is answered. Methods: Between January 1993 and December 2001, 156 patients ...

  11. A recombinant Bacille Calmette-Guerin construct expressing the Plasmodium falciparum circumsporozoite protein enhances dendritic cell activation and primes for circumsporozoite-specific memory cells in BALB/c mice

    NARCIS (Netherlands)

    Arama, Charles; Waseem, Shahid; Fernández, Carmen; Assefaw-Redda, Yohannes; You, Liya; Rodriguez, Ariane; Radošević, Katarina; Goudsmit, Jaap; Kaufmann, Stefan H. E.; Reece, Stephen T.; Troye-Blomberg, Marita

    2012-01-01

    A protective malaria vaccine may induce both high levels of neutralising antibodies and strong T-cell responses. The Plasmodium falciparum circumsporozoite protein (CSp) is a leading pre-erythrocytic vaccine candidate. CSp is a week immunogen per se, but Mycobacterium bovis Bacille Calmette-Guerin

  12. BCG vaccine powder-laden and dissolvable microneedle arrays for lesion-free vaccination.

    Science.gov (United States)

    Chen, Fan; Yan, Qinying; Yu, Yang; Wu, Mei X

    2017-06-10

    Live attenuated Bacille Calmette-Guerin (BCG) bacillus is the only licensed vaccine for tuberculosis prevention worldwide to date. It must be delivered intradermally to be effective, which causes severe skin inflammation and sometimes, permanent scars. To minimize the side effects, we developed a novel microneedle array (MNA) that could deliver live attenuated freeze-dried BCG powder into the epidermis in a painless, lesion-free, and self-applicable fashion. The MNA was fabricated with biocompatible and dissolvable hyaluronic acid with a deep cave formed in the basal portion of each microneedle, into which BCG powder could be packaged directly. Viability of BCG vaccine packaged in the caves and the mechanical strength of the powder-laden MNA did not alter significantly before and after more than two months of storage at room temperature. Following insertion of the MNA into the skin, individual microneedle shafts melted away by interstitial fluid from the epidermis and upper dermis, exposing the powder to epidermal tissues. The powder sucked interstitial fluid, dissolved slowly, and diffused into the epidermis in a day against the interstitial fluid influx. Vaccination with BCG-MNA caused no overt skin irritation, in marked contrast to intradermal vaccination that provoked severe inflammation and bruise. While causing little skin irritation, vaccination efficacy of BCG-MNAs was comparable to that of intradermal immunization whether it was evaluated by humoral or cellular immunity. This powder-laden and dissolvable MNA represents a novel technology to sufficiently deliver live attenuated vaccine powders into the skin. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. A TetR family transcriptional factor directly regulates the expression of a 3-methyladenine DNA glycosylase and physically interacts with the enzyme to stimulate its base excision activity in Mycobacterium bovis BCG.

    Science.gov (United States)

    Liu, Lei; Huang, Cheng; He, Zheng-Guo

    2014-03-28

    3-Methyladenine DNA glycosylase recognizes and excises a wide range of damaged bases and thus plays a critical role in base excision repair. However, knowledge on the regulation of DNA glycosylase in prokaryotes and eukaryotes is limited. In this study, we successfully characterized a TetR family transcriptional factor from Mycobacterium bovis bacillus Calmette-Guerin (BCG), namely BCG0878c, which directly regulates the expression of 3-methyladenine DNA glycosylase (designated as MbAAG) and influences the base excision activity of this glycosylase at the post-translational level. Using electrophoretic mobility shift assay and DNase I footprinting experiments, we identified two conserved motifs within the upstream region of mbaag specifically recognized by BCG0878c. Significant down-regulation of mbaag was observed in BCG0878c-overexpressed M. bovis BCG strains. By contrast, about 12-fold up-regulation of mbaag expression was found in bcg0878c-deleted mutant M. bovis BCG strains. β-Galactosidase activity assays also confirmed these results. Thus, BCG0878c can function as a negative regulator of mbaag expression. In addition, the regulator was shown to physically interact with MbAAG to enhance the ability of the glycosylase to bind damaged DNA. Interaction between the two proteins was further found to facilitate AAG-catalyzed removal of hypoxanthine from DNA. These results indicate that a TetR family protein can dually regulate the function of 3-methyladenine DNA glycosylase in M. bovis BCG both at the transcriptional and post-translational levels. These findings enhance our understanding of the expression and regulation of AAG in mycobacteria.

  14. ESAT6 inhibits autophagy flux and promotes BCG proliferation through MTOR

    Energy Technology Data Exchange (ETDEWEB)

    Dong, Hu, E-mail: austhudong@126.com [Department of Medical Immunology, Medical School, Anhui University of Science and Technology (China); Medical Inspection Center, Anhui University of Science and Technology, Huainan (China); Jing, Wu, E-mail: wujing8008@126.com [Department of Medical Immunology, Medical School, Anhui University of Science and Technology (China); Medical Inspection Center, Anhui University of Science and Technology, Huainan (China); Runpeng, Zhao; Xuewei, Xu; Min, Mu; Ru, Cai [Department of Medical Immunology, Medical School, Anhui University of Science and Technology (China); Yingru, Xing; Shengfa, Ni [Affiliated Cancer Hospital, Anhui University of Science and Technology (China); Rongbo, Zhang [Department of Medical Immunology, Medical School, Anhui University of Science and Technology (China); Medical Inspection Center, Anhui University of Science and Technology, Huainan (China)

    2016-08-19

    In recent years, increasing studies have found that pathogenic Mycobacterium tuberculosis (Mtb) inhibits autophagy, which mediates the anti-mycobacterial response, but the mechanism is not clear. We previously reported that secretory acid phosphatase (SapM) of Mtb can negatively regulate autophagy flux. Recently, another virulence factor of Mtb, early secretory antigenic target 6 (ESAT6), has been found to be involved in inhibiting autophagy, but the mechanism remains unclear. In this study, we show that ESAT6 hampers autophagy flux to boost bacillus Calmette-Guerin (BCG) proliferation and reveals a mechanism by which ESAT6 blocks autophagosome-lysosome fusion in a mammalian target of rapamycin (MTOR)-dependent manner. In both Raw264.7 cells and primary macrophages derived from the murine abdominal cavity (ACM), ESAT6 repressed autophagy flux by interfering with the autophagosome-lysosome fusion, which resulted in an increased load of BCG. Impaired degradation of LC3Ⅱ and SQSTM1 by ESAT6 was related to the upregulated activity of MTOR. Contrarily, inhibiting MTOR with Torin1 removed the ESAT6-induced autophagy block and lysosome dysfunction. Furthermore, in both Raw264.7 and ACM cells, MTOR inhibition significantly suppressed the survival of BCG. In conclusion, our study highlights how ESAT6 blocks autophagy and promotes BCG survival in a way that activates MTOR. - Highlights: • A mechanism for disruping autophagy flux induced by ESAT6. • ESAT6-inhibited autophagy is MTOR-dependent. • ESAT6-boosted BCG is MTOR-dependent.

  15. Immunogenic Properties of a BCG Adjuvanted Chitosan Nanoparticle-Based Dengue Vaccine in Human Dendritic Cells

    Science.gov (United States)

    Hunsawong, Taweewun; Sunintaboon, Panya; Warit, Saradee; Thaisomboonsuk, Butsaya; Jarman, Richard G.; Yoon, In-Kyu; Ubol, Sukathida; Fernandez, Stefan

    2015-01-01

    Dengue viruses (DENVs) are among the most rapidly and efficiently spreading arboviruses. WHO recently estimated that about half of the world’s population is now at risk for DENV infection. There is no specific treatment or vaccine available to treat or prevent DENV infections. Here, we report the development of a novel dengue nanovaccine (DNV) composed of UV-inactivated DENV-2 (UVI-DENV) and Mycobacterium bovis Bacillus Calmette-Guerin cell wall components (BCG-CWCs) loaded into chitosan nanoparticles (CS-NPs). CS-NPs were prepared by an emulsion polymerization method prior to loading of the BCG-CWCs and UVI-DENV components. Using a scanning electron microscope and a zetasizer, DNV was determined to be of spherical shape with a diameter of 372.0 ± 11.2 nm in average and cationic surface properties. The loading efficacies of BCG-CWCs and UVI-DENV into the CS-NPs and BCG-CS-NPs were up to 97.2 and 98.4%, respectively. THP-1 cellular uptake of UVI-DENV present in the DNV was higher than soluble UVI-DENV alone. DNV stimulation of immature dendritic cells (iDCs) resulted in a significantly higher expression of DCs maturation markers (CD80, CD86 and HLA-DR) and induction of various cytokine and chemokine productions than in UVI-DENV-treated iDCs, suggesting a potential use of BCG- CS-NPs as adjuvant and delivery system for dengue vaccines. PMID:26394138

  16. Immunogenic Properties of a BCG Adjuvanted Chitosan Nanoparticle-Based Dengue Vaccine in Human Dendritic Cells.

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    Taweewun Hunsawong

    2015-09-01

    Full Text Available Dengue viruses (DENVs are among the most rapidly and efficiently spreading arboviruses. WHO recently estimated that about half of the world's population is now at risk for DENV infection. There is no specific treatment or vaccine available to treat or prevent DENV infections. Here, we report the development of a novel dengue nanovaccine (DNV composed of UV-inactivated DENV-2 (UVI-DENV and Mycobacterium bovis Bacillus Calmette-Guerin cell wall components (BCG-CWCs loaded into chitosan nanoparticles (CS-NPs. CS-NPs were prepared by an emulsion polymerization method prior to loading of the BCG-CWCs and UVI-DENV components. Using a scanning electron microscope and a zetasizer, DNV was determined to be of spherical shape with a diameter of 372.0 ± 11.2 nm in average and cationic surface properties. The loading efficacies of BCG-CWCs and UVI-DENV into the CS-NPs and BCG-CS-NPs were up to 97.2 and 98.4%, respectively. THP-1 cellular uptake of UVI-DENV present in the DNV was higher than soluble UVI-DENV alone. DNV stimulation of immature dendritic cells (iDCs resulted in a significantly higher expression of DCs maturation markers (CD80, CD86 and HLA-DR and induction of various cytokine and chemokine productions than in UVI-DENV-treated iDCs, suggesting a potential use of BCG- CS-NPs as adjuvant and delivery system for dengue vaccines.

  17. Tumor associated macrophages polarization dictates the efficacy of BCG instillation in non-muscle invasive urothelial bladder cancer.

    Science.gov (United States)

    Suriano, Francesca; Santini, Daniele; Perrone, Giuseppe; Amato, Michela; Vincenzi, Bruno; Tonini, Giuseppe; Muda, Andrea; Boggia, Sara; Buscarini, Maurizio; Pantano, Francesco

    2013-11-05

    To evaluate the prognostic role of TAMs in patients affected by non-muscle invasive bladder cancer (NMIBC), undergone Trans Urethral Resection of Bladder (TURB) and Bacillus Calmette-Guerin (BCG) therapy. Data from 40 patients (36 men, 4 women), mean age 69 years (40-83 years), treated for NMIBC with TURB and BCG instillation were collected. Two different groups were considered: group with and group without bladder cancer recurrence. Correlations between immunofluorescence measured Mtot, M1 and M2 infiltration and clinicopathological parameters were evaluated using Spearman and Mann-Whitney methods. The recurrence-free survival rate was calculated using the Kaplan-Meier method. CD68 positive cells (Mtot) were observed in all specimens tested. High Mtot, M1 and M2 infiltration was observed in patients with disease recurrence, even before endovescical BCG instillation. Significant value for M2 infiltration (p = 0,042) was found calculating significativity between two group medians before BCG therapy. p = 0,072 and p = 0,180 were observed correlating median of Mtot and M1 between two groups of patients respectively. Values of p = 0,44, p = 0,23 and p = 0,64 from correlation between DFS and Mtot, M1 and M2 median in patients before endovescical BCG instillation, were calculated respectively. Comparing DFS and Mtot, M1 and M2 median in patients group after endovescical BCG instillation significant values were obtained (p = 0,020; p = 0,02; and p = 0,029 respectively). M2 tumor infiltration could be a prognostic value of recurrence in patients with NMIBC.

  18. BCG Increased Membrane Expression of TRIM59 Through the TLR2/ TLR4/IRF5 Pathway in RAW264.7 Macrophages.

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    Jin, Zheng; Tian, Yuan; Yan, Dongmei; Li, Dong; Zhu, Xun

    2017-01-01

    In our previous study, we showed that Bacillus Calmette-Guerin (BCG)- activated macrophages have the ability to directly kill tumor cells. One of the main properties of these macrophages is the high expression of tripartite motif family protein 59 (TRIM59). This study was conducted to investigate the mechanism of BCG-induced TRIM59 expression on macrophages and to identify the subcellular localization of TRIM59. TRIM59 expression and TNF-α secretion were compared in RAW264.7 macrophage cells that were stimulated using BCG with or without Toll-like receptor 2/4 (TLR2/4)-neutralizing antibodies. Next, small interfering RNA (siRNA) was used to down-regulated interferon regulatory factor 5 (IRF5) gene expression in RAW264.7 cells. Transfected cells were stimulated with BCG, after which TRIM59 expression and TNF-α secretion were evaluated in cells pre-treated with siRNA or scramble control. After treatments, supernatants were co-cultured with MCA207, and cell viabilities were determined. Moreover, BCG-stimulated RAW264.7 cells were stained for TRIM59 and F4/80 expression. In this study, we showed that TRIM59 was expressed on the membrane of RAW264.7 cells. After blocking TLR2/4, treatment with BCG failed to induce the expression of TRIM59, IRF5, and TNF-α on RAW264.7 cells. In addition, down-regulation of IRF5 inhibited TRIM59 and TNF-α expression. Our study showed that TRIM59 is a membrane protein, and that BCG treatment upregulated TRIM59 expression on macrophages via TLR2/4 and IRF5 pathways. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Loss of BCG Viability Adversely Affects the Direct Response of Urothelial Carcinoma Cells to BCG Exposure

    Science.gov (United States)

    Shah, Gopitkumar; Zhang, Guangjian; Chen, Fanghong; Cao, YanLi; Kalyanaraman, Balaraman; See, William

    2018-01-01

    INTRODUCTION The attenuated mycobacterium Bacille Calmette Guerin (BCG) is widely utilized as intravesical “immunotherapy” for the treatment of non-muscle invasive urothelial carcinoma. Previous studies have demonstrated that in both the laboratory and clinical setting, BCG viability is a variable that correlates with anti-tumor efficacy. This study evaluated how loss of BCG viability impacted a number of molecular and phenotypic intermediate endpoints that characterize, and/or contribute to, the direct effect of BCG on Urothelial carcinoma (UC) cells. MATERIALS AND METHODS Two human UC cell lines were used to study the effect of loss of BCG viability on the tumor cell response to BCG. The cellular response to BCG rendered non-viable by heat killing (hk) was compared to the response to viable BCG. The response endpoints evaluated included the induction of oxidative stress, activation of intracellular signaling pathways, gene transactivation, and phenotypic changes. RESULTS Loss of viability resulted in a quantitative decrease in the tumor cell response, relative to viable BCG, for all of the measured endpoints. The decrease in response varied by cell line, ranging from 15% to 100% of the response to viable BCG. While quantitatively different, non-viable BCG continued to induce responses that were qualitatively similar to BCG relative to untreated controls. CONCLUSIONS BCG viability is an important variable influencing the direct tumor cell response to BCG. Although the magnitude of it effects are attenuated, hkBCG remains active for the induction of BCG responsive biologic endpoints. PMID:24035882

  20. IFN Alfa-2B and BCG Therapy Is An Effective Method In Superficial Bladder Carcinoma

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    Ahmet Ozdemir

    2012-04-01

    Full Text Available Aim: The initial therapy for superficial bladder carcinoma is the transurethral resection of the tumor. In spite of successful resections, there are 60-79% recurrence and 15% progression rates. Additional therapies are suggested for the treatment of superficial bladder carcinoma. We compared the efficacy of interferon alfa-2b monotherapy with interferon alfa-2b plus Bacillus Calmette Guerin (BCG combination therapy with urine interleukin (IL 2, 6 and 10 levels of patients with superficial bladder carcinoma. Material and Method: The patients who underwent TUR-BT for superficial bladder tumor (pathological staging Ta-T1 between 2004 and 2007 at our hospital included in this prospective study. Intravesical immunotherapy was administered once a week for 6 weeks and there after a month for 6 months, starting 4 weeks after TUR-BT. IL levels were measured. Results: IL-2, IL-6 and IL- 10 levels in urine samples were taken at 2nd and 4th hours of intravesical therapy. A statistically significant difference was observed between mean urine IL-2 levels of patients treated with IFN%u03B1-2b monotherapy and IFN%u03B1- 2b plus BCG combination both at 2nd and 4th hours. (p=0.05 In IFN%u03B1-2b plus BCG combination group, there was a statistical significant difference between stages regarding IL-2 and IL-6 levels (p=0.05. Among patients with G3 tumors, IL-2 levels were higher at 2 and 4 hours (p=0.05 but there was no significant difference in IL-6 and IL-10 levels in this group of patients regardless of intravesical therapy received (p=0.05. Discussion: IFN%u03B1-2b and BCG combination therapy is a reliable and effective therapy in the management of superficial bladder tumors.

  1. Effect of high-dose vitamin A supplementation on the immune response to Bacille Calmette-Guerin vaccine

    DEFF Research Database (Denmark)

    Diness, Birgitte R; Fisker, Ane B; Roth, Adam

    2007-01-01

    objective was to examine whether VAS influences the immune response to simultaneously administered BCG vaccine. DESIGN: Within a randomized trial of 50,000 IU vitamin A or placebo given with BCG vaccine at birth in Guinea-Bissau, 2710 infants were examined for BCG scar formation and delayed-type...... hypersensitivity (DTH) to purified protein derivative of Mycobacterium tuberculosis (PPD) at 2 and 6 mo of age. The ex vivo cytokine response to PPD was measured in 607 infants. RESULTS: At 2 mo of age, 39% (43% of the boys and 34% of the girls) responded to PPD. The prevalence ratio of a measurable PPD reaction...... for VAS compared with placebo recipients was 0.90 (95% CI: 0.80, 1.02) for all infants, 0.81 (95% CI: 0.69, 0.95) for boys, and 1.04 (95% CI: 0.86, 1.26) for girls. At 6 mo of age, 42% of the infants responded to PPD. No difference was observed between VAS and placebo recipients. The prevalence of BCG...

  2. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes.

    Science.gov (United States)

    Kleinnijenhuis, Johanneke; Quintin, Jessica; Preijers, Frank; Joosten, Leo A B; Ifrim, Daniela C; Saeed, Sadia; Jacobs, Cor; van Loenhout, Joke; de Jong, Dirk; Stunnenberg, Hendrik G; Xavier, Ramnik J; van der Meer, Jos W M; van Crevel, Reinout; Netea, Mihai G

    2012-10-23

    Adaptive features of innate immunity, recently described as "trained immunity," have been documented in plants, invertebrate animals, and mice, but not yet in humans. Here we show that bacille Calmette-Guérin (BCG) vaccination in healthy volunteers led not only to a four- to sevenfold increase in the production of IFN-γ, but also to a twofold enhanced release of monocyte-derived cytokines, such as TNF and IL-1β, in response to unrelated bacterial and fungal pathogens. The enhanced function of circulating monocytes persisted for at least 3 mo after vaccination and was accompanied by increased expression of activation markers such as CD11b and Toll-like receptor 4. These training effects were induced through the NOD2 receptor and mediated by increased histone 3 lysine 4 trimethylation. In experimental studies, BCG vaccination induced T- and B-lymphocyte-independent protection of severe combined immunodeficiency SCID mice from disseminated candidiasis (100% survival in BCG-vaccinated mice vs. 30% in control mice). In conclusion, BCG induces trained immunity and nonspecific protection from infections through epigenetic reprogramming of innate immune cells.

  3. Effect of high-dose vitamin A supplementation on the immune response to Bacille Calmette-Guerin vaccine

    DEFF Research Database (Denmark)

    Diness, Birgitte R; Fisker, Ane B; Roth, Adam

    2007-01-01

    BACKGROUND: Vitamin A supplementation (VAS) at birth has been associated with decreased mortality in Asia. Bacille Calmette-Guérin (BCG) vaccine is given at birth in tuberculosis-endemic countries. Previous studies suggest that VAS may influence the immune response to vaccines. OBJECTIVE: Our obj...

  4. Repeated BCG treatment of mouse bladder selectively stimulates small GTPases and HLA antigens and inhibits single-spanning uroplakins

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    O'Donnell Michael A

    2007-11-01

    Full Text Available Abstract Background Despite being a mainstay for treating superficial bladder carcinoma and a promising agent for interstitial cystitis, the precise mechanism of Bacillus Calmette-Guerin (BCG remains poorly understood. It is particularly unclear whether BCG is capable of altering gene expression beyond its well-recognized pro-inflammatory effects and how this relates to its therapeutic efficacy. The objective of this study was to determine differentially expressed genes in the mouse bladder following repeated intravesical BCG therapy. Methods Mice were transurethrally instilled with BCG or pyrogen-free on days 1, 7, 14, and 21. Seven days after the last instillation, urothelia along with the submucosa was removed and amplified ds-DNA was prepared from control- and BCG-treated bladder mucosa and used to generate suppression subtractive hybridization (SSH. Plasmids from control- and BCG-specific differentially expressed clones and confirmed by Virtual Northern were then purified and the inserts were sequenced and annotated. Finally, chromatin immune precipitation combined with real-time polymerase chain reaction assay (ChIP/Q-PCR was used to validate SSH-selected transcripts. Results Repeated intravesical BCG treatment induced an up regulation of genes associated with antigen presentation (B2M, HLA-A, HLA-DQA1, HLA-DQB2, HLA-E, HLA-G, IGHG, and IGH and representatives of two IFNγ-induced small GTPase families: the GBPs (GBP1, GBP2, and GBP5 and the p47GTPases (IIGTP1, IIGTP2, and TGTP. Genes expressed in saline-treated bladders but down-regulated by BCG included: the single-spanning uroplakins (UPK3a and UPK2, SPRR2G, GSTM5, and RSP 19. Conclusion Here we introduced a hypothesis-generator approach to determine key genes involved in the urothelium/sumbmucosa responses to BCG therapy. Urinary bladder responds to repeated BCG treatment by up-regulating not only antigen presentation-related genes, but also GBP and p47 small GTPases, both potentially

  5. The effect of zinc supplementation during pregnancy on immune response to Hib and BCG vaccines in Bangladesh.

    Science.gov (United States)

    Osendarp, Saskia J M; Fuchs, George J; van Raaij, Joop M A; Mahmud, Hasan; Tofail, Fahmida; Black, Robert E; Prabhakar, Hari; Santosham, Mathuram

    2006-10-01

    An essential role for zinc in development of the fetal immune system has been documented. However, the effect of antenatal zinc supplementation on infants' postnatal immune response to vaccinations is unknown. The objective of this study was to evaluate the effect of zinc supplementation during pregnancy on immune response to the Bacillus Calmette-Guerin (BCG) vaccine and the Haemophilus influenzae type b (Hib) component of the combined diphtheria, tetanus toxoid and pertussis (DTP)-Haemophilus influenzae type-b (Hib)- conjugate vaccine in poor Bangladeshi infants. We immunized 405 infants whose mothers were supplemented daily with 30 mg elemental zinc or placebo beginning at 12-16 weeks gestation with the standard BCG vaccine at birth. A subcohort of 203 infants were in addition immunized at 1-month intervals with three doses of DTP-Hib vaccine starting at 9 weeks of age. The delayed hypersensitivity (PPD) skin test was performed in 345 infants at 24 weeks of age. Hib polysaccharide (PRP) antibodies were assessed for 91 infants at 4 and 24 weeks of age. In infants born with low birth weight (LBW) a lower proportion of negative responses to PPD skin test were observed in the zinc (66.2%) compared to placebo (78.5%) group (p = 0.07). No differences were observed in normal birth weight infants. There were no differences in proportion of infants above the protective thresholds for anti-PRP antibodies between zinc (81%) and placebo (89%) group. Geometric mean PRP antibody titres at 4 and 24 weeks of age were not different between groups. Zinc supplementation during pregnancy did not enhance immune response to Hib-conjugate vaccine but there was a suggestion of improved delayed hypersensitivity immune responses to BCG-vaccine in Bangladeshi LBW infants.

  6. Adaptive immunity in the colostrum-deprived calf: Response to early vaccination with Mycobacterium bovis, strain Bacille Calmette Guerin (BCG) and ovalbumin

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    Responses of the newborn calf to vaccination are variable and frequently characterized by marginal antibody (Ab) responses. The present study evaluated effects of colostrum ingestion on the adaptive immune response of the preruminant calf to early vaccination. Colostrum-fed (CF) and colostrum-depriv...

  7. Mycobacterium tuberculosis PPD-induced immune biomarkers measurable in vitro following BCG vaccination of UK adolescents by multiplex bead array and intracellular cytokine staining

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    Worth Andrew

    2010-07-01

    Full Text Available Abstract Background The vaccine efficacy reported following Mycobacterium bovis Bacillus Calmette Guerin (BCG administration to UK adolescents is 77% and defining the cellular immune response in this group can inform us as to the nature of effective immunity against tuberculosis. The aim of this study was to identify which cytokines and lymphocyte populations characterise the peripheral blood cellular immune response following BCG vaccination. Results Diluted blood from before and after vaccination was stimulated with Mycobacterium tuberculosis purified protein derivative for 6 days, after which soluble biomarkers in supernatants were assayed by multiplex bead array. Ten out of twenty biomarkers measured were significantly increased (p Mycobacterium tuberculosis purified protein derivative stimulation of PBMC samples from the 12 month group revealed that IFNγ expression was detectable in CD4 and CD8 T-cells and natural killer cells. Polyfunctional flow cytometry analysis demonstrated that cells expressing IFNγ alone formed the majority in each subpopulation of cells. Only in CD4 T-cells and NK cells were there a notable proportion of responding cells of a different phenotype and these were single positive, TNFα producers. No significant expression of the cytokines IL-2, IL-17 or IL-10 was seen in any population of cells. Conclusions The broad array of biomarker responses detected by multiplex bead array suggests that BCG vaccination is capable, in this setting, of inducing a complex immune phenotype. Although polyfunctional T-cells have been proposed to play a role in protective immunity, they were not present in vaccinated adolescents who, based on earlier epidemiological studies, should have developed protection against pulmonary tuberculosis. This may be due to the later sampling time point available for testing or on the kinetics of the assays used.

  8. Predictive Value of NRAMP1 and HGPX1 Gene Polymorphism for Maintenance BCG Response in Non-muscle-invasive Bladder Cancer.

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    Lenormand, Claire; Couteau, Jérôme; Nouhaud, François-Xavier; Maillet, Géraldine; Bou, Jacqueline; Gobet, Françoise; Pfister, Christian

    2016-04-01

    To assess the potential predictive value of natural resistance-associated macrophage protein 1 (NRAMP1) and human glutathione peroxidase 1 (hGPX1) polymorphism in non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin (BCG) instillation, we conducted an original ancillary multicenter study. We evaluated patients included in the multicenter URO-BCG 4 trial, who received three weekly instillations of one-third dose BCG every 6 months (group I) or two weekly instillations every 3 months (group II) for 3 years. For clinical evaluation we also evaluated tumor recurrence and muscle progression. NRAMP1 and hGPX1 polymorphism analyses were performed on blood DNA. NRAMP1 exon 15 and hGPX1 exon 1c were amplified using Type-it Microsatellite PCR Kit® for multiplex polymerase chain reaction. From June 2004 to April 2010, 146 randomized patients were included in this retrospective study. Blood samples were obtained from 107 patients. With 36 months of follow-up, 13.6% of patients had a tumor recurrence and muscle-invasive progression was observed in 4.3% of patients. Concerning NRAMP1 D543N polymorphism, patients with allele A had no tumor recurrence or muscle-invasive progression. No significant difference was observed in gene polymorphism distribution between groups I and II. Moreover, we did not observe any significant association of gene polymorphisms, tumor recurrence or muscle-invasive progression, event time and disease-free survival. Our results suggest that no significant difference was found for NRAMP1 and hGPX1 gene polymorphisms associated with recurrence time, muscle invasion frequency and disease-free survival, nevertheless, we observed that the NRAMP1 D543N GG genotype group had a shorter time to tumor recurrence. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  9. Bacillus Calmette-Guérin (BCG) Infection Following Intravesical BCG Administration as Adjunctive Therapy For Bladder Cancer

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    Pérez-Jacoiste Asín, María Asunción; Fernández-Ruiz, Mario; López-Medrano, Francisco; Lumbreras, Carlos; Tejido, Ángel; San Juan, Rafael; Arrebola-Pajares, Ana; Lizasoain, Manuel; Prieto, Santiago; Aguado, José María

    2014-01-01

    Abstract Bacillus Calmette-Guérin (BCG) is the most effective intravesical immunotherapy for superficial bladder cancer. Although generally well tolerated, BCG-related infectious complications may occur following instillation. Much of the current knowledge about this complication comes from single case reports, with heterogeneous diagnostic and therapeutic approaches and no investigation on risk factors for its occurrence. We retrospectively analyzed 256 patients treated with intravesical BCG in our institution during a 6-year period, with a minimum follow-up of 6 months after the last instillation. We also conducted a comprehensive review and pooled analysis of additional cases reported in the literature since 1975. Eleven patients (4.3%) developed systemic BCG infection in our institution, with miliary tuberculosis as the most common form (6 cases). A 3-drug antituberculosis regimen was initiated in all but 1 patient, with a favorable outcome in 9/10 cases. There were no significant differences in the mean number of transurethral resections prior to the first instillation, the time interval between both procedures, the overall mean number of instillations, or the presence of underlying immunosuppression between patients with or without BCG infection. We included 282 patients in the pooled analysis (271 from the literature and 11 from our institution). Disseminated (34.4%), genitourinary (23.4%), and osteomuscular (19.9%) infections were the most common presentations of disease. Specimens for microbiologic diagnosis were obtained in 87.2% of cases, and the diagnostic performances for acid-fast staining, conventional culture, and polymerase chain reaction (PCR)-based assays were 25.3%, 40.9%, and 41.8%, respectively. Most patients (82.5%) received antituberculosis therapy for a median of 6.0 (interquartile range: 4.0–9.0) months. Patients with disseminated infection more commonly received antituberculosis therapy and adjuvant corticosteroids, whereas those with

  10. High-sensitive and rapid detection of Mycobacterium tuberculosis infection by IFN-γ release assay among HIV-infected individuals in BCG-vaccinated area

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    Jiang Weimin

    2009-05-01

    Full Text Available Abstract Background An accurate test for Mycobacterium tuberculosis infection is urgently needed in immunosuppressed populations. The aim of this study was to investigate the diagnostic power of enzyme-linked immunospot (ELISPOT-based IFN-γ release assay in detecting active and latent tuberculosis in HIV-infected population in bacillus Calmette-Guerin (BCG-vaccinated area. A total of 100 HIV-infected individuals including 32 active tuberculosis patients were recruited. An ELISPOT-based IFN-γ release assay, T-SPOT.TB, was used to evaluate the M. tuberculosis ESAT-6 and CFP-10 specific IFN-γ response. Tuberculin skin test (TST was performed for all recruited subjects. Results The subjects were divided into group HIV+ATB (HIV-infected individuals with active tuberculosis, n = 32, group HIV+LTB (HIV-infected individuals with positive results of T-SPOT.TB assay, n = 46 and group HIV only (HIV-infected individuals with negative results of T-SPOT.TB assay and without evidence of tuberculosis infection, n = 22. In group HIV+ATB and HIV+LTB, T-SPOT.TB positive rate in subjects with TST P 85% in patients with TB treatment for less than 1 month and CD4+ T cells ≥200/μl, while for patients treated for more than 3 months and CD4+ T cells Conclusion ELISPOT-based IFN-γ release assay is more sensitive and rapid for the diagnosis of TB infection in Chinese HIV-infected individuals with history of BCG vaccination, and could be an effective tool for guiding preventive treatment with isoniazid in latently infected people and for TB control in China.

  11. Proteomic profile of culture filtrate from the Brazilian vaccine strain Mycobacterium bovis BCG Moreau compared to M. bovis BCG Pasteur

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    Degrave Wim M

    2011-04-01

    Full Text Available Abstract Background Bacille Calmette-Guerin (BCG is currently the only available vaccine against tuberculosis (TB and comprises a heterogeneous family of sub-strains with genotypic and phenotypic differences. The World Health Organization (WHO affirms that the characterization of BCG sub-strains, both on genomic and proteomic levels, is crucial for a better comprehension of the vaccine. In addition, these studies can contribute in the development of a more efficient vaccine against TB. Here, we combine two-dimensional electrophoresis (2DE and mass spectrometry to analyse the proteomic profile of culture filtrate proteins (CFPs from M. bovis BCG Moreau, the Brazilian vaccine strain, comparing it to that of BCG Pasteur. CFPs are considered of great importance given their dominant immunogenicity and role in pathogenesis, being available for interaction with host cells since early infection. Results The 2DE proteomic map of M. bovis BCG Moreau CFPs in the pH range 3 - 8 allowed the identification of 158 spots corresponding to 101 different proteins, identified by MS/MS. Comparison to BCG Pasteur highlights the great similarity between these BCG strains. However, quantitative analysis shows a higher expression of immunogenic proteins such as Rv1860 (BCG1896, Apa, Rv1926c (BCG1965c, Mpb63 and Rv1886c (BCG1923c, Ag85B in BCG Moreau when compared to BCG Pasteur, while some heat shock proteins, such as Rv0440 (BCG0479, GroEL2 and Rv0350 (BCG0389, DnaK, show the opposite pattern. Conclusions Here we report the detailed 2DE profile of CFPs from M. bovis BCG Moreau and its comparison to BCG Pasteur, identifying differences that may provide relevant information on vaccine efficacy. These findings contribute to the detailed characterization of the Brazilian vaccine strain against TB, revealing aspects that may lead to a better understanding of the factors leading to BCG's variable protective efficacy against TB.

  12. Proteomic profile of culture filtrate from the Brazilian vaccine strain Mycobacterium bovis BCG Moreau compared to M. bovis BCG Pasteur.

    Science.gov (United States)

    Berrêdo-Pinho, Marcia; Kalume, Dario E; Correa, Paloma R; Gomes, Leonardo H F; Pereira, Melissa P; da Silva, Renata F; Castello-Branco, Luiz R R; Degrave, Wim M; Mendonça-Lima, Leila

    2011-04-20

    Bacille Calmette-Guerin (BCG) is currently the only available vaccine against tuberculosis (TB) and comprises a heterogeneous family of sub-strains with genotypic and phenotypic differences. The World Health Organization (WHO) affirms that the characterization of BCG sub-strains, both on genomic and proteomic levels, is crucial for a better comprehension of the vaccine. In addition, these studies can contribute in the development of a more efficient vaccine against TB. Here, we combine two-dimensional electrophoresis (2DE) and mass spectrometry to analyse the proteomic profile of culture filtrate proteins (CFPs) from M. bovis BCG Moreau, the Brazilian vaccine strain, comparing it to that of BCG Pasteur. CFPs are considered of great importance given their dominant immunogenicity and role in pathogenesis, being available for interaction with host cells since early infection. The 2DE proteomic map of M. bovis BCG Moreau CFPs in the pH range 3-8 allowed the identification of 158 spots corresponding to 101 different proteins, identified by MS/MS. Comparison to BCG Pasteur highlights the great similarity between these BCG strains. However, quantitative analysis shows a higher expression of immunogenic proteins such as Rv1860 (BCG1896, Apa), Rv1926c (BCG1965c, Mpb63) and Rv1886c (BCG1923c, Ag85B) in BCG Moreau when compared to BCG Pasteur, while some heat shock proteins, such as Rv0440 (BCG0479, GroEL2) and Rv0350 (BCG0389, DnaK), show the opposite pattern. Here we report the detailed 2DE profile of CFPs from M. bovis BCG Moreau and its comparison to BCG Pasteur, identifying differences that may provide relevant information on vaccine efficacy. These findings contribute to the detailed characterization of the Brazilian vaccine strain against TB, revealing aspects that may lead to a better understanding of the factors leading to BCG's variable protective efficacy against TB.

  13. Fever of unknown origin (FUO) due to miliary BCG: The diagnostic importance of morning temperature spikes and highly elevated ferritin levels.

    Science.gov (United States)

    Cunha, Burke A; Apostolopoulou, Anna; Gian, John

    Fever of unknown origin (FUO) is defined as prolonged fever of >101 °F for at least 3 weeks that remains undiagnosed after a focused inpatient or outpatient workup. One of the most elusive FUO diagnoses is miliary tuberculosis (TB) which typically has few/no localizing signs/symptoms. Since the introduction of intravesicular Bacille Calmette-Guerin (BCG) treatment for bladder carcinoma, miliary BCG has only rarely been reported as a cause of FUO. As with miliary TB, there are few/no clues to suspect miliary BCG. We present an interesting case of FUO due to miliary BCG without any localizing signs, i.e., no lung, liver or prostate involvement. The only clues to the diagnosis of this FUO due to disseminated BCG were morning temperature spikes and otherwise unexplained highly elevated ferritin levels. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Disseminated Bacillus Calmette-Guérin (BCG) infections in infants with immunodeficiency.

    Science.gov (United States)

    Al-Hammadi, Suleiman; Alsuwaidi, Ahmed R; Alshamsi, Eman T; Ghatasheh, Ghassan A; Souid, Abdul-Kader

    2017-05-05

    The Bacillus Calmette-Guérin (BCG) preparations are live-attenuated derivatives of Mycobacterium bovis. These products are used to vaccinate infants at birth, a practice that may result in a disseminated infection in those patients who have an unidentified immunodeficiency. Patients who were immunized at birth with BCG and who developed a disseminated infection are reported here to emphasize the importance of taking an extensive medical history before ‎giving the BCG vaccine. Patient 1 has a sibling who had familial hemophagocytic lymphohistiocytosis. Patient 2 has a severe immunodeficiency with profound lymphopenia. Patient 3 has a sibling who had a disseminated BCG infection. Patient 4 has two siblings with an immunodeficiency disorder; one sibling passed away in infancy and one is receiving regular immunoglobulin infusions. Patient 5 has profound lymphopenia and his brother had cytomegalovirus (CMV) pneumonitis and passed away in infancy. These unfortunate events could have been avoided by compiling the relevant clinical and laboratory information. These cases also underscore the importance of a strict adherence to the BCG vaccine policies. Local and international registries that estimate the birth prevalence of primary immune deficiencies are needed prior to implementing universal BCG vaccination administration.

  15. Growth inhibition of HeLa cell by internalization of Mycobacterium bovis Bacillus Calmette-Guérin (BCG Tokyo

    Directory of Open Access Journals (Sweden)

    Asahina Izumi

    2009-12-01

    Full Text Available Abstract Background Intravesical BCG immunotherapy is effective for preventing recurrence and progression in none muscle-invasive bladder cancer but the dosing schedule and duration of treatment remain empirical. The mechanisms by which intravesical BCG treatment mediates antitumor activity are currently poorly understood. Results HeLa cell infected with Mycobacterium bovis Bacillus Calmette-Guérin(BCG Tokyo which were different multiplicity of infection(MOI. Proliferation of HeLa cell reduced in a dose-dependent manner by live BCG. The cytoplasm of the HeLa cell showed variety lysosomal stages by internalized and interacted BCG. Conclusion Proliferated Live BCG secreted the protein and depressed the growth of tumor. The possibility for clinical introduction of BCG therapy for carcinoma reported with review of literature.

  16. Adverse reactions to the Bacillus Calmette-Guérin (BCG) vaccine in new-born infants

    DEFF Research Database (Denmark)

    Nørrelykke Nissen, Thomas; Birk, Nina Marie; Kjærgaard, Jesper

    2016-01-01

    OBJECTIVE: To evaluate adverse reactions of the Bacillus Calmette-Guérin (BCG) Statens Serum Institut (SSI) (Danish strain 1331) used as intervention in a randomized clinical trial. DESIGN: A randomized clinical multicenter trial, The Danish Calmette Study, randomizing newborns to BCG...... and eighty four families consented to participate and 4262 children, gestational age 32 weeks and above, were randomized: 2129 to BCG vaccine and 2133 to no vaccine. None of the participants withdrew because of adverse reactions. MAIN OUTCOME AND MEASURE: Trial-registered adverse reactions after BCG...... vaccination at birth. Follow-up at 3 and 13 months by telephone interviews and clinical examinations. RESULTS: Among the 2118 BCG-vaccinated children we registered no cases of severe unexpected adverse reaction related to BCG vaccination and no cases of disseminated BCG disease. Two cases of regional...

  17. Bacillus Calmette-Guérin (BCG) complications associated with primary immunodeficiency diseases

    Science.gov (United States)

    Norouzi, Sayna; Aghamohammadi, Asghar; Mamishi, Setareh; Rosenzweig, Sergio D.; Rezaei, Nima

    2016-01-01

    Summary Primary immunodeficiency diseases (PIDs) are a group of inherited disorders, characterized by defects of the immune system predisposing individuals to variety of manifestations, including recurrent infections and unusual vaccine complications. There are a number of PIDs prone to Bacillus Calmette-Guérin (BCG) complications. This review presents an update on our understanding about the BCGosis-susceptible PIDs, including severe combined immunodeficiency, chronic granulomatous disease, and Mendelian susceptibility to mycobacterial diseases. PMID:22430715

  18. SEQUENTIAL INTRAVESICAL IMMUNOCHEMOTHERAPY FOR

    African Journals Online (AJOL)

    noma, immunotherapy, epirubicin, sequen- tial therapy. INTRODUCTION. Bacillus Calmette-Guerin (BCG) is the best adjuvant treatment, yet known, for the prophy- laxis against recurrence of superficial bladder tumors. However, toxicity of intravesical BCG is an important consideration before taking the decision to use this ...

  19. Non-specific Effects of Vaccines and Stunting: Timing May Be Essential

    NARCIS (Netherlands)

    Berendsen, M.L.; Smits, J.; Netea, M.G.; Ven, A. van der

    2016-01-01

    BACKGROUND: Bacillus Calmette-Guerin (BCG) vaccination possesses effects on health beyond its target disease, the so called "non-specific effects". We evaluate these effects, as well as the effect of timing of BCG and other vaccinations, on stunting in Sub-Saharan African (SSA) children under five.

  20. A single, low dose of a cGMP recombinant BCG vaccine elicits protective T cell immunity against the human respiratory syncytial virus infection and prevents lung pathology in mice.

    Science.gov (United States)

    Céspedes, Pablo F; Rey-Jurado, Emma; Espinoza, Janyra A; Rivera, Claudia A; Canedo-Marroquín, Gisela; Bueno, Susan M; Kalergis, Alexis M

    2017-02-01

    Human respiratory syncytial virus (hRSV) is a major health burden worldwide, causing the majority of hospitalizations in children under two years old due to bronchiolitis and pneumonia. HRSV causes year-to-year outbreaks of disease, which also affects the elderly and immunocompromised adults. Furthermore, both hRSV morbidity and epidemics are explained by a consistently high rate of re-infections that take place throughout the patient life. Although significant efforts have been invested worldwide, currently there are no licensed vaccines to prevent hRSV infection. Here, we describe that a recombinant Bacillus Calmette-Guerin (BCG) vaccine expressing the nucleoprotein (N) of hRSV formulated under current good manufacture practices (cGMP rBCG-N-hRSV) confers protective immunity to the virus in mice. Our results show that a single dose of the GMP rBCG-N-hRSV vaccine retains its capacity to protect mice against a challenge with a disease-causing infection of 1×10 7 plaque-forming units (PFUs) of the hRSV A2 clinical strain 13018-8. Compared to unimmunized infected controls, vaccinated mice displayed reduced weight loss and less infiltration of neutrophils within the airways, as well as reduced viral loads in bronchoalveolar lavages, parameters that are characteristic of hRSV infection in mice. Also, ex vivo re-stimulation of splenic T cells at 28days post-immunization activated a repertoire of T cells secreting IFN-γ and IL-17, which further suggest that the rBCG-N-hRSV vaccine induced a mixed, CD8 + and CD4 + T cell response capable of both restraining viral spread and preventing damage of the lungs. All these features support the notion that rBCG-N-hRSV is a promising candidate vaccine to be used in humans to prevent the disease caused by hRSV in the susceptible population. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Ultraviolet susceptibility of BCG and virulent tubercle bacilli

    International Nuclear Information System (INIS)

    Riley, R.L.; Knight, M.; Middlebrook, G.

    1976-01-01

    To test the effectiveness of irradiating the upper air of a room with ultraviolet light at reducing the concentration of airborne tubercle bacilli, the susceptibility to the germicidal effects of ultraviolet light, Z, was determined for various mycobacteria. Virulent tubercle bacilli and bacille Calmette-Guerin (BCG) were susceptible to ultraviolet radiation, whereas Mycobacterium phlei had 10 times their resistance (Z, approximately one-tenth that for M. tuberculosis). The effectiveness against BCG of upper air ultraviolet irradiation in a room was tested directly by nebulizing BCG into the air of the room and monitoring its rate of disappearance. With one 17-watt fixture operating, the rate of disappearance increased 6-fold; with 2 fixtures operating (46 watts total), the rate of disappearance increased 9-fold. This implies that under steady-state conditions, the concentrations of airborne organisms with ultraviolet light(s) on would have been one-sixth and one-ninth, respectively. The increase in rate of decay of the airborne organism using 1 fixture was equivalent to 10 air changes per hour, whereas that using 2 fixtures was approximately 25 air changes per hour (range: 18 to 33 air changes per hour). These increments are less than those reported previously for Serratia marcescens, because the Z value for BCG is approximately one-seventh that for serratia. These findings with BCG are believed to be directly applicable to virulent tubercle bacilli

  2. Bacillus Calmette-Guérin (BCG) Vaccination in Infancy and Risk of Childhood Diabetes.

    Science.gov (United States)

    Rousseau, Marie-Claude; El-Zein, Mariam; Conus, Florence; Legault, Laurent; Parent, Marie-Elise

    2016-03-01

    A narrow time window in infancy may be relevant for the aetiology of immune-mediated type 1 diabetes. We investigated whether a non-specific immune stimulation in the first year of life, as resulting from Bacillus Calmette-Guérin (BCG) vaccination, was associated with childhood diabetes. Using data from a birth cohort assembled through linkage of administrative databases, 78,492 subjects born in 1974 were the object of the present analysis. Information was extracted from the birth, death, and BCG vaccination registries. Diabetes-related health services were obtained from administrative health databases (physician billing claims and hospitalisation data) until 1994. Subjects were classified as having diabetes according to two validated definitions: (1) ≥2 diabetes-related medical visits within 2 years or ≥1 hospitalisation for diabetes; and 2) ≥4 diabetes-related medical visits within 2 years. Cox proportional hazards regression was used to estimate adjusted hazard ratios (HR) and 95% confidence interval (CI), adjusted for potential confounders. Forty-four per cent of subjects were BCG vaccinated in the first year of life. According to the first and second definition, respectively, 293 (0.37%) and 230 (0.29%) subjects were classified as having diabetes. There was no association between BCG vaccination in the first year of life and risk of diabetes with either definition (HR(def1)  = 0.92, 95% CI 0.73, 1.17; HR(def2)  = 1.04, 95% CI 0.80, 1.37), and results did not differ by sex. Given the potentially critical importance of the exposure window and paucity of studies addressing BCG vaccination timing in relation to diabetes risk, this question deserves further investigation. © 2015 John Wiley & Sons Ltd.

  3. BCG-associated heterologous immunity, a historical perspective: experimental models and immunological mechanisms.

    Science.gov (United States)

    Freyne, Bridget; Marchant, Arnaud; Curtis, Nigel

    2015-01-01

    Randomized controlled trials indicate that bacille Calmette-Guerin (BCG) has beneficial heterologous ('non-specific') effects on mortality in high mortality settings. These findings have stimulated interest in understanding the immunological mechanisms underlying these effects in the hope of harnessing them to reduce all-cause mortality. This line of investigation is especially important in light of BCG being discontinued in some countries as the prevalence of TB falls. Stopping routine BCG in this situation may have the unintended consequence of depriving children of the beneficial immune modulating effects of this vaccine. BCG has been recognized as a potent immunomodulator for decades. This review details experimental studies involving BCG and any heterologous antigen that aimed to interrogate potential immunological mechanisms. To provide a historical perspective, the evidence is presented chronologically. The lines of immunological enquiry can be seen to mirror the evolution of our understanding of cell-mediated immunity and its components. As new clinical trials to investigate the heterologous effects of BCG are undertaken, an understanding of the history of BCG-induced immunity against heterologous antigens may provide information on immunological pathways worthy of further interrogation using modern immunological methods. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Accuracy of the QuantiFERON-TB Gold in Tube for diagnosing tuberculosis in a young pediatric population previously vaccinated with Bacille Calmette-Guerin

    Directory of Open Access Journals (Sweden)

    Marcelo Genofre Vallada

    2014-03-01

    Full Text Available Objective: To evaluate the accuracy of an interferongamma release assay (QuantiFERON-TB Gold in Tube for diagnosing Mycobacterium tuberculosis infection in a young pediatric population. Methods: 195 children previously vaccinated with BCG were evaluated, being 184 healthy individuals with no clinical or epidemiological evidence of mycobacterial infection, and 11 with Mycobacterium tuberculosis infection, according to clinical, radiological, and laboratory parameters. A blood sample was obtained from each child and processed according to the manufacturer's instructions. The assay performance was evaluated by a Receiver Operating Characteristic (ROC curve. Results: In the group of 184 non-infected children, 130 (70.6% were under the age of four years (mean age of 35 months. In this group, 177 children (96.2% had negative test results, six (3.2% had indeterminate results, and one (0.5% had a positive result. In the group of 11 infected children, the mean age was 58.5 months, and two of them (18% had negative results. The ROC curve had an area under the curve of 0.88 (95%CI 0.82-0.92; p<0.001, disclosing a predictive positive value of 81.8% for the test (95%CI 46.3-97.4. The assay sensitivity was 81.8% (95%CI 48.2-97.2 and the specificity was 98.8% (95%CI 96-99.8. Conclusions: In the present study, the QuantiFERON-TB Gold in Tube performance for diagnosing M. tuberculosis infection was appropriate in a young pediatric population.

  5. Could Hyaluronic acid (HA) reduce Bacillus Calmette-Guérin (BCG) local side effects? Results of a pilot study

    Science.gov (United States)

    2014-01-01

    Background Bacillus Calmette-Guérin (BCG) is considered the most effective treatment to reduce recurrence and progression of non-muscle invasive bladder cancer (NMIBC) but can induce local side effects leading to treatment discontinuation or interruption. Aim of this exploratory study is to investigate if the sequential administration of Hyaluronic acid (HA) may reduce local side effects of BCG. Methods 30 consecutive subjects undergoing BCG intravesical administration for high risk NMIBC were randomized to receive BCG only (Group A) or BCG and HA (Group B). A 1 to 10 Visual Analog Scale (VAS) for bladder pain, International Prostate Symptom Score (IPSS) and number of micturitions per day were evaluated in the two groups before and after six weekly BCG instillations. Patients were also evaluated at 3 and 6 months by means of cystostopy and urine cytology. Results One out of 30 (3,3%) patients in group A dropped out from the protocol, for local side effects. Mean VAS for pain was significantly lower in group B after BCG treatment (4.2 vs. 5.8, p = 0.04). Post vs. pre treatment differences in VAS for pain, IPSS and number of daily micturitions were all significantly lower in group B. Three patients in group A and 4 in group B presented with recurrent pathology at 6 month follow up. Conclusions These preliminary data suggest a possible role of HA in reducing BCG local side effects and could be used to design larger randomized controlled trials, assessing safety and efficacy of sequential BCG and HA administration. Trial registration NCT02207608 (ClinicalTrials.gov) 01/08/2014 Policlinico Tor Vergata Ethics Committee, resolution n 69–2011. PMID:25123116

  6. Human β-defensin 2 may inhibit internalisation of bacillus Calmette-Guérin (BCG) in bladder cancer cells.

    Science.gov (United States)

    Kim, Jung Hoon; Kim, Soon-Ja; Lee, Kyung Mee; Chang, In Ho

    2013-10-01

    To investigate whether secretion of human β-defensin 2 (HBD-2) is induced by bacillus Calmette-Guérin (BCG) and to determine whether HBD-2 affects BCG internalisation in bladder cancer cells. Reverse transcription-polymerase chain reaction analysis was used to determine whether HBD-2 mRNA increases after incubation with BCG. HBD-2 proteins in 5637 and T24 human bladder cancer cell lines were assayed by enzyme-linked immunosorbent assay. The internalisation rate was evaluated by double immunofluorescence assay and confocal microscopy to test the optimal dose of HBD-2 for BCG internalisation. We also investigated the difference in internalisation rates and cell viability between recombinant HBD-2 protein, anti-HBD-2 antibody, and HBD-2 plus anti-HBD-2 antibody pretreatments. BCG induced HBD-2 mRNA expression and HBD-2 production dose and time-dependently in bladder cancer cells and affected BCG internalisation. Pretreatment with recombinant HBD-2 protein lowered internalisation of BCG dose-dependently. Moreover, anti-HBD-2 antibody prevented the effect of HBD-2 on BCG internalisation in bladder cancer cells. The internalisation rate of BCG pretreated with anti-HBD-2 antibody was higher than that in the control in 5637 (P internalisation rate in cells pretreated with anti-HBD-2 antibody plus recombinant HBD-2 protein was higher than that in the control in 5637 (P internalisation, which plays an important role during the initiation and propagation of the immunotherapeutic response in bladder cancer cells. © 2013 The Authors. BJU International © 2013 BJU International.

  7. International Journal of Basic, Applied and Innovative Research ...

    African Journals Online (AJOL)

    Uwaifoh

    2012-12-31

    Dec 31, 2012 ... Bacillus Calmette Guerin (BCG) is the only available vaccine against tuberculosis and has been in use for over seventy ... The resurgence of tuberculosis associated with HIV epidemic also demonstrates that loss .... Van Pinxteren, L.A., Cassidy, J.P., Smedegarrd, B.H., Agger, E.M. and Andersen, P. (2000).

  8. Evaluating the need for transurethral bladder biopsy at first follow up ...

    African Journals Online (AJOL)

    Introduction: Patients with high-risk superficial transitional cell carcinoma (TCC) of the bladder have a lifelong risk of progression and require particular attention. Intravesical Bacillus Calmette-Guerin (BCG) is recommended as a first-choice adjuvant treatment to reduce the risk of progression of high-grade tumors and ...

  9. Author Details

    African Journals Online (AJOL)

    Festus, OO. Vol 1, No 4 (2012) - Articles CD4 and CD8 counts of Bacillus Calmette Guerin (BCG) vaccinated neonates in parts of Edo and Delta States, Nigeria Abstract PDF · Vol 4, No 3 (2015) - Articles Intestinal helminthes infestation in relation to some haematological parameters among pregnant women attending ...

  10. Author Details

    African Journals Online (AJOL)

    Alika, S. Vol 1, No 4 (2012) - Articles CD4 and CD8 counts of Bacillus Calmette Guerin (BCG) vaccinated neonates in parts of Edo and Delta States, Nigeria Abstract PDF. ISSN: 2384-681X. AJOL African Journals Online. HOW TO USE AJOL... for Researchers · for Librarians · for Authors · FAQ's · More about AJOL · AJOL's ...

  11. Author Details

    African Journals Online (AJOL)

    Osagie, RN. Vol 1, No 4 (2012) - Articles CD4 and CD8 counts of Bacillus Calmette Guerin (BCG) vaccinated neonates in parts of Edo and Delta States, Nigeria Abstract PDF · Vol 4, No 3 (2015) - Articles Intestinal helminthes infestation in relation to some haematological parameters among pregnant women attending ...

  12. Effects of Bacillus Calmette-Guérin (BCG) vaccination at birth on T and B lymphocyte subsets

    DEFF Research Database (Denmark)

    Birk, Nina Marie; Nissen, Thomas Nørrelykke; Kjærgaard, Jesper

    2017-01-01

    , determined by flow cytometry. In 118 infants blood samples were obtained 4 (±2) days post randomization to BCG vaccination or no intervention, and at 3 and 13 months of age. No effects of BCG were found at 4 days. However, BCG increased proportions of effector memory cells at 3 months (Geometric mean ratio......The Bacillus Calmette-Guérin vaccine (BCG) has been associated with beneficial non-specific effects (NSEs) on infant health. Within a randomized trial on the effect of neonatal BCG on overall health, we investigated the possible immunological impact of neonatal BCG vaccination on lymphocyte subsets...... (GMR) 1.62, 95% confidence interval (CI) (1.20-2.21), p = 0.002 for CD4(+) T cells and GMR 1.69, 95% CI (1.06-2.70), p = 0.03 for CD8(+) T cells), and reduced proportions of late differentiated CD4(+) T cells (GMR = 0.62, 95% CI (0.38-1.00), p = 0.05) and apoptotic CD4(+) T cells at 13 months (GMR = 0...

  13. H2O2 generation by BCG induces the cellular oxidative stress response required for BCG’s direct effects on urothelial carcinoma tumor biology

    Science.gov (United States)

    Shah, Gopitkumar; Zielonka, Jacek; Chen, Fanghong; Zhang, Guangjian; Cao, YanLi; Kalyanaraman, Balaraman; See, William

    2018-01-01

    INTRODUCTION Exposure of urothelial carcinoma (UC) cells to Bacille Calmette Guerin (BCG) affects cellular redox status and tumor cell biology but mechanism(s) remains unclear. This study examined free radical production by BCG, and in tumor cells in response to BCG, using global profiling of Reactive oxygen species/reactive nitrogen species (ROS/RNS). The relationship between free radical generation and downstream cellular events was evaluated. MATERIALS AND METHODS Using fluorescent probes, global profiling of ROS/RNS was carried out in Heat killed (hk) BCG, viable BCG, and in two UC cell lines post BCG exposure (253J and T24). Inhibition of BCG internalization and pharmacologic scavenging of H2O2 was studied for their effect on cellular ROS/RNS generation and various physiological end points. RESULTS Viable BCG produced H2O2 (Hydrogen peroxide) and O2− (Superoxides) but did not show NO (Nitric oxide) generation. Loss of viability decreased production of H2O2 by 50% compared to viable BCG. BCG internalization was necessary for BCG induced ROS/RNS generation in UC cells. Pharmacologic H2O2 scavenging reversed the ROS/RNS mediated signaling in UC cells. BCG dependent alterations in tumor biology including intracellular signaling, gene expression and cytotoxicity were dependent on free radical generation. CONCLUSIONS This study demonstrates the importance of free radical generation by BCG, and intracellular generation of Cellular oxidative stress (COS), on the UC cell response to BCG. Manipulation of the BCG induced COS represents a potential target for increasing BCG efficacy. PMID:24928267

  14. Comparative Tuberculosis (TB) Prevention Effectiveness in Children of Bacillus Calmette-Guérin (BCG) Vaccines from Different Sources, Kazakhstan

    Science.gov (United States)

    Favorov, Michael; Ali, Mohammad; Tursunbayeva, Aigul; Aitmagambetova, Indira; Kilgore, Paul; Ismailov, Shakhimurat; Chorba, Terence

    2012-01-01

    Background Except during a 1-year period when BCG vaccine was not routinely administered, annual coverage of infants with Bacillus Calmette-Guérin (BCG) in Kazakhstan since 2002 has exceeded 95%. BCG preparations from different sources (Japan, Serbia, and Russia) or none were used exclusively in comparable 7-month time-frames, September through March, in 4 successive years beginning in 2002. Our objective was to assess relative effectiveness of BCG immunization. Methods/Findings We compared outcomes of birth cohorts from the 4 time-frames retrospectively. Three cohorts received vaccine from one of three manufacturers exclusively, and one cohort was not vaccinated. Cohorts were followed for 3 years for notifications of clinical TB and of culture-confirmed TB, and for 21 months for TB meningitis notifications. Prevention effectiveness based on relative risk of TB incidence was calculated for each vaccinated cohort compared to the non-vaccinated cohort. Although there were differences in prevention effectiveness observed among the three BCG vaccines, all were protective. The Japanese vaccine (currently used in Kazakhstan), the Serbian vaccine, and the Russian vaccine respectively were 69%, 43%, and 22% effective with respect to clinical TB notifications, and 92%, 82%, and 51% effective with respect to culture confirmed TB. All three vaccines were >70% effective with respect to TB meningitis. Limitations Potential limitations included considerations that 1) the methodology used was retrospective, 2) multiple risk factors could have varied between cohorts and affected prevention effectiveness measures, 3) most cases were clinically diagnosed, and TB culture-positive case numbers and TB meningitis case numbers were sparse, and 4) small variations in reported population TB burden could have affected relative risk of exposure for cohorts. Conclusions/Significance All three BCG vaccines evaluated were protective against TB, and prevention effectiveness varied by

  15. Comparative tuberculosis (TB prevention effectiveness in children of Bacillus Calmette-Guérin (BCG vaccines from different sources, Kazakhstan.

    Directory of Open Access Journals (Sweden)

    Michael Favorov

    Full Text Available BACKGROUND: Except during a 1-year period when BCG vaccine was not routinely administered, annual coverage of infants with Bacillus Calmette-Guérin (BCG in Kazakhstan since 2002 has exceeded 95%. BCG preparations from different sources (Japan, Serbia, and Russia or none were used exclusively in comparable 7-month time-frames, September through March, in 4 successive years beginning in 2002. Our objective was to assess relative effectiveness of BCG immunization. METHODS/FINDINGS: We compared outcomes of birth cohorts from the 4 time-frames retrospectively. Three cohorts received vaccine from one of three manufacturers exclusively, and one cohort was not vaccinated. Cohorts were followed for 3 years for notifications of clinical TB and of culture-confirmed TB, and for 21 months for TB meningitis notifications. Prevention effectiveness based on relative risk of TB incidence was calculated for each vaccinated cohort compared to the non-vaccinated cohort. Although there were differences in prevention effectiveness observed among the three BCG vaccines, all were protective. The Japanese vaccine (currently used in Kazakhstan, the Serbian vaccine, and the Russian vaccine respectively were 69%, 43%, and 22% effective with respect to clinical TB notifications, and 92%, 82%, and 51% effective with respect to culture confirmed TB. All three vaccines were >70% effective with respect to TB meningitis. LIMITATIONS: Potential limitations included considerations that 1 the methodology used was retrospective, 2 multiple risk factors could have varied between cohorts and affected prevention effectiveness measures, 3 most cases were clinically diagnosed, and TB culture-positive case numbers and TB meningitis case numbers were sparse, and 4 small variations in reported population TB burden could have affected relative risk of exposure for cohorts. CONCLUSIONS/SIGNIFICANCE: All three BCG vaccines evaluated were protective against TB, and prevention effectiveness

  16. Comparative tuberculosis (TB) prevention effectiveness in children of Bacillus Calmette-Guérin (BCG) vaccines from different sources, Kazakhstan.

    Science.gov (United States)

    Favorov, Michael; Ali, Mohammad; Tursunbayeva, Aigul; Aitmagambetova, Indira; Kilgore, Paul; Ismailov, Shakhimurat; Chorba, Terence

    2012-01-01

    Except during a 1-year period when BCG vaccine was not routinely administered, annual coverage of infants with Bacillus Calmette-Guérin (BCG) in Kazakhstan since 2002 has exceeded 95%. BCG preparations from different sources (Japan, Serbia, and Russia) or none were used exclusively in comparable 7-month time-frames, September through March, in 4 successive years beginning in 2002. Our objective was to assess relative effectiveness of BCG immunization. We compared outcomes of birth cohorts from the 4 time-frames retrospectively. Three cohorts received vaccine from one of three manufacturers exclusively, and one cohort was not vaccinated. Cohorts were followed for 3 years for notifications of clinical TB and of culture-confirmed TB, and for 21 months for TB meningitis notifications. Prevention effectiveness based on relative risk of TB incidence was calculated for each vaccinated cohort compared to the non-vaccinated cohort. Although there were differences in prevention effectiveness observed among the three BCG vaccines, all were protective. The Japanese vaccine (currently used in Kazakhstan), the Serbian vaccine, and the Russian vaccine respectively were 69%, 43%, and 22% effective with respect to clinical TB notifications, and 92%, 82%, and 51% effective with respect to culture confirmed TB. All three vaccines were >70% effective with respect to TB meningitis. Potential limitations included considerations that 1) the methodology used was retrospective, 2) multiple risk factors could have varied between cohorts and affected prevention effectiveness measures, 3) most cases were clinically diagnosed, and TB culture-positive case numbers and TB meningitis case numbers were sparse, and 4) small variations in reported population TB burden could have affected relative risk of exposure for cohorts. All three BCG vaccines evaluated were protective against TB, and prevention effectiveness varied by manufacturer. When setting national immunization policy, consideration

  17. Necrotizing Ulcer After BCG Vaccination in a Girl With Leukocyte-adhesion Deficiency Type 1.

    Science.gov (United States)

    Kurosawa, Hidemitsu; Mizukami, Tomoyuki; Nunoi, Hiroyuki; Kato, Masaya; Sato, Yuya; Okuya, Mayuko; Fukushima, Keitaro; Katsuyama, Yoshihiko; Arisaka, Osamu

    2018-01-01

    Leukocyte-adhesion deficiency-1 is a recessively inherited disorder associated with recurrent bacterial infections, severe periodontitis, peripheral leukocytosis, and impaired wound healing. We diagnosed moderate-type leukocyte-adhesion deficiency-1 in a 7-year-old girl who developed a necrotizing ulcer after Bacillus Calmette-Guerin vaccination. The patient showed moderate expression of CD18 in neutrophils with a homozygous splice mutation with c.41_c.58+2dup20 of ITGB2 and experienced recurrent severe infections complicated with systemic lupus erythematosus. She received hematopoietic stem cell transplantation from a matched elder brother with heterozygous mutation of ITGB2, and has since remained free of infection and systemic lupus erythematosus symptoms without immunosuppression therapy.

  18. Effects of Bacillus Calmette-Guérin (BCG) vaccination at birth on T and B lymphocyte subsets: Results from a clinical randomized trial.

    Science.gov (United States)

    Birk, Nina Marie; Nissen, Thomas Nørrelykke; Kjærgaard, Jesper; Hartling, Hans Jacob; Thøstesen, Lisbeth Marianne; Kofoed, Poul-Erik; Stensballe, Lone Graff; Andersen, Andreas; Pryds, Ole; Netea, Mihai G; Benn, Christine Stabell; Nielsen, Susanne Dam; Jeppesen, Dorthe Lisbeth

    2017-09-29

    The Bacillus Calmette-Guérin vaccine (BCG) has been associated with beneficial non-specific effects (NSEs) on infant health. Within a randomized trial on the effect of neonatal BCG on overall health, we investigated the possible immunological impact of neonatal BCG vaccination on lymphocyte subsets, determined by flow cytometry. In 118 infants blood samples were obtained 4 (±2) days post randomization to BCG vaccination or no intervention, and at 3 and 13 months of age. No effects of BCG were found at 4 days. However, BCG increased proportions of effector memory cells at 3 months (Geometric mean ratio (GMR) 1.62, 95% confidence interval (CI) (1.20-2.21), p = 0.002 for CD4 + T cells and GMR 1.69, 95% CI (1.06-2.70), p = 0.03 for CD8 + T cells), and reduced proportions of late differentiated CD4 + T cells (GMR = 0.62, 95% CI (0.38-1.00), p = 0.05) and apoptotic CD4 + T cells at 13 months (GMR = 0.55, 95% CI (0.32-0.92), p = 0.03). In conclusion, limited overall impact of neonatal BCG vaccination on lymphocyte subsets was found in healthy Danish infants within the first 13 months of life. This is in line with the limited clinical effects of BCG observed in our setting.

  19. In vivo evaluation of the efficacy of Sophora moorcroftiana alkaloids in combination with Bacillus Calmette-Guérin (BCG) treatment for cystic echinococcosis in mice.

    Science.gov (United States)

    Zhang, G; Wang, J; Luo, Y; Yuan, M; Gao, Q; Gao, H; Song, X; Shi, Y; Dong, K; Ma, X

    2017-10-24

    Human cystic echinococcosis is a widespread, chronic, endemic, helminthic zoonosis caused by larval tapeworms of the species Echinococcus granulosus. At present, there is no rational and effective therapy for patients with echinococcosis. The present study evaluated whether the combination of alkaloids from Sophora moorcroftiana seeds (SMSa2) and Bacillus Calmette-Guérin (BCG) was effective in the treatment of experimental echinococcosis. After 20 weeks of secondary infection with protoscoleces, mice were randomly allocated to five groups and treated for 6 weeks by daily intragastric administration of albendazole (ABZ, 100 mg/kg), SMSa2 (100 mg/kg), BCG (abdominal subcutaneous injection at 5 × 106 CFU), SMSa2 + BCG (100 mg/kg SMSa2 and 5 × 106 CFU BCG) or normal saline (untreated group), respectively. The results indicated a significant reduction in the weight of hydatid cysts in the SMSa2 + BCG group compared with the untreated, SMSa2 and BCG groups. The rate of inhibition of hydatid cyst growth in the SMSa2 + BCG group (76.1%) was obviously increased compared with that in the SMSa2 (25.7%) and BCG (26.6%) groups, respectively. Compared with the untreated control, the SMSa2 + BCG group showed a non-significant increase in serum interleukin-4 (IL-4). Furthermore, the serum levels of interferon-γ (IFN-γ) between the untreated and SMSa2 + BCG groups were not statistically different. Therefore, the combination of alkaloids from S. moorcroftiana seeds and BCG can reduce cyst burden and is an effective therapeutic regimen against echinococcosis.

  20. MBCP - Approach - Immunotherapy | Center for Cancer Research

    Science.gov (United States)

    Immunotherapy CCR investigators pioneered the use of the tuberculosis vaccine—Bacillus Calmette-Guerin (BCG)—in the treatment of bladder cancer. In cases where the tumor burden is not too high and direct contact can be made with the urothelium surface of the bladder, BCG application appears to elicit an immune response that attacks the tumor as well as the attenuated virus. Ongoing clinical trials focusing on enhancing the patient’s immune system are listed below.

  1. Contemporary management of patients with high-risk non-muscle-invasive bladder cancer who fail intravesical BCG therapy.

    Science.gov (United States)

    Yates, D R; Rouprêt, M

    2011-08-01

    It is advocated that patients with high-risk non-muscle-invasive bladder cancer (NMIBC) receive an adjuvant course of intravesical Bacille Calmette-Guerin (BCG) as first-line treatment. However, a substantial proportion of patients will 'fail' BCG, either early with persistent (refractory) disease or recur late after a long disease-free interval (relapsing). Guideline recommendation in the 'refractory' setting is radical cystectomy, but there are situations when extirpative surgery is not feasible due to competing co-morbidity, a patient's desire for bladder preservation or reluctance to undergo surgery. In this review, we discuss the contemporary management of NMIBC in patients who have failed prior BCG and are not suitable for radical surgery and highlight the potential options available. These options can be categorised as immunotherapy, chemotherapy, device-assisted therapy and combination therapy. However, the current data are still inadequate to formulate definitive recommendations, and data from ongoing trials and maturing studies will give us an insight into whether there is a realistic efficacious second-line treatment for patients who fail intravesical BCG but are not candidates for definitive surgery.

  2. Lactococcus lactis carrying a DNA vaccine coding for the ESAT-6 antigen increases IL-17 cytokine secretion and boosts the BCG vaccine immune response.

    Science.gov (United States)

    Pereira, V B; da Cunha, V P; Preisser, T M; Souza, B M; Turk, M Z; De Castro, C P; Azevedo, M S P; Miyoshi, A

    2017-06-01

    A regimen utilizing Bacille Calmette-Guerin (BCG) and another vaccine system as a booster may represent a promising strategy for the development of an efficient tuberculosis vaccine for adults. In a previous work, we confirmed the ability of Lactococcus lactis fibronectin-binding protein A (FnBPA+) (pValac:ESAT-6), a live mucosal DNA vaccine, to produce a specific immune response in mice after oral immunization. In this study, we examined the immunogenicity of this strain as a booster for the BCG vaccine in mice. After immunization, cytokine and immunoglobulin profiles were measured. The BCG prime L. lactis FnBPA+ (pValac:ESAT-6) boost group was the most responsive group, with a significant increase in splenic pro-inflammatory cytokines IL-17, IFN-γ, IL-6 and TNF-α compared with the negative control. Based on the results obtained here, we demonstrated that L. lactis FnBPA+ (pValac:ESAT-6) was able to increase the BCG vaccine general immune response. This work is of great scientific and social importance because it represents the first step towards the development of a booster to the BCG vaccine using L. lactis as a DNA delivery system. © 2017 The Society for Applied Microbiology.

  3. BCG Re-vaccination of Adults with Latent Mycobacterium tuberculosis Infection Induces Long-lived BCG-Reactive Natural Killer Cell Responses1

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    Suliman, Sara; Geldenhuys, Hennie; Johnson, John L.; Hughes, Jane E.; Smit, Erica; Murphy, Melissa; Toefy, Asma; Lerumo, Lesedi; Hopley, Christiaan; Pienaar, Bernadette; Chheng, Phalkun; Nemes, Elisa; Hoft, Daniel F.; Hanekom, Willem A.; Boom, W. Henry

    2016-01-01

    One third of the global population is estimated to be latently infected with Mycobacterium tuberculosis (M.tb). We performed a phase 1 randomized, controlled trial of isoniazid preventive therapy (IPT) before re-vaccination with Bacille Calmette-Guerin (BCG) in healthy, tuberculin skin test positive (≥15mm induration), HIV-negative, South African adults. We hypothesised that pre-clearance of latent bacilli with IPT modulates BCG immunogenicity following re-vaccination. Frequencies and co-expression of IFNγ, TNFα, IL-2, IL-17, and/or IL-22 in CD4, and IFNγ-expressing CD8, γδ T, CD3+CD56+ NKT-like and NK cells in response to BCG were measured using whole blood intracellular cytokine staining and flow cytometry. We analyzed 72 participants who were BCG re-vaccinated after IPT (n=33) or without prior IPT (n=39). IPT had little effect on frequencies or cytokine co-expression patterns of M.tb- or BCG-specific responses. Re-vaccination transiently boosted BCG-specific Th1 cytokine-expressing CD4, CD8 and γδ T cells. Despite high frequencies of IFNγ-expressing BCG-reactive CD3+CD56+ NKT-like, CD3−CD56dim and CD3−CD56hi NK cells at baseline, BCG re-vaccination boosted these responses, which remained elevated up to one year after re-vaccination. Such BCG-reactive memory NK cells were induced by BCG vaccination in infants, while in vitro IFN-γ expression by NK cells upon BCG stimulation was dependent on IL-12 and IL-18. Our data suggest that isoniazid pre-clearance of M.tb bacilli has little effect on the magnitude, persistence or functional attributes of lymphocyte responses boosted by BCG re-vaccination. Our study highlights surprising durability of BCG-boosted memory NKT-like and NK cells expressing anti-mycobacterial effector molecules, which may be novel targets for TB vaccines. PMID:27412415

  4. Children with lymphadenitis associated with Bacillus Calmette-Guérin (BCG) vaccination do not experience more infections when compared with BCG-vaccinated children without lymphadenitis: a three years paired-cohort in Mexico.

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    Chacon-Cruz, Enrique; Arellano-Estrada, Jorge Luis; Lopatynsky-Reyes, Erika; Alvelais-Palacios, Jorge; Becka, Chandra

    2017-08-01

    Vaccination against tuberculosis with live-attenuated Bacillus Calmette-Guérin (BCG) is widely used even though its effectiveness is controversial. BCG-lymphadenitis (BCG-LA) is its most common complication. Some studies have proposed that BCG-LA can be associated with primary immunodeficiencies (PIs). This study's aim is to see whether patients who developed BCG-LA (named as 'LA') developed more infections than BCG-vaccinated children without BCG-LA (named as 'NON-LA'). From January 2009 to April 2014, 31 LA children were seen at the outpatient clinic of the General Hospital of Tijuana, Mexico. Among them, 22 (70.97%), 5 (16.13%) and 4 (12.9%) had axillary, supraclavicular, or both BCG-LA, respectively. No treatment was given and complications were not seen. Per LA subject, a NON-LA not >1 month of age difference and same gender was paired and followed for 3 years to look for ambulatory infections (AINFs), acute otitis media (AOM) and hospitalizations. Surveillance per patient was performed by phone monthly, and they were seen at the clinic every 4 months. All patients were HIV-negative and had no family history of PI. Statistical analyses used were relative risk (RR) with confidence intervals (CI), t test for independent variables and z test. In total 62 subjects were enrolled: 31 LA paired with 31 NON-LA. Between them, there were no differences in age, day care attendance and breastfeeding. There were no differences in the total number of AINF per patient (LA: 18.61 avg. ± 5.03 SD versus NON-LA: 18.19 avg. ± 4.17 SD, RR = 1.06, 95% CI = 0.33-0.66), AOM total episodes (LA: 30 versus NON-LA: 26, RR = 0.87, 95% CI = 0.31-0.68) and hospitalizations (LA: 5 versus NON-LA: 4, RR = 1, 95% CI = 0.25-0.74). This cohort strongly suggests that BCG-LA in healthy children is not associated with more episodes of AINF and hospitalizations, when paired and compared with children BCG-vaccinated without BCG-LA.

  5. Bacillus Calmette-Guérin (BCG) Treatment Failures with Non-Muscle Invasive Bladder Cancer: A Data-Driven Definition for BCG Unresponsive Disease.

    Science.gov (United States)

    Steinberg, Ryan L; Thomas, Lewis J; Mott, Sarah L; O'Donnell, Michael A

    2016-04-27

    Objective: To create the first data-driven definition for those unlikely to benefit from further BCG treatment. Materials and Methods: The database created for the Phase 2 BCG-Interferon- α 2B (IFN) study was queried and BCG failure patients were identified ( n  = 334). Full study protocols have previously been published. Separate models were constructed for analysis of patients with any CIS (pure or concomitant) and pure papillary disease. Variables considered included age, gender, stage, grade, tumor size and focality (for papillary only), number of prior BCG courses, and prior BCG failure interval. Results: Patients with recurrent CIS within 6 months of their most recent prior BCG course (HR 2.56, p  disease within 6 months (HR 1.82, p  = 0.02), ≥2 BCG failures (HR 1.54, p  = 0.03), and multifocal disease (HR 2.05, p  disease remained disease free in 38% of cases (24-51% 95% CI) at 2 years with low rates of progression. Conclusions: Patients who fail two courses of BCG with either persistent or recurrent multifocal papillary disease within 6 months or CIS within 12 months of their prior BCG should be considered BCG unresponsive. Recurrent T1 disease respond reasonably well to another course with low progression rates but further investigation is warranted.

  6. Bacillus Calmette-Guérin (BCG) vaccination patterns in the province of Québec, Canada, 1956-1974.

    Science.gov (United States)

    Rousseau, Marie-Claude; Conus, Florence; Kâ, Khady; El-Zein, Mariam; Parent, Marie-Élise; Menzies, Dick

    2017-08-24

    In the province of Québec, Canada, the Bacillus Calmette-Guérin (BCG) vaccine was offered to newborns and school-age children from the 1950s to mid-1970s in an organized tuberculosis prevention program. We aimed to describe the annual rates of skin test administration, proportion of skin tests that were positive, and rates of BCG vaccination from 1956 to 1974 according to age, sex, and administrative region. For rates, numerators were extracted from the Québec BCG Vaccination Registry whereas population denominators were obtained from the Canadian Census and governmental publications. Time trends were assessed with linear regression. A total of 2,755,336 skin tests and 2,531,366 BCG vaccinations were administered. Yearly rates of skin tests, routinely administered before vaccination among all except newborns, were highest among children aged 5-9 (9.3 per 100) and 10-14years (7.9 per 100). The proportion of positive skin tests varied greatly by age, ranging from 10.2% among children BCG vaccination. Our results confirm that the targeted groups, newborns and school-age children, were preferentially reached. Socioeconomic, demographic, and organizational factors may explain regional differences in immunization rates. Beyond presenting a historical context for this vaccination campaign, our findings are relevant to contemporary uses of the Québec BCG Vaccination Registry in epidemiological research. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. A booster vaccine expressing a latency-associated antigen augments BCG induced immunity and confers enhanced protection against tuberculosis.

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    Bappaditya Dey

    Full Text Available BACKGROUND: In spite of a consistent protection against tuberculosis (TB in children, Mycobacterium bovis Bacille Calmette-Guerin (BCG fails to provide adequate protection against the disease in adults as well as against reactivation of latent infections or exogenous reinfections. It has been speculated that failure to generate adequate memory T cell response, elicitation of inadequate immune response against latency-associated antigens and inability to impart long-term immunity against M. tuberculosis infections are some of the key factors responsible for the limited efficiency of BCG in controlling TB. METHODS/PRINCIPAL FINDINGS: In this study, we evaluated the ability of a DNA vaccine expressing α-crystallin--a key latency antigen of M. tuberculosis to boost the BCG induced immunity. 'BCG prime-DNA boost' regimen (B/D confers robust protection in guinea pigs along with a reduced pathology in comparison to BCG vaccination (1.37 log(10 and 1.96 log(10 fewer bacilli in lungs and spleen, respectively; p<0.01. In addition, B/D regimen also confers enhanced protection in mice. Further, we show that B/D immunization in mice results in a heightened frequency of PPD and antigen specific multi-functional CD4 T cells (3(+ simultaneously producing interferon (IFNγ, tumor necrosis factor (TNFα and interleukin (IL2. CONCLUSIONS/SIGNIFICANCE: These results clearly indicate the superiority of α-crystallin based B/D regimen over BCG. Our study, also demonstrates that protection against TB is predictable by an increased frequency of 3(+ Th1 cells with superior effector functions. We anticipate that this study would significantly contribute towards the development of superior booster vaccines for BCG vaccinated individuals. In addition, this regimen can also be expected to reduce the risk of developing active TB due to reactivation of latent infection.

  8. BCG immune activation reduces growth and angiogenesis in an in vitro model of head and neck squamous cell carcinoma.

    Science.gov (United States)

    Sánchez-Rodríguez, Carolina; Cruces, Keyliz Peraza; Riestra Ayora, Juan; Martín-Sanz, Eduardo; Sanz-Fernández, Ricardo

    2017-11-07

    Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent cancers worldwide and is associated with poor survival and significant treatment morbidity. The immune profile in patients with HNSCC is immunosuppressive and presents cytokine-mediated adaptive immune responses, triggered apoptosis of T cells, and alterations in antigen processing machinery. Bacille Calmette-Guerin (BCG) immunotherapy has been used successfully as a treatment for several types of cancer. In the present study, we sought to determine the antitumor effect of soluble mediators from peripheral blood mononuclear immune cells (PBMCs) activated with BCG vaccine in a three-dimensional coculture model of HNSCC growth using FaDu hypopharynx carcinoma squamous cells. BCG activation of PBMCs led to an increase in CD4+ and CD8+ lymphocyte subsets concomitant with an elevation in the levels of the antitumor cytokines IL-6, TNF-α and IFN-γ, and a EGFR in FaDu cells. In addition, coculture with BCG-activated PBMCs reduced FaDu proliferation and increased cytotoxicity and apoptosis in parallel with an increase in caspase-3 activity and p53 expression. Finally, conditioned medium from BCG-activated PBMCs reduced the levels of the angiogenic factors vascular endothelial growth factor and angiopoietin-2 produced by human aortic endothelial cells (HAECs), and inhibited their proliferation and differentiation into capillary-like structures. Taken together, these results demonstrate that BCG vaccination induces antitumor responses in an HNSCC in vitro model and suggest that the BCG vaccine could be an effective alternative therapy for the treatment of HNSCC. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Expression of sialyl-Tn sugar antigen in bladder cancer cells affects response toBacillus Calmette Guérin(BCG) and to oxidative damage.

    Science.gov (United States)

    Severino, Paulo F; Silva, Mariana; Carrascal, Mylene; Malagolini, Nadia; Chiricolo, Mariella; Venturi, Giulia; Astolfi, Annalisa; Catera, Mariangela; Videira, Paula A; Dall'Olio, Fabio

    2017-08-15

    The sialyl-Tn (sTn) antigen is an O -linked carbohydrate chain aberrantly expressed in bladder cancer (BC), whose biosynthesis is mainly controlled by the sialyltransferase ST6GALNAC1. Treatment with Bacillus Calmette-Guérin (BCG) is the most effective adjuvant immunotherapy for superficial BC but one third of the patients fail to respond. A poorly understood correlation between the expression of sTn and BC patient's response to BCG was previously observed. By analyzing tumor tissues, we showed that patients with high ST6GALNAC1 and IL-6 mRNA expression were BCG responders. To investigate the role of sTn in BC cell biology and BCG response, we established the cell lines MCR sTn and MCR Nc by retroviral transduction of the BC cell line MCR with the ST6GALNAC1 cDNA or with an empty vector, respectively. Compared with MCR Nc , BCG-stimulated MCR sTn secreted higher levels of IL-6 and IL-8 and their secretome induced a stronger IL-6, IL-1β, and TNFα secretion by macrophages, suggesting the induction of a stronger inflammatory response. Transcriptomic analysis of MCR Nc and MCR sTn revealed that ST6GALNAC1 /sTn expression modulates hundreds of genes towards a putative more malignant phenotype and down-regulates several genes maintaining genomic stability. Consistently, MCR sTn cells displayed higher H 2 O 2 sensitivity. In MCR sTn ,, BCG challenge induced an increased expression of several regulatory non coding RNA genes. These results indicate that the expression of ST6GALNAC1 /sTn improves the response to BCG therapy by inducing a stronger macrophage response and alters gene expression towards malignancy and genomic instability, increasing the sensitivity of BC cells to the oxidizing agents released by BCG.

  10. Bacillus Calmette-Guérin (BCG) vaccine: A global assessment of demand and supply balance.

    Science.gov (United States)

    Cernuschi, Tania; Malvolti, Stefano; Nickels, Emily; Friede, Martin

    2018-01-25

    Over the past decade, several countries across all regions, income groups and procurement methods have been unable to secure sufficient BCG vaccine supply. While the frequency of stock-outs has remained rather stable, duration increased in 2014-2015 due to manufacturing issues and attracted the attention of national, regional and global immunization stakeholders. This prompted an in-depth analysis of supply and demand dynamics aiming to characterize supply risks. This analysis is unique as it provides a global picture, where previous analyses have focused on a portion of the market procuring through UN entities. Through literature review, supplier interviews, appraisal of shortages, stock-outs and historical procurement data, and through demand forecasting, this analysis shows an important increase in global capacity in 2017: supply is sufficient to meet forecasted BCG vaccine demand and possibly buffer market shocks. Nevertheless, risks remain mainly due to supply concentration and limited investment in production process improvements, as well as inflexibility in demand. Identification of these market risks will allow implementation of risk-mitigating interventions in three areas: (1) enhancing information sharing between major global health actors, countries and suppliers, (2) identifying interests and incentives to expand product registration and investment in the BCG manufacturing process, and (3) working with countries for tighter vaccine management. Copyright © 2017. Published by Elsevier Ltd.

  11. Castration Induced Neuroendocrine Mediated Progression of Prostate Cancer

    Science.gov (United States)

    2008-09-01

    Short-Term Therapy with Bacillus Calmette-Guerin (BCG) in Patients with Non-Muscle-Invasive Bladder Cancer. Eur Urol. epub. 10. 2007 Cambio A.J...Leonhardt M, Janssen M, Konrad L, Bjartell A, Abrahamsson PA. Neurogenic origin of human prostate endocrine cells. Urology 1999; 53: 1041–1048. 13 Luttrell...membrane (Corning, Inc.). A549 cells were then infected with a mix of DMEM, virus-containing supernatant (1:1), and polybrene (4 Ag/mL). After

  12. Observational study to estimate the changes in the effectiveness of bacillus Calmette-Guérin (BCG) vaccination with time since vaccination for preventing tuberculosis in the UK.

    Science.gov (United States)

    Mangtani, Punam; Nguipdop-Djomo, Patrick; Keogh, Ruth H; Trinder, Lucy; Smith, Peter G; Fine, Paul Em; Sterne, Jonathan; Abubakar, Ibrahim; Vynnycky, Emilia; Watson, John; Elliman, David; Lipman, Marc; Rodrigues, Laura C

    2017-07-01

    Until recently, evidence that protection from the bacillus Calmette-Guérin (BCG) vaccination lasted beyond 10 years was limited. In the past few years, studies in Brazil and the USA (in Native Americans) have suggested that protection from BCG vaccination against tuberculosis (TB) in childhood can last for several decades. The UK's universal school-age BCG vaccination programme was stopped in 2005 and the programme of selective vaccination of high-risk (usually ethnic minority) infants was enhanced. To assess the duration of protection of infant and school-age BCG vaccination against TB in the UK. Two case-control studies of the duration of protection of BCG vaccination were conducted, the first on minority ethnic groups who were eligible for infant BCG vaccination 0-19 years earlier and the second on white subjects eligible for school-age BCG vaccination 10-29 years earlier. TB cases were selected from notifications to the UK national Enhanced Tuberculosis Surveillance system from 2003 to 2012. Population-based control subjects, frequency matched for age, were recruited. BCG vaccination status was established from BCG records, scar reading and BCG history. Information on potential confounders was collected using computer-assisted interviews. Vaccine effectiveness was estimated as a function of time since vaccination, using a case-cohort analysis based on Cox regression. In the infant BCG study, vaccination status was determined using vaccination records as recall was poor and concordance between records and scar reading was limited. A protective effect was seen up to 10 years following infant vaccination [BCG vaccination were adjusted for confounders, including birth cohort and ethnicity. For school-aged BCG vaccination, VE was 51% (95% CI 21% to 69%) 10-15 years after vaccination and 57% (95% CI 33% to 72%) 15-20 years after vaccination, beyond which time protection appeared to wane. Ascertainment of vaccination status was based on self-reported history and scar

  13. Systemic BCG-osis following intravesical BCG instillation for bladder carcinoma.

    Science.gov (United States)

    Liaw, Frank; Tan, Yan Yu; Hendry, David

    2017-10-01

    Intravesical instillation of Bacillus Calmette-Guérin (BCG) has been shown to be an effective form of immunotherapy for bladder cancer. This case report describes a patient who develops systemic BCG-osis following intravesical BCG instillation and demonstrates the importance of being aware of more severe complications associated with BCG immunotherapy.

  14. Effectiveness of transurethral resection under the control of photodynamic diagnosis and intravesical instillation of bacillus Calmette–Guérin in case of poorly differentiated non-muscle-invasive bladder cancer

    Directory of Open Access Journals (Sweden)

    A. I. Rolevich

    2016-01-01

    Full Text Available Background. High-grade non-muscle-invasive bladder cancer (NMIBC is characterized by a high rate of recurrence, progression, and mortality associated with this disease. Organ-preserving treatment by transurethral resection and immunotherapy with bacillus Calmette-Guerin (BCG is an initial approach to therapy in these patients. However, the efficacy of such therapy is limited. This justifies the use of other methods of treatment, such as TUR under the control of photodynamic diagnosis (PDD. Aim of this study was to evaluate the effectiveness of therapeutic interventions in patients with high-grade NMIBC.Materials and methods. We have retrospectively analyzed results of follow-up of patients with primary or recurrent high-grade transitional cell NMIBC, treatment by TUR in conjunction with BCG or without it N.N. Alexandrov National Cancer Centre in the period from 2004 to 2013. In total, the study included 113 patients (27 women and 86 men, in the median age of 72 years. We have evaluated 5-year recurrence- and progression-free survival, analyzed an influence of prognostic factors and methods of treatment on the risk of recurrence and progression with Cox model and Kaplan–Meier method.Results. With a median of follow up of 59 (12–116 months the rates of 5-year recurrence- and progression-free survival were respectively 42.5 and 71.6 %. Statistically significant association with the risk of recurrence was observed in multivariate Cox regression analysis for recurrent tumors (hazard ratio (HR 2.73; 95 % confidence interval (CI 1.61–4.62 and immunotherapy with BCG (HR 0.56; 95 % CI 0.31–0.99. BCG significantly increased recurrence-free survival in patients with both primary tumors, and with recurrent ones. Significant factors in the multivariate analysis with regard to the risk of progression were suspicion for muscle-invasive tumors according to the cystoscopic picture (HR 3.36; 95 % CI 1.09–10.4, abnormal tumor-free bladder mucosa

  15. Interruption of persistent exposure to leprosy combined or not with recent BCG vaccination enhances the response to Mycobacterium leprae specific antigens.

    Science.gov (United States)

    de Carvalho, Fernanda Marques; Rodrigues, Luciana Silva; Duppre, Nádia Cristina; Alvim, Iris Maria Peixoto; Ribeiro-Alves, Marcelo; Pinheiro, Roberta Olmo; Sarno, Euzenir Nunes; Pessolani, Maria Cristina Vidal; Pereira, Geraldo Moura Batista

    2017-05-01

    Household contacts of multibacillary leprosy patients (HCMB) constitute the group of individuals at the highest risk of developing leprosy. Early diagnosis and treatment of their index cases combined with Bacille Calmette-Guerin (BCG) immunization remain important strategies adopted in Brazil to prevent HCMB from evolving into active disease. In the present study, we assessed the impact of these measures on the immune response to Mycobacterium leprae in HCMB. Peripheral blood mononuclear cells (PBMC) from HCMB (n = 16) were obtained at the beginning of leprosy index case treatment (T0). At this time point, contacts were vaccinated (n = 13) or not (n = 3) in accordance with their infancy history of BCG vaccination and PBMCs were recollected at least 6 months later (T1). As expected, a significant increase in memory CD4 and CD8 T cell frequencies responsive to M. leprae whole-cell sonicate was observed in most contacts. Of note, higher frequencies of CD4+ T cells that recognize M. leprae specific epitopes were also detected. Moreover, increased production of the inflammatory mediators IL1-β, IL-6, IL-17, TNF, IFN-γ, MIP1-β, and MCP-1 was found at T1. Interestingly, the increment in these parameters was observed even in those contacts that were not BCG vaccinated at T0. This result reinforces the hypothesis that the continuous exposure of HCMB to live M. leprae down regulates the specific cellular immune response against the pathogen. Moreover, our data suggest that BCG vaccination of HCMB induces activation of T cell clones, likely through "trained immunity", that recognize M. leprae specific antigens not shared with BCG as an additional protective mechanism besides the expected boost in cell-mediated immunity by BCG homologues of M. leprae antigens.

  16. Extraction and localization by electron microscopy of an immunosuppressor fraction from Mycobacterium bovis Bacillus Calmette-Guérin (BCG).

    Science.gov (United States)

    Hiu, I J

    1990-03-01

    BCG has been used all over the world to immunize against tuberculosis. Nevertheless in certain areas (South India) BCG vaccines failed to show any protective efficacy. Furthermore immunosuppressive cell populations have been reported in experimental mycobacterial infection in mice. The present work reports the localization and isolation of an immunosuppressor fraction from BCG. This lipid fraction called WDB inhibited the skin reactivity of delayed-type hypersensitivity (DTH) to the test antigen CEWA (crystalline egg white albumin) in guinea pigs and depressed the production of immune antibody to SRBC (sheep red blood cells) in mice. WDB is a glycolipid with an approximate mol.wt. of 62,000. By electron microscopy, WDB was located among the BCG extracellular metabolic products (ECMP) surrounding the BCG cell wall.

  17. Gluteal abscess: An unusual complication of Bacille Calmette-Guérin

    Directory of Open Access Journals (Sweden)

    Hakan Buyukoglan

    2011-01-01

    Full Text Available Bacille Calmette-Guerin (BCG has been used extensively as a vaccine against human tuberculosis. Herein, we describe gluteal tuberculosis abscess due to inadvertently injected BCG a patient with bladder cancer.

  18. Identification of Early Response Genes in Human Peripheral Leukocytes Infected with Orientia tsutsugamushi: The Emergent of a Unique Gene Expression Profile for Diagnosis of O. tsutsugamush Infection

    Science.gov (United States)

    2010-01-01

    Orientia tsutaugamushi, an obligate intracellular bacterium, is the etiologic agent of scrub typhus, which is transmitted by the bite of larvae of...gonorrhoeae co-infection Human papillomavirus Hepatitus C Syncytial virus bacillus Calmette-Guerin Pseudomanas aeruginosa rsmA mutant...Hepatitus C Syncytial virus bacillus Calmette-Guerin Pseudomanas aeruginosa rsmA mutant Neisseria meningitidis Malaria Aspergillus fumigatus Measles

  19. Adverse reactions to the Bacillus Calmette-Guérin (BCG) vaccine in new-born infants-an evaluation of the Danish strain 1331 SSI in a randomized clinical trial.

    Science.gov (United States)

    Nissen, Thomas Nørrelykke; Birk, Nina Marie; Kjærgaard, Jesper; Thøstesen, Lisbeth Marianne; Pihl, Gitte Thybo; Hoffmann, Thomas; Jeppesen, Dorthe Lisbeth; Kofoed, Poul-Erik; Greisen, Gorm; Benn, Christine Stabell; Aaby, Peter; Pryds, Ole; Stensballe, Lone Graff

    2016-05-11

    To evaluate adverse reactions of the Bacillus Calmette-Guérin (BCG) Statens Serum Institut (SSI) (Danish strain 1331) used as intervention in a randomized clinical trial. A randomized clinical multicenter trial, The Danish Calmette Study, randomizing newborns to BCG or no intervention. Follow-up until 13 months of age. Pediatric and maternity wards at three Danish university hospitals. All women planning to give birth at the three study sites (n=16,521) during the recruitment period were invited to participate in the study. Four thousand one hundred and eighty four families consented to participate and 4262 children, gestational age 32 weeks and above, were randomized: 2129 to BCG vaccine and 2133 to no vaccine. None of the participants withdrew because of adverse reactions. Trial-registered adverse reactions after BCG vaccination at birth. Follow-up at 3 and 13 months by telephone interviews and clinical examinations. Among the 2118 BCG-vaccinated children we registered no cases of severe unexpected adverse reaction related to BCG vaccination and no cases of disseminated BCG disease. Two cases of regional lymphadenitis were hospitalized and thus classified as serious adverse reactions related to BCG. The most severe adverse reactions were 10 cases of suppurative lymphadenitis. This was nearly a fivefold increase compared to what was expected based on the summary of product characteristics of the vaccine. All cases were treated conservatively and recovered. Six of 10 (60%) families of children experiencing suppurative lymphadenitis compared to 117/2071 (6%) of those with no lymphadenitis indicated that the vaccine had more adverse effects than expected (p-value <0.001). BCG vaccination was associated with only mild morbidity and no mortality. A higher incidence of suppurative lymphadenitis than expected was observed. All children were treated conservatively without sequelae or complications. Trial registration number NCT01694108 at www

  20. Immunization with Bacillus Calmette-Guérin (BCG) alleviates neuroinflammation and cognitive deficits in APP/PS1 mice via the recruitment of inflammation-resolving monocytes to the brain.

    Science.gov (United States)

    Zuo, Zejie; Qi, Fangfang; Yang, Junhua; Wang, Xiao; Wu, Yingying; Wen, Yaru; Yuan, Qunfang; Zou, Juntao; Guo, Kaihua; Yao, Zhi Bin

    2017-05-01

    The immune system plays a crucial role in the progression of Alzheimer's disease (AD). Recently, immune-dependent cascade induced by systemic immune activation has been verified to play a beneficial role in AD mouse models. Here, we tested whether Bacillus Calmette-Guérin (BCG) immunization alters AD pathology and cognitive dysfunction in APP/PS1 AD mouse model, and with 4Aβ1-15 vaccination as positive control. It was found that BCG treatment reversed the cognitive decline to the extent observed in 4Aβ1-15 group, but did not reduce the β-amyloid (Aβ) burden in the brain. Then, we demonstrated the enhanced recruitment of inflammation-resolving monocytes across the choroid plexus and perivascular spaces to cerebral sites of plaque pathology in APP/PS1 mice immunized with BCG. Furthermore, elevated splenocyte Foxp3 + regulatory T cell levels in the control APP/PS1 mice were down-regulated back to the wild-type (WT) levels by BCG treatment but not 4Aβ1-15 vaccination. In addition, BCG treatment induced the production of more circulating interferon (IFN)-γ than the controls and 4Aβ1-15 vaccination. Though the similar reductions in brain levels of pro-inflammatory cytokines were observed in the BCG and 4Aβ1-15 groups compared to the controls, only BCG had the great effect in upregulating cerebral anti-inflammatory cytokine levels as well as elevating the expression of neurotrophic factors in the brain of APP/PS1 mice. Thus, it is suggested that BCG exerts a beneficial immunomodulatory effect in APP/PS1 mice through mitigation of systemic immune suppression, induction of IFN-γ response and alleviation of the neuroinflammatory response. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Therapeutic response of untreatable hepatocellular carcinoma after application of the immune modulators IL-2, BCG and melatonin.

    Science.gov (United States)

    Tomov, Bojidar; Popov, Dimitar; Tomova, Radosveta; Vladov, Nicola; Den Otter, Willem; Krastev, Zachary

    2013-10-01

    Application of immunotherapy to a patient with untreatable hepatocellular carcinoma. The patient had a tumor of 60 mm in the liver. The pathological anatomic diagnosis was adenoma. However, after surgery of the tumor seven new lesions arose, showing that the original tumor had been a hepatocellular carcinoma. In addition, when hepatocellular adenomas grow to a size of more than 6-8 cm, they are considered cancerous and thus become a risk for hepatocellular carcinoma. The patient was treated with interleukin-2, Bacillus Calmette Guerin, and melatonin. During treatment, the alpha-fetoprotein levels in blood fell from 5,000 IU/ml to zero, at which level it remained during the follow-up period of two years. No tumor was detectable on MRI and CT. Six years after the diagnosis of untreatable hepatocellular carcinoma, the patient remains in a good condition. In this case, combined immunomodulating therapy was effective. For patients with metastasized tumors of the liver who are not suitable for conventional therapy, immunomodulation may delay tumor progression, induce tumor regression, or even be curative in some patients. Immunotherapeutic approaches combined with conventional methods for hepatocellular carcinoma treatment may be able to improve therapeutic efficacy.

  2. Increased TNF-alpha/IFN-gamma/IL-2 and decreased TNF-alpha/IFN-gamma production by central memory T cells are associated with protective responses against bovine tuberculosis following BCG vaccination

    Directory of Open Access Journals (Sweden)

    Mayara Fernanda Maggioli

    2016-10-01

    Full Text Available Central memory T cells (Tcm and polyfunctional CD4 T cell responses contribute to vaccine-elicited protection with both human and bovine tuberculosis (TB; however, their combined role in protective immunity to TB is unclear. To address this question, we evaluated polyfunctional cytokine responses by CD4 T cell effector / memory populations from bacille Calmette Guerin (BCG vaccinated and non-vaccinated calves prior to and after aerosol challenge with virulent Mycobacterium bovis. Polyfunctional cytokine expression patterns in the response by Tcm, effector memory, and effector T cell subsets were similar between BCG-vaccinated and M. bovis-infected calves; only differing in magnitude (i.e., infected > vaccinated. BCG vaccination, however, did alter the kinetics of the ensuing response to virulent M. bovis infection. Early after challenge (three weeks post-infection, non-vaccinates had greater antigen-specific IFN-γ/TNF-α and lesser IFN-γ/TNF-α/IL-2 responses by Tcm cells than did vaccinated animals. Importantly, these differences were also associated with mycobacterial burden upon necropsy. Polyfunctional responses to ESAT-6:CFP10 (antigens not synthesized by BCG strains were detected in memory subsets, as well as in effector cells, as early as three weeks after challenge. These findings suggest that cell fate divergence may occur early after antigen priming in the response to bovine TB and that memory and effector T cells may expand concurrently during the initial phase of the immune response. In summary, robust IFN-γ/TNF-α response by Tcm cells is associated with greater mycobacterial burden while IFN-γ/TNF-α/IL-2 response by Tcm cells are indicative of a protective response to bovine TB.

  3. A case of infectious endocarditis due to BCG

    Directory of Open Access Journals (Sweden)

    Alice Fournier

    2015-06-01

    Full Text Available The occurrence of bacillus Calmette–Guérin (BCG disease following instillation for bladder cancer is commonly documented. The intravesical administration of BCG is generally safe, but may present severe complications. A fatal case of native aortic valve infectious endocarditis with septicemia due to BCG in a patient treated with intravesical instillation is reported herein.

  4. Clinical manifestations of pulmonary and extra-pulmonary tuberculosis

    Directory of Open Access Journals (Sweden)

    Robert L. Serafino Wani

    2013-08-01

    Full Text Available The clinical manifestations of tuberculosis are dependent on a number of factors: age, immune status, co-existing diseases, immunization status to the bacillus Calmette-Guerin (BCG; virulence of the infecting organism and host-microbe interaction. Before the advent of the HIV epidemic, approximately 85% of reported tuberculosis cases were pulmonary only, with the remaining 15% being extra-pulmonary or both pulmonary and extra-pulmonary sites [1]. One large retrospective study [2] of tuberculosis in patients with advanced HIV infection reported: Pulmonary involvement alone 38%, Extrapulmonary sites alone 30%, Both pulmonary and nonpulmonary 32%

  5. Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study.

    Directory of Open Access Journals (Sweden)

    Nádia C Düppre

    Full Text Available BACKGROUND: Contacts of leprosy patients are at increased risk of developing leprosy and need to be targeted for early diagnosis. Seropositivity to the phenolic glycolipid I (PGL-I antigen of Mycobacterium leprae has been used to identify contacts who have an increased risk of developing leprosy. In the present study, we studied the effect of seropositivity in patient contacts, on the risk of developing leprosy, stratified by Bacille Calmette Guerin (BCG vaccination after index case diagnosis. METHODOLOGY/PRINCIPAL FINDINGS: Leprosy contacts were examined as part of the surveillance programme of the Oswaldo Cruz Institute Leprosy Outpatient Clinic in Rio de Janeiro. Demographic, social, epidemiological and clinical data were collected. The presence of IgM antibodies to PGL-I in sera and BCG vaccination status at the time of index case diagnosis were evaluated in 2,135 contacts. During follow-up, 60 (2.8%; 60/2,135 leprosy cases were diagnosed: 41 among the 1,793 PGL-I-negative contacts and 19 among the 342 PGL-I-positive contacts. Among PGL-I-positive contacts, BCG vaccination after index case diagnosis increased the adjusted rate of developing clinical manifestations of leprosy (Adjusted Rate Ratio (aRR = 4.1; 95% CI: 1.8-8.2 compared with the PGL-I-positive unvaccinated contacts (aRR = 3.2; 95% CI: 1.2-8.1. The incidence density was highest during the first year of follow-up for the PGL-I-positive vaccinated contacts. However, all of those contacts developed PB leprosy, whereas most MB cases (4/6 occurred in PGL-I-positive unvaccinated contacts. CONCLUSION: Contact examination combined with PGL-I testing and BCG vaccination remain important strategies for leprosy control. The finding that rates of leprosy cases were highest among seropositive contacts justifies targeting this specific group for close monitoring. Furthermore, it is recommended that PGL-I-positive contacts and contacts with a high familial bacteriological index

  6. Methylation status as a predictor of intravesical Bacillus Calmette-Guérin (BCG) immunotherapy response of high grade non-muscle invasive bladder tumor.

    Science.gov (United States)

    Husek, Petr; Pacovsky, Jaroslav; Chmelarova, Marcela; Podhola, Miroslav; Brodak, Milos

    2017-06-01

    Genetic and epigenetic alterations play an important role in urothelial cancer pathogenesis. Deeper understanding of these processes could help us achieve better diagnosis and management of this life-threatening disease. The aim of this research was to evaluate the methylation status of selected tumor suppressor genes for predicting BCG response in patients with high grade non-muscle-invasive bladder tumor (NMIBC). We retrospectively evaluated 82 patients with high grade non-muscle-invasive bladder tumor (stage Ta, T1, CIS) who had undergone BCG instillation therapy. We compared epigenetic methylation status in BCG-responsive and BCG-failure groups. We used the MS-MLPA (Methylation-Specific Multiplex Ligation-Dependent Probe Amplification probe sets ME001 and ME004. The control group was 13 specimens of normal urotel (bladder tissue)). Newly identified methylations in high grade NMIBC were found in MUS81a, NTRK1 and PCCA. The methylation status of CDKN2B (P=0.00312 ** ) and MUS81a (P=0.0191 * ) is associated with clinical outcomes of BCG instillation therapy response. CDKN2B and MUS81a unmethylation was found in BCG failure patients. The results show that the methylation status of selected tumor suppressor genes (TSGs) has the potential for predicting BCG response in patients with NMIBC high grade tumors. Tumor suppressor genes such as CDKN2b, MUS81a, PFM-1, MSH6 and THBS1 are very promising for future research.

  7. Bladder Cancer Immunotherapy: BCG and Beyond

    Directory of Open Access Journals (Sweden)

    Eric J. Askeland

    2012-01-01

    Full Text Available Mycobacterium bovis bacillus Calmette-Guérin (BCG has become the predominant conservative treatment for nonmuscle invasive bladder cancer. Its mechanism of action continues to be defined but has been shown to involve a T helper type 1 (Th1 immunomodulatory response. While BCG treatment is the current standard of care, a significant proportion of patients fails or do not tolerate treatment. Therefore, many efforts have been made to identify other intravesical and immunomodulating therapeutics to use alone or in conjunction with BCG. This paper reviews the progress of basic science and clinical experience with several immunotherapeutic agents including IFN-α, IL-2, IL-12, and IL-10.

  8. Deep sequencing analysis of the heterogeneity of seed and commercial lots of the bacillus Calmette-Guérin (BCG) tuberculosis vaccine substrain Tokyo-172

    Science.gov (United States)

    Wada, Takayuki; Maruyama, Fumito; Iwamoto, Tomotada; Maeda, Shinji; Yamamoto, Taro; Nakagawa, Ichiro; Yamamoto, Saburo; Ohara, Naoya

    2015-01-01

    BCG, only vaccine available to prevent tuberculosis, was established in the early 20th century by prolonged passaging of a virulent clinical strain of Mycobacterium bovis. BCG Tokyo-172, originally distributed within Japan in 1924, is one of the currently used reference substrains for the vaccine. Recently, this substrain was reported to contain two spontaneously arising, heterogeneous subpopulations (Types I and II). The proportions of the subpopulations changed over time in both distributed seed lots and commercial lots. To maintain the homogeneity of live vaccines, such variations and subpopulational mutations in lots should be restrained and monitored. We incorporated deep sequencing techniques to validate such heterogeneity in lots of the BCG Tokyo-172 substrain without cloning. By bioinformatics analysis, we not only detected the two subpopulations but also detected two intrinsic variations within these populations. The intrinsic variants could be isolated from respective lots as colonies cultured on plate media, suggesting analyses incorporating deep sequencing techniques are powerful, valid tools to detect mutations in live bacterial vaccine lots. Our data showed that spontaneous mutations in BCG vaccines could be easily monitored by deep sequencing without direct isolation of variants, revealing the complex heterogeneity of BCG Tokyo-172 and its daughter lots currently in use. PMID:26635118

  9. Infection of an axillo-bifemoral bypass graft following intravesical bacillus Calmette–Guerin (BCG immunotherapy for urothelial cancer due to Mycobacterium bovis and Staphylococcus aureus

    Directory of Open Access Journals (Sweden)

    Daniel C. DeSimone

    2016-12-01

    Full Text Available We report a case of occult Mycobacterium bovis left axillary-bifemoral bypass graft infection, with superimposed acute methicillin-susceptible Staphylococcus aureus (MSSA infection in an 82 year old male following intravesicular bacillus Calmette–Guerin (BCG for adjuvant therapy of urothelial cancer. The patient underwent partial removal of the bypass graft and treated with antimycobacterial therapy—rifampin and isoniazid for 9 months, and intravenous cefazolin followed by oral cephalexin for chronic suppressive therapy for MSSA. This presentation highlights the need to consider indolent infection masquerading as mechanical erosion, even when an alternate infection is present. Keywords: Mycobacterium bovis, Bacille Calmette–Guerin, Vascular graft infection, Urothelial cancer, Staphylococcus aureus

  10. Current clinical practice gaps in the treatment of intermediate- and high-risk non-muscleinvasive bladder cancer (NMIBC) with emphasis on the use of bacillus Calmette- Guérin (BCG): results of an international individual patient data survey (IPDS)

    Science.gov (United States)

    Witjes, J Alfred; Palou, Joan; Soloway, Mark; Lamm, Donald; Kamat, Ashish M; Brausi, Maurizio; Persad, Raj; Buckley, Roger; Colombel, Marc; Böhle, Andreas

    2013-01-01

    Objectives To examine the management of intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC), particularly with regard to the use of bacillus Calmette-Guérin (BCG) therapy, in North America and Europe. To compare NMIBC management practices to European Association of Urology (EAU) and American Urological Association (AUA) guideline recommendations for the management of intermediate- and high-risk NMIBC. Patients and Methods In all, 102 urologists from Europe and North America participated in this retrospective on-line chart review, which was conducted between 1 April 2011 and 30 April 2012. Participants selected the charts of the first 10 intermediate- (defined as multiple or recurrent low-grade tumours) or high-risk (defined as any T1 and/or high-grade/G3 tumours and/or carcinoma in situ) patients who underwent transurethral resection of bladder tumour in 2009. Physicians retrospectively reviewed the charts and completed an on-line survey consisting of questions related to diagnosis, planned treatment, treatment status and follow-up. In all, 971 patients (197 intermediate-risk; 774 high-risk) were included in the analysis; frequency counts and associated percentages were used to analyse treatment variables. Results In all, 47% of intermediate-risk patients received EAU or AUA guideline-recommended intravesical therapy: intravesical chemotherapy, BCG induction therapy or BCG induction plus maintenance. Of the high-risk patients, 50% received maintenance BCG as recommended by the EAU and the AUA; although not recommended for high-risk NMIBC, 12.5% received intravesical chemotherapy. Of patients prescribed maintenance BCG, 93% were scheduled for at least 1 year of therapy. Notably, only 15% discontinued BCG maintenance and, of these discontinuations, 65% were due to reasons unrelated to BCG-associated adverse events. Conclusions There is significant non-adherence to EAU and AUA guideline recommendations for BCG use in intermediate- and high

  11. Immunisation of colorectal cancer patients with autologous tumour cells

    DEFF Research Database (Denmark)

    Diederichsen, Axel Cosmus Pyndt; Stenholm, A C; Kronborg, O

    1998-01-01

    . There was an inverse relation between survival and HLA class II expression. This highlights an essential problem, in the absence of CD80 expression the expression of HLA class II may induce anergy. In future attempts to develop improved vaccines this problem should be addressed.......Patients with colorectal cancer were entered into a clinical phase I trial of immunotherapy with an autologous tumour cell/bacillus Calmette-Guerin (BCG) vaccine. We attempted to describe the possible effects and side effects of the immunisation, and further to investigate whether expression...... of immune-response-related surface molecules on the tumour cells in the vaccine correlated with survival. The first and second vaccine comprised of 107 irradiated tumour cells mixed with BCG, the third of irradiated tumour cells only. Thirty-nine patients were considered, but only 6 patients fulfilled...

  12. Foreign body granuloma caused by monosodium glutamate after BCG vaccination.

    Science.gov (United States)

    Chiu, Yao-Kun; Huang, Chao-Cheng; Jeng, Jingyueh; Shiea, Jentaie; Chen, Wei-Jen

    2006-08-01

    We describe a 7-month-old male infant with a foreign body granuloma caused by monosodium glutamate (MSG) after a Bacille Calmette-Guérin (BCG) immunization. A ridged, erythematous, indurated plaque developed over a BCG injection site on his left upper arm 1 month after the first BCG immunization. Biopsy showed multiple noncaseating foreign body granulomas without detectable mycobacteria by both Ziehl-Neelsen stain and polymerase chain reaction assay. Birefringent crystals were identified in the foreign body giant cells with polarized light microscopy. The crystals were further determined to be glutamic acid by the method of fast atom bombardment. Hence, MSG, the only composite of BCG vaccine except the bacillus, was believed to be responsible for the granulomatous foreign body reaction. On review of the literature, we could find no previous report of an adverse reaction of BCG immunization attributable to MSG (glutamic acid).

  13. Post-Bacillus Calmette-Gue´ rin lymphadenitis in Egyptian children ...

    African Journals Online (AJOL)

    Thus, we were dealing with a multidrug- resistant strain of the BCG vaccine when compared with other strains that were multidrug sensitive such as BCG-. Bulgaria (SL 222 Sofia), BCG-Connaught, BCG-Denmark. Table 5 The course of Bacillus Calmette-Guérin lymphadenitis in the studied groups during 9 months. N (%).

  14. Effectiveness of BCG vaccination to aged mice

    Directory of Open Access Journals (Sweden)

    Ito Tsukasa

    2010-09-01

    Full Text Available Abstract Background The tuberculosis (TB still increases in the number of new cases, which is estimated to approach 10 million in 2010. The number of aged people has been growing all over the world. Ageing is one of risk factors in tuberculosis because of decreased immune responses in aged people. Mycobacterium bovis Bacillus Calmette Guérin (BCG is a sole vaccine currently used for TB, however, the efficacy of BCG in adults is still a matter of debate. Emerging the multidrug resistant Mycobacterium tuberculosis (MDR-TB make us to see the importance of vaccination against TB in new light. In this study, we evaluated the efficacy of BCG vaccination in aged mice. Results The Th1 responses, interferon-γ production and interleukin 2, in BCG inoculated aged mice (24-month-old were comparable to those of young mice (4- to 6-week-old. The protection activity of BCG in aged mice against Mycobacterium tuberculosis H37Rv was also the same as young mice. Conclusion These findings suggest that vaccination in aged generation is still effective for protection against tuberculosis.

  15. Tuberculosis case finding for vaccine trials in young children in high-incidence settings: a randomised trial

    NARCIS (Netherlands)

    Moyo, S.; Verver, S.; Hawkridge, A.; Geiter, L.; Hatherill, M.; Workman, L.; Ontong, C.; Msemburi, W.; Tameris, M.; Geldenhuys, H.; Mulenga, H.; Snowden, M. A.; Hanekom, W. A.; Hussey, G.; Mahomed, H.

    2012-01-01

    SETTING: A high tuberculosis (TB) burden rural area in South Africa. OBJECTIVE: To compare TB case yield and disease profile among bacille Calmette-Guerin (BCG) vaccinated children using two case-finding strategies from birth until 2 years of age. DESIGN: BCG-vaccinated infants were enrolled within

  16. Successful Handling of Disseminated BCG Disease in a Child with Severe Combined Immunodeficiency

    Directory of Open Access Journals (Sweden)

    Sílvia Bacalhau

    2011-01-01

    Full Text Available In high-burden countries, Mycobacterium bovis Bacillus Calmette-Guérin (BCG vaccine is administered in newborn to prevent severe Mycobacterium tuberculosis infection. Because life-threatening disseminated BCG disease may occur in children with primary immunodeficiency, vaccination strategy against tuberculosis should be redefined in non-high-burden countries. We report the case of a patient with X-linked severe combined immunodeficiency (SCID who developed disseminated BCG disease, highlighting the specific strategies adopted.

  17. Successful Handling of Disseminated BCG Disease in a Child with Severe Combined Immunodeficiency

    OpenAIRE

    Bacalhau, S; Freitas, C; Valente, R; Barata, D; Neves, C; Schäfer, K; Lubatschofski, A; Schulz, A; Farela Neves, J

    2011-01-01

    In high-burden countries, Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccine is administered in newborn to prevent severe Mycobacterium tuberculosis infection. Because life-threatening disseminated BCG disease may occur in children with primary immunodeficiency, vaccination strategy against tuberculosis should be redefined in non-high-burden countries. We report the case of a patient with X-linked severe combined immunodeficiency (SCID) who developed disseminated BCG disease, highligh...

  18. Immunotherapy of murine bladder cancer by irradiated tumor vaccine

    Energy Technology Data Exchange (ETDEWEB)

    Lamm, D.L.; Riggs, D.R.; DeHaven, J.I.; Bryner, R.W. (West Virginia Univ. School of Medicine, Morgantown (USA))

    1991-01-01

    This investigation explored the efficacy of irradiated autologous mouse bladder tumor (Ir-MBT2) as an active specific immunotherapeutic agent and as adjuvant therapy with Bacillus Calmette-Guerin (BCG) against a subcutaneously transplanted murine bladder tumor. Tumor incidence was significantly reduced in groups receiving BCG (27%, p less than 0.005) or Ir-MBT2 with BCG (53%, p less than 0.025), compared to control (93%). Survival was significantly improved in groups treated with BCG (100%, p less than 0.005), 10(5) Ir-MBT2 with BCG (53%, p less than 0.01), or 10(7) Ir-MBT2 with BCG (47%, p less than 0.025) compared with control (13%). Surprisingly, Ir-MBT2 consistently reduced the efficacy of BCG alone. Ir-MBT2 alone (10(7)) appeared to enhance tumor growth. Autologous irradiated bladder tumor vaccine, alone or in combination with BCG, displayed no immunotherapeutic advantage. The use of irradiated tumor cell vaccine for bladder cancer therapy may reduce the results achievable with BCG alone.

  19. Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children

    DEFF Research Database (Denmark)

    Aaby, Peter; Ravn, Henrik; Roth, Adam Anders Edvin

    2012-01-01

    Studies from low-income countries have suggested that diphtheria-tetanus-pertussis (DTP) vaccine provided after Bacille Calmette-Guerin (BCG) vaccination may have a negative effect on female survival. The authors examined the effect of DTP in a cohort of low birthweight (LBW) infants.......Studies from low-income countries have suggested that diphtheria-tetanus-pertussis (DTP) vaccine provided after Bacille Calmette-Guerin (BCG) vaccination may have a negative effect on female survival. The authors examined the effect of DTP in a cohort of low birthweight (LBW) infants....

  20. Dendritic Cell Activity Driven by Recombinant Mycobacterium bovis BCG Producing Human IL-18, in Healthy BCG Vaccinated Adults

    Directory of Open Access Journals (Sweden)

    Piotr Szpakowski

    2015-01-01

    Full Text Available Tuberculosis remains an enormous global burden, despite wide vaccination coverage with the Bacillus Calmette-Guérin (BCG, the only vaccine available against this disease, indicating that BCG-driven immunity is insufficient to protect the human population against tuberculosis. In this study we constructed recombinant BCG producing human IL-18 (rBCGhIL-18 and investigated whether human IL-18 produced by rBCGhIL-18 modulates DC functions and enhances Th1 responses to mycobacterial antigens in humans. We found that the costimulatory CD86 and CD80 molecules were significantly upregulated on rBCGhIL-18-infected DCs, whereas the stimulation of DCs with nonrecombinant BCG was less effective. In contrast, both BCG strains decreased the DC-SIGN expression on human DCs. The rBCGhIL-18 increased IL-23, IL-10, and IP-10 production by DCs to a greater extent than nonrecombinant BCG. In a coculture system of CD4+ T cells and loaded DCs, rBCGhIL-18 favoured strong IFN-γ but also IL-10 production by naive T cells but not by memory T cells. This was much less the case for nonrecombinant BCG. Thus the expression of IL-18 by recombinant BCG increases IL-23, IP-10, and IL-10 expression by human DCs and enhances their ability to induce IFN-γ and IL-10 expression by naive T cells, without affecting the maturation phenotype of the DCs.

  1. Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer.

    Directory of Open Access Journals (Sweden)

    Kathrin Buffen

    2014-10-01

    Full Text Available The anti-tuberculosis-vaccine Bacillus Calmette-Guérin (BCG is the most widely used vaccine in the world. In addition to its effects against tuberculosis, BCG vaccination also induces non-specific beneficial effects against certain forms of malignancy and against infections with unrelated pathogens. It has been recently proposed that the non-specific effects of BCG are mediated through epigenetic reprogramming of monocytes, a process called trained immunity. In the present study we demonstrate that autophagy contributes to trained immunity induced by BCG. Pharmacologic inhibition of autophagy blocked trained immunity induced in vitro by stimuli such as β-glucans or BCG. Single nucleotide polymorphisms (SNPs in the autophagy genes ATG2B (rs3759601 and ATG5 (rs2245214 influenced both the in vitro and in vivo training effect of BCG upon restimulation with unrelated bacterial or fungal stimuli. Furthermore, pharmacologic or genetic inhibition of autophagy blocked epigenetic reprogramming of monocytes at the level of H3K4 trimethylation. Finally, we demonstrate that rs3759601 in ATG2B correlates with progression and recurrence of bladder cancer after BCG intravesical instillation therapy. These findings identify a key role of autophagy for the nonspecific protective effects of BCG.

  2. Cutaneous necrotic ulceration due to BCG re-vaccination

    DEFF Research Database (Denmark)

    Gyldenløve, Mette; Andersen, Ase Bengård; Halkjær, Liselotte Brydensholt

    2012-01-01

    The case report describes a severe local reaction with large cutaneous necrotic ulcer following bacillus Calmette-Guérin (BCG) re-vaccination. This is a very rare adverse event, and only a few reports have been described in the literature.......The case report describes a severe local reaction with large cutaneous necrotic ulcer following bacillus Calmette-Guérin (BCG) re-vaccination. This is a very rare adverse event, and only a few reports have been described in the literature....

  3. The efficacy of BCG TICE and BCG Connaught in a cohort of 2,099 patients with T1G3 non-muscle-invasive bladder cancer.

    Science.gov (United States)

    Witjes, J Alfred; Dalbagni, Guido; Karnes, Robert J; Shariat, Shahrokh; Joniau, Steven; Palou, Joan; Serretta, Vincenzo; Larré, Stéphane; di Stasi, Savino; Colombo, Renzo; Babjuk, Marek; Malmström, Per-Uno; Malats, Nuria; Irani, Jacques; Baniel, Jack; Cai, Tommaso; Cha, Eugene; Ardelt, Peter; Varkarakis, John; Bartoletti, Riccardo; Spahn, Martin; Pisano, Francesca; Gontero, Paolo; Sylvester, Richard

    2016-11-01

    Potential differences in efficacy of different bacillus Calmette-Guérin (BCG) strains are of importance for daily practice, especially in the era of BCG shortage. To retrospectively compare the outcome with BCG Connaught and BCG TICE in a large study cohort of pT1 high-grade non-muscle-invasive bladder cancer patients. Individual patient data were collected for 2,451 patients with primary T1G3 tumors from 23 centers who were treated with BCG for the first time between 1990 and 2011. Using Cox multivariable regression and adjusting for the most important prognostic factors in this nonrandomized comparison, BCG Connaught and TICE were compared for time to recurrence, progression, and the duration of cancer specific survival and overall survival. Information on the BCG strain was available for 2,099 patients: 957 on Connaught and 1,142 on TICE. Overall, 765 (36%) patients received some form of maintenance BCG, 560 (59%) on Connaught and 205 (18%) on TICE. Without maintenance, Connaught was more effective than TICE only for the time to first recurrence (hazard ratio [HR] = 1.48; 95% CI: 1.20-1.82; PBCG significantly reduced the risk of recurrence, progression and death, both overall, and disease specific, for TICE, but not for Connaught. We found that BCG Connaught results in a lower recurrence rate as compared with BCG TICE when no maintenance is used. However, the opposite is true when maintenance is given. As there is currently a BCG shortage, information on the efficacy of different BCG strains is important. In this nonrandomized retrospective comparison in over 2,000 patients, we found that BCG Connaught reduces the recurrence rate compared to BCG TICE when no maintenance is used, but the opposite is true when maintenance is given. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. The immunological effects of oral polio vaccine provided with BCG vaccine at birth

    DEFF Research Database (Denmark)

    Jensen, Kristoffer Jarlov; Karkov, Hanne Sophie; Lund, Najaaraq

    2014-01-01

    BACKGROUND: Vaccines may have non-specific effects. An observational study from Guinea-Bissau suggested that oral polio vaccine at birth (OPV0) provided with Bacillus Calmette-Guérin (BCG) vaccine was associated with down-regulation of the immune response to BCG vaccine 6 weeks later. Based...... BCG alone at birth, and subsequently randomised to have a blood sample taken at 2, 4 or 6 weeks post-randomisation. Excreted levels of cytokines (IL-2, IL-5, IL-10, TNF-α and IFN-γ) were measured from whole blood in vitro stimulations with a panel of recall vaccine antigens (BCG, PPD, OPV), mitogen...

  5. Specific T-cell epitopes for immunoassay-based diagnosis of Mycobacterium tuberculosis infection

    DEFF Research Database (Denmark)

    Brock, I; Weldingh, K; Leyten, EM

    2004-01-01

    Specific T-cell epitopes for immunoassay-based diagnosis of Mycobacterium tuberculosis infection.Brock I, Weldingh K, Leyten EM, Arend SM, Ravn P, Andersen P. Department of Infectious Disease Immunology, Statens Serum Institute, Artillerivej 5, DK-2300 Copenhagen S, Denmark. The currently used...... method for immunological detection of tuberculosis infection, the tuberculin skin test, has low specificity. Antigens specific for Mycobacterium tuberculosis to replace purified protein derivative are therefore urgently needed. We have performed a rigorous assessment of the diagnostic potential of four...... recently identified antigens (Rv2653, Rv2654, Rv3873, and Rv3878) from genomic regions that are lacking from the Mycobacterium bovis bacillus Calmette-Guerin (BCG) vaccine strains as well as from the most common nontuberculous mycobacteria. The fine specificity of potential epitopes in these molecules...

  6. Surgical adjuvant immunotherapy for colorectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Enker, W.E.; Jacobitz, J.L.; Craft, K.; Wissler, R.W.

    1978-01-01

    One hundred forty-four Wistar-Furth rats in 12 therapeutic groups have been studied in a long-term comparison of the effectiveness of nonspecific immunotherapy with MER (methanol extraction residue) vs active-specific immunotherapy with neuraminidase-modified tumor cells. Six months after surgical adjuvant immunotherapy a 100% improvement in survival was achieved with MER immunotherapy compared to untreated control animals. In addition, the use of MER enhanced the value of active-specific immunotherapy where both modalities were combined in sequence. The predicted value of MER-BCG (Bacillus Calmette-Guerin) for the immunotherapy of solid tumors was borne out by these results suggesting that present ongoing clinical trials of MER as adjuvant therapy for large bowel cancer should prove to be successful if properly controlled. The pattern of survival in these experiments suggests that surgical adjuvant immunotherapy is cytostatic rather than cytocidal, and implies the need for long-term, repeated immunizations.

  7. Determinants of BCG scarification among children in rural Guinea-Bissau: A prospective cohort study.

    Science.gov (United States)

    Funch, Katarina M; Thysen, Sanne M; Rodrigues, Amabelia; Martins, Cesario L; Aaby, Peter; Benn, Christine S; Fisker, Ane B

    2018-01-02

    Bacillus Calmette-Guérin (BCG) vaccination may have beneficial non-specific effects on child survival, the effects being stronger for children developing a scar. In a prospective cohort study, we examined determinants for not developing a BCG scar within 6 months of vaccination. Bandim Health Project (BHP) runs a Health and Demographic Surveillance System site in rural Guinea-Bissau. BHP provides BCG at monthly visits. We studied determinants for not developing a BCG scar using binomial regression models to obtain relative risks (RR). From May 2012 until October 2014, BHP nurses vaccinated 2415 infants with BCG. We assessed BCG scar between 6 and 12 months of age for 2156 (89%) of these children and 2115 (98%) had developed a scar. In comparison, among 785 children BCG vaccinated elsewhere, 622 (79%) had a scar, the RR of not having a scar being 10.91 (7.52-15.85) compared with children vaccinated by BHP. Among children vaccinated by BHP, those receiving the Russian BCG strain were more likely not to develop a scar (RR = 2.98 (1.52-5.81)) compared with children receiving Danish BCG strain. Children with no post-injection wheal or a wheal BCG scar development while nutritional status and socioeconomic status were not. Scarring rate may therefore be a better indicator of vaccination programme performance than coverage.

  8. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity

    NARCIS (Netherlands)

    Arts, Rob J W; Moorlag, Simone J C F M; Novakovic, Boris; Li, Yang; Wang, Shuang-Yin; Oosting, Marije; Kumar, Vinod; Xavier, Ramnik J; Wijmenga, Cisca; Joosten, Leo A B; Reusken, Chantal B E M; Benn, Christine S; Aaby, Peter; Koopmans, Marion P; Stunnenberg, Hendrik G; van Crevel, Reinout; Netea, Mihai G

    2018-01-01

    The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide

  9. [Disseminated BCG infection in patients with urinary bladder carcinoma].

    Science.gov (United States)

    Korać, Milos; Milosević, Branko; Lavadinović, Lidija; Janjić, Aleksandar; Brmbolić, Branko

    2009-01-01

    Bacillus Calmette-Guërin--a live, attenuated strain of Mycobacterium bovis has been used in immunotherapy of patients with superficial urinary bladder carcinoma. Some patients develop complications after intravesical instillation of BCG: high temperature followed by hematuria or granulomatous prostatits, epidydimoorchitis, urethral obstruction, and less than 1% have a systemic disease followed by dissemination of bacteria into other organs. A 50-year-old man underwent transurethral resection of a bladder tumor. One month after the operation BCG intravesical installations were administered for three weeks. After the fourth installation, our patient developed high fever, fatigue, vomiting, dark urine, light stools, and jaundice. On admission he was jaundiced with a high fever, enlarged liver and spleen and laboratory findings which included high erythrocyte sedimentation rate, pancytopenia, elevated liver enzymes, especially alkaline phosphatase and aminotranspherases. The bone-marrow biopsy showed granulomatous inflamation suggesting mycobacterial spread in the bone marrow, liver and spleen and sepsis. The patient was initially treated with antituberculous therapy, but his state did not improve until corticosteroids were added to the antituberculous treatment regimen. Although dissemination of BCG is a rare complication of intravesical BCG treatment of the bladder carcinoma, it may result in prolonged fever and granulomatous inflamation of the liver, spleen, lungs, bone marrow and BCG sepsis. Antituberclous agents in combination with corticosteroids comprise the treatment of choice for disseminated BCG infection.

  10. BCG and protection against inflammatory and auto-immune diseases.

    Science.gov (United States)

    Kowalewicz-Kulbat, Magdalena; Locht, Camille

    2017-07-01

    Bacillus Calmette-Guérin (BCG) is the only available vaccine against tuberculosis. Although its protective efficacy against pulmonary tuberculosis is still under debate, it provides protection against other mycobacterial diseases. BCG is also an effective therapy against superficial bladder cancer and potentially decreases overall childhood mortality. Areas covered: The purpose of this paper is to provide a state-of-the-art summary of the beneficial effects of BCG in inflammatory and auto-immune diseases. As a strong inducer of Th1 type immunity, BCG has been reported to protect against atopic conditions, such as allergic asthma, a Th2-driven disorder. Its protective effect has been well documented in mice, but still awaits definitive evidence in humans. Similarly, murine studies have shown a protective effect of BCG against auto-immune diseases, such as multiple sclerosis and insulin-dependent diabetes, but studies in humans have come to conflicting conclusions. Expert commentary: Studies in mice have shown a beneficial effect of the BCG vaccine against allergic asthma, multiple sclerosis and diabetes. However, the understanding of its mechanism is still fragmentary and requires further in depth research. Some observational or intervention studies in humans have also suggested a beneficial effect, but definitive evidence for this requires confirmation in carefully conducted prospective studies.

  11. Immunology of bovine tuberculosis: Perspectives on one health approaches and defining correlates of protection versus infection

    Science.gov (United States)

    Tuberculosis (TB), primarily due to Mycobacterium tuberculosis in humans and Mycobacterium bovis in cattle, is an exemplary model of the One Health Concept. The human TB vaccine, M. bovis bacille Calmette-Guerin (BCG), was first proven effective in cattle prior to use in humans. Recent experimental ...

  12. Neonatal BCG vaccination and atopic dermatitis before 13 months of age

    DEFF Research Database (Denmark)

    Thøstesen, Lisbeth Marianne; Kjaergaard, Jesper; Pihl, Gitte Thybo

    2018-01-01

    in the control group (RR=0.90 (95% confidence intervals 0.80 to 1.00)). The effect of neonatal BCG vaccination differed significantly between children with atopic predisposition (RR 0.84 (0.74 to 0.95)) and children without atopic predisposition (RR 1.09 (0.88 to 1.37)) (test of no interaction, p=0.04). Among......Studies have suggested that Bacillus Calmette-Guérin (BCG) vaccination may reduce the risk of allergic diseases, including atopic dermatitis. The Danish Calmette Study was conducted 2012-2015. Within 7 days of birth new-borns were randomised 1:1 to BCG or no BCG. Exclusion criteria were gestational...... age children in the BCG group and 495/1,952 (25.4%) children...

  13. Mycotic aortic aneurysm due to intravesical BCG immunotherapy: Clinical manifestations and diagnostic challenges

    Directory of Open Access Journals (Sweden)

    Brittany J Holmes

    2014-01-01

    Full Text Available A live, attenuated form of Mycobacterium bovis, bacillus Calmette–Guérin (BCG, is commonly used as intravesical immunotherapy for non-invasive urothelial bladder carcinoma. While complications are rare, dissemination can occur. A case of mycotic aortic aneurysm following BCG administration with recovery of Mycobacterium bovis in culture is reported. A review of the published experience with this problem is also presented.

  14. [BCG vaccination in the world].

    Science.gov (United States)

    Toida, I

    2000-01-01

    BCG vaccination programme and BCG vaccination coverage in the world were summarized mainly based on the published informations from official organizations, such as World Health Organization (WHO), International Union Against Tuberculosis and Lung Disease (IUATLD) and Centers for Disease Control and Prevention (CDC). From this review, we can see how widely BCG has been used for the prevention of tuberculosis in the world. In most of the developing countries, especially in Africa, the Americas, and Pacific Region, BCG vaccination is carried out to newborn babies soon after birth by intradermal injection according to the recommendations from WHO, but some of the developing countries in Asia and Europe have their own modified BCG vaccination programmes. In economically developed countries, BCG vaccination programme has been established according to the tuberculosis status of each countries. Some countries have general vaccination policy, and other countries have selected vaccination policy, but there is no country where BCG vaccination is not carried out at all. Among G8 contries, as representatives of the economically developed countries, Japan, United Kingdom, France and Russian Federation have BCG general vaccination policy for the specified age group. In these 4 countries revaccination (s) of BCG are still carried out. In Germany, some provinces have general vaccination policy and some others have selected vaccination policy. In the United States of America, BCG vaccination is recommended to selected high risk infants and health care workers by CDC. There are many debates as for the efficacy and safety of BCG vaccination, and the development of new vaccine better than BCG has been actively discussed and some encouraging results in animal models have been reported from several laboratories. But, there is almost no possibility to be able to use a new vaccine in the routine practice within a couple of years. From the practical point of view, therefore, the operational

  15. Emerging intravesical therapies for management of nonmuscle invasive bladder cancer

    Directory of Open Access Journals (Sweden)

    Jeffrey J Tomaszewski

    2010-05-01

    Full Text Available Jeffrey J Tomaszewski, Marc C SmaldoneDepartment of Urology, University of Pittsburgh School of Medicine, Pennsylvania, USAAbstract: Transitional cell carcinoma (TCC is the second most common urologic malignancy, and 70% of patients present with superficial or nonmuscle invasive bladder cancer (NMIBC. Intravesical bacillus Calmette-Guerin (BCG is the most effective agent for preventing disease recurrence, and the only therapy able to inhibit disease progression. However, recurrence rates as high as 30% and significant local and systemic toxicity have led to increased interest in alternative intravesical therapies. In patients refractory or intolerant to BCG, BCG-interferon α2b, gemcitabine, and anthracyclines (doxorubicin, epirubicin, valrubicin have demonstrated durable clinical responses. Phase I trials investigating alternative cytotoxic agents, such as apaziquone, taxanes (docetaxel, paclitaxel, and suramin are reporting promising data. Novel immunomodulating agents have demonstrated promise as efficacious alternatives in patients refractory to BCG. Optimization of existing chemotherapeutic regimens using hyperthermia, photodynamic therapy, magnetically-targeted carriers, and liposomes remains an area of active investigation. Despite enthusiasm for new intravesical agents, radical cystectomy remains the treatment of choice for patients with NMIBC who have failed intravesical therapy and selected patients with naïve T1 tumors and aggressive features. This report provides a comprehensive review of contemporary intravesical therapy for NMIBC and refractory NMIBC, with an emphasis on emerging agents and novel treatment modalities.Keywords: transitional cell carcinoma, nonmuscle, invasive, intravesical therapy, BCG

  16. BCG-mediated bladder cancer immunotherapy: identifying determinants of treatment response using a calibrated mathematical model.

    Directory of Open Access Journals (Sweden)

    Cyrill A Rentsch

    Full Text Available Intravesical Bacillus Calmette Guérin (BCG immunotherapy is considered the standard of care for treatment of non-muscle invasive bladder cancer; however the treatment parameters were established empirically. In order to evaluate potential optimization of clinical parameters of BCG induction therapy, we constructed and queried a new mathematical model. Specifically, we assessed the impact of (1 duration between resection and the first instillation; (2 BCG dose; (3 indwelling time; and (4 treatment interval of induction therapy - using cure rate as the primary endpoint. Based on available clinical and in vitro experimental data, we constructed and parameterized a stochastic mathematical model describing the interactions between BCG, the immune system, the bladder mucosa and tumor cells. The primary endpoint of the model was the probability of tumor extinction following BCG induction therapy in patients with high risk for tumor recurrence. We theoretically demonstrate that extending the duration between the resection and the first BCG instillation negatively influences treatment outcome. Simulations of higher BCG doses and longer indwelling times both improved the probability of tumor extinction. A remarkable finding was that an inter-instillation interval two times longer than the seven-day interval used in the current standard of care would substantially improve treatment outcome. We provide insight into relevant clinical questions using a novel mathematical model of BCG immunotherapy. Our model predicts an altered regimen that may decrease side effects of treatment while improving response to therapy.

  17. Nonspecific effect of BCG vaccination at birth on early childhood infections

    DEFF Research Database (Denmark)

    Kjærgaard, Jesper; Birk, Nina Marie; Nissen, Thomas N

    2016-01-01

    BACKGROUND: Childhood infections are common and Bacillus Calmette-Guérin (BCG) vaccination at birth may prevent these via nonspecific effects. METHODS: A randomized, clinical multicenter trial. All women planning to give birth (n = 16,521) at the three study sites were invited during the recruitm......BACKGROUND: Childhood infections are common and Bacillus Calmette-Guérin (BCG) vaccination at birth may prevent these via nonspecific effects. METHODS: A randomized, clinical multicenter trial. All women planning to give birth (n = 16,521) at the three study sites were invited during...... during the first 3 mo....

  18. BCG stimulated dendritic cells induce an interleukin-10 producing T-cell population with no T helper 1 or T helper 2 bias in vitro

    DEFF Research Database (Denmark)

    Madura Larsen, Jeppe; Benn, Christine Stabell; Fillie, Yvonne

    2007-01-01

    Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine has been associated with beneficial effects on overall childhood mortality in low-income countries; this cannot be explained merely by the prevention of tuberculosis (TB) deaths. The beneficial effects of BCG vaccine could be the result o...

  19. Neonatal BCG-vaccination and atopic dermatitis before 13 months of age. A randomised clinical trial

    DEFF Research Database (Denmark)

    Thøstesen, Lisbeth Marianne; Kjaergaard, Jesper; Pihl, Gitte Thybo

    2017-01-01

    Studies have suggested that Bacillus Calmette-Guérin (BCG) vaccination may reduce the risk of allergic diseases, including atopic dermatitis. The Danish Calmette Study was conducted 2012-2015. Within 7 days of birth new-borns were randomised 1:1 to BCG or no BCG. Exclusion criteria were gestational...... in the control group (RR=0.90 (95% confidence intervals 0.80 to 1.00)). The effect of neonatal BCG vaccination differed significantly between children with atopic predisposition (RR 0.84 (0.74 to 0.95)) and children without atopic predisposition (RR 1.09 (0.88 to 1.37)) (test of no interaction, p=0.04). Among...

  20. Active Mycobacterium Infection Due to Intramuscular BCG Administration Following Multi-Steps Medication Errors

    Directory of Open Access Journals (Sweden)

    MohammadReza Rafati

    2015-10-01

    Full Text Available Bacillus Calmette-Guérin (BCG is indicated for treatment of primary or relapsing flat urothelial cell carcinoma in situ (CIS of the urinary bladder. Disseminated infectious complications occasionally occur due to BCG as a vaccine and intravesical therapy.  Intramuscular (IM or Intravenous (IV administrations of BCG are rare medication errors which are more probable to produce systemic infections. This report presents 13 years old case that several steps medication errors occurred consequently from physician handwriting, pharmacy dispensing, nursing administration and patient family. The physician wrote βHCG instead of HCG in the prescription. βHCG was read as BCG by the pharmacy staff and 6 vials of intravesical BCG were administered IM twice a week for 3 consecutive weeks. The patient experienced fever and chills after each injection, but he was admitted 2 months after first IM administration of BCG with fever and pancytopenia. Unfortunately four month after using drug, during second admission duo to cellulitis at the sites of BCG injection the physicians diagnosed the medication error. Using handwritten prescription and inappropriate abbreviations, spending inadequate time for taking a brief medical history in pharmacy, lack of verifying name, dose and wrote before medication administration and lack of considering medication error as an important differential diagnosis had roles to occur this multi-steps medication error.

  1. Murine Splenic Natural Killer Cells Do Not Develop Immunological Memory after Re-Encounter with Mycobacterium bovis BCG

    Science.gov (United States)

    Kawahara, Mamoru; Hasegawa, Nozomi; Takaku, Hiroshi

    2016-01-01

    Several lines of evidence have recently suggested that natural killer (NK) cells develop immunological memory against viral infections. However, there is no apparent evidence that NK cells acquire specific memory against Mycobacterium bovis bacillus Calmette—Guérin (BCG), the only currently licensed vaccine for preventing tuberculosis. In the present study, we investigated whether murine splenic NK cells can be activated by BCG in a dendritic cell (DC)-independent or -dependent manner, and furthermore examined whether these NK cells acquire specific memory following BCG vaccination. NK cells isolated from spleens of BCG-immunized mice produced interferon (IFN)γ through direct BCG stimulation in the absence of antigen-presenting cells; however, NK cells from control animals similarly directly responded to BCG, and the response level was not statistically significant between the immunized and the naïve NK cells. When purified NK cells that had been exposed to BCG were cocultured with RAW murine macrophages infected with BCG, the antibacterial activity of the macrophages was strongly enhanced; however, its level was similar to that by naïve NK cells, which had not been exposed to BCG. When splenocytes harvested from BCG-immunized mice were stimulated with purified protein derivative (PPD) derived from Mycobacterium tuberculosis, a specific IFNγ response was clearly observed, mainly attributed to NK cells and memory CD4+ T cells. To investigate whether these NK cells as well as the T cells are activated by cell−cell interaction with DCs presenting mycobacterial antigens, NK cells isolated from BCG-immunized mice were cocultured with splenocytes harvested from naïve mice in the presence of PPD stimulation. However, no IFNγ response was found in the NK cells. These results suggest that murine splenic NK cells do not develop BCG-specific immunological memory in either a DC-independent or -dependent manner. PMID:26999357

  2. A cocktail regimen of intravesical mitomycin-C, doxorubicin, and cisplatin (MDP) for non-muscle-invasive bladder cancer.

    Science.gov (United States)

    Chen, Chung-Hsin; Yang, Hung-Ju; Shun, Chia-Tung; Huang, Chao-Yuan; Huang, Kuo-How; Yu, Hong-Jeng; Pu, Yeong-Shiau

    2012-01-01

    To compare the efficacy and toxicity profiles of 3 intravesical regimens, including doxorubicin alone, bacillus Calmette-Guerin (BCG), and a cocktail regimen, in the prevention of bladder cancer recurrence. Two hundred ninety patients with newly diagnosed non-muscle-invasive bladder cancer treated with transurethral resection (TUR) between March 1996 and December 2004 were analyzed retrospectively. Each cycle of the cocktail regimen contained 30 mg each of sequential weekly intravesical mitomycin-C (MMC), doxorubicin, and cisplatin (MDP). Two cycles of MDP were given within the first 6 weeks of TUR, followed by 1 cycle each at 3, 6, and 12 months, and every 6 months until 36 months after a negative cystoscopy. Doxorubicin and BCG alone was given at similar time points as the MDP and BCG protocols. There were no demographic differences among the 3 groups. The median follow-up duration was 50 months. Dropout rates due to intolerance and/or poor compliance with the BCG, doxorubicin, and MDP protocols were 22.5%, 16.8%, and 11.0%, respectively. The MDP and BCG groups had similar bladder recurrence rates (37.9% vs. 33.9% at 5 years, respectively; P = 0.69). The doxorubicin group had significantly more recurrences than the BCG or MDP groups (HR = 1.9 (vs. BCG; P = 0.02) and 1.8 (vs. MDP; P = 0.01)). MDP was associated with less major adverse events than BCG (5.8% vs. 15.0%, respectively; P = 0.02). Compared with maintenance BCG, the MDP group had a similar recurrence rate but less side effects. Large randomized study is warranted to further determine the benefit of MDP adjuvant intravesical therapy. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Sepse fatal após instilação intravesical de BCG: relato de caso Fatal sepsis after intravesical instillation of BCG: case report

    Directory of Open Access Journals (Sweden)

    Ulysses Vasconcellos de Andrade e Silva

    2011-03-01

    Full Text Available A instilação intravesical do bacilo de Calmette-Guérin (BCG é o tratamento de escolha para carcinoma de bexiga in situ ou tumores superficiais de bexiga de alto grau não invasivos. Este tratamento geralmente é bem tolerado, mas podem ocorrer complicações graves. Paciente idoso, coronariopata, portador de carcinoma superficial de bexiga de alto grau recidivado foi submetido à instilação intravesical de BCG, evoluindo com choque séptico. Recebeu antibioticoterapia de amplo espectro, tuberculostáticos, corticóide, aminas vasoativas, suporte ventilatório e tratamento hemodialítico, sem melhora. Faleceu nove dias após a instilação intravesical de BCG por insuficiência de múltiplos órgãos.Intravesical instillation of bacillus Calmette-Guérin (BCG is the treatment of choice for carcinoma in situ and non-invasive high-grade superficial tumors of the urinary bladder. This treatment is well tolerated overall, but serious complications can occur. An elderly man with coronary disease and recurrent high-grade superficial carcinoma of the bladder underwent intravesical instillation of BCG and developed septic shock. He received wide range antibiotics, tuberculostatic and vasoactive drugs, corticosteroids, mechanical ventilation and renal replacement therapy without improvement. He died nine days after the intravesical instillation of BCG because of multiple organ failure.

  4. Role of urothelial cells in BCG immunotherapy for superficial bladder cancer

    NARCIS (Netherlands)

    Bevers, R. F. M.; Kurth, K.-H.; Schamhart, D. H. J.

    2004-01-01

    Intravesical instillation of Bacillus Calmette-Guérin (BCG) is used for the treatment of superficial bladder cancer, both to reduce the recurrence rate of bladder tumour and to diminish the risk of progression. Since its first therapeutic application in 1976, major research efforts have been

  5. Ultrasonographic features of BCG lymphadenitis

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Do Youn; Lee, Sun Wha; Hwang, Ji Young [College of Medicine, Ewha Womans University, Seoul (Korea, Republic of)

    2005-07-15

    To evaluate the ultrasonographic findings of BCG lymphadenitis complicated by BCG vaccination in children. Ultrasonography was performed for 22 cases of BCG lymphadenitis in 21 patients who were diagnosed by clinical (n=10) or pathological (n=11) examinations. Their age ranged from 4 months to 3 years (mean age; 14 months). We retrospectively analyzed the ultrasonographic findings for location, multiplicity, size, shape, margin, echogenecity, posterior enhancement, calcifications, inner anechoic portion and Doppler pattern of the BCG lymphadenitis. The BCG lymphadenitis was found at the axillary area in 15 cases (68%) and at the supraclavicular area in 7 cases (32%). There were ten cases (45%) of solitary lesion and 12 cases (55%) of multiple conglomerated lesions. The maximum diameter ranged from about 0.9 cm to 3.2 cm. The BCG lymphadenitis showed as round (82%), well defined (86%), or heterogeneous hypoechoic (68%) lesions with posterior enhancement (78%). Calcifications were found in 6 cases (27%) and 5 cases (83%) had been vaccinated more than 5 months ago. There were eccentric inner anechoic portions in 16 cases (73%), which were pathologically confirmed as having caseating necrosis. There were increased Doppler flow patterns in 15 cases (68%); 4 cases (18%) were of the central type, 6 cases (27%) were of the peripheral type and 5 cases (23%) were of mixed type. BCG lymphadenitis is frequently located at the axillary area adjacent to a vaccination site. The ultrasonographic findings of BCG lymphadenitis are well-defined, round, heterogeneously hypoechoic lesions with posterior enhancement, calcifications and inner eccentric anechoic portion.

  6. Ultrasonographic features of BCG lymphadenitis

    International Nuclear Information System (INIS)

    Kim, Do Youn; Lee, Sun Wha; Hwang, Ji Young

    2005-01-01

    To evaluate the ultrasonographic findings of BCG lymphadenitis complicated by BCG vaccination in children. Ultrasonography was performed for 22 cases of BCG lymphadenitis in 21 patients who were diagnosed by clinical (n=10) or pathological (n=11) examinations. Their age ranged from 4 months to 3 years (mean age; 14 months). We retrospectively analyzed the ultrasonographic findings for location, multiplicity, size, shape, margin, echogenecity, posterior enhancement, calcifications, inner anechoic portion and Doppler pattern of the BCG lymphadenitis. The BCG lymphadenitis was found at the axillary area in 15 cases (68%) and at the supraclavicular area in 7 cases (32%). There were ten cases (45%) of solitary lesion and 12 cases (55%) of multiple conglomerated lesions. The maximum diameter ranged from about 0.9 cm to 3.2 cm. The BCG lymphadenitis showed as round (82%), well defined (86%), or heterogeneous hypoechoic (68%) lesions with posterior enhancement (78%). Calcifications were found in 6 cases (27%) and 5 cases (83%) had been vaccinated more than 5 months ago. There were eccentric inner anechoic portions in 16 cases (73%), which were pathologically confirmed as having caseating necrosis. There were increased Doppler flow patterns in 15 cases (68%); 4 cases (18%) were of the central type, 6 cases (27%) were of the peripheral type and 5 cases (23%) were of mixed type. BCG lymphadenitis is frequently located at the axillary area adjacent to a vaccination site. The ultrasonographic findings of BCG lymphadenitis are well-defined, round, heterogeneously hypoechoic lesions with posterior enhancement, calcifications and inner eccentric anechoic portion

  7. The patterns of in vitro cell-death and inflammatory cytokines induced by distinct BCG vaccine strains are differentially induced in human mononuclear cells.

    Science.gov (United States)

    Ponte, C; Hacker, M; Moraes, M; Castello-Branco, L; Silva, F; Antas, P

    2018-01-02

    Tuberculosis (TB) remains among the world's leading cause of mortality. For its control, studies of TB vaccines are needed. Since live-attenuated Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only TB vaccine currently in use, studies on the protective role of BCG are required. In this study, we analyzed host cells purified directly from whole blood of human immunodeficiency virus (HIV)-negative volunteers, comprising adult healthy donors (HD) and neonates (umbilical cord bloods, UCB), with the aim to directly compare in vitro immune responses with distinct BCG strains in human mononuclear cells. The Moreau, Pasteur, and Danish BCG strains were used to infect mononuclear cells in vitro for 48 h; bacilli viability and cell-death were subsequently detected by flow cytometry. In addition, cell culture supernatants were used in cytokine detection assays. Overall, the Moreau BCG strain induced higher levels of apoptosis than the Pasteur and Danish BCG strains in both the HD and UCB groups (p-value BCG infection. The Moreau BCG strain, exclusively, induced Th1 cytokines at the highest levels in cells from adults (p-value BCG strains, whereas TGF-β1 levels were reduced significantly (p-value BCG vaccine. As expected, eight out of 22 pro-inflammatory cytokines were secreted at significant levels (p-value BCG-infected cell cultures, in the HD group only. When analyzing these results, we excluded confounding factors related to storage and viability of the BCG strains used. These findings suggest that Moreau BCG is a more potent immunostimulating agent than the Pasteur and Danish BCG strains. Clinical trials will be needed to confirm these findings.

  8. BCG strain S4-Jena: An early BCG strain is capable to reduce the proliferation of bladder cancer cells by induction of apoptosis

    Directory of Open Access Journals (Sweden)

    Hermann Inge-Marie

    2010-06-01

    Full Text Available Abstract Background Intravesical immunotherapy with Mycobacterium bovis bacillus Calmette-Guérin has been established as the most effective adjuvant treatment for high risk non-muscle-invasive bladder cancer (NMIBC. We investigated the differences between the S4-Jena BCG strain and commercially available BCG strains. We tested the genotypic varieties between S4-Jena and other BCG strains and analysed the effect of the BCG strains TICE and S4-Jena on two bladder cancer cell lines. Results In contrast to commercially available BCG strains the S4-Jena strain shows genotypic differences. Spoligotyping verifies the S4-Jena strain as a BCG strain. Infection with viable S4-Jena or TICE decreased proliferation in the T24 cell line. Additionally, hallmarks of apoptosis were detectable. In contrast, Cal29 cells showed only a slightly decreased proliferation with TICE. Cal29 cells infected with S4-Jena, though, showed a significantly decreased proliferation in contrast to TICE. Concordantly with these results, infection with TICE had no effect on the morphology and hallmarks of apoptosis of Cal29 cells. However, S4-Jena strain led to clearly visible morphological changes and caspases 3/7 activation and PS flip. Conclusions S4-Jena strain has a direct influence on bladder cancer cell lines as shown by inhibition of cell proliferation and induction of apoptosis. The data implicate that the T24 cells are responder for S4-Jena and TICE BCG. However, the Cal29 cells are only responder for S4-Jena and they are non-responder for TICE BCG. S4-Jena strain may represent an effective therapeutic agent for NMIBC.

  9. Evaluation of Immunogenicity and Protective Efficacy Elicited by Mycobacterium bovis BCG Overexpressing Ag85A Protein against Mycobacterium tuberculosis Aerosol Infection.

    Science.gov (United States)

    Xu, Zheng Zhong; Chen, Xiang; Hu, Ting; Meng, Chuang; Wang, Xiao Bo; Rao, Yan; Zhang, Xiao Ming; Yin, Yue Lan; Pan, Zhi Ming; Jiao, Xin An

    2016-01-01

    Mycobacterium bovis bacillus Calmette-Guérin (BCG) is currently the only vaccine available for preventing tuberculosis (TB), however, BCG has varying success in preventing pulmonary TB. In this study, a recombinant BCG (rBCG::Ag85A) strain overexpressing the immunodominant Ag85A antigen was constructed, and its immunogenicity and protective efficacy were evaluated. Our results indicated that the Ag85A protein was successfully overexpressed in rBCG::Ag85A, and the Ag85A peptide-MHC complexes on draining lymph node dendritic cells of C57BL/6 mice infected with rBCG::Ag85A were detectable 4 h post-infection. The C57BL/6 mice infected with this strain had stronger antigen-specific interferon-gamma (IFN-γ) responses and higher antibody titers than those immunized with BCG, and the protective experiments showed that rBCG::Ag85A can enhance protection against Mycobacterium tuberculosis (M. tuberculosis) H37Rv infection compared to the BCG vaccine alone. Our results demonstrate the potential of rBCG::Ag85A as a candidate vaccine against TB.

  10. Deletion of nuoG from the Vaccine Candidate Mycobacterium bovis BCG ΔureC::hly Improves Protection against Tuberculosis

    Science.gov (United States)

    Gengenbacher, Martin; Nieuwenhuizen, Natalie; Vogelzang, Alexis; Liu, Haipeng; Kaiser, Peggy; Schuerer, Stefanie; Lazar, Doris; Wagner, Ina; Mollenkopf, Hans-Joachim

    2016-01-01

    ABSTRACT The current tuberculosis (TB) vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), provides insufficient protection against pulmonary TB. Previously, we generated a listeriolysin-expressing recombinant BCG strain, which to date has successfully completed phase I and phase IIa clinical trials. In an attempt to further improve efficacy, we deleted the antiapoptotic virulence gene nuoG, encoding NADH dehydrogenase 1 subunit G, from BCG ΔureC::hly. In vitro, deletion of nuoG unexpectedly led to strongly increased recruitment of the autophagosome marker LC3 to the engulfed vaccine, suggesting that nuoG also affects xenophagic pathways. In mice, BCG ΔureC::hly ΔnuoG vaccination was safer than BCG and improved protection over that of parental BCG ΔureC::hly, significantly reducing TB load in murine lungs, ameliorating pulmonary pathology, and enhancing immune responses. Transcriptome analysis of draining lymph nodes after vaccination with either BCG ΔureC::hly or BCG ΔureC::hly ΔnuoG demonstrated earlier and stronger induction of immune responses than that with BCG SSI and suggested upregulation of inflammasome activation and interferon-induced GTPases. In summary, BCG ΔureC::hly ΔnuoG is a promising next-generation TB vaccine candidate with excellent efficacy and safety. PMID:27222470

  11. PO and ID BCG vaccination in humans induce distinct mucosal and systemic immune responses and CD4+T cell transcriptomal molecular signatures.

    Science.gov (United States)

    Hoft, D F; Xia, M; Zhang, G L; Blazevic, A; Tennant, J; Kaplan, C; Matuschak, G; Dube, T J; Hill, H; Schlesinger, L S; Andersen, P L; Brusic, V

    2017-08-30

    Protective efficacy of Bacillus Calmette-Guérin (BCG) may be affected by the methods and routes of vaccine administration. We have studied the safety and immunogenicity of oral (PO) and/or intradermal (ID) administration of BCG in healthy human subjects. No major safety concerns were detected in the 68 healthy adults vaccinated with PO and/or ID BCG. Although both PO and ID BCG could induce systemic Th1 responses capable of IFN-γ production, ID BCG more strongly induced systemic Th1 responses. In contrast, stronger mucosal responses (TB-specific secretory IgA and bronchoalveolar lavage T cells) were induced by PO BCG vaccination. To generate preliminary data comparing the early gene signatures induced by mucosal and systemic BCG vaccination, CD4 + memory T cells were isolated from subsets of BCG vaccinated subjects pre- (Day 0) and post-vaccination (Days 7 and 56), rested or stimulated with BCG infected dendritic cells, and then studied by Illumina BeadArray transcriptomal analysis. Notably, distinct gene expression profiles were identified both on Day 7 and Day 56 comparing the PO and ID BCG vaccinated groups by GSEA analysis. Future correlation analyses between specific gene expression patterns and distinct mucosal and systemic immune responses induced will be highly informative for TB vaccine development.Mucosal Immunology advance online publication 30 August 2017; doi:10.1038/mi.2017.67.

  12. Effects of whole body x-irradiation and cyclophosphamide treatment on induction of macrophage tumoricidal function in mice

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    Schultz, R.M.; Pavlidis, N.A.; Chirigos, M.A.; Weiss, J.F.

    1978-07-01

    The influence of whole-body x irradiation (200 to 800 R) and subcutaneous cyclophosphamide (CY) treatment (150 to 500 mg/kg) was studied on the ability of adjuvants to induce cytotoxic macrophages in vivo. Surprisingly, radiation or CY therapy alone produced growth inhibitory macrophages whose function peaked within 2 days after treatment. When adjuvants such as Bacillus Calmette Guerin (BCG), pyran copolymer, or glucan were administered ip within 2 hr after sublethal (600 R) x irradiation, adjuvant-induced cytotoxic function was depressed but not ablated. In addition, when noninduced peritoneal macrophages were obtained 6 days after lethal (800 R) x irradiation, their ability to be activated in vitro by lymphokine or fibroblast-derived interferon preparations was only slightly depressed at all concentrations of inducer tested. When BCG, pyran, or glucan was administered ip concurrently with sc CY treatment, only the ability of BCG to activate macrophages was markedly reduced, indicating separate mechanisms for the induction of tumoricidal macrophages. A better understanding of the interaction of chemotherapeutic and/or radiation regimens with adjuvants which affect macrophage function may be instrumental to rationalized immunotherapy protocols.

  13. A polymerase chain reaction and enzyme linked immunosorbent assay based approach for diagnosis and differentiation between vaccinated and infected cattle with Mycobacterium bovis

    Science.gov (United States)

    Sabry, Mohamed; Elkerdasy, Ahmed

    2014-01-01

    Background: In most African and Arabic countries tuberculosis (TB) causes great economic losses in bovine species and constitutes serious zoonotic problem. As the traditional diagnostic method delay the research because of low sensitivity and specificity, a rapid method of diagnosis is of outmost importance. Aim: The study was designed to evaluate the two rapid diagnostic methods of TB in cattle, further to differentiate between infected and bacillus Calmette-Guerin (BCG) vaccinated animals. Materials and Methods: Intradermal tuberculin test was applied to 300 cattle. Of these cattle, 15 cattle were vaccinated from cattle negative to tuberculin test with BCG. Blood samples were taken for lymphocyte separation to apply polymerase chain reaction (PCR) upon and for serum preparation for the enzyme-linked immunosorbent assay (ELISA) application, this blood collected from 65 cattle classified into three groups, viz. positive tuberculin test (35 animals), negative tuberculin test (15 animals), and vaccinated cow with BCG (15 animals). From blood samples lymphocytes were separated and the isolated lymphocytes were subjected to PCR and serum for ELISA application. Blood samples, specimens from lymph nodes and specific tissues were taken for PCR and for cultivation and isolation of Mycobacterium bovis. Results and Conclusions: The results of this study revealed that PCR can be used as rapid efficient and accurate diagnostic test in detection of ruminant TB. Moreover, cattle's ELISA reading showed higher sensitivity in positive tuberculin animals. However, the differentiations between vaccinated and infected animals not clear by using a single antigen only. PMID:24741280

  14. Effects of whole body x-irradiation and cyclophosphamide treatment on induction of macrophage tumoricidal function in mice

    International Nuclear Information System (INIS)

    Schultz, R.M.; Pavlidis, N.A.; Chirigos, M.A.; Weiss, J.F.

    1978-01-01

    The influence of whole-body x irradiation (200 to 800 R) and subcutaneous cyclophosphamide (CY) treatment (150 to 500 mg/kg) was studied on the ability of adjuvants to induce cytotoxic macrophages in vivo. Surprisingly, radiation or CY therapy alone produced growth inhibitory macrophages whose function peaked within 2 days after treatment. When adjuvants such as Bacillus Calmette Guerin (BCG), pyran copolymer, or glucan were administered ip within 2 hr after sublethal (600 R) x irradiation, adjuvant-induced cytotoxic function was depressed but not ablated. In addition, when noninduced peritoneal macrophages were obtained 6 days after lethal (800 R) x irradiation, their ability to be activated in vitro by lymphokine or fibroblast-derived interferon preparations was only slightly depressed at all concentrations of inducer tested. When BCG, pyran, or glucan was administered ip concurrently with sc CY treatment, only the ability of BCG to activate macrophages was markedly reduced, indicating separate mechanisms for the induction of tumoricidal macrophages. A better understanding of the interaction of chemotherapeutic and/or radiation regimens with adjuvants which affect macrophage function may be instrumental to rationalized immunotherapy protocols

  15. Individual-level factors associated with variation in mycobacterial-specific immune response: Gender and previous BCG vaccination status.

    Science.gov (United States)

    Rhodes, Sophie J; Knight, Gwenan M; Fielding, Katherine; Scriba, Thomas J; Pathan, Ansar A; McShane, Helen; Fletcher, Helen; White, Richard G

    2016-01-01

    A more effective tuberculosis (TB) vaccine is needed to eliminate TB disease. Many new vaccine candidates enhance the immunogenicity of the existing vaccine, Bacillus Calmette-Guérin (BCG). Understanding BCG induced immune variation is key to developing a new vaccine. We aimed to establish if individual-level covariates were associated with cell-mediated immune response (interferon gamma (IFN-γ)) at vaccine trial enrolment (baseline) in a long-term retrospective analysis (LTR) and after BCG vaccination in a short-term prospective analysis (STP). Four covariates were analysed: gender, country, BCG vaccination history and monocyte/lymphocyte cell count ratio. Univariable and multivariable linear regression were conducted on IFN-γ response at baseline for LTR, and area under the curve (AUC), 24 week and peak IFN-γ response for STP. Previous BCG vaccination was strongly associated with higher IFN-γ response at baseline (LTR analysis) (p-values response (p-value = 0.1). BCG revaccination was strongly associated with a larger response increase than primary-vaccination (AUC & peak p-values 0.1). This analysis suggests that previous BCG vaccination and gender are associated with durable IFN-γ responses. Vaccine trials may need to stratify by BCG vaccination history and gender. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  16. Immunotherapeutic effect of BCG-polysaccharide nucleic acid powder on Mycobacterium tuberculosis-infected mice using microneedle patches.

    Science.gov (United States)

    Yan, Qinying; Liu, Houming; Cheng, Zhigang; Xue, Yun; Cheng, Zhide; Dai, Xuyong; Shan, Wanshui; Chen, Fan

    2017-11-01

    Polysaccharide nucleic acid fractions of bacillus Calmette-Guérin, termed BCG-PSN, have traditionally been used as immunomodulators in the treatment of dermatitis and allergic diseases. While the sales of injectable BCG-PSN have shown steady growth in recent years, no reports of using BCG-PSN powder or its immunotherapeutic effects exist. Here, BCG-PSN powder was applied directly to the skin to evaluate the immunotherapeutic effects on mice infected with Mycobacterium tuberculosis (MTB). In total, 34 μg of BCG-PSN powder could be loaded into a microneedle patch (MNP). Mice receiving BCG-PSN powder delivered via MNP exhibited significantly increased IFN-γ and TNF-α production in peripheral blood CD4 + T cells and improved pathological changes in their lungs and spleens compared to control group mice. The immunotherapeutic effect of BCG-PSN powder delivered via MNP was better than that delivered via intramuscular injection to some extent. Furthermore, MNPs eliminate the side effects of syringes, and this study demonstrated that BCG-PSN can be clinically administrated in powder form.

  17. Neonatal BCG has no effect on allergic sensitization and suspected food allergy until 13 months.

    Science.gov (United States)

    Thøstesen, Lisbeth Marianne; Kjaer, Henrik Fomsgaard; Pihl, Gitte Thybo; Nissen, Thomas Nørrelykke; Birk, Nina Marie; Kjaergaard, Jesper; Jensen, Aksel Karl Georg; Aaby, Peter; Olesen, Annette Wind; Stensballe, Lone Graff; Jeppesen, Dorthe Lisbeth; Benn, Christine Stabell; Kofoed, Poul-Erik

    2017-09-01

    Vaccination with Bacillus Calmette-Guérin (BCG) is used in many countries as protection against tuberculosis. Studies have suggested that BCG may also have non-specific effects, reducing non-tuberculosis mortality, morbidity, and atopic manifestations. In this study, we evaluated the effect of neonatal BCG vaccination on allergic sensitization and suspected food allergy at 13 months of age. The Danish Calmette Study was conducted from 2012 to 2015 at three Danish hospitals. Within 7 days of birth, the 4262 newborns of 4184 included mothers were randomized 1:1 to BCG or to a no-intervention control group. Exclusion criteria were gestational age BCG group and 6.1% (126/2061) of the control group suspected food allergy, resulting in a risk ratio comparing BCG-vaccinated children with control children of 0.91 (95% CI 0.71-1.16). Among 1370 blood samples, sensitization (Phadiatop Infant >0.35 kUA/L) was found in 55 of 743 (7.4%) children in the BCG group and 50 of 627 (8.0%) of the control group (risk ratio 0.94 [0.65-1.36]). In this randomized clinical trial, neonatal BCG had no significant effect on suspected food allergy or on sensitization at 13 months of age. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

  18. Recombinant Mycobacterium bovis BCG producing IL-18 reduces IL-5 production and bronchoalveolar eosinophilia induced by an allergic reaction.

    Science.gov (United States)

    Biet, F; Duez, C; Kremer, L; Marquillies, P; Amniai, L; Tonnel, A-B; Locht, C; Pestel, J

    2005-08-01

    Allergic reactions occur through the exacerbated induction of a Th2 cell type expression profile and can be prevented by agents favoring a Th1 profile. Bacillus Calmette-Guérin (BCG) is able to induce high IFN-gamma levels and has been shown to decrease experimentally induced allergy. The induction of IFN-gamma is mediated by interleukin (IL)-12 known to be secreted upon mycobacterial infections and can be enhanced by IL-18 acting in synergy with IL-12. We evaluated the ability of a recombinant BCG strain producing IL-18 (rBCG) to modify the Th2 type responses in a murine model of ovalbumin (OVA)-dependent allergic reaction. Mice were injected intraperitoneally or intranasally with OVA at days 0 and 15 and exposed to an OVA aerosol challenge at days 29, 30, 31 and 34. At days 0 and 15, two additional groups of mice received OVA together with 5 x 10(6) colony forming units of either rBCG or nonrecombinant BCG. A time-course analysis of OVA-specific immunoglobulin (Ig)E, IgG1 and IgG2a levels indicated no significant difference between the three groups of mice. However, following in vitro stimulation with OVA, lymph node cells from rBCG-treated mice produced less IL-5 and more IFN-gamma than those of mice injected with nonrecombinant BCG. In addition, 48 h after the last OVA challenge, a strong reduction of bronchoalveolar eosinophilia was found in the rBCG-injected mice compared to the nontreated or nonrecombinant BCG-treated groups. These results indicate that the production of IL-18 by rBCG may enhance the immunomodulatory properties of BCG that suppress pulmonary Th2 responses and, in particular, decrease airway eosinophilia.

  19. Mitogen-activated protein kinases and NFκB are involved in SP-A-enhanced responses of macrophages to mycobacteria

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    Vigerust David J

    2009-07-01

    Full Text Available Abstract Background Surfactant protein A (SP-A is a C-type lectin involved in surfactant homeostasis as well as host defense in the lung. We have recently demonstrated that SP-A enhances the killing of bacillus Calmette-Guerin (BCG by rat macrophages through a nitric oxide-dependent pathway. In the current study we have investigated the role of tyrosine kinases and the downstream mitogen-activated protein kinase (MAPK family, and the transcription factor NFκB in mediating the enhanced signaling in response to BCG in the presence of SP-A. Methods Human SP-A was prepared from alveolar proteinosis fluid, and primary macrophages were obtained by maturation of cells from whole rat bone marrow. BCG-SP-A complexes were routinely prepared by incubation of a ratio of 20 μg of SP-A to 5 × 105 BCG for 30 min at 37°C. Cells were incubated with PBS, SP-A, BCG, or SP-A-BCG complexes for the times indicated. BCG killing was assessed using a 3H-uracil incorporation assay. Phosphorylated protein levels, enzyme assays, and secreted mediator assays were conducted using standard immunoblot and biochemical methods as outlined. Results Involvement of tyrosine kinases was demonstrated by herbimycin A-mediated inhibition of the SP-A-enhanced nitric oxide production and BCG killing. Following infection of macrophages with BCG, the MAPK family members ERK1 and ERK2 were activated as evidence by increased tyrosine phosphorylation and enzymatic activity, and this activation was enhanced when the BCG were opsonized with SP-A. An inhibitor of upstream kinases required for ERK activation inhibited BCG- and SP-A-BCG-enhanced production of nitric oxide by approximately 35%. Macrophages isolated from transgenic mice expressing a NFκB-responsive luciferase gene showed increased luciferase activity following infection with BCG, and this activity was enhanced two-fold in the presence of SP-A. Finally, lactacystin, an inhibitor of IκB degradation, reduced BCG- and SP-A-BCG

  20. Lupus vulgaris: report of two cases.

    Science.gov (United States)

    Wozniacka, Anna; Schwartz, Robert A; Sysa-Jedrzejowska, Anna; Borun, Marta; Arkuszewska, Cecylia

    2005-04-01

    Although there has been a steady decline in the incidence of tuberculosis in recent years, it persists in some regions, and where AIDS is especially prevalent, the number of new cases has been increasing. Thus, cutaneous tuberculosis has re-emerged in areas with a high incidence of HIV infection and multidrug-resistant pulmonary tuberculosis. Lupus vulgaris has been and remains the most common form of cutaneous tuberculosis. Cutaneous manifestations of disseminated tuberculosis are unusual, being seen in less than 0.5% of cases. Scrofuloderma, tuberculosis verrucosa cutis and lupus vulgaris comprise most cutaneous tuberculosis cases. Bacillus Calmette-Guerin (BCG) is derived from an attenuated strain of Mycobacterium bovis and is employed beneficially as a relatively safe vaccination in Poland and other countries in which the prevalence of tuberculosis is high. However, BCG vaccination may produce complications, including disseminated BCG and lupus vulgaris, the latter seen in one of our two patients in whom lupus vulgaris at the inoculation site followed a second vaccination with BCG 12 years after the initial one. A similar phenomenon has been described after immunotherapy with BCG vaccination. Re-infection (secondary) inoculation cutaneous tuberculosis may also occur as a result of BCG vaccination, producing either lupus vulgaris or tuberculosis verrucosa cutis, probably depending upon the patient's degree of cell-mediated immunity. However, most lupus vulgaris cases are not associated with vaccination with BCG, as occurred in our first patient. For those who do develop lupus vulgaris, it can be persistent for a long period, in some cases for many decades. In the second patient we describe a lengthy duration and cutaneous reactivation at distant sites after more than 40 years.

  1. Mycobacterium bovis BCG promotes tumor cell survival from tumor necrosis factor-α-induced apoptosis.

    Science.gov (United States)

    Holla, Sahana; Ghorpade, Devram Sampat; Singh, Vikas; Bansal, Kushagra; Balaji, Kithiganahalli Narayanaswamy

    2014-09-11

    Increased incidence of lung cancer among pulmonary tuberculosis patients suggests mycobacteria-induced tumorigenic response in the host. The alveolar epithelial cells, candidate cells that form lung adenocarcinoma, constitute a niche for mycobacterial replication and infection. We thus explored the possible mechanism of M. bovis Bacillus Calmette-Guérin (BCG)-assisted tumorigenicity in type II epithelial cells, human lung adenocarcinoma A549 and other cancer cells. Cancer cell lines originating from lung, colon, bladder, liver, breast, skin and cervix were treated with tumor necrosis factor (TNF)-α in presence or absence of BCG infection. p53, COP1 and sonic hedgehog (SHH) signaling markers were determined by immunoblotting and luciferase assays, and quantitative real time PCR was done for p53-responsive pro-apoptotic genes and SHH signaling markers. MTT assays and Annexin V staining were utilized to study apoptosis. Gain- and loss-of-function approaches were used to investigate the role for SHH and COP1 signaling during apoptosis. A549 xenografted mice were used to validate the contribution of BCG during TNF-α treatment. Here, we show that BCG inhibits TNF-α-mediated apoptosis in A549 cells via downregulation of p53 expression. Substantiating this observation, BCG rescued A549 xenografts from TNF-α-mediated tumor clearance in nude mice. Furthermore, activation of SHH signaling by BCG induced the expression of an E3 ubiquitin ligase, COP1. SHH-driven COP1 targeted p53, thereby facilitating downregulation of p53-responsive pro-apoptotic genes and inhibition of apoptosis. Similar effects of BCG could be shown for HCT116, T24, MNT-1, HepG2 and HELA cells but not for HCT116 p53(-/-) and MDA-MB-231 cells. Our results not only highlight possible explanations for the coexistence of pulmonary tuberculosis and lung cancer but also address probable reasons for failure of BCG immunotherapy of cancers.

  2. BCG+MMC trial: adding mitomycin C to BCG as adjuvant intravesical therapy for high-risk, non-muscle-invasive bladder cancer: a randomised phase III trial (ANZUP 1301)

    International Nuclear Information System (INIS)

    Hayne, Dickon; Stockler, Martin; McCombie, Steve P.; Chalasani, Venu; Long, Anne; Martin, Andrew; Sengupta, Shomik; Davis, Ian D.

    2015-01-01

    Despite adequate trans-urethral resection of the bladder tumour (TURBT), non-muscle-invasive bladder cancer (NMIBC) is associated with high rates of recurrence and progression. Instillation of Bacillus Calmette-Guérin (BCG) into the urinary bladder after TURBT (adjuvant intravesical administration) reduces the risk of both recurrence and progression, and this is therefore the standard of care for high-risk tumours. However, over 30 % of people still recur or progress despite optimal delivery of BCG. Our meta-analysis suggests that outcomes might be improved further by using an adjuvant intravesical regimen that includes both mitomycin and BCG. These promising findings require corroboration in a definitive, large scale, randomised phase III trial using standard techniques for intravesical administration. The BCG + MMC trial (ANZUP 1301) is an open-label, randomised, stratified, two-arm multi-centre phase III trial comparing the efficacy and safety of standard intravesical therapy (BCG alone) against experimental intravesical therapy (BCG and mitomycin) in the treatment of adults with resected, high-risk NMIBC. Participants in the control group receive standard treatment with induction (weekly BCG for six weeks) followed by maintenance (four-weekly BCG for ten months). Participants in the experimental group receive induction (BCG weeks 1, 2, 4, 5, 7, and 8; mitomycin weeks 3, 6, and 9) followed by four-weekly maintenance (mitomycin weeks 13, 17, 25, 29, 37, and 41; BCG weeks 21, 33, and 45). The trial aims to include 500 participants who will be centrally randomised to one of the two treatment groups in a 1:1 ratio stratified by T-stage, presence of CIS, and study site. The primary endpoint is disease-free survival; secondary endpoints are disease activity, time to recurrence, time to progression, safety, health-related quality of life, overall survival, feasibility, and resource use

  3. [Disseminated BCG infection revealing X-linked severe combined immunodeficiency].

    Science.gov (United States)

    Marchand, I; Mahé, E; Clérici, T; Saiag, P; Chevallier, B

    2008-01-01

    Live attenuated Bacillus Calmette-Guérin (BCG) vaccine is rarely responsible for disseminated infection. We report a case of X-linked severe combined immunodeficiency (SCID) revealed by a disseminated skin infection. A 4-month-old baby was hospitalized for prolonged gastroenteritis. He was in poor general condition, with prolonged fever, oral and gluteal candidiasis and purple nodules associated with ulceration of the BCG scar. The absence of a thymus, T-cells and NK-cells, and the presence of nonfunctional B-lymphocytes led to a diagnosis of SCID. Biopsies of nodules revealed a dermal infiltrate without necrosis. A Ziehl-Neelson stain was highly positive and the culture grew Mycobacterium bovis. Treatment consisted of a four-drug antibiotic regimen directed against M. bovis combined with gamma interferon, immunoglobulins and antibiotic prophylaxis by cotrimoxazole and was followed by a haploid-identical bone marrow transplant without rejection at six months. The early death of the child's maternal uncle from sepsis suggested X-linked transmission, which was subsequently confirmed by genetic analysis. BCG vaccination can cause serious infections in immunocompromised subjects. Skin involvement is extremely rare but may be the first sign of SCID, of which the X-linked form is the most common and corresponds to a variety of mutations in the gene coding for the gamma chain common to several interleukin receptors. Genetic counselling is essential to identify female carriers and allow early antenatal diagnosis. Bone marrow transplantation is the only treatment.

  4. Early versus late BCG vaccination in HIV-1-exposed infants in Uganda: study protocol for a randomized controlled trial.

    Science.gov (United States)

    Nankabirwa, Victoria; Tumwine, James K; Namugga, Olive; Tylleskär, Thorkild; Ndeezi, Grace; Robberstad, Bjarne; Netea, Mihai G; Sommerfelt, Halvor

    2017-03-31

    Bacillus Calmette-Guérin (BCG) vaccination may have nonspecific effects, i.e., effects on childhood morbidity and mortality that go beyond its effect on the risk of childhood tuberculosis (TB). Though the available scientific literature is mostly from observational studies, and is fraught with controversy, BCG vaccination at birth may protect infants in high-mortality populations against serious infections other than TB. Yet, other studies indicate that giving BCG later in infancy may modify immune responses to non-TB antigens and potentially enhance immunity, potentially also against tuberculosis (TB). It is unclear whether BCG vaccination very early in life offers adequate protection against TB and other infections among HIV-1-exposed children because even those who remain uninfected with HIV-1 show signs of impaired immunocompetence early in infancy. This study will compare BCG vaccination at birth with BCG vaccination at 14 weeks of age in HIV-1-exposed infants. This is an individually randomized controlled trial in 2200 HIV-1-exposed infants. The intervention is BCG vaccination within 24 h of birth while the comparator is BCG given at 14 weeks of age. The study co-primary outcomes are severe illness in the first 14 weeks of life, and production of tumor necrosis factor, interleukin (IL)-1β, IL-6 and interferon-γ in response to mycobacterial and nonmycobacterial antigens. The study is being conducted in three health centers in Uganda. A well-timed BCG vaccination could have important nonspecific effects in HIV-1-exposed infants. This trial could inform the development of appropriate timing of BCG vaccination for HIV-1-exposed infants. ClinicalTrials.gov, identifier: NCT02606526 . Registered on 12 November 2015.

  5. Low birth weight infants and Calmette-Guérin bacillus vaccination at birth

    DEFF Research Database (Denmark)

    Roth, Adam Anders Edvin; Jensen, Henrik; Garly, May-Lill

    2004-01-01

    In developing countries, low birth weight (LBW) children are often not vaccinated with Calmette-Guérin bacillus (BCG) at birth. Recent studies have suggested that BCG may have a nonspecific beneficial effect on infant mortality. We evaluated the consequences of not vaccinating LBW children at birth...

  6. Bacillus Calmette-Guérin vaccine- induced lupus vulgaris in a child.

    Science.gov (United States)

    Najem, Nabeel M; Zadeh, Valid Bagher; Al-Abdulrazzaq, Adel H; Al-Otaibi, Sultan R; Kadyan, S; Joneja, Munish

    2009-12-01

    Lupus vulgaris (LV) is a rare form of cutaneous mycobacterial infection in children. Most cases follow hematogenous or lymphatic seeding, and more rarely from exposure to bacillus Calmette- Guérin (BCG) vaccine. We report a child that received BCG vaccination and developed LV 2 months later.

  7. Bacillus Calmette-Guérin immunisation at birth and morbidity among Danish children

    DEFF Research Database (Denmark)

    Thøstesen, Lisbeth Marianne; Nissen, Thomas Nørrelykke; Kjærgaard, Jesper

    2015-01-01

    BACKGROUND: Studies from low-income countries report positive non-specific effects of early Bacillus Calmette-Guérin (BCG) immunisation on childhood health and survival. Neonatal immunisation with BCG may prime the immune system and offer partial protection against other infectious and possibly a...

  8. Evaluation of immunogenicity and protective efficacy elicited by Mycobacterium bovis BCG overexpressing Ag85A protein against Mycobacterium tuberculosis aerosol infection

    Directory of Open Access Journals (Sweden)

    Zheng Zhong Xu

    2016-01-01

    Full Text Available Mycobacterium bovis bacillus Calmette-Guérin (BCG is currently the only vaccine available against tuberculosis (TB, however, it has various levels of efficacy for preventing pulmonary TB. In this study, a recombinant BCG (rBCG::Ag85A strain overexpressing the immunodominant Ag85A antigen was constructed, and its immunogenicity and protective efficacy were evaluated. The results showed that the Ag85A protein was successfully overexpressed in rBCG::Ag85A, the Ag85A peptide–MHC complexes on draining lymph node dendritic cells of C57BL/6 mice infected with rBCG were detectable 4 h post-infection. The C57BL/6 mice infected with this strain had stronger antigen-specific interferon-gamma (IFN-γ responses and higher antibody titers than those immunized with BCG, and the protective experiments showed that the rBCG::Ag85A can provide higher but not significantly protective efficacy against Mycobacterium tuberculosis (M. tuberculosis H37Rv infection compared with BCG vaccine. Therefore, our results demonstrated the potential of rBCG::Ag85A as a vaccine candidate against TB.

  9. Differential Adverse Event Profiles Associated with BCG as a Preventive Tuberculosis Vaccine or Therapeutic Bladder Cancer Vaccine Identified by Comparative Ontology-Based VAERS and Literature Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Jiangan Xie

    Full Text Available M. bovis strain Bacillus Calmette-Guérin (BCG has been the only licensed live attenuated vaccine against tuberculosis (TB for nearly one century and has also been approved as a therapeutic vaccine for bladder cancer treatment since 1990. During its long time usage, different adverse events (AEs have been reported. However, the AEs associated with the BCG preventive TB vaccine and therapeutic cancer vaccine have not been systematically compared. In this study, we systematically collected various BCG AE data mined from the US VAERS database and PubMed literature reports, identified statistically significant BCG-associated AEs, and ontologically classified and compared these AEs related to these two types of BCG vaccine. From 397 VAERS BCG AE case reports, we identified 64 AEs statistically significantly associated with the BCG TB vaccine and 14 AEs with the BCG cancer vaccine. Our meta-analysis of 41 peer-reviewed journal reports identified 48 AEs associated with the BCG TB vaccine and 43 AEs associated with the BCG cancer vaccine. Among all identified AEs from VAERS and literature reports, 25 AEs belong to serious AEs. The Ontology of Adverse Events (OAE-based ontological hierarchical analysis indicated that the AEs associated with the BCG TB vaccine were enriched in immune system (e.g., lymphadenopathy and lymphadenitis, skin (e.g., skin ulceration and cyanosis, and respiratory system (e.g., cough and pneumonia; in contrast, the AEs associated with the BCG cancer vaccine mainly occurred in the urinary system (e.g., dysuria, pollakiuria, and hematuria. With these distinct AE profiles detected, this study also discovered three AEs (i.e., chills, pneumonia, and C-reactive protein increased shared by the BCG TB vaccine and bladder cancer vaccine. Furthermore, our deep investigation of 24 BCG-associated death cases from VAERS identified the important effects of age, vaccine co-administration, and immunosuppressive status on the final BCG

  10. Differential Adverse Event Profiles Associated with BCG as a Preventive Tuberculosis Vaccine or Therapeutic Bladder Cancer Vaccine Identified by Comparative Ontology-Based VAERS and Literature Meta-Analysis

    Science.gov (United States)

    Xie, Jiangan; Codd, Christopher; Mo, Kevin; He, Yongqun

    2016-01-01

    M. bovis strain Bacillus Calmette–Guérin (BCG) has been the only licensed live attenuated vaccine against tuberculosis (TB) for nearly one century and has also been approved as a therapeutic vaccine for bladder cancer treatment since 1990. During its long time usage, different adverse events (AEs) have been reported. However, the AEs associated with the BCG preventive TB vaccine and therapeutic cancer vaccine have not been systematically compared. In this study, we systematically collected various BCG AE data mined from the US VAERS database and PubMed literature reports, identified statistically significant BCG-associated AEs, and ontologically classified and compared these AEs related to these two types of BCG vaccine. From 397 VAERS BCG AE case reports, we identified 64 AEs statistically significantly associated with the BCG TB vaccine and 14 AEs with the BCG cancer vaccine. Our meta-analysis of 41 peer-reviewed journal reports identified 48 AEs associated with the BCG TB vaccine and 43 AEs associated with the BCG cancer vaccine. Among all identified AEs from VAERS and literature reports, 25 AEs belong to serious AEs. The Ontology of Adverse Events (OAE)-based ontological hierarchical analysis indicated that the AEs associated with the BCG TB vaccine were enriched in immune system (e.g., lymphadenopathy and lymphadenitis), skin (e.g., skin ulceration and cyanosis), and respiratory system (e.g., cough and pneumonia); in contrast, the AEs associated with the BCG cancer vaccine mainly occurred in the urinary system (e.g., dysuria, pollakiuria, and hematuria). With these distinct AE profiles detected, this study also discovered three AEs (i.e., chills, pneumonia, and C-reactive protein increased) shared by the BCG TB vaccine and bladder cancer vaccine. Furthermore, our deep investigation of 24 BCG-associated death cases from VAERS identified the important effects of age, vaccine co-administration, and immunosuppressive status on the final BCG-associated death

  11. Lupus Vulgaris Following Bcg Vaccination

    Directory of Open Access Journals (Sweden)

    R K Pandhi

    1982-01-01

    Full Text Available Three cases of lupus vulgaris developing at the site of BCG vaccination are reported. All the patients had lesions starting before the age of 15 years. Clinically and histologically the lesions ′were indistinguishable from spontaneous lupus vulgarism Treatment with streptomycin and isonicotinic acid hydrazide for 1 year produced complete resolution of lesions.

  12. Superficial Bladder Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Emmanuel Schenkman

    2004-01-01

    Full Text Available Bladder cancer treatment remains a challenge despite significant improvements in preventing disease progression and improving survival. Intravesical therapy has been used in the management of superficial transitional cell carcinoma (TCC of the urinary bladder (i.e. Ta, T1, and carcinoma in situ with specific objectives which include treating existing or residual tumor, preventing recurrence of tumor, preventing disease progression, and prolonging survival. The initial clinical stage and grade remain the main determinant factors in survival regardless of the treatment. Prostatic urethral mucosal involvement with bladder cancer can be effectively treated with Bacillus Calmette-Guerin (BCG intravesical immunotherapy. Intravesical chemotherapy reduces short-term tumor recurrence by about 20%, and long-term recurrence by about 7%, but has not reduced progression or mortality. Presently, BCG immunotherapy remains the most effective treatment and prophylaxis for TCC (Ta, T1, CIS and reduces tumor recurrence, disease progression, and mortality. Interferons, Keyhole-limpet hemocyanin (KLH, bropirimine and Photofrin-Photodynamic Therapy (PDT are under investigation in the management of TCC and early results are encouraging. This review highlights and summarizes the recent advances in therapy for superficial TCC.

  13. Increased serum anti-mycobacterial antibody titers in rheumatoid arthritis patients: Is there any specific antigenic target?

    International Nuclear Information System (INIS)

    Cetin, Emel S.; Aksoy, Ali M

    2007-01-01

    Objective was to investigate the presence of immunoreactivity against mycobacterial antigens in the sera of patients with rheumatoid arthritis (Ra) and to detect the target of the immune reaction. This study was carried out on 60 patients with RA, and 25 patients with no joint diseases in the laboratory of Clinical Microbiology Department of Ankara University Medical Faculty, Ankara, Turkey between July 2003 to January 2004. Secreted and cellular antigens of Mycobacterium tuberculosis (M. tuberculosis) H37Rv and Mycobacterium bovis (M. bovis) were isolated and purified by high performance liquid chromatography to antigenic fractions. The immunoreactivity of patient and control sera against these antigens were determined by enzyme-linked immunosorbent assay (ELISA). Immunoreactivity against mycobacterial antigens in RA patients were significantly higher than controls. Significant difference between patients and controls has been determined with M. bovis Bacillus Calmette Guerin (BCG) culture fluid and sonicate antigens, but not with M. tuberculosis H37Rv. This suggests that the antigen triggering immune response in patients with RA may belong to or mainly expressed on M. bovis BCG. The ELISA results showed significant difference between RA patients and controls with all antigenic fractions. Presence of increased immunoreactivity against mycobacterial antigens in the sera of patients with RA was detected. When statistical analysis was considered, we cannot put forward any antigenic fraction alone as the one responsible for the increased reactivity. (author)

  14. [Hemocyanins as immunostimulants].

    Science.gov (United States)

    Del Campo, Miguel; Arancibia, Sergio; Nova, Esteban; Salazar, Fabián; González, Andrea; Moltedo, Bruno; De Ioannes, Pablo; Ferreira, Jorge; Manubens, Augusto; Becker, María Inés

    2011-02-01

    Hemocyanins, the giant oxygen transporter glycoproteins of diverse mollusks, are xenogenic to the mammalian immune system and they display a remarkable immuno-genicity. Therefore they are ideal non-specific immunostimulants to treat some types of cancer. They are used as an alternative therapy for superficial urinary bladder cancer (SBC), that has been traditionally treated with Bacillus Calmette-Guerin (BCG). In contrast to BCG, hemocyanins do not cause side-effects, making them ideal for long-term repetitive treatments. Hemocyanins have also been exploited as carriers to develop antibodies against hapten molecules and peptides, as carrier-adjuvants for cutting-edge vaccines against cancer, drug addiction, and infectious diseases and in the diagnosis of parasitic diseases, such as Schistosomiasis. The hemocyanin from Megathura crenulata, also known as keyhole limpet hemocyanin (KLH), has been used for over thirty years for the purposes described above. More recently, hemoc yanin from the Chilean mollusk Concholepas concholepas (CCH) has proved to be a reliable alternative to KLH, either as carrier protein, and as a likely alternative for the immunotherapy of SBC. Despite KLH and CCH differ significantly in their origin and structure, we have demonstrated that both hemocyanins stimulate the immune system of mammals in a similar way by inducing a potent Thl-polarized cellular and humoral response.

  15. Prophylactic Sublingual Immunization with Mycobacterium tuberculosis Subunit Vaccine Incorporating the Natural Killer T Cell Agonist Alpha-Galactosylceramide Enhances Protective Immunity to Limit Pulmonary and Extra-Pulmonary Bacterial Burden in Mice

    Directory of Open Access Journals (Sweden)

    Arshad Khan

    2017-12-01

    Full Text Available Infection by Mycobacterium tuberculosis (Mtb remains a major global concern and the available Bacillus Calmette-Guerin (BCG vaccine is poorly efficacious in adults. Therefore, alternative vaccines and delivery strategies focusing on Mtb antigens and appropriate immune stimulating adjuvants are needed to induce protective immunity targeted to the lungs, the primary sites of infections and pathology. We present here evidence in support of mucosal vaccination by the sublingual route in mice using the subunit Mtb antigens Ag85B and ESAT-6 adjuvanted with the glycolipid alpha-galactosylceramide (α-GalCer, a potent natural killer T (NKT cell agonist. Vaccinated animals exhibited strong antigen-specific CD4 and CD8 T cells responses in the spleen, cervical lymph nodes and lungs. In general, inclusion of the α-GalCer adjuvant significantly enhanced these responses that persisted over 50 days. Furthermore, aerosolized Mtb infection of vaccinated mice resulted in a significant reduction of bacterial load of the lungs and spleens as compared to levels seen in naïve controls or those vaccinated with subunit proteins, adjuvant , or BCG alone. The protection induced by the Mtb antigens and-GalCer vaccine through sublingual route correlated with a TH1-type immunity mediated by antigen-specific IFN-γ and IL-2 producing T cells.

  16. Effectiveness of Routine BCG Vaccination on Buruli Ulcer Disease: A Case-Control Study in the Democratic Republic of Congo, Ghana and Togo

    Science.gov (United States)

    Phillips, Richard Odame; Phanzu, Delphin Mavinga; Beissner, Marcus; Badziklou, Kossi; Luzolo, Elysée Kalundieko; Sarfo, Fred Stephen; Halatoko, Wemboo Afiwa; Amoako, Yaw; Frimpong, Michael; Kabiru, Abass Mohammed; Piten, Ebekalisai; Maman, Issaka; Bidjada, Bawimodom; Koba, Adjaho; Awoussi, Koffi Somenou; Kobara, Basile; Nitschke, Jörg; Wiedemann, Franz Xaver; Kere, Abiba Banla; Adjei, Ohene; Löscher, Thomas; Fleischer, Bernhard; Bretzel, Gisela; Herbinger, Karl-Heinz

    2015-01-01

    Background The only available vaccine that could be potentially beneficial against mycobacterial diseases contains live attenuated bovine tuberculosis bacillus (Mycobacterium bovis) also called Bacillus Calmette-Guérin (BCG). Even though the BCG vaccine is still widely used, results on its effectiveness in preventing mycobacterial diseases are partially contradictory, especially regarding Buruli Ulcer Disease (BUD). The aim of this case-control study is to evaluate the possible protective effect of BCG vaccination on BUD. Methodology The present study was performed in three different countries and sites where BUD is endemic: in the Democratic Republic of the Congo, Ghana, and Togo from 2010 through 2013. The large study population was comprised of 401 cases with laboratory confirmed BUD and 826 controls, mostly family members or neighbors. Principal Findings After stratification by the three countries, two sexes and four age groups, no significant correlation was found between the presence of BCG scar and BUD status of individuals. Multivariate analysis has shown that the independent variables country (p = 0.31), sex (p = 0.24), age (p = 0.96), and presence of a BCG scar (p = 0.07) did not significantly influence the development of BUD category I or category II/III. Furthermore, the status of BCG vaccination was also not significantly related to duration of BUD or time to healing of lesions. Conclusions In our study, we did not observe significant evidence of a protective effect of routine BCG vaccination on the risk of developing either BUD or severe forms of BUD. Since accurate data on BCG strains used in these three countries were not available, no final conclusion can be drawn on the effectiveness of BCG strain in protecting against BUD. As has been suggested for tuberculosis and leprosy, well-designed prospective studies on different existing BCG vaccine strains are needed also for BUD. PMID:25569674

  17. Evolution and Strain Variation in BCG

    KAUST Repository

    Abdallah, Abdallah

    2017-11-07

    BCG vaccines were derived by in vitro passage, during the years 1908–1921, at the Pasteur Institute of Lille. Following the distribution of stocks of BCG to vaccine production laboratories around the world, it was only a few decades before different BCG producers recognized that there were variants of BCG, likely due to different passaging conditions in the different laboratories. This ultimately led to the lyophilization of stable BCG products in the 1950s and 1960s, but not before considerable evolution of the different BCG strains had taken place. The application of contemporary research methodologies has now revealed genomic, transcriptomic and proteomic differences between BCG strains. These molecular differences in part account for phenotypic differences in vitro between BCG strains, such as their variable secretion of antigenic proteins. Yet, the relevance of BCG variability for immunization policy remains elusive. In this chapter we present an overview of what is known about BCG evolution and its resulting strain variability, and provide some speculation as to the potential relevance for a vaccine given to over 100 million newborns each year.

  18. Evolution and Strain Variation in BCG.

    Science.gov (United States)

    Abdallah, Abdallah M; Behr, Marcel A

    2017-01-01

    BCG vaccines were derived by in vitro passage, during the years 1908-1921, at the Pasteur Institute of Lille. Following the distribution of stocks of BCG to vaccine production laboratories around the world, it was only a few decades before different BCG producers recognized that there were variants of BCG, likely due to different passaging conditions in the different laboratories. This ultimately led to the lyophilization of stable BCG products in the 1950s and 1960s, but not before considerable evolution of the different BCG strains had taken place. The application of contemporary research methodologies has now revealed genomic, transcriptomic and proteomic differences between BCG strains. These molecular differences in part account for phenotypic differences in vitro between BCG strains, such as their variable secretion of antigenic proteins. Yet, the relevance of BCG variability for immunization policy remains elusive. In this chapter we present an overview of what is known about BCG evolution and its resulting strain variability, and provide some speculation as to the potential relevance for a vaccine given to over 100 million newborns each year.

  19. Identification of surrogates and correlates of protection in protective immunity against Mycobacterium bovis infection induced in neonatal calves by vaccination with M. bovis BCG Pasteur and M. bovis BCG Danish.

    Science.gov (United States)

    Hope, J C; Thom, M L; McAulay, M; Mead, E; Vordermeier, H M; Clifford, D; Hewinson, R G; Villarreal-Ramos, B

    2011-03-01

    Vaccination of neonatal calves with Mycobacterium bovis bacillus Calmette-Guérin (BCG) induces a significant degree of protection against infection with virulent M. bovis, the causative agent of bovine tuberculosis (bTB). We compared two strains of BCG, Pasteur and Danish, in order to confirm that the current European human vaccine strain (BCG Danish) induced protective immunity in calves, and we assessed immune responses to determine correlates of protection that could assist future vaccine evaluation in cattle. Both vaccine strains induced antigen (purified protein derivate [PPD])-specific gamma interferon (IFN-γ) in whole-blood cultures. These responses were not significantly different for BCG Pasteur and BCG Danish and peaked at week 2 to 4 postvaccination. Vaccination with either BCG Danish or BCG Pasteur induced significant protection against bTB, with reductions in both lesion score and bacteriological burden evident in both groups of vaccinated calves compared with nonvaccinated control calves. Measurement of IFN-γ-expressing T lymphocytes postvaccination and postchallenge revealed both correlates and surrogates of protective efficacy. The frequency of central memory T lymphocytes present at 12 weeks postvaccination (at the time of M. bovis challenge) correlated significantly with protection. Conversely, the number of IFN-γ-expressing effector T cells present after M. bovis challenge was correlated with disease. These results demonstrate that vaccination of neonatal calves with either BCG Pasteur or BCG Danish induces protective immune responses against TB. In addition, we show that measurement of antigen-specific T lymphocyte populations may provide a reliable means for identifying protective vaccine candidates.

  20. A Case of Pott’s Disease with Epidural Abscess and Probable Cerebral Tuberculoma following Bacillus Calmette-Guérin Therapy for Superficial Bladder Cancer

    Directory of Open Access Journals (Sweden)

    Colin B Josephson

    2010-01-01

    Full Text Available Intravesical Bacillus Calmette-Guérin (BCG immunotherapy is an accepted treatment for transitional cell carcinoma of the bladder. Carcinoma in situ of the bladder progresses to invasive muscular disease in approximately 54% of untreated patients, mandating early initiation of therapy once the diagnosis is confirmed. Should BCG treatment fail, an additional course of BCG combined with interferon-alpha, both administered intravesically, is a promising second-line immunotherapy. In greater than 95% of patients, BCG is tolerated without significant morbidity or mortality. However, both early (within three months of the original treatment and late presentations of systemic infection resulting from intravesical BCG treatment have been described. The present study describes the course of a 75-year-old man with a late presentation of BCG vertebral osteomyelitis, discitis, epidural abscess, bilateral psoas abscesses and probable cerebral tuberculoma, following treatment regimens of intravesical BCG followed by intravesical BCG plus interferon-alpha 2b.

  1. The BCGΔBCG1419c strain, which produces more pellicle in vitro, improves control of chronic tuberculosis in vivo.

    Science.gov (United States)

    Pedroza-Roldán, César; Guapillo, Carolina; Barrios-Payán, Jorge; Mata-Espinosa, Dulce; Aceves-Sánchez, Michel de Jesús; Marquina-Castillo, Brenda; Hernández-Pando, Rogelio; Flores-Valdez, Mario Alberto

    2016-09-14

    Mycobacterium tuberculosis (Mtb) has been a threat to humans since ancient times, and it is the main causative agent of tuberculosis (TB). Until today, the only licensed vaccine against Mtb is the live attenuated M. bovis Bacillus Calmette-Guérin (BCG), which has variable levels of protection against the pulmonary form of infection. The quest for a new vaccine is a priority given the rise of multidrug-resistant Mtb around the world, as well as the tremendous burden imposed by latent TB. The objective of this study was to evaluate the immunogenicity and capacity of protection of a modified BCG strain (BCGΔBCG1419c) lacking the c-di-GMP phosphodiesterase gene BCG1419c, in diverse mice models. In a previous report, we have shown that BCGΔBCG1419c was capable of increasing biofilm production and after intravenous infection of immunocompetent mice; this strain persisted longer in lungs than parental BCG Pasteur. This led us to hypothesize that BCGΔBCG1419c might therefore possess some advantage as vaccine candidate. Our results in this report indicate that compared to conventional BCG, vaccination with BCGΔBCG1419c induced a better activation of specific T-lymphocytes population, was equally effective in preventing weight loss despite being used at lower dose, reduced tissue damage (pneumonic scores), increased local IFNγ(+) T cells, and diminished bacterial burden in lungs of BALB/c mice infected intratracheally with high dose Mtb H37Rv to induce progressive TB. Moreover, vaccination with BCGΔBCG1419c improved resistance to reactivation after immunosuppression induced by corticosterone in a murine model of chronic infection similar to latent TB. Furthermore, despite showing increased persistence in immunocompetent mice, BCGΔBCG1419c was as attenuated as parental BCG in nude mice. To our knowledge, this is the first demonstration that a modified BCG vaccine candidate with increased pellicle/biofilm production has the capacity to protect against Mtb challenge in

  2. Anti-tumour research of recombinant BCG using BZLF1 and hGM-CSF fusion genes.

    Science.gov (United States)

    Xue, Qing-Jie; Li, Yun-Qing; Yang, Chun-Qing; Chen, Ting; Li, Xiu-Zhen; Cheng, Baohua; Wang, Chun-Mei

    2017-03-14

    The random primer Oligo(dT) 15 was used in RT-PCR to obtain cDNA from the human granulocyte macrophage colony stimulating factor (hGM-CSF) gene and the Epstein-Barr virus (EBV) gene BZLF1. Then, the sequence splicing overlap extension method was used to obtain a GCBF fusion gene containing a linker sequence that encoded the polypeptide (Gly 4 Ser) 3 . The GCBF fusion gene was inserted into pMV261, which was then transformed into competent E. coli DH5 alpha cells, and positive cells were selected based on kanamycin resistance on LB plates. The recombinant plasmid pMVBZLF1 was extracted from E. coli, and BCG (Bacillus Calmette-Guérin) was transformed into competent cells. According to the RT-PCR results, the target genes hGM-CSF and BZLF1 were 461bp and 788bp in size, which was in agreement with the expected values. Construction of the recombinant plasmid by double enzyme digestion, amplification, sequencing and Western blotting confirmed that the GCBF fusion gene (1204bp) was correctly inserted into pMV261, successfully transformed into BCG competent cells, and properly expressed. After mice were injected with rBCG (recombinant BCG), antibody levels were detected using ELISA, and spleen cells were obtained and the killing rates of specific CTLs by rBCG were detected using a CTL assay kit. Then, the influence of rBCG on tumour cells was analysed in C57BL/6 mice. We found that rBCG-secreting cytokines hybridized with hGM-CSF and BZLF1 antibodies and that the rBCG vaccine stimulated antibody production in C57BL/6 mice. The specific cytotoxic effects of the spleen cells from the rBCG group on EB virus-positive tumour cells was significantly different from the cytotoxic effects of the control group cells (P<0.01). CD8 + T and CD4 + T lymphocytes were detected in the tumour tissues of the rBCG group mice by flow cytometry, indicating that CD8 + T and CD4 + T lymphocytes infiltrated into the tumour tissue in the mice. Morphological observations of the tumour sections from

  3. Granulomatous epididymo-orchitis, a rare complication of intravesical bacillus Calmette-Guérin therapy for urothelial cancer

    DEFF Research Database (Denmark)

    Harving, Signe Sofienberg; Asmussen, Lisa; Roosen, Jens U

    2009-01-01

    Only a few cases of tuberculous epididymo-orchitis after bacillus Calmette-Guérin (BCG) therapy have been published. This report presents a case of granulomatous epididymo-orchitis after intravesical BCG therapy in a patient presenting with pain and unilateral swelling of the scrotal content....... This complication should always be considered when a patient presents with these symptoms after BCG therapy. Isoniazid may be used as a first choice of treatment....

  4. Non-specific effects of BCG vaccination on morbidity among children in Greenland: a population-based cohort study.

    Science.gov (United States)

    Haahr, S; Michelsen, S W; Andersson, M; Bjorn-Mortensen, K; Soborg, B; Wohlfahrt, J; Melbye, M; Koch, A

    2016-12-01

    The potential non-specific effects of BCG (Bacillus Calmette-Guérin) vaccination, with reported reduction of infectious disease morbidity among vaccinated children, in addition to the protective effect against tuberculosis (TB), are highly debated. In Greenland, BCG vaccination was introduced in 1955, but temporarily discontinued from 1991 to 1996 due to nationwide policy changes. Using the transient vaccination stop, we aimed to investigate possible non-specific effects of BCG vaccination by measuring nation-wide hospitalization rates due to infectious diseases other than TB among vaccinated and unvaccinated children. A retrospective cohort study including all children born in Greenland aged 3 months to 3 years from 1989 to 2004. A personal identification number assigned at birth allowed for follow-up through national registers. Information on hospitalization due to infectious diseases was obtained from the Greenlandic inpatient register using ICD-8 and ICD-10 codes. Participants with notified TB were censored. Incidence rate ratios (IRR) were estimated using Poisson regression. Overall, 19 363 children, hereof 66% BCG-vaccinated, were followed for 44 065 person-years and had 2069 hospitalizations due to infectious diseases. IRRs of hospitalization in BCG-vaccinated as compared with BCG-unvaccinated children were 1.07 [95% confidence interval (CI) 0.96-1.20] for infectious diseases overall, and specifically 1.10 (95% CI 0.98-1.24) for respiratory tract infections. Among BCG-vaccinated children aged 3 to 11 months, the IRR of hospitalization due to infectious diseases was 1.00 (95% CI 0.84-1.19) as compared with BCG-unvaccinated children. Our results do not support the hypothesis that neonatal BCG vaccination reduces morbidity in children caused by infectious diseases other than TB. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association

  5. Characterization of inflammasome-related genes in urine sediments of patients receiving intravesical BCG therapy.

    Science.gov (United States)

    Poli, Giulia; Cochetti, Giovanni; Boni, Andrea; Egidi, Maria Giulia; Brancorsini, Stefano; Mearini, Ettore

    2017-12-01

    Nowadays, the intravesical Bacillus Calmette-Guérin (BCG) instillation is the method of choice for the postsurgical treatment of high-grade nonmuscle-invasive bladder cancer , to reduce both recurrence rate and risk of progression. BCG is hypothesized to correct the immune system disequilibrium occurring during carcinogenesis, through an immunostimulation with detrimental effects for tumoral cells. Inflammation plays a crucial role in tumor progression. The deregulation of inflammasomes upon carcinogenesis underlines its importance both in physiologic and pathologic human conditions. Nucleotide oligomerization domain-like receptors (NLRs) are key components of this molecular platform and the increase in expression of some members of nucleotide oligomerization domain-like receptors family (NLRP3, NLRP4, NLRP9, and NLR family apoptosis inhibitory protein [NAIP]) in urothelial carcinoma was already demonstrated in our previous work. The first aim of the present work was to estimate whether these inflammasome-related genes show alterations during BCG instillations. The expression levels of NLRP3, NLRP4, NLRP9, and NAIP were assessed in the urine sediments from patients, which underwent surgery for superficial high-grade bladder cancer and further subjected to serial BCG instillations. The eventual association between NLR expression and recurrence was also evaluated. The expression of CK20 mRNA as confirmed marker of bladder cancer was also assayed. Urine were sampled from patients harboring high-grade superficial bladder cancer and treated postsurgically with weekly BCG instillations for 6 weeks (induction cycle, I). Urine sediments were processed and resulting RNA was reverse transcribed and used for amplification by real-time PCR. After surgery, CK20 levels decreased significantly whereas NLRP4 and NLRP9 genes showed an increase. NLRP3 and NAIP remained substantially unmodified. CK20 mRNA decreased at the end of the induction cycle. NLRP3 did not show relevant

  6. Improvement of Thermal Stability of BCG Vaccine

    Science.gov (United States)

    Jahanbakhsh Sefidi, Fatemeh; Kaghazian, Homan; Moradli, Gholam Ali; Hassanzadeh, Seyed Mehdi

    2017-11-01

    Thermal stability (TS) is a part of the BCG vaccine characterization by which the consistency of process in BCG vaccine production could be confirmed. To enhance the TS of the vaccine, some prevalent stabilizers in different concentrations were added to the final formulation of BCG bulk prior to Freeze-drying process. We found a formulation more effective than the current stabilizer for retaining the higher viability of lyophilized BCG vaccine produced by Pasteur Institute of Iran. In the design of experiments using Taguchi method, lactose, trehalose, glucose, dextran, and monosodium glutamate were added to the final formulation of BCG bulk prior to freeze-drying process. Viability of the samples was determined by counting the colony forming unit. Maximum signal-to-noise ratio equal to maximum TS and viability was obtained by adding lactose, dextran, and glutamate in defined concentrations. Adding the stabilizers had a significant impact on TS of BCG vaccine to meet the quality requirements.

  7. Tuberculous spondylitis following BCG vaccination

    International Nuclear Information System (INIS)

    Mueller-Miny, H.; Bick, U.; Lengerke, H.J. von; Ritter, J.; Reiser, M.

    1990-01-01

    A case of a rare form of BCG osteomyelitis in the spine is presented. After vaccination, the disease started with a lymphadenitis. Later an abscess extended from the pelvic along the psoas muscles into the retroperitoneum. The soft tissue mass extended paraspinally and epidural involvement was also apparent. The vertebral involvement was detected by CT. The radiological findings are discussed with reference to the literature. (orig.)

  8. Tuberculin reaction and BCG scar

    DEFF Research Database (Denmark)

    Timmermann, Clara Amalie Gade; Biering-Sørensen, Sofie; Aaby, Peter

    2015-01-01

    rate ratio (MRR) comparing children with a BCG scar with those without was 0.42 (95% CI = 0.19; 0.93). There was a similar tendency for TST positivity: MRR = 0.47 (95% CI = 0.14; 1.54). For LBW children who had both a positive TST reaction and a scar, the MRR was 0.22 (95% CI = 0.05; 0.87). For NBW...

  9. Tuberculosis: looking beyond BCG vaccines.

    Directory of Open Access Journals (Sweden)

    Mustafa Abu S

    2003-01-01

    Full Text Available Tuberculosis (TB is an infectious disease of international importance and ranks among the top 10 causes of death in the World. About one-third of the world′s population is infected with Mycobacterium tuberculosis. Every year, approximately eight million people develop active disease and two million die of TB. The currently used BCG vaccines have shown variable protective efficacies against TB in different parts of the world. Moreover, being a live vaccine, BCG can be pathogenic in immunocompromised recipients. Therefore, there is an urgent need to develop new vaccines against TB. The comparative genome analysis has revealed the existence of several M. tuberculosis-specific regions that are deleted in BCG. The work carried out to determine the immunological reactivity of proteins encoded by genes located in these regions revealed several major antigens of M. tuberculosis, including the 6 kDa early secreted antigen target (ESAT6. Immunization with ESAT6 and its peptide (aa51-70 protects mice challenged with M. tuberculosis. The protective efficacy of immunization further improves when ESAT6 is recombinantly fused with M. tuberculosis antigen 85B. In addition, ESAT6 delivered as a DNA vaccine is also protective in mice. Whether these vaccines would be safe or not cannot be speculated. The answer regarding the safety and efficacy of these vaccines has to await human trials in different parts of the world.

  10. Genomic expression catalogue of a global collection of BCG vaccine strains show evidence for highly diverged metabolic and cell-wall adaptations

    KAUST Repository

    Abdallah, Abdallah

    2015-10-21

    Although Bacillus Calmette-Guérin (BCG) vaccines against tuberculosis have been available for more than 90 years, their effectiveness has been hindered by variable protective efficacy and a lack of lasting memory responses. One factor contributing to this variability may be the diversity of the BCG strains that are used around the world, in part from genomic changes accumulated during vaccine production and their resulting differences in gene expression. We have compared the genomes and transcriptomes of a global collection of fourteen of the most widely used BCG strains at single base-pair resolution. We have also used quantitative proteomics to identify key differences in expression of proteins across five representative BCG strains of the four tandem duplication (DU) groups. We provide a comprehensive map of single nucleotide polymorphisms (SNPs), copy number variation and insertions and deletions (indels) across fourteen BCG strains. Genome-wide SNP characterization allowed the construction of a new and robust phylogenic genealogy of BCG strains. Transcriptional and proteomic profiling revealed a metabolic remodeling in BCG strains that may be reflected by altered immunogenicity and possibly vaccine efficacy. Together, these integrated-omic data represent the most comprehensive catalogue of genetic variation across a global collection of BCG strains.

  11. Genomic expression catalogue of a global collection of BCG vaccine strains show evidence for highly diverged metabolic and cell-wall adaptations

    Science.gov (United States)

    Abdallah, Abdallah M.; Hill-Cawthorne, Grant A.; Otto, Thomas D.; Coll, Francesc; Guerra-Assunção, José Afonso; Gao, Ge; Naeem, Raeece; Ansari, Hifzur; Malas, Tareq B.; Adroub, Sabir A.; Verboom, Theo; Ummels, Roy; Zhang, Huoming; Panigrahi, Aswini Kumar; McNerney, Ruth; Brosch, Roland; Clark, Taane G.; Behr, Marcel A.; Bitter, Wilbert; Pain, Arnab

    2015-01-01

    Although Bacillus Calmette-Guérin (BCG) vaccines against tuberculosis have been available for more than 90 years, their effectiveness has been hindered by variable protective efficacy and a lack of lasting memory responses. One factor contributing to this variability may be the diversity of the BCG strains that are used around the world, in part from genomic changes accumulated during vaccine production and their resulting differences in gene expression. We have compared the genomes and transcriptomes of a global collection of fourteen of the most widely used BCG strains at single base-pair resolution. We have also used quantitative proteomics to identify key differences in expression of proteins across five representative BCG strains of the four tandem duplication (DU) groups. We provide a comprehensive map of single nucleotide polymorphisms (SNPs), copy number variation and insertions and deletions (indels) across fourteen BCG strains. Genome-wide SNP characterization allowed the construction of a new and robust phylogenic genealogy of BCG strains. Transcriptional and proteomic profiling revealed a metabolic remodeling in BCG strains that may be reflected by altered immunogenicity and possibly vaccine efficacy. Together, these integrated-omic data represent the most comprehensive catalogue of genetic variation across a global collection of BCG strains. PMID:26487098

  12. Initial conservative treatment for grade 3 Ta-1 superficial bladder cancer

    International Nuclear Information System (INIS)

    Fujimoto, Kiyohide; Chihara, Yoshitomo; Kondo, Hideaki; Hirao, Yoshihiko

    2006-01-01

    We retrospectively investigated the therapeutic outcomes of our series of 7 Ta and 62 T1 bladder cancers with grade 3 (G3) malignancy in 61 men and 8 women having a mean age of 66.2 years. Following transurethral resection of bladder tumor (TURBT), 35 and 6 patients received intravesical instillations of bacillus Calmette-Guerin (BCG) and anthracycline-derivants, respectively, whereas 15 received no adjuvant therapy. Five and 2 patients received systemic and local chemotherapy with irradiation, respectively, and six underwent radical cystectomy for invasive potential. The 5-year non-recurrence, progression-free, and overall (cancer-specific) survival rates were 66, 82%, and 76 (88)%, respectively, after a median follow-up of 52 months. The 5-year non-recurrence rates were 24% in non-adjuvant, 85% in BCG, 0% in anthracycline-derivants, 65% in systemic and local chemoradiation therapy, and 68% in cystectomy. The 5-year progression-free and overall (cancer-specific) survival rates of the patients treated with BCG instillation were 91% and 94 (100)%. There were no significant differences in the 5-year non-recurrence and progression-free rates between 12 patients with carcinoma in situ (CIS) and 23 patients without CIS. Complete TUR of all visible tumors and a reliable histopathological diagnosis of appropriate specimens bearing the muscle layer are mandatory for assessment of recurrence. G3 Ta-1 bladder cancers and CIS showed a high risk of recurrence, and required aggressive treatment. Since BCG therapy following TURBT significantly reduced the risk of recurrence and progression, adjuvant BCG therapy is considered to be the most promising initial conservative treatment for G3 Ta-1 bladder cancers. (author)

  13. Disseminated Mycobacterium bovis Infection Complicating Intravesical BCG Instillation for the Treatment of Superficial Transitional Cell Carcinoma of the Bladder.

    Science.gov (United States)

    Elzein, Fatehi; Albogami, Nada; Saad, Mustafa; El Tayeb, Nazik; Alghamdi, Abdullah; Elyamany, Ghaleb

    2016-01-01

    Intravesical instillation of Bacillus Calmette-Guérin (BCG) remains a first-line treatment for superficial transitional cell carcinoma of the bladder. Although its use is relatively safe, severe complications such as granulomatous hepatitis, osteomyelitis, pneumonitis, and sepsis occur in few patients. Complications of intravesical instillation of BCG can be local or systemic, with early or late presentation. Here, we report an 88-year-old man who developed fever, rigors, and episodes of syncope following fourth intravesical BCG instillation for the treatment of superficial transitional cell carcinoma of the bladder. Pancytopenia, disseminated intravascular coagulation, ground glass appearance on computerized tomography of the chest scan in addition to multiple bone marrow granulomas, suggested the diagnosis of disseminated BCG infection. All these features recovered on antituberculosis treatment. Our case study highlights the importance of early recognition and prompt treatment of patients with disseminated BCG infection following intravesical instillation. Although isolation of mycobacterium is desirable to make the diagnosis, it is not unusual to have negative smears and cultures and this should not be used to dismiss the possibility of BCG infection.

  14. BCG lymphadenopathy detected in a BCG-vaccinated infant

    Directory of Open Access Journals (Sweden)

    A.S. Barouni

    2004-05-01

    Full Text Available Large-scale vaccination with BCG, the live attenuated strain of Mycobacterium bovis, is being adopted around the world, although sporadic complications have occurred after the procedure. Lymphadenopathy is not uncommon especially in babies under one year (0.73% of vaccinated infants, but the swelling subsides within 2 months in most cases, with no medical or surgical treatment. Brazil adopted BCG vaccination program earlier in the seventies and by 1995 more than 96% of the infant population received this immunization. We report here the occurrence of lymphadenopathy in a two-year-old child vaccinated with the Brazilian BCG strain. The diagnosis was made using a lymph node biopsy and intestinal aspirates that yielded a positive mycobacterial culture. The isolate was resistant to isoniazid, rifampicin, pyrazinamide and thiophen-2-carbonic acid hydrazide, sensitive to streptomycin, ethambutol, and p-nitrobenzoic acid, and reacted positively to cyclo-serine and negatively to niacin. The pncA gene involved in bacterial activation of pyrazinamide contains in M. bovis a point mutation that renders pyrazinamidase unable to catalyze drug activation. Therefore, this polymorphism is a good option for developing methods to differentiate M. bovis and M. tuberculosis. Taking advantage of this difference we further analyzed the isolates by single-stranded conformation polymorphism electrophoresis of DNA following PCR of the pncA gene. The isolate identity was confirmed by RFLP electrophoretic analysis of the amplified fragment following Eco065I digestion, which selectively cleaves M. tuberculosis DNA. From this result it is proposed that RFLP of pncA gene represents an alternative for differential diagnosis of M. bovis.

  15. Health-Care Associated Mycobacterium bovis-BCG Infection in Cancer Patients without prior BCG Instillation.

    Science.gov (United States)

    Meije, Y; Martínez-Montauti, J; Caylà, J A; Loureiro, J; Ortega, L; Clemente, M; Sanz, X; Ricart, M; Santomà, M J; Coll, P; Sierra, M; Calsina, M; Vaqué, M; Ruiz-Camps, I; López-Sánchez, C; Montes, M; Ayestarán, A; Carratalà, J; Orcau, A

    2017-05-29

    Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is widely used as adjunctive therapy for superficial bladder cancer. Intravesical administration of BCG has been associated with systemic infection. Disseminated infection due to M. bovis is otherwise uncommon. After identification of three patients with health-care associated BCG infection (HCBCGI) who had never received intravesical BCG administration, an epidemiologic study was performed. All patients with HCBCGI in the Barcelona tuberculosis (TB) program were reviewed from January 1, 2005 to December 31, 2015 searching for infections caused by M. bovis-BCG. Patients with HCBCGI who had not received intravesical BCG instillation were selected and the source of infection was investigated. Nine oncology patients with infection caused by M. bovis-BCG were studied. All had permanent central venous catheters. Catheter maintenance was performed at four different outpatient clinics in the same room in which other patients underwent BCG instillations for bladder cancer without required biological precautions. All patients developed pulmonary TB, either alone or with extrapulmonary disease. Catheter-related infection was considered the mechanism of acquisition based on the epidemiologic association and positive catheter cultures for BCG in patients in whom mycobacterial cultures were performed. Physicians should be alerted to the possibility of TB due to nosocomially acquired, catheter-related infections with M. bovis-BCG in patients with indwelling catheters. This problem may be more common than expected in centers providing BCG therapy for bladder cancer without adequate precautions.

  16. BCG coverage and barriers to BCG vaccination in Guinea-Bissau

    DEFF Research Database (Denmark)

    Thysen, Sanne Marie; Byberg, Stine; Pedersen, Marie

    2014-01-01

    BACKGROUND: BCG vaccination is recommended at birth in low-income countries, but vaccination is often delayed. Often 20-dose vials of BCG are not opened unless at least ten children are present for vaccination ("restricted vial-opening policy"). BCG coverage is usually reported as 12-month coverage......, not disclosing the delay in vaccination. Several studies show that BCG at birth lowers neonatal mortality. We assessed BCG coverage at different ages and explored reasons for delay in BCG vaccination in rural Guinea-Bissau. METHODS: Bandim Health Project (BHP) runs a health and demographic surveillance system...... in selected intervention regions. Factors associated with delayed BCG vaccination were evaluated using logistic regression models. Coverage between intervention and control regions were evaluated in log-binomial regression models providing prevalence ratios. RESULTS: Among 3951 children born in 2010...

  17. Tuberculin Reaction Among Healthy BCG Vaccinated Primary ...

    African Journals Online (AJOL)

    Objective: To assess the Mantoux test reaction pattern in healthy BCG vaccinated Primary School Children aged 6 -10 years in Nnewi, South–East Nigeria. Materials and methods:Four Primary Schools were randomly selected out of 43 government owned primary schools in the town. The entire BCG vaccinated pupils in ...

  18. Genetic and immunologic determinants of intravesical BCG therapy in non-muscle-invasive urothelial bladder cancer

    Directory of Open Access Journals (Sweden)

    Wojciech Krajewski

    2014-03-01

    Full Text Available Bladder cancer (BCA is one of the most common cancers. In 2010 in Poland, 6296 people developed bladder cancer and 3110 people died of it. Immunotherapy with BCG (Bacillus Calmette-Guérin is by far the most effective adjuvant therapy. Noninfiltrating muscle membrane changes, that is, stages Ta, Tis and T1 qualify for BCG immunotherapy. BCG immunotherapy comprises series of bladder instillations, containing attenuated strain of Mycobacterium bovis. The effectiveness of immunotherapy in non-invasive bladder cancer is 70% 5-year survival without recurrence of the tumor. The treatment leads to a reduction of the residual tumor mass, but also to the delay and/or prevention of relapse, disease progression and ultimately death. Cytokines, as key mediators of immune response, play an important role in the pathogenesis of bladder cancer, which occurrence is stimulated by the inflammatory process. BCG immunotherapy provokes an intensive immunological response by the increase of cytokine production. Genetic variants determine inter-individual differences in the incidence of this cancer, as well as the response to the therapy. This is evidenced by the presence of differences in genetic variants of cytokines correlated with the varied risk of bladder cancer incidence. It is believed that concentrations of particular cytokines in urine after installation of BCG may indicate response to the therapy. Increased levels of Th1 cytokines – IFN-γ, IL-2 and TNF-α are correlated with longer survival time without recurrence, whereas high levels of Th2 cytokines such as IL-10, predict unsuccessful BCG therapy.

  19. M2-Polarized Macrophages Compose Lupus Vulgaris Arising from a Bacillus Calmette-Guérin Vaccination Site

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    Yota Sato

    2016-07-01

    Full Text Available Since bacillus Calmette-Guérin (BCG is an attenuated strain of Mycobacterium bovis, lupus vulgaris (LV is reported as one of the rare complications after BCG vaccination, correlating with immunosuppression in the lesional skin. In this report, we describe a case of LV arising from the BCG vaccination site 22 years after vaccination. Interestingly, in the present case, granuloma cells were composed of M2-polarized macrophages. Our case might explain the contribution of M2-polarized macrophages to the biology of LV arising from a BCG vaccination site.

  20. M2-Polarized Macrophages Compose Lupus Vulgaris Arising from a Bacillus Calmette-Guérin Vaccination Site.

    Science.gov (United States)

    Sato, Yota; Fujimura, Taku; Furudate, Sadanori; Kakizaki, Aya; Iizawa, Osamu; Aiba, Setsuya

    2016-01-01

    Since bacillus Calmette-Guérin (BCG) is an attenuated strain of Mycobacterium bovis , lupus vulgaris (LV) is reported as one of the rare complications after BCG vaccination, correlating with immunosuppression in the lesional skin. In this report, we describe a case of LV arising from the BCG vaccination site 22 years after vaccination. Interestingly, in the present case, granuloma cells were composed of M2-polarized macrophages. Our case might explain the contribution of M2-polarized macrophages to the biology of LV arising from a BCG vaccination site.

  1. The Effect of Oral Vaccination with Mycobacterium bovis BCG on the Development of Tuberculosis in Captive European Badgers (Meles meles).

    Science.gov (United States)

    Chambers, Mark A; Aldwell, Frank; Williams, Gareth A; Palmer, Si; Gowtage, Sonya; Ashford, Roland; Dalley, Deanna J; Davé, Dipesh; Weyer, Ute; Salguero, Francisco J; Nunez, Alejandro; Nadian, Allan K; Crawshaw, Timothy; Corner, Leigh A L; Lesellier, Sandrine

    2017-01-01

    The European badger ( Meles meles ) is a reservoir host of Mycobacterium bovis and responsible for a proportion of the tuberculosis (TB) cases seen in cattle in the United Kingdom and Republic of Ireland. An injectable preparation of the bacillus Calmette-Guérin (BCG) vaccine is licensed for use in badgers in the UK and its use forms part of the bovine TB eradication plans of England and Wales. However, there are practical limitations to the widespread application of an injectable vaccine for badgers and a research priority is the development of an oral vaccine deliverable to badgers in bait. Previous studies reported the successful vaccination of badgers with oral preparations of 10 8 colony forming units (CFU) of both Pasteur and Danish strains of BCG contained within a lipid matrix composed of triglycerides of fatty acids. Protection against TB in these studies was expressed as a reduction in the number and apparent progression of visible lesions, and reductions in the bacterial load and dissemination of infection. To reduce the cost of an oral vaccine and reduce the potential for environmental contamination with BCG, it is necessary to define the minimal efficacious dose of oral BCG for badgers. The objectives of the two studies reported here were to compare the efficacy of BCG Danish strain in a lipid matrix with unformulated BCG given orally, and to evaluate the efficacy of BCG Danish in a lipid matrix at a 10-fold lower dose than previously evaluated in badgers. In the first study, both BCG unformulated and in a lipid matrix reduced the number and apparent progression of visible lesions and the dissemination of infection from the lung. In the second study, vaccination with BCG in the lipid matrix at a 10-fold lower dose produced a similar outcome, but with greater intra-group variability than seen with the higher dose in the first study. Further research is needed before we are able to recommend a final dose of BCG for oral vaccination of badgers against TB

  2. Nonclinical Development of BCG Replacement Vaccine Candidates

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    Bernd Eisele

    2013-04-01

    Full Text Available The failure of current Mycobacterium bovis bacille Calmette–Guérin (BCG vaccines, given to neonates to protect against adult tuberculosis and the risk of using these live vaccines in HIV-infected infants, has emphasized the need for generating new, more efficacious and safer replacement vaccines. With the availability of genetic techniques for constructing recombinant BCG (rBCG strains containing well-defined gene deletions or insertions, new vaccine candidates are under evaluation at both the preclinical and clinical stages of development. Since most BCG vaccines in use today were evaluated in clinical trials decades ago and are produced by outdated processes, the development of new BCG vaccines offers a number of advantages that include a modern well-defined manufacturing process along with state-of-the-art evaluation of safety and efficacy in target populations. We provide a description of the preclinical development of two novel rBCGs, VPM1002 that was constructed by adding a modified hly gene coding for the protein listeriolysin O (LLO from Listeria monocytogenes and AERAS-422, which carries a modified pfoA gene coding for the protein perfringolysin O (PFO from Clostridium perfringens, and three genes from Mycobacterium tuberculosis. Novel approaches like these should be helpful in generating stable and effective rBCG vaccine candidates that can be better characterized than traditional BCG vaccines.

  3. Molecular Characterization of Heterologous HIV-1gp120 Gene Expression Disruption in Mycobacterium bovis BCG Host Strain: A Critical Issue for Engineering Mycobacterial Based-Vaccine Vectors

    Directory of Open Access Journals (Sweden)

    Joan Joseph

    2010-01-01

    Full Text Available Mycobacterium bovis Bacillus Calmette-Guérin (BCG as a live vector of recombinant bacterial vaccine is a promising system to be used. In this study, we evaluate the disrupted expression of heterologous HIV-1gp120 gene in BCG Pasteur host strain using replicative vectors pMV261 and pJH222. pJH222 carries a lysine complementing gene in BCG lysine auxotrophs. The HIV-1 gp120 gene expression was regulated by BCG hsp60 promoter (in plasmid pMV261 and Mycobacteria spp. α-antigen promoter (in plasmid pJH222. Among 14 rBCG:HIV-1gp120 (pMV261 colonies screened, 12 showed a partial deletion and two showed a complete deletion. However, deletion was not observed in all 10 rBCG:HIV-1gp120 (pJH222 colonies screened. In this study, we demonstrated that E. coli/Mycobacterial expression vectors bearing a weak promoter and lysine complementing gene in a recombinant lysine auxotroph of BCG could prevent genetic rearrangements and disruption of HIV 1gp120 gene expression, a key issue for engineering Mycobacterial based vaccine vectors.

  4. What have we learned after 30 years of BCG intravesical therapy for superficial bladder cancer?

    Directory of Open Access Journals (Sweden)

    Marcos Tobias-Machado

    2009-12-01

    Full Text Available Objectives: To discuss the role of bacillus Calmette-Guérin (BCG immunotherapy in the treatment of superficial bladder cancer after 30 years of clinical experience. Methods: Research on LILACS and PubMed databases, including 31 clinical studies with scientific relevance and importance in the decision-making process. Results: The BCG therapy with induction and maintenance therapy seems to be the best practice in tumors classified as high risk when compared to intravesical chemotherapy. In management of carcinoma in situ, BCG is undoubtedly the therapy of choice, presenting 84.4% of efficacy. As an adjuvant treatment to transurethral resection, there was a 31% reduction in recurrence confirmed in four out of five meta-analyses assessed. The reduction in progression, despite preliminary favorable evidence, still needs further studies to be confirmed. Conclusions: Intravesical BCG is an excellent therapeutic option in cases of carcinoma in situ and it is recommended as an adjuvant treatment in tumors with a high risk of recurrence and progression.

  5. Efficient Activation of Human T Cells of Both CD4 and CD8 Subsets by Urease-Deficient Recombinant Mycobacterium bovis BCG That Produced a Heat Shock Protein 70-M. tuberculosis-Derived Major Membrane Protein II Fusion Protein

    Science.gov (United States)

    Mukai, Tetsu; Tsukamoto, Yumiko; Maeda, Yumi; Tamura, Toshiki

    2014-01-01

    For the purpose of obtaining Mycobacterium bovis bacillus Calmette-Guérin (BCG) capable of activating human naive T cells, urease-deficient BCG expressing a fusion protein composed of Mycobacterium tuberculosis-derived major membrane protein II (MMP-II) and heat shock protein 70 (HSP70) of BCG (BCG-DHTM) was produced. BCG-DHTM secreted the HSP70-MMP-II fusion protein and effectively activated human monocyte-derived dendritic cells (DCs) by inducing phenotypic changes and enhanced cytokine production. BCG-DHTM-infected DCs activated naive T cells of both CD4 and naive CD8 subsets, in an antigen (Ag)-dependent manner. The T cell activation induced by BCG-DHTM was inhibited by the pretreatment of DCs with chloroquine. The naive CD8+ T cell activation was mediated by the transporter associated with antigen presentation (TAP) and the proteosome-dependent cytosolic cross-priming pathway. Memory CD8+ T cells and perforin-producing effector CD8+ T cells were efficiently produced from the naive T cell population by BCG-DHTM stimulation. Single primary infection with BCG-DHTM in C57BL/6 mice efficiently produced T cells responsive to in vitro secondary stimulation with HSP70, MMP-II, and M. tuberculosis-derived cytosolic protein and inhibited the multiplication of subsequently aerosol-challenged M. tuberculosis more efficiently than did vector control BCG. These results indicate that the introduction of MMP-II and HSP70 into urease-deficient BCG may be useful for improving BCG for control of tuberculosis. PMID:24152387

  6. microRNA-124 negatively regulates TLR signaling in alveolar macrophages in response to mycobacterial infection.

    Science.gov (United States)

    Ma, Chunyan; Li, Yong; Li, Min; Deng, Guangcun; Wu, Xiaoling; Zeng, Jin; Hao, Xiujing; Wang, Xiaoping; Liu, Jing; Cho, William C S; Liu, Xiaoming; Wang, Yujiong

    2014-11-01

    The emerging roles of microRNAs (miRNAs) in regulating immune responses have attracted increasing attention in recent years; and the alveolar macrophages (AMs) are the main targets of mycobacterial infection, which play a pivotal role in the pathogenesis of Mycobacterium tuberculosis infection. However, the immunoregulatory role of miRNAs in AMs has not been fully demonstrated. In this study, we find that miR-124 is up-regulated in the peripheral leukocytes of patients with pulmonary tuberculosis; furthermore, the expression miR-124 can be induced upon Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection in both RAW264.7 AM cells in vitro and murine AMs in vivo. Mechanistically, miR-124 is able to modulate toll-like receptor (TLR) signaling activity in RAW264.7 cells in response to BCG infection. In this regard, multiple components of TLR signaling cascade, including the TLR6, myeloid differentiation factor 88 (MyD88), TNFR-associated factor 6 and tumor necrosis factor-α are directly targeted by miR-124. In addition, both overexpression of TLR signaling adaptor MyD88 and BCG infection are able to augment miR-124 transcription, while MyD88 expression silenced by small interfering RNA dramatically suppresses miR-124 expression in AMs in vitro. Moreover, the abundance of miR-124 transcript in murine AMs of MyD88 deficient mice is significantly less than that of their wild-type or heterozygous littermates; and the BCG infection fails to induce miR-124 expression in the lung of MyD88 deficient mouse. These results indicate a negative regulatory role of miR-124 in fine-tuning inflammatory response in AMs upon mycobacterial infection, in part through a mechanism by directly targeting TLR signaling. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Intravesical treatment for interstitial cystitis/painful bladder syndrome: a network meta-analysis.

    Science.gov (United States)

    Zhang, Wei; Deng, Xiaojing; Liu, Chunyu; Wang, Xu

    2017-04-01

    Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic inflammatory condition of the submucosal and muscular layers of the bladder. So far, there is no effective and targeted treatment strategy for IC/PBS. This study aimed to assess the efficacy and safety of intravesical instillation treatment in IC/PBS patients. We searched various databases up to October 2015. A network meta-analysis was performed to compare global response assessment (GRA) for different treatment strategies, including botulinum toxin A (BoNTA), bacillus Calmette-Guerin (BCG), resiniferatoxin (RTX), lidocaine, chondroitin sulfate (CS), oxybutynin, and pentosan polysulfate (PPS). A traditional meta-analysis was also performed. Sixteen trials evaluating 905 patients were included. Network meta-analysis indicated that BoNTA had the highest probability of being the best treatment course according to GRA assessment results (probability 81.7 %). BCG or BoNTA therapy yielded significant improvement in GRA incidence according to traditional meta-analysis. Patients who received PPS showed higher urinary frequency results compared with the placebo groups. BCG- and PPS-treated patients had elevated urinary urgency treatment effects compared with placebo groups. Bladder capacity restoration results also showed significant improvements in patients who received BoNTA compared with placebo-treated individuals. These findings indicate that BoNTA therapy has the highest probability of being the best therapy according to GRA, and significantly improves bladder capacity in IC/PBS patients. BCG treatment also significantly increases the incidence of GRA and improves the symptoms of urinary urgency. PPS can significantly improve urinary frequency and urgency symptoms in IC/PBS patients.

  8. THE IMMUNOPATHOBIOLOGY OF SYPHILIS: THE MANIFESTATIONS AND COURSE OF SYPHILIS ARE DETERMINED BY THE LEVEL OF DELAYED-TYPE HYPERSENSITIVITY

    Science.gov (United States)

    Carlson, J. Andrew; Dabiri, Ganary; Cribier, Bernard; Sell, Stewart

    2013-01-01

    Syphilis has plagued mankind for centuries and is currently resurgent in the Western hemisphere. While there has been a significant reduction of tertiary disease, and recognition of facilitative interactions with HIV infection, the natural history of syphilis has remained largely unchanged; thus, new strategies are required to more effectively combat this pathogen. The immunopathologic features of experimental syphilis in the rabbit; the course, stages, and pathology of human syphilis; and a comparison of human syphilis with leprosy suggest that the clinical course of syphilis and its tissue manifestations are determined by the balance between delayed type hypersensitivity (DTH) and humoral immunity to the causative agent, Treponema pallidum. A strong DTH response is associated with clearance of the infecting organisms in a well-developed chancre, whereas a cytotoxic T-cell response or strong humoral antibody response is associated with prolonged infection and progression to tertiary disease. Many of the protean symptoms/appearances of secondary and tertiary human syphilis are manifestations of immune reactions that fail to clear the organism, due to a lack of recruitment and more importantly, activation of macrophages by sensitized CD4 T-cells. The Bacillus Calmette Guerin (BCG) vaccination can enhance DTH and has been shown to produce a low, but measurable beneficial effect in the prevention of leprosy, a disease that shows a disease spectrum with characteristics in common with syphilis. In the prevention of syphilis, a potential vaccine protective against syphilis should be designed to augment the DTH response. PMID:21694502

  9. Comparison of antigen-specific T-cell responses of tuberculosis patients using complex or single antigens of Mycobacterium tuberculosis

    DEFF Research Database (Denmark)

    Mustafa, A S; Amoudy, H A; Wiker, H G

    1998-01-01

    We have screened peripheral blood mononuclear cells (PBMC) from tuberculosis (TB) patients for proliferative reactivity and interferon-gamma (IFN-gamma) secretion against a panel of purified recombinant (r) and natural (n) culture filtrate (rESAT-6, nMPT59, nMPT64 and nMPB70) and somatic-derived (r......GroES, rPstS, rGroEL and rDnaK) antigens of Mycobacterium tuberculosis. The responses of PBMC to these defined antigens were compared with the corresponding results obtained with complex antigens, such as whole-cell M. tuberculosis, M. tuberculosis culture filtrate (MT-CF) and cell wall antigens, as well...... as the vaccine strain, Mycobacterium bovis bacillus Calmette-Guerin (BCG). In addition, M. tuberculosis and MT-CF-induced T-cell lines were tested in the same assays against the panel of purified and complex antigens. The compiled data from PBMC and T-cell lines tested for antigen-induced proliferation and IFN...

  10. Mechanisms of immunological eradication of a syngeneic guinea pig tumor. II. Effect of methotrexate treatment and T cell depletion of the recipient on adoptive immunity

    Energy Technology Data Exchange (ETDEWEB)

    Shu, S.; Fonseca, L.S.; Hunter, J.T.; Rapp, H.J.

    1983-01-01

    The influence of methotrexate on the development of immunity to the line 10 hepatoma was studied in guinea pigs. Chronic methotrexate treatment had no apparent effect on the ability of immune guinea pigs to suppress the growth of inoculated tumor cells. In contrast, the same methotrexate regimen inhibited the development of tumor immunity if started before the 8th day after immunization with a vaccine containing viable line 10 cells admixed with Bacillus Calmette-Guerin (BCG) cell walls. Thus, methotrexate selectively inhibited the afferent limb of the immune response. In adoptive transfer experiments, methotrexate-treated recipient guinea pigs were capable of being passively sensitized with immune spleen cells, indicating that the primary cell-mediated immune response of the recipient was not required for adoptive immunity. The contribution of recipient T cells in adoptive immunity was further investigated in guinea pigs deleted of T cells by thymectomy, irradiation, and bone marrow reconstitution. Despite demonstrable deficiency in T lymphocyte reactions, B animals were fully capable of rejecting tumors after transfer of immune cells. These results suggest that the expression of adoptive immunity was independent of recipient T cell participation. In addition, sublethal irradiation of immune spleen cells prior to adoptive transfer abolished their efficacy. Proliferation of transferred immune cells in the recipient may be essential for expression of adoptive immunity.

  11. Immunogenic Human Papillomavirus Pseudovirus-Mediated Suicide-Gene Therapy for Bladder Cancer

    Directory of Open Access Journals (Sweden)

    Rim Hojeij

    2016-07-01

    Full Text Available Bladder cancer is the second most common urological malignancy in the world. In 70% of cases it is initially diagnosed as non-muscle-invasive bladder cancer (NMIBC and it is amenable to local treatments, with intravesical (IVES Bacillus-Calmette-Guerin (BCG immunotherapy being routinely used after transurethral resection of the lesion. However, this treatment is associated with significant side-effects and treatment failures, highlighting the necessity of novel strategies. One potent approach is the suicide-gene mediated therapy/prodrug combination, provided tumor-specificity can be ensured and anti-tumor immune responses induced. Using the mouse syngeneic orthotopic MB49-bladder tumor model, here we show that IVES human papillomavirus non-replicative pseudovirions (PsV can pseudoinfect tumors with a ten-fold higher efficacy than normal bladders. In addition, PsV carrying the suicide-gene herpes-simplex virus thymidine kinase (PsV-TK combined to Ganciclovir (GCV led to immunogenic cell-death of tumor cells in vitro and to MB49-specific CD8 T-cells in vivo. This was associated with reduction in bladder-tumor growth and increased mice survival. Altogether, our data show that IVES PsV-TK/GCV may be a promising alternative or combinatory treatment for NMIBC.

  12. Intravesical therapy for urothelial carcinoma of the urinary bladder: a critical review

    Directory of Open Access Journals (Sweden)

    Daher C. Chade

    2009-12-01

    Full Text Available The management of non-muscle-invasive urothelial carcinoma of the bladder (UCB is a challenge for physicians and patients alike. This is largely due to the heterogeneous natural history of this disease, in which tumors range from indolent to rapidly progressive and eventually fatal. Moreover, the high rate of recurrence and progression cause significant morbidity, expense, and detriment to quality of life. The advent of effective and safe intravesical therapies has improved the management of non-muscle-invasive UCB. Nevertheless, despite over 30 years of research and clinical experience, the mechanism, risks, benefits, and optimal regimens and treatment algorithms remain unclear. Although immunotherapy with bacillus Calmette-Guerin (BCG has been the mainstay of intravesical treatment and represents a significant advance in the interaction of immunology and oncology, its clinical effectiveness is accompanied by a wide range of adverse events. Here, we review the literature on intravesical immunotherapy and chemotherapy with the aim of evaluating the clinical utility of the different treatments and providing recommendations. Many studies over the years have compared efficacy and toxicities of different agents and regimens, and certain conclusions are now well supported by high-level evidence. Future perspectives and promising advances in drug development are discussed and areas of improvement are identified in order to promote better cancer control and decrease the rate and severity of side-effects.

  13. Construction of two Listeria ivanovii attenuated strains expressing Mycobacterium tuberculosis antigens for TB vaccine purposes.

    Science.gov (United States)

    Lin, Qingqing; Zhou, Mengying; Xu, Zongkai; Khanniche, Asma; Shen, Hao; Wang, Chuan

    2015-02-20

    Bacillus Calmette-Guerin (BCG) has failed in complete control of tuberculosis (TB), thus, novel tuberculosis vaccines are urgently needed. We have constructed several TB vaccine candidates, which are characterized by the use of Listeria ivanovii (LI) strain as an antigen delivery vector. Two L. ivanovii attenuated recombinant strains L. ivanovii△actAplcB-Rv0129c and L. ivanovii△actAplcB-Rv3875 were successfully screened. Results from genome PCR and sequencing showed that the Mycobacterium tuberculosis antigen gene cassette coding for Ag85C or ESAT-6 protein respectively had been integrated into LI genome downstream of mpl gene. Western blot confirmed the secretion of Ag85C or ESAT-6 protein from the recombinant LI strains. These two recombinant strains showed similar growth curves as wide type strain in vitro. In vivo, they transiently propagated in mice spleen and liver, and induced specific CD8(+) IFN-γ secretion. Therefore, in this paper, two novel LI attenuated strains expressing specific TB antigens were successfully constructed. The promising growth characteristics in mice immune system and the capability of induction of IFN-γ secretion make them of potential interest for development of TB vaccines. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Síntese e avaliação farmacológica de N’-benzilideno-cumarinas-3-carboidrazidas frente ao Mycobacterium causador da tuberculose

    Directory of Open Access Journals (Sweden)

    Felipe R. Vicente

    2010-04-01

    Full Text Available This article describes a series of twenty-one N’-benzylidene-2-oxo-2H-chromene-3-carbohydrazides (5a-5v which were synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv using the Alamar Blue susceptibility test (MABA and the activity expressed as the minimum inhibitory concentration (MIC in μg/mL. Afterwards, the compounds which showed antitubercular activity (50-100 μg/mL 5c, 5g, 5h, 5j, 5l, 5p and 5t were evaluated for their cell viabilities in macrophages infected and non infected with Mycobacterium bovis Bacillus Calmette-Guerin (BCG. The compounds 5c, 5g, 5h, 5j, 5l were not cytotoxic in their respective MIC values, indicating that these compounds could be considered a good starting point to further studies aiming to develop a new lead compound to treat multidrug-resistant tuberculosis (TB-MDR/XDR.

  15. Mechanisms of immunological eradication of a syngeneic guinea pig tumor. II. Effect of methotrexate treatment and T cell depletion of the recipient on adoptive immunity

    International Nuclear Information System (INIS)

    Shu, S.; Fonseca, L.S.; Hunter, J.T.; Rapp, H.J.

    1983-01-01

    The influence of methotrexate on the development of immunity to the line 10 hepatoma was studied in guinea pigs. Chronic methotrexate treatment had no apparent effect on the ability of immune guinea pigs to suppress the growth of inoculated tumor cells. In contrast, the same methotrexate regimen inhibited the development of tumor immunity if started before the 8th day after immunization with a vaccine containing viable line 10 cells admixed with Bacillus Calmette-Guerin (BCG) cell walls. Thus, methotrexate selectively inhibited the afferent limb of the immune response. In adoptive transfer experiments, methotrexate-treated recipient guinea pigs were capable of being passively sensitized with immune spleen cells, indicating that the primary cell-mediated immune response of the recipient was not required for adoptive immunity. The contribution of recipient T cells in adoptive immunity was further investigated in guinea pigs deleted of T cells by thymectomy, irradiation, and bone marrow reconstitution. Despite demonstrable deficiency in T lymphocyte reactions, B animals were fully capable of rejecting tumors after transfer of immune cells. These results suggest that the expression of adoptive immunity was independent of recipient T cell participation. In addition, sublethal irradiation of immune spleen cells prior to adoptive transfer abolished their efficacy. Proliferation of transferred immune cells in the recipient may be essential for expression of adoptive immunity

  16. Circadian rhythm in experimental granulomatous inflammation is modulated by melatonin.

    Science.gov (United States)

    Lopes, C; deLyra, J L; Markus, R P; Mariano, M

    1997-09-01

    Biological rhythms are detected in a variety of physiological and pathological conditions in man and animals, such as rheumatoid arthritis and asthma. Here we describe a circadian rhythm in experimental infectious and non-infectious granuloma. After 30 days of BCG (Bacillus Calmette-Guerin) or nystatin inoculation in the left hind foot of C57B1/6 mice, there is an oscillation with a period of approximately 24 hr in the variation of paw thickness, indicating a circadian rhythm. The acrophase occurred during the light phase, between 9:00 and 13:00 hr, while the nadir occurred in the dark phase, between 21:00 and 01:00 hr. The vascular permeability around the granulomatous lesions was higher at 12:00 hr than at 24:00 hr. This is in agreement with the observation that the thickness of a paw with granulomatous lesion is larger during the light phase. This rhythmic variation was eliminated by either pinealectomy or superior cervical ganglionectomy, which greatly reduce melatonin levels in the blood. Nocturnal replacement of melatonin in pinealectomized mice led to the re-establishment of the circadian rhythm. Thus, the rhythm of the granulomatous lesion is due to the rhythmic melatonin release by the pineal gland. This approach opens new questions regarding the modulation of chronic inflammation in inflammatory diseases that present rhythmic symptoms throughout the day.

  17. [Study on new extraction technology and protective effect of hugan buzure granule on liver injury in mice].

    Science.gov (United States)

    Wu, Tao; Jiang, Lan; Hajiakber, Aisa; Sun, Yuhua

    2011-02-01

    To study on the new preparation technology of Hugan Buzure granule and to compare protective effect on liver injury in rats by different extraction processes. Volatile oil extraction technology, inclusion condition and ethanol extraction condition were selected by orthogonal experiments. The experiment models of liver injury were induced by carbon tetrachloride, bacillus calmette-guerin (BCG) and plus lipolysaccharides (LPS) in rats, respectively. ALT, AST in serum, and MDA, SOD in liver were measured and the rats were killed to calculate the liver coefficient to evaluate the protective effect of Hugan Buzure granule on experimental injury in rats. The optimum conditions of volatile oil extraction were 1:12 of solid-liquid ratio, 2 h of soaking time, and 8 h of extracting time. The optimal beta-cyclodextrin inclusion complex condition was as follows: the volatile oils formed complex with the beta-CD in a ratio of 1: 6 and stirring for 1 h at 40 degrees C. The optimum ethanol extraction was as follows: refluxing and extracting 3 times with 10-fold 50% ethanol, 2 h for each time. Compared with the model group, the new technology extraction of Hugan Buzure granule could obviously inhibite the elevation of serum ALT (P technology was feasible. The new extraction could protect the liver injury in rats, which was better than extraction of current preparation technology.

  18. Intravesical electro-osmotic administration of mitomycin C.

    Science.gov (United States)

    Di Stasi, Savino M; Verri, Cristian; Celestino, Francesco; De Carlo, Francesco; Pagliarulo, Vincenzo

    2016-10-04

    Bladder cancer is very common and most cases are diagnosed as nonmuscle invasive disease, which is characterized by its propensity to recur and progress. Intravesical therapy is used to delay recurrence and progression, while cystectomy is reserved for patients who are refractory to transurethral resection and intravesical therapy. There is an increasing interest in methods to enhance the delivery of intravesical chemotherapeutic agents to improve efficacy. In vitro and in vivo studies demonstrated that electro-osmosis of mitomycin C (MMC) is more effective in delivering this drug into the urothelium, lamina propria, and superficial muscle layers of the bladder wall than is passive transport. Higher MMC tissue concentrations might have a clinical impact in the treatment of nonmuscle invasive bladder cancer (NMIBC). In randomized trials, intravesical electro-osmotic MMC was associated with superior response rate in high-risk NMIBC cancer, compared with passive diffusion MMC transport. New strategies such as intravesical Bacillus Calmette-Guerin (BCG) combined with electro-osmotic MMC as well as intravesical pre-operative electro-osmotic MMC provided promising results in terms of higher remission rates and longer remission times.Device-assisted intravesical chemotherapy may be a useful ancillary procedure in the treatment of NMIBC. Its evaluation must be planned with respect to the technical functioning of equipment and their use for a clear purpose to avoid the financial and human costs associated with incorrect therapies.

  19. Granulomatous hepatitis, choroiditis and aortoduodenal fistula complicating intravesical Bacillus Calmette-Guérin therapy: Case report

    Directory of Open Access Journals (Sweden)

    Antoine John

    2011-09-01

    Full Text Available Abstract Background Intravesical instillation of Bacillus Calmette-Guérin (BCG is the treatment of choice for superficial bladder carcinoma. Complications of BCG therapy include local infections and disseminated BCG infection with multiple endorgan complications. Case Presentation We report a case of disseminated, post-treatment BCG infection that initially presented with granulomatous hepatitis and choroiditis. After successful anti-mycobacterial therapy and resolution of the hepatic and ocular abnormalities, the patient developed an acute upper gastrointestinal hemorrhage from an aortoduodenal fistula that required emergency surgery. The resection specimen revealed multifocal, non-caseating granulomas, indicating mycobacterial involvement. Conclusions This case highlights the varied end organ complications of disseminated BCG infection, and the need for vigilance even in immuno-competent patients with a history of intravesical BCG treatment.

  20. Immunotherapy with autologous tumor cell-BCG vaccine in patients with colon cancer: a prospective study of medical and economic benefits

    NARCIS (Netherlands)

    Uyl-de Groot, C. A.; Vermorken, J. B.; Hanna, M. G.; Verboom, P.; Groot, M. T.; Bonsel, G. J.; Meijer, C. J. L. M.; Pinedo, H. M.

    2005-01-01

    We have completed a multicenter, randomized controlled phase III clinical trial in Stages II and III colon cancer patients with active specific immunotherapy (ASI) using autologous tumor cells with an immunomodulating adjuvant bacillus Callmette-Guerin (BCG) vaccine (OncoVAX (R)) in an adjuvant

  1. Hepatitis in Disseminated Bacillus Calmette-Guérin Infection

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    Markus U Göttke

    2000-01-01

    Full Text Available Local immunotherapy with an attenuated live strain of Mycobacterium bovis, bacillus Calmette-Guérin (BCG, is an effective and frequently used treatment for in situ transitional cell carcinoma (TCC of the bladder. Success rates are high, and serious side effects are infrequent but can affect every organ system. A 79-year-old patient with recently diagnosed TCC who was treated with intravesical BCG for a recurrence after initial surgical treatment is reported. After unsuccessful attempts at bladder catheterization with the creation of a false passage for his third treatment, BCG was instilled via a suprapubic catheter the same day and again a week later. Two weeks after the third BCG instillation, the patient presented with profound lethargy and weakness to the point of not being able to get up out of a chair. He was febrile, anorexic, icteric and had hepatosplenomegaly. Disseminated BCG infection was suspected on the basis of history, clinical examination and a liver biopsy that showed noncaseating granulomatous hepatitis. Empirical treatment was started with antituberculous combination therapy. A short course of an oral corticosteroid was given. Clinical improvement was marked and sustained so that the patient could be discharged home for the full six-month course of his treatment. Disseminated BCG infection with granulomatous hepatitis can be severe and life-threatening in cases where a large intravascular inoculum of BCG may have been given inadvertently.

  2. Recombinant BCG: Innovations on an old vaccine. Scope of BCG strains and strategies to improve long lasting memory

    Directory of Open Access Journals (Sweden)

    Adeliane C da Costa

    2014-04-01

    Full Text Available BCG (Bacille Calmette-Guérin, an attenuated vaccine derived from Mycobacterium bovis, is the current vaccine of choice against tuberculosis (TB. Despite its protection against active TB in children, BCG has failed to protect adults against TB infection and active disease development, especially in developing countries where the disease is endemic. Currently, there is a significant effort towards the development of a new TB vaccine. This review article aims to address publications on recombinant BCG (rBCG published in the last 5 years, to highlight the strategies used to develop rBCG, with a focus on the criteria used to improve immunological memory and protection compared with BCG. The literature review was done in April 2013, using the key words tuberculosis, rBCG vaccine and memory. This review discusses the BCG strains and strategies currently used for the modification of BCG, including: overexpression of M. tuberculosis (Mtb immunodominant antigens already present in BCG; gene insertion of immunodominant antigens from Mtb absent in the BCG vaccine; combination of introduction and over expression of genes that are lost during the attenuation process of BCG; BCG modifications for the induction of CD8+ T cell immune responses and cytokines expressing rBCG. Among the vaccines discussed, VPM1002, also called rBCGΔureC::hly, is currently in human clinical trials. Much progress has been made in the effort to improve BCG, with some promising candidates, but considerable work is still required to address functional long-lasting memory.

  3. Lack of a Negative Effect of BCG-Vaccination on Child Psychomotor Development

    DEFF Research Database (Denmark)

    Kjærgaard, Jesper; Stensballe, Lone Graff; Birk, Nina Marie

    2016-01-01

    MEASURES: Psychomotor development measured using Ages and Stages Questionnaire (ASQ) completed by the parents at 12 months. Additionally, parents of premature children (gestational age Developmental assessment was available for 3453/4262 (81%). RESULTS......OBJECTIVES: To assess the non-specific effect of Bacillus Calmette-Guérin (BCG) vaccination at birth on psychomotor development. DESIGN: This is a pre-specified secondary outcome from a randomised, clinical trial. SETTING: Maternity units and paediatric wards at three university hospitals...... was -7.8 points (-20.6 to 5.0, p = 0.23), d = -0.23 (-0.62 to 0.15). CONCLUSIONS: A negative non-specific effect of BCG vaccination at birth on psychomotor development was excluded in term children. TRIAL REGISTRATION: ClinicalTrials.gov NCT01694108....

  4. Heterologous boosting with recombinant VSV-846 in BCG-primed mice confers improved protection against Mycobacterium infection.

    Science.gov (United States)

    Zhang, Ming; Dong, Chunsheng; Xiong, Sidong

    2017-04-03

    Tuberculosis (TB) remains a major health problem worldwide, and the development of effective vaccines is urgently needed. Vaccination strategies based on heterologous prime-boost protocols using Mycobacterium bovis bacillus Calmette-Guérin (BCG) as primer and modified vaccinia virus Ankara strain expressing the mycobacterial antigen Ag85A (MVA85A) as booster may increase the protective efficacy of BCG. In addition, vaccination with the recombinant viral vaccine vesicular stomatitis virus (VSV)-846 (Rv3615c, Mtb10.4, and Rv2660c) can elicit a remarkable T-cell-mediated immune response and provide an effective long-term protection after the BCG challenge. In this study, we used VSV-846 to boost BCG and evaluated its immunogenicity in BALB/c mice. In this prime-boost approach, boosting with VSV-846 significantly enhanced IFN-γ CD4 T cell responses, which are crucial for anti-TB immune responses. Moreover, VSV-846 boosting significantly reduced pathology compared with mock vaccination, and decreased the bacterial loads in lung tissues compared with BCG or VSV-846 vaccination alone. The analysis of vaccine-induced immunity identified that polyfunctional T cells might contribute to the enhanced protection by VSV-846 boosting. This study proved that viral booster VSV-846 in mice improved the protection against mycobacteria infection, which could be helpful in designing an efficient vaccination strategy against TB in humans.

  5. Boosting BCG with inert spores improves immunogenicity and induces specific IL-17 responses in a murine model of bovine tuberculosis.

    Science.gov (United States)

    Garcia-Pelayo, M Carmen; Kaveh, Daryan A; Sibly, Laura; Webb, Paul R; Bull, Naomi C; Cutting, Simon M; Hogarth, Philip J

    2016-05-01

    Tuberculosis (TB) remains a global pandemic, in both animals and man, and novel vaccines are urgently required. Heterologous prime-boost of BCG represents a promising strategy for improved TB vaccines, with respiratory delivery the most efficacious to date. Such an approach may be an ideal vaccination strategy against bovine TB (bTB), but respiratory vaccination presents a technical challenge in cattle. Inert bacterial spores represent an attractive vaccine vehicle. Therefore we evaluated whether parenterally administered spores are efficacious when used as a BCG boost in a murine model of immunity against Mycobacterium bovis. Here we report the use of heat-killed, TB10.4 adsorbed, Bacillus subtilis spores delivered via subcutaneous injection to boost immunity primed by BCG. We demonstrate that this approach improves the immunogenicity of BCG. Interestingly, this associated with substantial boosting of IL-17 responses; considered to be important in protective immunity against TB. These data demonstrate that parenteral delivery of spores represents a promising vaccine vehicle for boosting BCG, and identifies potential for optimisation for use as a vaccine for bovine TB. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

  6. Outcome after BCG treatment for urinary bladder cancer may be influenced by polymorphisms in the NOS2 and NOS3 genes.

    Science.gov (United States)

    Ryk, Charlotta; Koskela, Lotta Renström; Thiel, Tomas; Wiklund, N Peter; Steineck, Gunnar; Schumacher, Martin C; de Verdier, Petra J

    2015-12-01

    Bacillus Calmette-Guérin (BCG)-treatment is an established treatment for bladder cancer, but its mechanisms of action are not fully understood. High-risk non-muscle invasive bladder-cancer (NMIBC)-patients failing to respond to BCG-treatment have worse prognosis than those undergoing immediate radical cystectomy and identification of patients at risk for BCG-failure is of high priority. Several studies indicate a role for nitric oxide (NO) in the cytotoxic effect that BCG exerts on bladder cancer cells. In this study we investigated whether NO-synthase (NOS)-gene polymorphisms, NOS2-promoter microsatellite (CCTTT)n, and the NOS3-polymorphisms-786T>C (rs2070744) and Glu298Asp (rs1799983), can serve as possible molecular markers for outcome after BCG-treatment for NMIBC. All NMIBC-patients from a well-characterized population based cohort were analyzed (n=88). Polymorphism data were combined with information from 15-years of clinical follow-up. The effect of BCG-treatment on cancer-specific death (CSD), recurrence and progression in patients with varying NOS-genotypes were studied using Cox proportional hazard-models and log rank tests. BCG-treatment resulted in significantly better survival in patients without (Log rank: p=0.006; HR: 0.12, p=0.048), but not in patients with a long version ((CCTTT)n ≧13 repeats) of the NOS2-promoter microsatellite. The NOS3-rs2070744(TT) and rs1799983(GG)-genotypes showed decreased risk for CSD (Log rank(TT): p=0.001; Log rank(GG): p=0.010, HR(GG): 0.16, p=0.030) and progression (Log rank(TT): p<0.001, HR(TT): 0.05, p=0.005; Log rank(GG): p<0.001, HR(GG): 0.10, p=0.003) after BCG-therapy compared to the other genotypes. There was also a reduction in recurrence in BCG-treated patients that was mostly genotype independent. Analysis of combined genotypes identified a subgroup of 30% of the BCG-treated patients that did not benefit from BCG-treatment. Our results suggest that the investigated polymorphisms influence patient response

  7. Positive impact of rescheduling Bacillus Calmette-Gu?rin vaccination on vaccinations at birth

    OpenAIRE

    Oberoi, Simmi; Amarjit, Singh; Avneet, Randhawa; Neha, Chaudhary; Patnaik, Siriesha

    2017-01-01

    Context: Inimitable among the trio of recommended immunizations administered to newborns at delivery centers of institutions is hepatitis B. While it is necessary for hepatitis B to be given within 24 hours of birth, the same cannot be said for Bacillus Calmette-Guérin (BCG) and zero-dose oral polio vaccine (OPV). Objective: To assess the impact of rescheduling of BCG vaccination from the current twice weekly to daily to cover newborn vaccinations at the Government Medical College, Patial...

  8. INTRAVESICULAR IMMUNOTHERAPY WITH BCG VACCINE AND INTERFERON-αα2B FOR NON-INVASIVE CARCINOMA OF THE URINARY BLADDER: RESULTS OF PROSPECTIVE RANDOMIZED STUDY

    Directory of Open Access Journals (Sweden)

    A. A. Minich

    2009-01-01

    Full Text Available Background: Both bacillus Calmette-Gue’rin (BCG and interferon-alpha (IFN-α are active against urinary bladder cancer. In this studywe evaluate the therapeutic efficacy and toxicity of combined intravesical BCG plus IFN-α for treating non-invasive bladder cancer.Subjects and methods: A total of 149 patients (mean age 63.2 years were enrolled for the study. The inclusion criteria were histologically verifiednon-invasive transitional cell carcinoma with intermediate and high risks of recurrence and progression. After transurethral tumor resection, all thepatients were randomized in three groups. Group 1 (n=60 was treated with a 6-week course of BCG, 125 mg, starting 14 to 21 days after TUR, Group2 (n=60 patients received 6-week instillations of BCG, 125 mg, plus IFN-α, 6 million units, Group 3 patients (n = 29 had 4-month courses ofintravesical IFN-α, 6 million units, twice daily during 3 consecutive days. A response was assessed by cystoscopy every 3 months after treatment.Results: A median follow-up of 30.9 months revealed recurrences in 26 (43.3% patients in the BCG group, 8 (13.3% patients in the BCG + IFN-αgroup and 18 (62.1% patients in the IFN-α group. Progression to muscle invasion occurred in 12% and 7% in Groups 1 and 3, respectively, withno progression in Group 2 patients. Three-year relapse-free survival was higher in the BCG+IFN group (78.5% versus 62.6 and 40.2% in theBCG and IFN-α groups, respectively. There was no significant difference between the BCG groups in relapse-free survival. Monotherapy withIFN-α showed a significantly lower response rate than did BCG therapies (p = 0.007. Adverse reactions were observed in 25, 116, and 6.9% ofpatients from Groups 1, 2 and 3, respectively. Toxicity-related withdrawal and treatment delay were similar in both BCG groups. Comparison ofthe rate of adverse reactions revealed a significant difference between the BCG + IFN-α and BCG groups (p = 0.025. The respective rates ofmoderate

  9. INTRAVESICULAR IMMUNOTHERAPY WITH BCG VACCINE AND INTERFERON-αα2B FOR NON-INVASIVE CARCINOMA OF THE URINARY BLADDER: RESULTS OF PROSPECTIVE RANDOMIZED STUDY

    Directory of Open Access Journals (Sweden)

    A. A. Minich

    2014-07-01

    Full Text Available Background: Both bacillus Calmette-Gue’rin (BCG and interferon-alpha (IFN-α are active against urinary bladder cancer. In this studywe evaluate the therapeutic efficacy and toxicity of combined intravesical BCG plus IFN-α for treating non-invasive bladder cancer.Subjects and methods: A total of 149 patients (mean age 63.2 years were enrolled for the study. The inclusion criteria were histologically verifiednon-invasive transitional cell carcinoma with intermediate and high risks of recurrence and progression. After transurethral tumor resection, all thepatients were randomized in three groups. Group 1 (n=60 was treated with a 6-week course of BCG, 125 mg, starting 14 to 21 days after TUR, Group2 (n=60 patients received 6-week instillations of BCG, 125 mg, plus IFN-α, 6 million units, Group 3 patients (n = 29 had 4-month courses ofintravesical IFN-α, 6 million units, twice daily during 3 consecutive days. A response was assessed by cystoscopy every 3 months after treatment.Results: A median follow-up of 30.9 months revealed recurrences in 26 (43.3% patients in the BCG group, 8 (13.3% patients in the BCG + IFN-αgroup and 18 (62.1% patients in the IFN-α group. Progression to muscle invasion occurred in 12% and 7% in Groups 1 and 3, respectively, withno progression in Group 2 patients. Three-year relapse-free survival was higher in the BCG+IFN group (78.5% versus 62.6 and 40.2% in theBCG and IFN-α groups, respectively. There was no significant difference between the BCG groups in relapse-free survival. Monotherapy withIFN-α showed a significantly lower response rate than did BCG therapies (p = 0.007. Adverse reactions were observed in 25, 116, and 6.9% ofpatients from Groups 1, 2 and 3, respectively. Toxicity-related withdrawal and treatment delay were similar in both BCG groups. Comparison ofthe rate of adverse reactions revealed a significant difference between the BCG + IFN-α and BCG groups (p = 0.025. The respective rates ofmoderate

  10. New-onset guttate psoriasis following intravesical immunotherapy of Bacillus Calmette–Guerin

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    Chih-Tsung Hung

    2012-09-01

    Full Text Available Intravesical Bacillus Calmette–Guerin (BCG is usually a well-tolerated treatment for urethelial carcinoma of the bladder. A 60-year-old male endured multiple erythematous white-scaled maculopapules over his trunk, back, and four extremities after 2 months of the 6-weekly intravesical instillation of BCG. Skin biopsy revealed parakeratotic hyperkeratosis, intracorneal neutrophilic Munro's abscess, and acanthosis. Guttate psoriasis was diagnosed, and he was treated successfully with topical steroid and narrow band UV-B phototherapy. We present the first Asian case of guttate psoriasis associated with intravesical BCG immunotherapy and review the literatures.

  11. Spinocellulært karcinom opstået ved cikatrice efter Calmette-vaccination

    DEFF Research Database (Denmark)

    Nielsen, Rikke Maria; Andersen, F.; Salskov-Iversen, Maria Luise

    2014-01-01

    Marjolin's ulcer is an aggressive squamous cell carcinoma (SCC) found in chronically inflamed skin. SCC has been reported in smallpox vaccination sites, whereas basal cell carcinomas are more common in scar after bacille Calmette-Guerin (BCG) vaccination. A 72-year-old man presented with a chronic...... ulcer at the site of his childhood BCG vaccination. At the time of examination, a 3 x 1.5 cm fleshy and secreting ulcer was found on the shoulder. Biopsy revealed SCC, and the tumour was surgically removed. In conclusion, chronic ulcers, especially those originating in chronically inflamed skin, should...

  12. BCG and Kawasaki disease in Mexico and Japan.

    Science.gov (United States)

    Gamez-Gonzalez, Luisa Berenise; Hamada, Hiromichi; Llamas-Guillen, Beatriz Adriana; Ruiz-Fernandez, Miguel; Yamazaki-Nakashimada, Marco

    2017-05-04

    Dr. Tomisaku Kawasaki was the first to describe BCG reactivation in Kawasaki Disease (K D ), and this sign is present in about 30-50% of K D patients. It is a very specific early sign of the disease and although it has been recognized for decades, its pathophysiology continues to be an enigma. Recently, Yamada et al. reported a severe BCG reaction with tuberculid in 2 Japanese K D patients. We present 2 cases with K D and severe BCG reaction, one from Japan and the other from Mexico and review the policies of administration of BCG in both countries. The BCG vaccine has a worldwide coverage of 88%. Differences in BCG strains and methods of administration may influence BCG reactions in K D . The BCG reaction in the inoculation site may represent the most useful sign in K D .

  13. Enhanced expression of PD-L1 and IFN-γ on dendritic cells is associated with BCG-induced Th2 inhibition.

    Science.gov (United States)

    Gouveia, A C C; Braga, F G; Mota, M; Silva, F M C; Brugiolo, A S S; Oliveira, E E; Ayupe, M C; Teixeira, H C; Ferreira, A P

    2017-11-01

    Accumulating evidence indicates that the exposure to Mycobacterium bovis bacillus Calmette-Guérin (BCG) prevents the development of allergy and the airway dendritic cells (DCs) may be involved in this protective effect. However, studies to better characterize the specific interactions between BCG and DCs and their role in this mycobacteria-mediated Th2 cell suppression are still ongoing. This study aimed to evaluate the effect of the neonatal BCG vaccination in the innate immune response in a mouse model of ovalbumin (OVA)-induced airway inflammation. BCG treated neonatal BALB/c mice were sensitized and challenged with aerosolized OVA. Twenty-four hours after the last challenge, samples were collected for analysis. The intranasal BCG treatment inhibited the allergic Th2-response by decreasing the allergen-induced eosinophilic inflammation, EPO activity, CCL11, IL-25, TSLP, IL-4 and IL-5 lung levels, and serum levels of IgE. Mycobacteria treatment increased lung levels of IL-10 and TGF-β, and the TLR2 and TLR4 expressions by pulmonary CD11c + CD103 + CD8α + DCs. Additionally an enhanced expression of PD-L1 was observed besides an increased production of IFN-γ by these cells. These results indicated that neonatal BCG vaccination inhibits key features of allergic airway inflammation, probably by promoting T regulatory immune response via an enhanced expression of TLR2, TLR4 and PD-L1 on DCs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. The response of variant histology bladder cancer to intravesical immunotherapy compared to conventional cancer

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    Ofer Nathan Gofrit

    2016-03-01

    Full Text Available Background: High-grade urothelial carcinomas (UC often show foci of variant differentiation. There is limited information in the literature about the response of these variant urothelial tumors to immunotherapy with Bacillus Calmette Guerin (BCG. We compared the response to treatment with BCG of UC containing glandular, squamous, nested and micropapillary types of differentiation to response of conventional non-muscle invasive high-grade urothelial carcinoma. Methods: A total of 100 patients were diagnosed with variant histology urothelial cancer between June 1995 and December 2013. 41 patients with Ta or T1, confirmed by 2nd look biopsies, received immunotherapy with BCG. Fourteen patients in this group were diagnosed with micropapillary differentiation 13 patients with squamous differentiation, in 9 patients glandular differentiation was seen and in 7 patients nested variant. The control group included 140 patients with conventional high-grade UC. Both groups have been treated and followed similarly. Findings: Patients with variant tumors had similar clinical features to patients with conventional disease including: age, males to female ratio, stage, presence of Tis and median follow-up. Patients with variant tumors had a significantly worse prognosis compared to patients with conventional high-grade UC including: 5-year recurrence-free survival (63.5% Vs. 71.5%, p=0.05, 5-year progression to≥T2 -free survival (60% Vs. 82.5%, p=0.002, 5-year disease-specific survival (73% Vs. 92.5%, p=0.0004 and overall survival (66% Vs. 89.5%, 0.05. Interpretation: A patient with variant bladder cancer treated with intra-vesical immunotherapy has a 27% chance of dying from this disease within 5-years compared to 7.5% for a patient with conventional high-grade UC.

  15. Protective effect of mycelial polysaccharides from Cordyceps sinensis on immunological liver injury in mice

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    Kai-zhong DONG

    2016-04-01

    Full Text Available Objective  To explore the protective effects of mycelial polysaccharides from Cordyceps sinensis (MPCS on BCG+LPS-induced liver injury in mice. Methods  The immunological liver injury mice model was reproduced by giving bacillus Calmette-Guerin (BCG and lipopolysaccharide (LPS. Sixty NIH mice were randomly assigned into 6 groups (10 each: normal control group, model group, mycelium polysaccharide in high (100mg/kg, medium (50mg/kg and low (25mg/kg dose group, and bifendate (150mg/kg treatment group. The serum transaminase levels of alanine ALT and AST were assayed with ELISA, nitric oxide (NO in serum was measured by nitrate reductase method, and the liver homogenate was prepared for the determination of the contents of interleukin-1β(IL-1β and tumor necrosis factor-α(TNF-α. The mRNA expression levels of IL-6 and iNOS in hepatic tissue were assessed using RT-PCR . Results  In the mice of immunological liver injury, mycelial polysaccharides from Cordyceps sinensis obviously lowered the serum ALT and AST levels (P<0.01, high dose MPCS significantly reduced the serum NO and liver tissue IL-1βand TNF-αlevels (P<0.01. Compared with the model group, high and medium dose MPCS significantly reduced the expression levels of IL-6 and iNOS mRNA in hepatic tissues (P<0.01. Conclusion  MPCS shows a certain protective effect on immunological liver injury induced by BCG plus LPS in mice. DOI: 10.11855/j.issn.0577-7402.2016.04.05

  16. Assessing the Feasibility of Replacing Standard-Dose Bacillus Calmette–Guérin Immunotherapy with Other Intravesical Instillation Therapies in Bladder Cancer Patients: A Network Meta-Analysis

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    Cheng Wu

    2017-03-01

    Full Text Available Background: Bacillus Calmette–Guérin (BCG immunotherapy plays a key role in patients with bladder cancer. The shortage of intravesical BCG has motivated researchers to seek alternatives with equivalent efficacy If other alternative intravesical agents have equivalent efficacy compared to BCG, then it may be feasible to replace standard BCG with alternative options. Methods: We searched all relevant evidence in multiple sources and key data was extracted from included studies. Conventional and network meta-analysis were conducted so that pooled odds ratios (ORs for the event of tumor recurrence and progression can be computed. The relative efficacy of different intravesical instillation procedures was computed by pooled odds ratios and their 95% confidence or creditable intervals. Besides, several key model assumptions were evaluated in our analysis. Results: Three intravesical instillation procedures have the potential for preventing tumor recurrence: standard-dose BCG (BCG_SD, Epirubicin (EPI and Mitomycin C (MMC (ORs < 1. Patients with BCG SD also exhibited a decreased risk of tumor recurrence and progression compared to those with EPI. No significant difference in the risk of tumor recurrence or progression was detected between patients treated with BCG_ SD and those with low-dose BCG (BCG_LD. Results of SUCRA indicated that BCG_EPI, BCG_ MMC and BCG SD had higher rankings with respect to tumor recurrence and progression. Conclusions: BCG SD, EPI and MMC exhibited established efficacy for preventing tumor recurrence in postoperative BC patients. The efficacy of BCG may not be significantly reduced if standard dose was reduced to a lower level. However, there is no consensus suggesting that intravesical BCG with standard dose can be replaced by alternating or sequentially combined intravesical instillation therapies.

  17. Non-specific immunity of BCG vaccine: A perspective of BCG immunotherapy

    Directory of Open Access Journals (Sweden)

    Najeeha Talat Iqbal

    2014-01-01

    Full Text Available BCG is a widely used vaccine worldwide for neonates including Pakistan. BCG has more than 90% coverage through the EPI program which was introduced in 1965 in Pakistan. BCG has limited efficacy against the transmissible form of pulmonary tuberculosis in high TB endemic countries. However, BCG vaccination continues in these countries because BCG confers protection against the disseminated form of TB in children. BCG has also shown some protection against leprosy and certain forms of cancers. One reason for such nonspecific protection may be that BCG activates APCs via PAMPS that interacts with TLRs (2, 4 & 8, which initiate the inflammatory cascade thereby recruiting inflammatory cells to the site of infection and providing maturation signals for neutrophils, macrophages and dendritic cells. Such activation may be crucial for restricting the infection at the initial site. Furthermore, activation of the pro-inflammatory cascade also results in expression of adhesion molecules, co-stimulatory molecules as well as MHC class II molecule. MHC class II molecules engage CD4+ cells via the TCR receptor while the adhesion and costimulatory molecules bind to their respective receptors on CD4+ T cells for additional high affinity binding for T cell activation. Although activation of the innate arm may not provide subsequent memory, activation of T cells may introduce a certain level of memory response and therefore, may form a rational basis for BCG immunotherapy. This review, therefore, focuses on the immune activation related to both the innate and adaptive arm of the immune response that has been reported and further explores the utility of BCG immunotherapy related to non TB conditions.

  18. BCG protects against tuberculosis irrespective of HIV status

    DEFF Research Database (Denmark)

    Faurholt-Jepsen, Daniel; Range, Nyagosya; PrayGod, George

    2013-01-01

    While BCG vaccine protects against severe tuberculosis (TB) in children, its effect against adult TB is questionable. Furthermore, it is not known if HIV co-infection modifies the effect of BCG. Among 352 pairs of Tanzanian TB cases and matched controls, the BCG scar was associated with a reduced...

  19. BCG protects toddlers during a tuberculosis outbreak.

    LENUS (Irish Health Repository)

    Gaensbauer, J T

    2009-05-01

    In 2007, an outbreak of tuberculosis occurred in a toddler population attending two child care centres in Cork, Ireland. Of 268 children exposed, 18 were eventually diagnosed with active tuberculosis. We present the initial clinical and radiographic characteristics of the active disease group. Mantoux testing was positive in only 66% of cases. All cases were either pulmonary or involved hilar adenopathy on chest radiograph; there were no cases of disseminated disease or meningitis. 24% of the exposed children had been previously vaccinated with BCG, and no case of active disease was found in this group (p = 0.016), suggesting a profound protective effect of BCG in this population. Our experience provides evidence supporting a protective effect of BCG against pulmonary disease in young children.

  20. Spinal tuberculosis with severe neurological symptoms as a complication of intravesical BCG therapy for carcinoma of the bladder.

    Science.gov (United States)

    Białecki, Jerzy; Nowak-Misiak, Mirosława; Rąpała, Kazimierz; Marczyński, Wojciech; Suchodolski, Gracjan; Truszczyńska, Aleksandra

    2016-01-01

    Non-invasive bladder cancer is effectively treated with intravesical BCG therapy. The administration of the BCG vaccine is to destroy the neoplastic lesion or prevent further recurrences. The activity of the vaccine involves boosting the immune system through the stimulation of the inflammation in the bladder. Adverse reactions after this immunotherapy are rare. The aim of the study was to present complications in the form of spinal tuberculosis and serious neurological symptoms that occurred during intravesical BCG immunotherapy for carcinoma of the bladder. The manuscript also describes a method for neurosurgical spinal cord decompression of the thoracic spine. In the first patient, aged 66, after intravesical BCG therapy for bladder carcinoma, back pain and spastic paralysis of the lower limbs were observed. The MRI and CT revealed destruction of the intervertebral disc and vertebral endplates Th11-Th12. Mycobacterium tuberculosis complex bacilli were cultured from the material obtained by puncture aspiration. In the second patient, aged 35 years, during intravesical BCG immunotherapy for carcinoma of the bladder, girdle thoracic spine pain was observed. The MRI and CT of the spine showed visible lesions characteristic of tuberculosis. Immobilization in a plaster corset and implementation of antituberculous treatment resulted in quick relief of the pain and healing of the tuberculosis focus in the spine. The cases described in the work are the first documented reports in the Polish literature of spinal tuberculosis which occurred as a complication of intravesical administration of bacilli Calmette-Guérin. The diagnosis was based on the finding of BCG vaccine bacillus with molecular methods or PCR. Full antimycobacterial treatment was implemented. Copyright © 2015 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  1. Nano-BCG: A Promising Delivery System for Treatment of Human Bladder Cancer

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    Julieti Huch Buss

    2018-01-01

    Full Text Available Mycobacterium bovis bacillus Calmette–Guerin (BCG remains at the forefront of immunotherapy for treating bladder cancer patients. However, the incidence of recurrence and progression to invasive cancer is commonly observed. There are no established effective intravesical therapies available for patients, whose tumors recur following BCG treatment, representing an important unmet clinical need. In addition, there are very limited options for patients who do not respond to or tolerate chemotherapy due to toxicities, resulting in poor overall treatment outcomes. Within this context, nanotechnology is an emergent and promising tool for: (1 controlling drug release for extended time frames, (2 combination therapies due to the ability to encapsulate multiple drugs simultaneously, (3 reducing systemic side effects, (4 increasing bioavailability, (5 and increasing the viability of various routes of administration. Moreover, bladder cancer is often characterized by high mutation rates and over expression of tumor antigens on the tumor cell surface. Therapeutic targeting of these biomolecules may be improved by nanotechnology strategies. In this mini-review, we discuss how nanotechnology can help overcome current obstacles in bladder cancer treatment, and how nanotechnology can facilitate combination chemotherapeutic and BCG immunotherapies for the treatment of non-muscle invasive urothelial bladder cancer.

  2. Quality control and safety assessment of BCG vaccines in the post-genomic era

    Science.gov (United States)

    Stefanova, Tzvetelina

    2014-01-01

    A hundred and five years ago, Albert Calmette and Camille Guérin began a daunting task, which is unmatched even today, that led to the most widely used vaccine in human history. Despite a century of scientific advances, BCG (an acronym for Bacillus Calmette–Guérin) remains the only vaccine for prevention of tuberculosis. Due to the fact that the use of BCG vaccines will continue, either as a stand-alone or as a prime vaccine in prime-boost immunization strategies, the World Health Organization (WHO) has underlined the necessity for further work toward better characterization, evaluation and quality control of the BCG vaccine, taking into account recent advances in genetics and molecular biology. The potential benefit of such improved characterization could be addressed to better and easier differentiation between sub-strains used by different manufacturers. It may help to ensure consistency of production in terms of genetic stability and it may also help the clinical evaluation of new antituberculosis vaccines. Last but not least, the state-of-the-art technologies could facilitate the quality control performed by the manufacturers and by National Control Authorities as well. PMID:26019525

  3. Th1 Cytokine-Secreting Recombinant Mycobacterium bovis Bacillus Calmette-Guérin and Prospective Use in Immunotherapy of Bladder Cancer

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    Yi Luo

    2011-01-01

    Full Text Available Intravesical instillation of Mycobacterium bovis bacillus Calmette-Guérin (BCG has been used for treating bladder cancer for 3 decades. However, BCG therapy is ineffective in approximately 30–40% of cases. Since evidence supports the T helper type 1 (Th1 response to be essential in BCG-induced tumor destruction, studies have focused on enhancing BCG induction of Th1 immune responses. Although BCG in combination with Th1 cytokines (e.g., interferon-α has demonstrated improved efficacy, combination therapy requires multiple applications and a large quantity of cytokines. On the other hand, genetic manipulation of BCG to secrete Th1 cytokines continues to be pursued with considerable interest. To date, a number of recombinant BCG (rBCG strains capable of secreting functional Th1 cytokines have been developed and demonstrated to be superior to BCG. This paper discusses current rBCG research, concerns, and future directions with an intention to inspire the development of this very promising immunotherapeutic modality for bladder cancer.

  4. MEK inhibition enhances efficacy of bacillus Calmette-Guérin on bladder cancer cells by reducing release of Toll-like receptor 2-activated antimicrobial peptides.

    Science.gov (United States)

    Whang, Young Mi; Jin, Su Bin; Park, Serk In; Chang, In Ho

    2017-08-08

    Bacillus Calmette-Guérin (BCG) is one of the standard treatment options for non-muscle-invasive bladder cancer. The details of the biological defense mechanisms against BCG remain unclear. Here, we investigated whether BCG-induced release of antimicrobial peptides (AMPs; e.g., human β-defensin-2, -3, and cathelicidin) is involved with mitogen-activated protein kinase (MAPK) pathways, and investigated the enhanced anticancer effect of BCG through the down-regulation of Toll-like receptors (TLRs) and MAPK pathways in bladder cancer cells. BCG-infected bladder cancer cells produced AMPs as a defense mechanism against BCG, which were reduced by MEK inhibitors by blocking phosphorylation of extracellular signal-regulated kinase (ERK1/2 or MEK) and c-Jun. MEK inhibitors enhanced inhibition of bladder cancer cell growth by decreased binding of c-Jun, p65 and Pol II to the activated protein-1 promoter. Knockdown of TLR2 and TLR4 reduced ERK phosphorylation. Knockdown of TLR 2 decreased release of AMPs, which was similar to the efficacy of MEK inhibitor on BCG-infected cells. BCG-infected bladder cancer cells were more prone to induction of AMP release following TLR2 activation via ERK and c-Jun pathway mediators. In conclusion, our data suggest that the BCG-induced release of AMPs in bladder cancer cells is a promising molecular target for enhancing the immunotherapeutic efficacy of BCG in bladder cancer patients.

  5. Reiter's syndrome postintravesical Bacillus Calmette–Guérin instillations

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    Keng Lim Ng

    2017-03-01

    Full Text Available Intravesical Bacillus Calmette–Guérin (BCG has been a proven and effective immunotherapy treatment for superficial transitional cell carcinoma (TCC of the bladder, especially for high-grade tumors and carcinoma in situ. Nevertheless, significant side effects are associated with BCG instillations, including fever, myalgia, malaise, dysuria, hematuria, and irritable lower urinary tract symptoms. We herein report the case of a patient who developed Reiter's syndrome following intravesical BCG instillations. A 39-year-old Chinese man presented with a 3-week history of dysuria, suprapubic pain, and pain at the tip of the penis postmicturition. Initial investigations revealed that he had microhematuria, and an ultrasound with computed tomography scan of the abdomen showed a bladder mass. Transurethral resection of the bladder tumor was performed and the patient received a single dose of intravesical mitomycin postoperatively. Results of histopathological examination revealed high-grade bladder TCC (G3pT1, and the patient was managed with intravesical BCG for 2 weeks following the surgery. Four weekly cycles of BCG were administered uneventfully; however, before the fifth instillation, the patient complained of urethral discharge, bilateral conjunctivitis, and low back pain. Reiter's syndrome was diagnosed as a rare but known complication of BCG instillation and the BCG immunotherapy was withheld. The patient was treated with nonsteroidal antiinflammatory drugs (for back pain and eye ointment (for conjunctivitis and his condition improved. This case report of Reiter's syndrome should be highlighted as a rare but significant complication of BCG immunotherapy and urologists should have a high index of suspicion to diagnose this rare complication.

  6. Recombinant BCG: Innovations on an Old Vaccine. Scope of BCG Strains and Strategies to Improve Long-Lasting Memory

    Science.gov (United States)

    da Costa, Adeliane Castro; Nogueira, Sarah Veloso; Kipnis, André; Junqueira-Kipnis, Ana Paula

    2014-01-01

    Bacille Calmette–Guérin (BCG), an attenuated vaccine derived from Mycobacterium bovis, is the current vaccine of choice against tuberculosis (TB). Despite its protection against active TB in children, BCG has failed to protect adults against TB infection and active disease development, especially in developing countries where the disease is endemic. Currently, there is a significant effort toward the development of a new TB vaccine. This review article aims to address publications on recombinant BCG (rBCG) published in the last 5 years, to highlight the strategies used to develop rBCG, with a focus on the criteria used to improve immunological memory and protection compared with BCG. The literature review was done in April 2013, using the key words TB, rBCG vaccine, and memory. This review discusses the BCG strains and strategies currently used for the modification of BCG, including: overexpression of Mycobacterium tuberculosis (Mtb) immunodominant antigens already present in BCG; gene insertion of immunodominant antigens from Mtb absent in the BCG vaccine; combination of introduction and overexpression of genes that are lost during the attenuation process of BCG; BCG modifications for the induction of CD8+ T-cell immune responses and cytokines expressing rBCG. Among the vaccines discussed, VPM1002, also called rBCGΔureC:hly, is currently in human clinical trials. Much progress has been made in the effort to improve BCG, with some promising candidates, but considerable work is still required to address functional long-lasting memory. PMID:24778634

  7. [The practice of BCG vaccination in 1930 s' China].

    Science.gov (United States)

    Shi, R S

    2017-07-28

    Wang Liang introduced Bacille-Calmatte-Guerin(BCG) to China in 1933 in order to prevent tuberculosis. He established a BCG laboratory and make BCG strains by himself in Chongqing, and vaccinated children around, until he was forced to stop doing it by the government in November, 1937. In 1938 Shanghai Pasteur Institute was established, and they built a BCG laboratory to promote BCG vaccination in Shanghai, and these actions were insisted during 1940s. But in 1930s the medical profession all over the world was skeptical to BCG efficacy, which impeded the promotion of BCG vaccination in China. Without the collaboration of the government and the national medical profession, tuberculosis problem in China couldn't be improved by the effort of single doctor or an institute.

  8. Bladder Contracture – A Rare and Serious Side Effect of Intravesical Bacillus Calmette-Guérin Therapy

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    Cindy Garcia

    2016-01-01

    Full Text Available Instillation of intravesical bacillus Calmette-Guérin (BCG is an effective treatment for non-muscle invasive bladder cancer (NMIBC. The high incidence of side effects may limit its tolerability in patients. Local side effects including cystitis and hematuria are common but generally self-limiting. Bladder contractures are a rare but serious consequence of BCG treatment. In this case, an 82 year-old male developed BCG reactivation and subsequent bladder contractures following transurethral resection of the prostate (TURP three years post-BCG. To our knowledge, this is the first reported case of BCG reactivation post-TURP leading to the rare but serious effect of bladder contractures.

  9. Age at BCG administration during routine immunization.

    African Journals Online (AJOL)

    Age at BCG administration during routine immunization. R.D. Wammanda , M.J. Gambo and I. Abdulkadir. Department of Paediatrics,. Ahmadu Bello University Teaching Hospital,. Zaria. Correspondence to: Dr.R.D. Wammanda. Email: wammanda@yahoo.com. Summary. In Nigeria, as part of the National Programme on ...

  10. Osteomielitis esternal y escrofuloderma por vacuna BCG.

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    Ivohne Fernanda Corrales

    2003-06-01

    Full Text Available La vacuna BCG se ha usado en todo el mundo desde principios del siglo XX para la prevención de la tuberculosis. Se describe el caso de una niña de 13 meses de edad, previamente sana, que consultó por una masa esternal. El estudio radiológico mostró erosión perióstica. La lesión fue resecada y en la histopatología se encontró una reacción inflamatoria crónica con granulomas caseificantes con compromiso óseo y cutáneo. Se realizó una amplificación por PCR con iniciadores específicos de Mycobacterium tuberculosis del ADN obtenido a partir del tejido incluido en parafina, cuyo resultado fue negativo. Los antecedentes de vacunación con BCG, la aparición de este tipo de granulomas y la ausencia de ADN de M. tuberculosis en el tejido resecado apoyan el diagnóstico de osteomielitis esternal y escrofuloderma por BCG. La osteomielitis es una complicación infrecuente de la vacunación por BCG, que puede presentarse especialmente en pacientes inmunosuprimidos. La evolución clínica de la paciente no ha demostrado ninguna forma de inmunodeficiencia.

  11. Mycotic Aneurysm after Bacillus Calmette-Guérin Treatment: Case Report and Review of the Literature

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    Nathaniel D. Coddington

    2017-01-01

    Full Text Available Background. Intravesicular Bacillus Calmette-Guérin (BCG is an effective adjunctive therapy for superficial bladder cancer that has been shown to delay recurrence and progression of disease. Serious side effects are relatively rare but are difficult to diagnosis and commonly overlooked. Case Presentation. We report the case of a patient who was found to have mycotic aortic aneurysms secondary to treatment with BCG after a prolonged course with multiple intervening hospitalizations. Conclusion. Through this report, we discuss our present understanding of BCG infection following treatment and review the literature regarding this particular rare manifestation.

  12. Randomized trial of BCG vaccination at birth to low-birth-weight children

    DEFF Research Database (Denmark)

    Aaby, Peter; Roth, Adam Anders Edvin; Ravn, Henrik

    2011-01-01

    Observational studies have suggested that BCG may have nonspecific beneficial effects on survival. Low-birth-weight (LBW) children are not given BCG at birth in Guinea-Bissau; we conducted a randomized trial of BCG at birth (early BCG) vs delayed BCG....

  13. Bacillus Calmette–Guérin and Bladder Cancer

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    Azad H.A. Razack

    2007-10-01

    Full Text Available Bladder cancer is the second most common cancer of the urinary tract, and overall it is among the top 10 cancers in men. Transitional cell carcinoma (TCC is the most common type, with the majority being superficial disease, i.e. the tumour has not gone beyond the lamina propria. The main problem with superficial TCC is the high recurrence rate. Various forms of treatment methods have been attempted to reduce the recurrence rate, with intravesical bacillus Calmette–Guérin (BCG being the most successful to date. In fact, intravesical BCG is one of the most successful forms of immunotherapy in the treatment of any form of cancer. This article is a general review of BCG in bladder cancer with an emphasis on the indication and mechanism of action in reducing recurrence and progression.

  14. Bacillus Calmette-Guérin vaccination at birth

    DEFF Research Database (Denmark)

    Kjærgaard, Jesper; Stensballe, Lone Graff; Birk, Nina Marie

    2016-01-01

    BACKGROUND: Bacillus Calmette-Guérin vaccine (BCG) induces a complex, pro-inflammatory immune response. Obesity is associated with low-grade inflammation. AIMS: The purpose of the study was to test whether BCG at birth has effects on infant growth and body composition. STUDY DESIGN, SUBJECTS......, AND OUTCOME MEASURES: The Danish Calmette Study is a randomized, clinical trial. The study was conducted at three university hospitals and randomized 4262 children of gestational age ≥32weeks to receive BCG within seven days of birth or to a no-intervention control group. Follow-up consisted of clinical...... examinations. Outcome measures were weight and length at 3months, and weight, length, mid upper-arm circumference, and triceps and subscapular skinfold at 13months. Data collectors were blinded to allocation. Anthropometric measurements were converted to z-scores using WHO reference population. RESULTS: Follow...

  15. Síndrome de reconstitución inmune por BCG en niños tratados por VIH Immune reconstitution syndrome due to BCG in HIV-treated children

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    Edwin Miranda-Choque

    2012-12-01

    Full Text Available El objetivo del estudio fue describir el perfil clínico del síndrome de reconstitución inmune por Mycobacterium bovis Bacillus Calmette-Guérin (SIRI-BCG en niños con infección VIH que reciben tratamiento antirretroviral de gran actividad (TARGA en el Instituto Nacional de Salud del Niño de Lima, Perú. Se realizó un estudio de serie de casos, que incluyó ocho niños con SIRI-BCG, definido como la presencia de linfadenopatía regional o inflamación en sitio de inoculación de BCG con disminución de al menos un logaritmo en la carga viral o mejoría inmunológica. Todos los pacientes tenían estadio SIDA (C3. La mediana de edad de inicio del TARGA fue de 7,2 meses y el evento se produjo entre 3 a 11 semanas luego de haberlo iniciado. En siete casos se produjo adenitis axilar. Al comparar con el grupo sin SIRI-BCG se encontró asociación significativa con la edad de inicio del TARGA de un año, estado de inmunodepresión severa, y carga viral incrementada. Se concluye que el SIRI-BCG está relacionado con una rápida progresión clínica de la infección VIH/SIDA de trasmisión vertical, estadio de inmunosupresión severa, y carga viral alta al momento del inicio del TARGA.The objective of this study is to describe the clinical profile of the immune reconstitution syndrome due to Mycobacterium bovis Bacillus Calmette-Guérin (IRS-BCG in children with HIV infection who receive highly active antiretroviral treatment (HAART at Instituto Nacional de Salud del Niño de Lima (National Children’s Health Institute of Lima, Peru. A case study was conducted, including 8 children with IRS-BCG, defined as the presence of regional lymphadenopathy or inflammation on the BCG vaccination site with at least one less logarithm in the viral load or immune improvement. All patients had AIDS (C3. The starting median age in HAART was 7.2 months and the event occurred 3 to 11 weeks after the treatment was started. 7 cases showed axillary adenitis. When

  16. Differential effects of Radix Paeoniae Rubra (Chishao on cytokine and chemokine expression inducible by mycobacteria

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    Li James

    2011-03-01

    Full Text Available Abstract Background Upon initial infection with mycobacteria, macrophages secrete multiple cytokines and chemokines, including interleukin-6 (IL-6, IL-8 and tumor necrosis factor-α (TNF-α, to mediate host immune responses against the pathogen. Mycobacteria also induce the production of IL-10 via PKR activation in primary human monocytes and macrophages. As an anti-inflammatory cytokine, over-expression of IL-10 may contribute to mycobacterial evasion of the host immunity. Radix Paeoniae Rubra (RPR, Chishao, a Chinese medicinal herb with potentials of anti-inflammatory, hepatoprotective and neuroprotective effects, is used to treat tuberculosis. This study investigates the immunoregulatory effects of RPR on primary human blood macrophages (PBMac during mycobacterial infection. Methods The interaction of Bacillus Calmette-Guerin (BCG with PBMac was used as an experimental model. A series of procedures involving solvent extraction and fractionation were used to isolate bioactive constituents in RPR. RPR-EA-S1, a fraction with potent immunoregulatory effects was obtained with a bioactivity guided fractionation scheme. PBMac were treated with crude RPR extracts or RPR-EA-S1 before BCG stimulation. The expression levels of IL-6, IL-8, IL-10 and TNF-α were measured by qPCR and ELISA. Western blotting was used to determine the effects of RPR-EA-S1 on signaling kinases and transcriptional factors in the BCG-activated PBMac. Results In BCG-stimulated macrophages, crude RPR extracts and fraction RPR-EA-S1 specifically inhibited IL-10 production while enhanced IL-8 expression at both mRNA and protein levels without affecting the expressions of IL-6 and TNF-α. Inhibition of BCG-induced IL-10 expression by RPR-EA-S1 occurred in a dose- and time-dependent manner. RPR-EA-S1 did not affect the phosphorylation of cellular protein kinases including MAPK, Akt and GSK3β. Instead, it suppressed the degradation of IκBα in the cytoplasm and inhibited the

  17. Naive helper T cells from BCG-vaccinated volunteers produce IFN-gamma and IL-5 to mycobacterial antigen-pulsed dendritic cells.

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    JoĂŤl Pestel

    2008-06-01

    Full Text Available Mycobacterium bovis bacillus Calmette-GuĂŠrin (BCG is a live vaccine that has been used in routine vaccination against tuberculosis for nearly 80 years. However, its efficacy is controversial. The failure of BCG vaccination may be at least partially explained by the induction of poor or inappropriate host responses. Dendritic cells (DCs are likely to play a key role in the induction of immune response to mycobacteria by polarizing the reactivity of T lymphocytes toward a Th1 profile, contributing to the generation of protective cellular immunity against mycobacteria. In this study we aimed to investigate the production of Th1 and Th2 cytokines by naive CD4+ T cells to mycobacterial antigen-pulsed DCs in the group of young, healthy BCG vaccinated volunteers. The response of naive helper T cells was compared with the response of total blood lymphocytes. Our present results clearly showed that circulating naive CD45RA+CD4+ lymphocytes from BCG-vaccinated subjects can become effector helper cells producing IFN-gamma and IL-5 under the stimulation by autologous dendritic cells presenting mycobacterial protein antigen-PPD or infected with live M. bovis BCG bacilli.

  18. [NURSING CARE TO A PATIENT WITH INTRAVESICAL TREATMENT].

    Science.gov (United States)

    Marcos Espino, Míriam Paula; Tizón Bouza, Eva

    2015-12-01

    Bladder cancer is one of the most frequent in developed countries. It is the 4th most frequent cancer in men and the 9th in women. The main risk factor is the smoking habit and its main symptom is hematuria. One of the therapies used in its treatment is the Bacillus Calmette-Guerin intravesical (BCG). TO carry out a specific care plan to a patient treated with BCG and improve the information delivered to the patient and family. An observational study of a nursing plan of care through a clinical case. A bibliographical research was carried out in the main Spanish and English databases to collect articles published in the last 5 years. Subsequently, the studies of the Spanish M.a T Luis, C. Ferndndez and M.a V. Navarro were adopted in the model suggested by V. Henderson and NANDA, NIC and NOC taxonomy. The nursing assessment is performed through V. Henderson's 14 needs and the Collaboration Problem was detected: Hematuria, secondary to bladder cancer and the nursing diagnosis: . For the planning and execution the following NOC were selected: Knowledge: management of the cancer and Knowledge: therapeutic procedure, and the NIC and its corresponding activities and their evaluation. The Nursing Care Process application with a personalised and standardised language, guarantees a quality healthcare and continuity. Moreover, it sets common targets for the nursing team. It tries to show how an appropriate control of the symptoms can be carried out at home, when the cares are taught and organised by adapting the oral or written information to each patient.

  19. Expression of cellular components in granulomatous inflammatory response in Piaractus mesopotamicus model.

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    Wilson Gómez Manrique

    Full Text Available The present study aimed to describe and characterize the cellular components during the evolution of chronic granulomatous inflammation in the teleost fish pacus (P. mesopotamicus induced by Bacillus Calmette-Guerin (BCG, using S-100, iNOS and cytokeratin antibodies. 50 fish (120±5.0 g were anesthetized and 45 inoculated with 20 μL (40 mg/mL (2.0 x 10(6 CFU/mg and five inoculated with saline (0,65% into muscle tissue in the laterodorsal region. To evaluate the inflammatory process, nine fish inoculated with BCG and one control were sampled in five periods: 3rd, 7th, 14th, 21st and 33rd days post-inoculation (DPI. Immunohistochemical examination showed that the marking with anti-S-100 protein and anti-iNOS antibodies was weak, with a diffuse pattern, between the third and seventh DPI. From the 14th to the 33rd day, the marking became stronger and marked the cytoplasm of the macrophages. Positivity for cytokeratin was initially observed in the 14th DPI, and the stronger immunostaining in the 33rd day, period in which the epithelioid cells were more evident and the granuloma was fully formed. Also after the 14th day, a certain degree of cellular organization was observed, due to the arrangement of the macrophages around the inoculated material, with little evidence of edema. The arrangement of the macrophages around the inoculum, the fibroblasts, the lymphocytes and, in most cases, the presence of melanomacrophages formed the granuloma and kept the inoculum isolated in the 33rd DPI. The present study suggested that the granulomatous experimental model using teleost fish P. mesopotamicus presented a similar response to those observed in mammals, confirming its importance for studies of chronic inflammatory reaction.

  20. A survey of health professions students for knowledge, attitudes, and confidence about tuberculosis, 2005

    Directory of Open Access Journals (Sweden)

    Catanzaro Antonino

    2007-08-01

    Full Text Available Abstract Background In 2003 the NIH perceived a need to strengthen teaching about tuberculosis (TB to health professions students. The National Tuberculosis Curriculum Consortium (NTCC was funded to meet this need. The purpose of this study was to survey students enrolled in NTCC schools prior to NTCC-developed educational materials being made available to faculty. Methods A self-administered survey for students in NTCC schools to establish a baseline level of knowledge, attitudes, and confidence about tuberculosis. Results 1480/2965 (50% students in 28 programs in 20 NTCC schools completed the survey. If public health students are eliminated from totals (only 61 respondents of 765 public health students, the overall response proportion for the seven clinically-related disciplines was 64.5%. The majority (74% were in schools of medicine (MD/DO, undergraduate nursing (BSN, and pharmacy (PharmD; others were in programs for physician assistants (PA, advanced practice nursing (NP/APN, respiratory therapy (RT, clinical laboratory sciences (MT/CLS, and public health (MPH. Almost 90% had attended at least one lecture about TB. Although 91.4% knew TB was transmitted via aerosols, about one-third did not know the method for administering tuberculin, or that Bacillus Calmette-Guerin (BCG vaccine was not a contraindication to TB skin testing. Fewer than two-thirds knew that about 10% of people in the U.S.A. who have latent tuberculosis infection (LTBI and a normal immune system will develop TB disease, or that BCG is not part of the routine vaccination program in the U.S.A. because it complicates surveillance for new TB infection. Conclusion There is room for improvement in knowledge, attitudes, and confidence about TB by health professions students surveyed. The NTCC-developed educational products may be used by faculty to improve student performance to be assessed with future surveys.

  1. Multiparametric ultrasound findings of tuberculous orchitis following bacillus Calmette-Guérin therapy

    Directory of Open Access Journals (Sweden)

    Rumman Ahmed, MB BS, BSc (Hons, FRCR

    2017-12-01

    Full Text Available Granulomatous bacillus Calmette-Guérin (BCG infection, both localized and disseminated, as a complication of intravesical therapy for transitional cell carcinoma of the bladder is a recognized but highly unusual phenomenon. We report the case of an 89-year-old gentleman with a history of bladder transitional cell carcinoma and subsequent intravesical BCG instillation of the bladder who presented to his general practitioner with a non-tender lump in his left testis. Histopathologic and microbiological evaluation of the subsequent orchidectomy specimen revealed granuloma formation secondary to BCG infection. The use of bubble contrast agents and elastography in ultrasound to evaluate focal testicular lesions is a relatively novel concept, and we aim to highlight the imaging features of testicular BCG infection using these techniques.

  2. [Bacillus Calmette-Guérin osteomyelitis. A case report in a former preterm baby].

    Science.gov (United States)

    Milleret, A; Bost-Bru, C; Bustamante, J; Durand, C; Recule, C

    2016-07-01

    Postvaccination osteo-articular mycobacterial infectious disease is a rare and potentially serious complication after Bacillus Calmette-Guérin (BCG) vaccine. We report on a case of a former preterm baby born at 30 weeks of gestation who was vaccinated with BCG Copenhagen strain at 2 months of age. He presented 6 months later with a painful limp, which was found to be a mono-articular osteitis of the right ankle. Histology of the biopsy showed signs of mycobacterial infection and molecular analysis confirmed a BCG infection. Blood tests did not reveal any immunodeficiency associated with the disease (IFN-gamma levels were normal). The course of the disease was favorable with 9 months of antibiotic therapy against mycobacteria. BCG complications should lead to screening for immunodeficiency. The prognosis of BCG osteitis is excellent if the disease is localized. No link between prematurity and BCG complications has been found to date. BCG vaccination of premature infant should be the same as for the general population. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  3. Asthmatic Children And Immunological Effects Of BCG Vaccine Key words: Asthmatic children, BCG vaccine

    International Nuclear Information System (INIS)

    Saaed, A.I.

    2011-01-01

    A TH2 screwed immune response is known to play a crucial role in the pathogenesis of allergy, so, preventing the differentiation of TH cells. The TH2 cells are appeared as a logical therapeutic approach to atopic asthma. The purpose of TH1 study was to determine the possible role of BCG vaccine on asthma and whether a TH1 type immune response elicited by BCG immunization could suppress the allergic sensitization in childhood asthma. Seventy asthmatic patients (50 atopic and 20 non-atopic) and fifty healthy individuals were subjected to TH1 study. Tuberculin test was performed for all groups then subjects with positive tuberculin test were excluded. The BCG vaccine was given for all groups with assessment of TH1 and TH2 cytokine response by measuring total IgE, IL-4 (for TH2 response) and INF-γ (for TH1 response). Significant reduction in IgE and IL-4, and elevation in INF-γ were determined in group I (atopic asthma) following BCG vaccination. There was non-significant change observed in IgE and IL-4 levels of group II while significant reduction in IL-4 and significant increase in INF-γ was observed after BCG vaccine

  4. Rodent malaria: BCG-induced protection and immunosuppression

    International Nuclear Information System (INIS)

    Smrkovski, L.L.; Strickland, G.T.

    1978-01-01

    One dose of 10 7 viable units of Mycobacterium bovis, strain BCG, protected a significant number of Swiss mice from a primary challenge with 10 4 thoracic sporozoites of Plasmodium berghei. Immunization with irradiated sporozoites induced greater protection than that observed in BCG-treated animals. Mice treated with BCG and surviving a primary sporozoite challenge were not protected from rechallenge, whereas mice immunized with irradiated sporozoites and surviving initial challenge of sporozoites were solidly immune to further challenge. Immunizing mice with BCG and irradiated sporozoites simulataneously resulted in a synergistic effect of increased protection against a primary challenge of sporozoites only if the two immunogens were administered on the same day and if the mice were challenged 1 to 3 days later. Mice given BCG and irradiated sporozoites and surviving a primary challenge of sporozoites were unable to survive rechallenge. BCG given to mice previously immunized with irradiated sporozoites suppressed their protective immunity against sporozoite challenge

  5. [BCG vaccination--controversy and compromise].

    Science.gov (United States)

    Petrini, B

    2000-11-29

    In Sweden, BCG-vaccination is recommended to certain risk groups only, as the incidence of TB is very low. Children from high-endemic areas, as well as health care personnel, especially those working in risk areas, are the most important target groups. The efficacy of BCG vaccination has varied in different investigations, but early Nordic studies have shown approximately 80 percent protection. Vaccination prevents disseminated but not localized pulmonary disease. There are no data supporting revaccination. Today some Swedish children are vaccinated without a clear indication, due to caretakers' fear of TB. The risk of new infection is very low in Sweden today, and is for all practical purposes limited to the closest family members of affected individuals. If large numbers of refugees from high-endemic countries arrive in Sweden, the epidemiological situation must be closely monitored.

  6. Molecular analysis of Mycobacterium isolates from patients with BCG-induced lymphadenitis

    Directory of Open Access Journals (Sweden)

    Farahnoosh Doustdar

    2015-01-01

    Conclusion: As all of the strains isolated from the patients were confirmed as M. bovis BCG strain Pasteur, the other possible factors causing BCG complications, including BCG overdose, faulty intradermal technique, and disturbance of cellular immunity, must be considered.

  7. Central memory CD4+ T cells are responsible for the recombinant Bacillus Calmette-Guérin ΔureC::hly vaccine's superior protection against tuberculosis.

    Science.gov (United States)

    Vogelzang, Alexis; Perdomo, Carolina; Zedler, Ulrike; Kuhlmann, Stefanie; Hurwitz, Robert; Gengenbacher, Martin; Kaufmann, Stefan H E

    2014-12-15

    Bacillus Calmette-Guérin (BCG) has been used for vaccination against tuberculosis for nearly a century. Here, we analyze immunity induced by a live tuberculosis vaccine candidate, recombinant BCG ΔureC::hly vaccine (rBCG), with proven preclinical and clinical safety and immunogenicity. We pursue in-depth analysis of the endogenous mycobacteria-specific CD4(+) T-cell population, comparing the more efficacious rBCG with canonical BCG to determine which T-cell memory responses are prerequisites for superior protection against tuberculosis. rBCG induced higher numbers and proportions of antigen-specific memory CD4(+) T cells than BCG, with a CXCR5(+)CCR7(+) phenotype and low expression of the effector transcription factors T-bet and Bcl-6. We found that the superior protection of rBCG, compared with BCG, correlated with higher proportions and numbers of these central memory T cells and of T follicular helper cells associated with specific antibody responses. Adoptive transfer of mycobacteria-specific central memory T cells validated their critical role in protection against pulmonary tuberculosis. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

  8. BCG Vaccination: Is there light at end of the Tunnel?

    OpenAIRE

    PARTHASARATHY, A; HITT, Sharma

    2010-01-01

    The first Human BCG Vaccine was developed in 1921.Since 1960s billions of beneficiaries have received the vaccine in almost all the countries of the world .However its efficacy has been rated from 0 - 80% in several studies world over which include large randomized/controlled/case-control studies. Since 1974 BCG vaccine was included in the Expanded Program on Immunization(EPI) benefitting approx. 2 billion infants. Despite controversy BCG vaccine efficacy has been established in preventing he...

  9. Tuberculin reaction, BCG scar, and lower female mortality

    DEFF Research Database (Denmark)

    Roth, Adam Anders Edvin; Sodemann, Morten; Jensen, Henrik

    2006-01-01

    Recent studies have suggested that bacille Calmette-Guérin (BCG) immunization may have a nonspecific beneficial effect on infant survival and that the effect may be more pronounced among girls. In a prospective birth cohort, we examine whether a positive tuberculin skin test and BCG scar...... in response to BCG immunization were related to better overall survival in Guinea-Bissau and, if so, whether the effect was sex-specific....

  10. Short Communication: Age at BCG administration during routine ...

    African Journals Online (AJOL)

    In Nigeria, as part of the National Programme on Immunization (NPI), BCG should be given at birth. A survey of the ages at which mothers bring their children for BCG vaccination showed that only 22% of children receive their BCG within the first 3 days of life and 36.2% within the first 7 days of life. The place of birth and ...

  11. Preparation of a working seed lot of BCG and quality control by PCR genotyping Preparación de un lote semilla de trabajo de BCG y control de calidad por genotipificación por PCR

    Directory of Open Access Journals (Sweden)

    A Trovero

    2010-02-01

    Full Text Available The bacillus Calmette-Guérin (BCG was obtained in 1920 after successive passages leading to the attenuation of a Mycobacterium bovis strain. For the following 40 years, BCG had been replicated, resulting in substrains with genotypic and phenotypic differences. Several genomic studies have compared two BCG strains, M. bovis and Mycobacterium tuberculosis, and observed that deleted regions in the different strains could be related to differences in antigenic properties. In this work, a working seed lot was obtained from a lyophilized secondary seed lot from the BCG Pasteur strain 1173 P2 and genetically characterized. The genome was analyzed by PCR directed to five regions (RD1, RD2, RD14, RD15, DU2, using the seed lot and different available strains as templates. No genetic differences were found in the fragments studied as compared to the Pasteur strain. A total of 20 passages were carried out and no differences were found in the size of the fragments amplified by PCR. In conclusion, this method allows to control a working seed lot genotypically and to assess the stability of the BCG genome.El bacilo de Calmette-Guérin (BCG se obtuvo en 1920, después de sucesivos pasajes que llevaron a la atenuación de una cepa de Mycobacterium bovis. A lo largo de los 40 años subsiguientes la cepa BCG fue replicada y surgieron subcepas con diferencias fenotípicas y genotípicas. Se realizaron varios estudios de comparación genómica de diferentes cepas de BCG, M. bovis y Mycobacterium tuberculosis, y se observó que las deleciones de regiones en las diferentes cepas podrían estar relacionadas con diferencias en las propiedades antigénicas. En este trabajo se describe la preparación y caracterización genética de un lote semilla de trabajo obtenido a partir de un lote semilla secundaria liofilizado de la cepa BCG Pasteur 1173 P2. Se analizaron por PCR cinco regiones (RD1, RD2, RD14, RD15, DU2 en el lote semilla de trabajo utilizando como control las

  12. [BCG vaccine against tuberculosis: its protective effect and vaccination policies].

    Science.gov (United States)

    Pereira, Susan M; Dantas, Odimariles Maria Souza; Ximenes, Ricardo; Barreto, Mauricio L

    2007-09-01

    The BCG vaccine has been in use since 1921, but still arouses controversy and uncertainties. The objective was to analyze the protective effect of the BCG vaccine in its first and second doses and the accompanying vaccination policies. A systematic review of the literature in both English and Spanish was carried out, covering the period 1948 to 2006, using the PubMed database. The main search terms used included BCG vaccine, BCG efficacy, BCG and tuberculosis. The studies were grouped by design, with the main results from the clinic tests, case-control studies and meta-analyses presented separately. The protective effect of the first dose of the BCG vaccine against tuberculosis in its miliary and meningeal forms is high. However, the results vary in relation to the pulmonary form of the disease, with some indicating zero effect and others levels of nearly 80%. Research is being carried out to develop new vaccines that could substitute the BCG or be used as a booster. There are evidences that the protective effect of the BCG vaccine does not increase with a second dose. In spite of its limitations and the expectation that a new tuberculosis vaccine will be developed in the future, the BCG vaccine remains an important tool in controlling the harmful effects of tuberculosis, particularly in countries with medium or high incidence levels of the disease.

  13. Variable BCG efficacy in rhesus populations: Pulmonary BCG provides protection where standard intra-dermal vaccination fails.

    Science.gov (United States)

    Verreck, Frank A W; Tchilian, Elma Z; Vervenne, Richard A W; Sombroek, Claudia C; Kondova, Ivanela; Eissen, Okke A; Sommandas, Vinod; van der Werff, Nicole M; Verschoor, Ernst; Braskamp, Gerco; Bakker, Jaco; Langermans, Jan A M; Heidt, Peter J; Ottenhoff, Tom H M; van Kralingen, Klaas W; Thomas, Alan W; Beverley, Peter C L; Kocken, Clemens H M

    2017-05-01

    M.bovis BCG vaccination against tuberculosis (TB) notoriously displays variable protective efficacy in different human populations. In non-human primate studies using rhesus macaques, despite efforts to standardise the model, we have also observed variable efficacy of BCG upon subsequent experimental M. tuberculosis challenge. In the present head-to-head study, we establish that the protective efficacy of standard parenteral BCG immunisation varies among different rhesus cohorts. This provides different dynamic ranges for evaluation of investigational vaccines, opportunities for identifying possible correlates of protective immunity and for determining why parenteral BCG immunisation sometimes fails. We also show that pulmonary mucosal BCG vaccination confers reduced local pathology and improves haematological and immunological parameters post-infection in animals that are not responsive to induction of protection by standard intra-dermal BCG. These results have important implications for pulmonary TB vaccination strategies in the future. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. Mycobacterium bovis Bacillus Calmette–Guérin Alters Melanoma Microenvironment Favoring Antitumor T Cell Responses and Improving M2 Macrophage Function

    Directory of Open Access Journals (Sweden)

    Ricardo D. Lardone

    2017-08-01

    Full Text Available Intralesional Mycobacterium bovis bacillus Calmette–Guérin (BCG has long been a relatively inexpensive therapy for inoperable cutaneous metastatic melanoma (CMM, although intralesional BCG skin mechanisms remain understudied. We analyzed intralesional BCG-treated CMM lesions combined with in vitro studies to further investigate BCG-altered pathways. Since macrophages play a pivotal role against both cancer and mycobacterial infections, we hypothesized BCG regulates macrophages to promote antitumor immunity. Tumor-associated macrophages (M2 infiltrate melanomas and impair antitumor immunity. BCG-treated, in vitro-polarized M2 (M2-BCG showed transcriptional changes involving inflammation, immune cell recruitment, cross talk, and activation pathways. Mechanistic network analysis indicated M2-BCG potential to improve interferon gamma (IFN-γ responses. Accordingly, frequency of IFN-γ-producing CD4+ T cells responding to M2-BCG vs. mock-treated M2 increased (p < 0.05. Moreover, conditioned media from M2-BCG vs. M2 elevated the frequency of granzyme B-producing CD8+ tumor-infiltrating lymphocytes (TILs facing autologous melanoma cell lines (p < 0.01. Furthermore, transcriptome analysis of intralesional BCG-injected CMM relative to uninjected lesions showed immune function prevalence, with the most enriched pathways representing T cell activation mechanisms. In vitro-infected MM-derived cell lines stimulated higher frequency of IFN-γ-producing TIL from the same melanoma (p < 0.05. Our data suggest BCG favors antitumor responses in CMM through direct/indirect effects on tumor microenvironment cell types including macrophages, T cells, and tumor itself.

  15. BCG and BCG/DNAhsp65 vaccinations promote protective effects without deleterious consequences for experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Zorzella-Pezavento, Sofia Fernanda Gonçalves; Guerino, Clara Pires Fujiara; Chiuso-Minicucci, Fernanda; França, Thais Graziela Donegá; Ishikawa, Larissa Lumi Watanabe; Masson, Ana Paula; Silva, Célio Lopes; Sartori, Alexandrina

    2013-01-01

    A prime-boost strategy conserving BCG is considered the most promising vaccine to control tuberculosis. A boost with a DNA vaccine containing the mycobacterial gene of a heat shock protein (pVAXhsp65) after BCG priming protected mice against experimental tuberculosis. However, anti-hsp65 immunity could worsen an autoimmune disease due to molecular mimicry. In this investigation, we evaluated the effect of a previous BCG or BCG/pVAXhsp65 immunization on experimental autoimmune encephalomyelitis (EAE) development. Female Lewis rats were immunized with BCG or BCG followed by pVAXhsp65 boosters. The animals underwent EAE induction and were daily evaluated for weight loss and clinical score. They were euthanized during recovery phase to assess immune response and inflammatory infiltration at the central nervous system. Previous immunization did not aggravate or accelerate clinical score or weight loss. In addition, this procedure clearly decreased inflammation in the brain. BCG immunization modulated the host immune response by triggering a significant reduction in IL-10 and IFN-γ levels induced by myelin basic protein. These data indicated that vaccination protocols with BCG or BCG followed by boosters with pVAXhsp65 did not trigger a deleterious effect on EAE evolution.

  16. BCG and BCG/DNAhsp65 Vaccinations Promote Protective Effects without Deleterious Consequences for Experimental Autoimmune Encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Sofia Fernanda Gonçalves Zorzella-Pezavento

    2013-01-01

    Full Text Available A prime-boost strategy conserving BCG is considered the most promising vaccine to control tuberculosis. A boost with a DNA vaccine containing the mycobacterial gene of a heat shock protein (pVAXhsp65 after BCG priming protected mice against experimental tuberculosis. However, anti-hsp65 immunity could worsen an autoimmune disease due to molecular mimicry. In this investigation, we evaluated the effect of a previous BCG or BCG/pVAXhsp65 immunization on experimental autoimmune encephalomyelitis (EAE development. Female Lewis rats were immunized with BCG or BCG followed by pVAXhsp65 boosters. The animals underwent EAE induction and were daily evaluated for weight loss and clinical score. They were euthanized during recovery phase to assess immune response and inflammatory infiltration at the central nervous system. Previous immunization did not aggravate or accelerate clinical score or weight loss. In addition, this procedure clearly decreased inflammation in the brain. BCG immunization modulated the host immune response by triggering a significant reduction in IL-10 and IFN-γ levels induced by myelin basic protein. These data indicated that vaccination protocols with BCG or BCG followed by boosters with pVAXhsp65 did not trigger a deleterious effect on EAE evolution.

  17. The feasibility of the interferon gamma release assay and predictors of discordance with the tuberculin skin test for the diagnosis of latent tuberculosis infection in a remote Aboriginal community.

    Directory of Open Access Journals (Sweden)

    Gonzalo G Alvarez

    Full Text Available The tuberculin skin test (TST is the standard test used to screen for latent TB infection (LTBI in the northern Canadian territory of Nunavut. Interferon gamma release assays (IGRA are T cell blood-based assays to diagnose LTBI. The Bacillus Calmette-Guerin (BCG vaccine is part of the routine immunization schedule in Nunavut. The objective of this study was to test the feasibility, and predictors of discordance between the Tuberculin Skin Test (TST and the IGRA assay in a medically under-serviced remote arctic Aboriginal population.Both the TST and QuantiFERON-TB Gold (Qiagen group IGRA tests were offered to people in their homes as part of a public health campaign aimed at high TB risk residential areas in Iqaluit, Nunavut, Canada. Feasibility was measured by the capacity of the staff to do the test successfully as measured by the proportion of results obtained.In this population of predominantly young Inuit who were mostly BCG vaccinated, the use of IGRA for the diagnosis of LTBI was feasible. IGRA testing resulted in more available test results reaching patients (95.6% vs 90.9% p = 0.02 but took longer (median 8 days (IGRA vs 2 days (TST, p value < 0.0001. 44/256 participants (17.2% had discordant results. Multivariable regression analysis suggested that discordant results were most likely to have received multiple BCG vaccinations (RR 20.03, 95% CI, 3.94-101.82, followed by BCG given post infancy (RR 8.13, 95% CI, 2.54-26.03 and then to a lesser degree when BCG was given in infancy (RR 6.43, 95% CI, 1.72-24.85.IGRA is feasible in Iqaluit, Nunavut, a remote Arctic community. IGRA testing results in more test results available to patients compared to TST. This test could result in fewer patients requiring latent TB treatment among those previously vaccinated with BCG in a region with limited public health human resources.

  18. Invitro immune responses in children following BCG vaccination

    Directory of Open Access Journals (Sweden)

    Vijayalakshmi V

    2006-01-01

    Full Text Available Introduction: There is still no consensus on the efficacy of BCG vaccine in the prevention of tuberculosis. This study therefore addressed the question of the magnitude of immunity afforded by BCG, by studying the effector mechanisms of protection in children. The main objectives were to assess the degree of immunity conferred by BCG vaccine in children and to identify the most immunogenic antigen(s of BCG by conducting in-vitro studies. Materials and methods: Children in the age-group of 1 to 10 years, were categorized: (A normal, and vaccinated with BCG during the first year, n=45, (B normal, without scar and with no evident history of vaccination, n=31: and (C children admitted in the hospital with a confirmed diagnosis of tuberculosis, n=31. Fractions of BCG were obtained by lysis, sonication, separation by gel chromatography, HPLC and confirmed by SDS-PAGE. In lymphoproliferative assays PBMC were cultured and stimulated with either Concanavalin-A or Tuberculin or the fractions of BCG. Stimulation indices (SI in lymphoproliferation, CD4/CD8 cells, levels of Interferon-γ (IFN- γ in the culture supernatants were measured by ELISA. Results: The vaccinated children displayed significantly high (P< 0.05 mean values of SI in LTT, CD4/CD8 cell ratio against the unfractionated, 67kDa fraction and BCG-CF Ags. While 100% of the vaccinated children had positive lymphoproliferation indices to BCG-CF, only 8.3% of the unvaccinated children were positive. Conclusion: Some of the components of BCG induced a strong Thl cell response in children. These immunogenic antigens were present in the whole cell lysate. The use of BCG vaccine for tuberculosis is worthwhile till a new vaccine is developed.

  19. Prevalence of BCG scar among BCG-vaccinated children in a ...

    African Journals Online (AJOL)

    Background: The burden of tuberculosis is high in Nigeria as in other developing countries. The administration of BCG vaccine to neonates is essential in the control of tuberculosis. A scar usually develops 6 – 8 weeks later at the site of vaccination, which can be used clinically as a proof of vaccination. Not all vaccinated ...

  20. Variable Virulence and Efficacy of BCG Vaccine Strains in Mice and Correlation With Genome Polymorphisms

    Science.gov (United States)

    Zhang, Lu; Ru, Huan-wei; Chen, Fu-zeng; Jin, Chun-yan; Sun, Rui-feng; Fan, Xiao-yong; Guo, Ming; Mai, Jun-tao; Xu, Wen-xi; Lin, Qing-xia; Liu, Jun

    2016-01-01

    Bacille Calmette–Guérin (BCG), an attenuated strain of Mycobacterium bovis, is the only vaccine available for tuberculosis (TB) control. However, BCG is not an ideal vaccine and has two major limitations: BCG exhibits highly variable effectiveness against the development of TB both in pediatric and adult populations and can cause disseminated BCG disease in immunocompromised individuals. BCG comprises a number of substrains that are genetically distinct. Whether and how these genetic differences affect BCG efficacy remains largely unknown. In this study, we performed comparative analyses of the virulence and efficacy of 13 BCG strains, representing different genetic lineages, in SCID and BALB/c mice. Our results show that BCG strains of the DU2 group IV (BCG-Phipps, BCG-Frappier, BCG-Pasteur, and BCG-Tice) exhibit the highest levels of virulence, and BCG strains of the DU2 group II (BCG-Sweden, BCG-Birkhaug) are among the least virulent group. These distinct levels of virulence may be explained by strain-specific duplications and deletions of genomic DNA. There appears to be a general trend that more virulent BCG strains are also more effective in protection against Mycobacterium tuberculosis challenge. Our findings have important implications for current BCG vaccine programs and for future TB vaccine development. PMID:26643797

  1. Differential Cell Composition and Cytokine Expression Within Lymph Node Granulomas from BCG-Vaccinated and Non-vaccinated Cattle Experimentally Infected with Mycobacterium bovis.

    Science.gov (United States)

    Salguero, F J; Gibson, S; Garcia-Jimenez, W; Gough, J; Strickland, T S; Vordermeier, H M; Villarreal-Ramos, B

    2017-12-01

    Cattle vaccination against bovine tuberculosis (bTB) has been proposed as a supplementary method to help control the incidences of this disease. Bacillus Calmette-Guérin (BCG) is currently the only viable candidate vaccine for immunization of cattle against bTB, caused by Mycobacterium bovis (M. bovis). In an attempt to characterize the differences in the immune response following M. bovis infection between BCG-vaccinated and non-vaccinated animals, a combination of gross pathology, histopathology and immunohistochemical (IHC) analyses was used. BCG vaccination was found to significantly reduce the number of gross and microscopic lesions present within the lungs and lymph nodes. Additionally, the microscopically visible bacterial load of stages III and IV granulomas was reduced. IHC using cell surface markers revealed the number of CD68+ (macrophages), CD3+ (T lymphocytes) and WC1+ cells (γδ T cells) to be significantly reduced in lymph node granulomas of BCG-vaccinated animals, when compared to non-vaccinated animals. B lymphocytes (CD79a+) were significantly increased in BCG-vaccinated cattle for granulomas at stages II, III and IV. IHC staining for iNOS showed a higher expression in granulomas from BCG-vaccinated animals compared to non-vaccinated animals for all stages, being statistically significant in stages I and IV. TGFβ expression decreased alongside the granuloma development in non-vaccinated animals, whereas BCG-vaccinated animals showed a slight increase alongside lesion progression. IHC analysis of the cytokines IFN-γ and TNF-α demonstrated significantly increased expression within the lymph node granulomas of BCG-vaccinated cattle. This is suggestive of a protective role for IFN-γ and TNF-α in response to M. bovis infection. Findings shown in this study suggest that the use of BCG vaccine can reduce the number and severity of lesions, induce a different phenotypic response and increase the local expression of key cytokines related to

  2. Mycobacterium bovis endophthalmitis from BCG immunotherapy for bladder cancer

    NARCIS (Netherlands)

    Gerbrandy, S. J. F.; Schreuders, L. C.; de Smet, M. D.

    2008-01-01

    BACKGROUND: We report a patient who developed BCG endophthalmitis after BCG immunotherapy for bladder cancer. Comparison of this case with 2 other reported cases reveals a similar pattern of elderly, debilitated and immunocompromised patients with poor response to systemic antituberculous therapy in

  3. Murine model of BCG lung infection: Dynamics of lymphocyte ...

    Indian Academy of Sciences (India)

    Unknown

    pulmonary BCG infection. Few T cells in tracheal LN of BCG infected mice produce IFNγ, suggesting that maturational changes associated with migration to the lungs or residence in the lungs enhance the capability of some T cells to produce this cytokine. [Saxena R K, Weissman D, Simpson J and Lewis D M 2002 Murine ...

  4. BCG vaccination reduces risk of tuberculosis infection in vaccinated badgers and unvaccinated badger cubs.

    Directory of Open Access Journals (Sweden)

    Stephen P Carter

    Full Text Available Wildlife is a global source of endemic and emerging infectious diseases. The control of tuberculosis (TB in cattle in Britain and Ireland is hindered by persistent infection in wild badgers (Meles meles. Vaccination with Bacillus Calmette-Guérin (BCG has been shown to reduce the severity and progression of experimentally induced TB in captive badgers. Analysis of data from a four-year clinical field study, conducted at the social group level, suggested a similar, direct protective effect of BCG in a wild badger population. Here we present new evidence from the same study identifying both a direct beneficial effect of vaccination in individual badgers and an indirect protective effect in unvaccinated cubs. We show that intramuscular injection of BCG reduced by 76% (Odds ratio = 0.24, 95% confidence interval (CI 0.11-0.52 the risk of free-living vaccinated individuals testing positive to a diagnostic test combination to detect progressive infection. A more sensitive panel of tests for the detection of infection per se identified a reduction of 54% (Odds ratio = 0.46, 95% CI 0.26-0.88 in the risk of a positive result following vaccination. In addition, we show the risk of unvaccinated badger cubs, but not adults, testing positive to an even more sensitive panel of diagnostic tests decreased significantly as the proportion of vaccinated individuals in their social group increased (Odds ratio = 0.08, 95% CI 0.01-0.76; P = 0.03. When more than a third of their social group had been vaccinated, the risk to unvaccinated cubs was reduced by 79% (Odds ratio = 0.21, 95% CI 0.05-0.81; P = 0.02.

  5. Intravesical ALT-803 and BCG treatment reduces tumor burden in a carcinogen induced bladder cancer rat model; a role for cytokine production and NK cell expansion.

    Science.gov (United States)

    Gomes-Giacoia, Evan; Miyake, Makito; Goodison, Steve; Sriharan, Aravindhan; Zhang, Ge; You, Lijing; Egan, Jack O; Rhode, Peter R; Parker, Alexander S; Chai, Karl X; Wong, Hing C; Rosser, Charles J

    2014-01-01

    Intravesical Bacillus Calmette-Guérin (BCG) has been shown to induce a specific immunologic response (i.e., activation of IL-2 and effector T-cells), while preclinical studies using ALT-803 (mutated IL-15 analogue combined with IL-15Rα-Fc fusion) have shown promising results by prolonging the agent's half-life and stimulating CD8+ T-cells. Based on these results, we hypothesized that the intravesical administration of ALT-803 along with BCG will generate an immunologic response leading to significant bladder tumor burden reduction. Using a well-established carcinogen induced rat non-muscle invasive bladder cancer (NMIBC) model, we studied the effects of intravesical ALT-803 with and without BCG. Rat tissues were evaluated to document treatment response. Intravesical ALT-803 was safe and well tolerated alone and in combination with BCG. As a single treatment agent, ALT-803 reduced tumor burden by 35% compared to control whereas BCG alone only reduced tumor burden by 15%. However, the combination of ALT-803 plus BCG reduced tumor burden by 46% compared to control. Immune monitoring suggested that the antitumor response was linked to the production and secretion of IL-1α, IL-1β and RANTES, which in turn, induced the proliferation and activation of NK cells. Lastly, tumoral responses of the combinational treatment were associated with 76% reduction in angiogenesis, which is significantly higher than when assessed with either agent alone. The enhanced therapeutic index seen with this duplet provides justification for the development of this regimen for future clinical trials.

  6. BCG: the only available vaccine against tuberculosis: review article

    Directory of Open Access Journals (Sweden)

    Roghayeh Teimourpour

    2017-01-01

    Full Text Available Background: Despite advances in the vaccinology and chemotherapy in the past century, tuberculosis is still responsible for two million deaths every year. Emergence of multi-drug resistant strain and coinfection of TB-HIV make it a serious concern. Treatment and control of tuberculosis is a great health burden in every community. Active tuberculosis in children has very severe consequences especially those who are under 5-years-old, therefore vaccine indication should be taken. Bacille Calmette-Guérin (BCG is a live attenuated strain of Mycobacterium bovis that has been used for providing immunity or protection against tuberculosis (TB. In addition, BCG provides relative protection against leprosy and Buruli ulcer, it also can be used for treatment of bladder cancer. BCG is the most widely administered vaccine around the world. It has been given to over three billion individuals over the past decades. At first it was developed in 1908 at the Pasteur Institute in Lille by Albert Calmette and Camille Guérin. In fact BCG is a strain of Mycobacterium bovis that bear deletion in its genome following too long subculture in special media. Deletion in region of deletion 1 (RD1, a specific region of Mycobacterium bovis genome, has decreased pathogenicity of BCG strain. Following culture of BCG on different media since 1921 make genetic variation in the BCG strains that have specific characteristics. BCG should begin given to only immune-competent individuals and should not be administered to immunocompromised people. This vaccine is not effective in people formerly infected or sensitized with environmental mycobacteria. Previous meta-analysis studies indicate that BCG has variable range of protection from 0 to 80 percent against pulmonary TB, but is very effective against severe disseminated forms such as meningitis and miliary form of TB. Despite many research and develop new generation vaccine against TB, BCG vaccine still remains as the only

  7. Oral bacillus Calmette-Guérin vaccine against tuberculosis: why not?

    Directory of Open Access Journals (Sweden)

    Renata Monteiro-Maia

    2014-09-01

    Full Text Available The bacillus Calmette-Guérin (BCG vaccine is the only licensed vaccine for human use against tuberculosis (TB. Although controversy exists about its efficacy, the BCG vaccine is able to protect newborns and children against disseminated forms of TB, but fails to protect adults against active forms of TB. In the last few years, interest in the mucosal delivery route for the vaccine has been increasing owing to its increased capacity to induce protective immune responses both in the mucosal and the systemic immune compartments. Here, we show the importance of this route of vaccination in newly developed vaccines, especially for vaccines against TB.

  8. STUDY OF BCG SCAR AND SERUM ADA LEVELS IN INFANTS

    Directory of Open Access Journals (Sweden)

    Harishchandra Venkata Yanamandala

    2017-11-01

    Full Text Available BACKGROUND In developing countries, in both adults and children, tuberculosis is an important cause of morbidity and mortality. In 1993, it is declared as the first infectious disease by global health emergency.1 According to WHO report globally, there were an estimated 9.27 million ancient cases of TB in 2009. The cases reported were 8.3 million, the children covered an estimated percentage of 11 and it ranged from 3-25 percent.2 BCG vaccination was advocated for prevention of tuberculosis in children. The aim of the study is to estimate serum ADA levels in newborns before BCG vaccination, serum ADA levels in children with and without BCG scar, after receiving BCG vaccination, serum ADA levels in children without BCG vaccination and to find significance of serum ADA levels in BCG vaccinated children by comparing the above groups. MATERIALS AND METHODS This study was conducted at the Department of Paediatrics, Gitam Institute of Medical Sciences and Research Institute, October 2015 to September 2016. Babies who were in postnatal ward and infants of age of 12 weeks attending for BCG vaccination were included in the study. The total numbers of infants studied were 150. RESULTS In our study, out of 120 children included in the study before BCG vaccination comprising group-1, 61% were males and 39% were females. Out of 120 children received BCG vaccination, only 100 came for follow up comprising group-2, of which 67 (67% were males and 33 (33% were females. 15 children who did not receive BCG vaccination at 12 weeks of age were included in group 3 out of which 11 (73.33% were males and 4 (26.67% were females. Mean ADA levels at the age of 12 weeks in group-2 who were vaccinated at birth were 30.89 ± 5.27 U/L compared to mean ADA levels at the age of 12 weeks in group-3, which was 15.47 ± 1.85 U/L. This shows significant rise in mean ADA levels at 12 weeks of age in those who were vaccinated at birth comprising group-2 compared to their mean ADA

  9. BCG Induced Necrosis of the Entire Bladder Urothelium

    Directory of Open Access Journals (Sweden)

    Malte Krönig

    2015-09-01

    Full Text Available Instillation therapy with attenuated tuberculosis bacteria (BCG can significantly reduce rates of recurrence of non-muscle invasive bladder cancer. Local and systemic side effects such as dysuria, irritative voiding symptoms or partial bladder contracture and systemic inflammation were reported. A 75 year-old male patient with recurrent non muscle invasive bladder cancer developed necrosis of the entire bladder urothelium more than six years after BCG instillation immunotherapy. The resulting irritative voiding symptoms and low bladder capacity required radical cystectomy. BCG instillation can cause severe side effects, which develop gradually and eventually need radical surgical therapy such as cystectomy without tumor recurrence.

  10. Hubungan antara Pembentukan Scar Vaksin BCG dan Kejadian Infeksi Tuberkulosis

    Directory of Open Access Journals (Sweden)

    Fajriah Rosandali

    2016-08-01

    Full Text Available AbstrakTuberkulosis adalah penyakit menular yang disebabkan oleh kuman Mycobacterium tuberculosis. Orang dewasa yang menderita tuberkulosis sangat mudah menularkan kuman TB kepada orang disekitarnya terutama pada anak-anak. Salah satu cara pencegahan penyakit tuberkulosis adalah pemberian imunisasi BCG pada saat bayi baru lahir. Scar vaksin BCG dapat terbentuk setelah penyuntikan, kadang Scar tidak terbentuk setelah penyuntikan. Tujuan penelitian ini adalah menentukan hubungan antara pembentukan Scar vaksin BCG dan kejadian infeksi tuberkulosis. Penelitian ini menggunakan desain cross sectional dengan jumlah subjek sebanyak 80 orang. Pengambilan data berupa melakukan pengamatan terhadap Scar pada lengan atas serta wawancara kepada responden dengan menggunakan pedoman wawancara. Kemudian data ditabulasi dalam bentuk persentase dan dianalisis dengan uji chi-square . Hasil penelitian menunjukan bahwa responden yang terbanyak adalah perempuan dan usia yang terbanyak 35-44 tahun. Terdapat hubungan yang bermakna antara pembentukan Scar  vaksin BCG dengan kejadian infeksi tuberkulosis (p < 0,05. Disimpulkan bahwa terdapat pengaruh antara pembentukan Scar vaksin BCG terhadap kejadian infeksi tuberkulosis.Kata kunci: tuberkulosis, vaksin BCG, Scar. AbstractTuberculosis is an infectious disease caused by Mycobacterium tuberculosis with the number of sufferers tend to increase every years. Adults who suffer  tuberculosis is very easy to spread it to around, especially to children. One of the way to prevent tuberculosis is immunization of BCG vaccine which given since infant. The Scar of BCG vaccine can formed after injection or not. The objective of this study was to determine the relation of BCG vaccine Scar formation on  the incidence of tuberculosis infection.This research used a cross sectional design with 80 total subjects. The data was collected by observations of the scar on the upper arm while interviewed  respondents using interview guide

  11. Bacillus Coagulans

    Science.gov (United States)

    ... and, as a result, is often misclassified as lactic acid bacteria such as lactobacillus. In fact, some commercial products ... sporogenes or "spore-forming lactic acid bacterium." Unlike lactic acid bacteria such as lactobacillus or bifidobacteria, Bacillus coagulans forms ...

  12. Reaction of the BCG Scar in the Acute Phase of Kawasaki Disease in Mexican Children.

    Science.gov (United States)

    Garrido-García, Luis Martín; Castillo-Moguel, Ariel; Vázquez-Rivera, Mirella; Cravioto, Patricia; Fernando, Galván

    2017-10-01

    Kawasaki disease (KD) is an acute self-limited systemic vasculitis that primarily affects children BCG) inoculation site has been reported as a common finding in patients with KD where BCG vaccination is mandatory. The purpose of this study was to evaluate the frequency of reactivation of the BCG in Mexican children diagnosed with KD. A retrospective study of all patients diagnosed with KD from August 1, 1995, to August 31, 2015, at our Institution was performed. The clinical profile, laboratory results, treatment used and coronary artery abnormalities in the BCG reactive and the BCG nonreactive groups were analyzed and compared. We included 399 patients with KD. Ninety-seven (24.3%) had BCG reaction at the inoculation site. The BCG(+) group was younger than the BCG(-) group (P BCG(+) group compared with 65 (21.52%) in the BCG(-) group without statistical significance. The BCG+ group developed coronary artery aneurysms in 37 cases and the BCG(-) group developed coronary artery aneurysms in 111 cases without statistical significance. Multivariate analysis showed that younger age at diagnosis was the only variable associated with a reaction at the BCG inoculation site in patients with KD. In Mexico, a country with a National BCG Vaccination Program and a low incidence of KD, reaction at the BCG inoculation site could be a useful diagnostic sign of KD.

  13. Bacillus cucumis

    Science.gov (United States)

    Kämpfer, Peter; Busse, Hans-Jürgen; Glaeser, Stefanie P; Kloepper, Joseph W; Hu, Chia-Hui; McInroy, John A

    2016-02-01

    A facultative anaerobic, Gram-positive staining, endospore-forming bacterium, isolated from the rhizosphere of cucumber ( Cucumis sativus ), was taxonomically investigated. Based on 16S rRNA gene sequence similarity comparisons, strain AP-6 T clustered together with other species of the genus Bacillus and showed highest similarities with Bacillus drentensis LMG 21831 T (99.1 %), Bacillus vireti LMG 21834 T (98.7 %) and Bacillus soli LMG 21838 T (98.5 %). The 16S rRNA gene sequence similarity to the sequences of the type strains of other species of the genus Bacillus was 98.5 % or less. Chemotaxonomic features supported the grouping of the strain in the genus Bacillus ; for example, the major fatty acids were anteiso-C 15 : 0 , iso-C 15 : 0 and C 16 : 0 , the polar lipid profile contained the major components diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and an unidentified glycolipid, the major quinone was menaquinone MK-7 and the major compound in the polyamine pattern was spermidine. Additionally, DNA-DNA hybridization with B. drentensis LMG 21831 T , B. vireti LMG 21834 T and B. soli LMG 21838 T resulted in relatedness values that were clearly below 70 %. Physiological and biochemical test results were also different from those of the most closely related species. As a consequence, AP-6 T represents a novel species of the genus Bacillus , for which the name Bacillus cucumis sp. nov. is proposed, with AP-6 T ( = CIP 110974 T  = CCM 8651 T ) as the type strain.

  14. [Investigation on immunization program coverage rate and its safety in children with tuberous sclerosis].

    Science.gov (United States)

    Gao, Y; Zou, L P; Zhang, M N; Pang, L Y; Wang, Y Y; Ma, S F; Huang, L L

    2017-01-02

    Objective: To investigate the status of immunization of National Immunization Program (NIP) and its adverse reaction rate in children with tuberous sclerosis. Method: Questionnaire survey was adopted to identify the vaccination coverage and its adverse events; 72 cases of children with tuberous sclerosis and 78 normal controls (healthy children completing age-appropriate NIP) admitted to Chinese People's Liberation Army General Hospital from December 2014 to November 2015 were involved into this study. Result: The age-appropriate NIP coverage rate of tuberous sclerosis was 36%(26/72). The coverage rate of bacillus calmette-guerin (BCG), hepatitis B vaccine 1 st to 3 rd doses (HepB1-3), oral poliovaccine 1 st dose (OPV1), diphtheria, pertussis and tetanus 1 st dose (DPT1), DPT1-3, meningococcal polysaccharide vaccine group A (MPVA), measles amd rubella vaccine/measles vaccine 1 st dose (MRV/MCV1), and Japanese encephalitis vaccine 1 st dose (JEV1) were 100%(72 cases), 75%(51 cases), 97%(66 cases), 91%(62 cases), 82%(56 cases), 66%(45 cases), 69%(42 cases), and 61%(37 cases) respectively. The reasons why the children did not complete the vaccination plan were that parents were concerned about vaccination-induced seizures or seizures had not been controlled. Among 72 children with TSC, the rate of adverse events or suspected adverse events after vaccination was 17% (12 cases), which was higher than the normal control children (2 cases, 3%) (χ 2 =8.799, P children with tuberous sclerosis is low. The high incidence of adverse events may be associated with a fact that there are some nervous system abnormalities in cases with tuberous sclerosis. TSC children vaccination is relatively safe, with no serious adverse events.

  15. Timeliness of Childhood Primary Immunization and Risk Factors Related with Delays: Evidence from the 2014 Zhejiang Provincial Vaccination Coverage Survey.

    Science.gov (United States)

    Hu, Yu; Li, Qian; Chen, Yaping

    2017-09-20

    Background: this study aimed to assess both immunization coverage and timeliness, as well as reasons for non-vaccination, and identity the risk factors of delayed immunization, for the vaccines scheduled during the first year of life, in Zhejiang province, east China. Methods: A cluster survey among children aged 24-35 months was conducted. Demographic information and socio-economic characteristics of the selected child, the mother, and the household were collected. Immunization data were transcribed from immunization cards. Timeliness was assessed with Kaplan-Meier analysis for each vaccine given before 12 months of age, based on the time frame stipulated by the expanded program on immunization of China. Cox proportional hazard regression was applied to identify risk factors of delayed immunization. Results: A total of 2772 eligible children were surveyed. The age-appropriate coverage ranged from 25.4% (95% CI: 23.7-27.0%) for Bacillus Calmette-Guerin (BCG) to 91.3% (95% CI: 90.2-92.3%) for the first dose of oral poliomyelitis vaccine (OPV1). The most frequent reason for non-vaccination was parent's fear of adverse events of immunization. Delayed immunizations were associated with mother having a lower education level, mother having a job, delivery at home, increasing number of children per household, and having a lower household income. Conclusions: Although the timeliness of immunization has improved since 2011, necessary steps are still needed to achieve further improvement. Timeliness of immunization should be considered as another important indicator of expanded program on immunization (EPI) performance. Future interventions on vaccination coverage should take into consideration demographic and socio-economic risk factors identified in this study. The importance of adhering to the recommended schedule should be explained to parents.

  16. The cells that mediate innate immune memory and their functional significance in inflammatory and infectious diseases.

    Science.gov (United States)

    Gardiner, Clair M; Mills, Kingston H G

    2016-08-01

    Immunological memory mediated by antigen-specific T and B cells is the foundation of adaptive immunity and is fundamental to the heightened and rapid protective immune response induced by vaccination or following re-infection with the same pathogen. While the innate immune system has classically been considered to be non-specific and devoid of memory, it now appears that it can be trained following exposure to microbes or their products and that this may confer a form of memory on innate immune cells. The evidence for immunological memory outside of T and B cells has been best established for natural killer (NK) cells, where it has been known for decades that NK cells have heighten responses following immunological re-challenge. Furthermore, recent studies have demonstrated that monocyte/macrophages, and probably dendritic cells, can be re-programmed through epigenetic modification, following exposure to pathogens or their products, resulting in heighted responses following a second stimulation. Unlike antigen-specific memory of the adaptive immune system, the second stimulation does not have to be with the same pathogen or antigen. Indirect evidence for this comes from reports on the non-specific beneficial effect of certain live vaccines, such as Bacillus Calmette Guerin (BCG) against unrelated childhood infectious diseases. It also appears that certain pathogen or pathogen-derived molecules can prime immune cells, especially macrophages, to secrete more anti-inflammatory and less pro-inflammatory cyokines, thus opening up the possibility of exploiting innate immune training as a new therapeutic approach for inflammatory diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Uptake and accumulation of oxidized low-density lipoprotein during Mycobacterium tuberculosis infection in guinea pigs.

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    Gopinath S Palanisamy

    Full Text Available The typical host response to infection of humans and some animals by M. tuberculosis is the accumulation of reactive oxygen species generating inflammatory cells into discrete granulomas, which frequently develop central caseous necrosis. In previous studies we showed that infection of immunologically naïve guinea pigs with M. tuberculosis leads to localized and systemic oxidative stress that results in a significant depletion of serum total antioxidant capacity and the accumulation of malondialdehyde, a bi-product of lipid peroxidation. Here we show that in addition, the generation of excessive reactive oxygen species in vivo resulted in the accumulation of oxidized low density lipoproteins (OxLDL in pulmonary and extrapulmonary granulomas, serum and lung macrophages collected by bronchoalveolar lavage. Macrophages from immunologically naïve guinea pigs infected with M. tuberculosis also had increased surface expression of the type 1 scavenger receptors CD36 and LOX1, which facilitate the uptake of oxidized host macromolecules including OxLDL. Vaccination of guinea pigs with Bacillus Calmette Guerin (BCG prior to aerosol challenge reduced the bacterial burden as well as the intracellular accumulation of OxLDL and the expression of macrophage CD36 and LOX1. In vitro loading of guinea pig lung macrophages with OxLDL resulted in enhanced replication of bacilli compared to macrophages loaded with non-oxidized LDL. Overall, this study provides additional evidence of oxidative stress in M. tuberculosis infected guinea pigs and the potential role OxLDL laden macrophages have in supporting intracellular bacilli survival and persistence.

  18. Effect of media use on mothers' vaccination of their children in sub-Saharan Africa.

    Science.gov (United States)

    Jung, Minsoo; Lin, Leesa; Viswanath, Kasisomayajula

    2015-05-21

    While several studies have examined the crucial role that parents' vaccination behaviors play in reducing disease spread and severity among children, few have evaluated the connection between parents' media use and their decision on whether or not to vaccinate their child, specifically in relation to the BCG (Bacillus Calmetter Guerin), DPT (Diptheria, Pertussis, Tetanus) polio, and measles vaccines. Media channels are a critical source of health information for parents, which is especially true in Sub-Saharan Africa, as there is often a dearth of local healthcare providers. The aim of this paper is to investigate the role that media use plays in a mothers' choice to vaccinate their infant children in sub-Saharan Africa, specifically focusing on whether media use is associated with socioeconomic status (SES) and a mothers' vaccination of their children. Cross-sectional data from the Demographic Health Surveys of 13 sub-Saharan countries (2004-2010) were pooled. A multivariate Poisson regression of 151,209 women was used to calculate adjusted relative ratios and 95% confidence intervals for the associations among SES, media use, and immunization. Education and wealth were found to be strongly and positively associated with vaccine-uptake behaviors. The effects of media use (radio and television) were found to be associated with the relationships between SES and vaccine uptake. However, it did not reduce the impact of SES on vaccination. These findings indicate that mass media may be an important tool for future efforts to reduce the health discrepancies between children from high- and low-socioeconomic backgrounds. Going forward, immunization strategies should include communication plans that will address and mitigate potential immunization disparities among parents of different SES backgrounds. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Impact of conflict on infant immunisation coverage in Afghanistan: a countrywide study 2000–2003

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    Seino Kaoruko

    2007-06-01

    Full Text Available Abstract Background Infant immunisation is an effective public health intervention to reduce the morbidity and mortality of vaccine preventable diseases. However, some developing countries fail to achieve desirable vaccination coverage; Afghanistan is one such country. The present study was performed to evaluate the progress and variation in infant immunisation coverage by district and region in Afghanistan and to assess the impact of conflict and resource availability on immunisation coverage. Results This study analysed reports of infant immunisation from 331 districts across 7 regions of Afghanistan between 2000 and 2003. Geographic information system (GIS analysis was used to visualise the distribution of immunisation coverage in districts and to identify geographic inequalities in the process of improvement of infant immunisation coverage. The number of districts reporting immunisation coverage increased substantially during the four years of the study. Progress in Bacillus Calmette-Guerin (BCG immunisation coverage was observed in all 7 regions, although satisfactory coverage of 80% remained unequally distributed. Progress in the third dose of Diphtheria-Pertussis-Tetanus (DPT3 immunisation differed among regions, in addition to the unequal distribution of immunisation coverage in 2000. The results of multivariate logistic regression analysis indicated a significant negative association between lack of security in the region and achievement of 80% coverage of immunisation regardless of available resources for immunisation, while resource availability showed no relation to immunisation coverage. Conclusion Although progress was observed in all 7 regions, geographic inequalities in these improvements remain a cause for concern. The results of the present study indicated that security within a country is an important factor for affecting the delivery of immunisation services.

  20. BCG vaccination at birth and early childhood hospitalization

    DEFF Research Database (Denmark)

    Stensballe, Lone Graff; Sørup, Signe; Aaby, Peter

    2017-01-01

    BACKGROUND: The BCG vaccine is administered to protect against tuberculosis, but studies suggest there may also be non-specific beneficial effects upon the infant immune system, reducing early non-targeted infections and atopic diseases. The present randomised trial tested the hypothesis that BCG...... vaccination at birth would reduce early childhood hospitalisation in Denmark, a high-income setting. METHODS: Pregnant women planning to give birth at three Danish hospitals were invited to participate. After parental consent, newborn children were allocated to BCG or no intervention within 7 days of age.......94). The effect was also similar in the two sexes and across study sites. The results were essentially identical in the per-protocol analysis and after adjustment for baseline characteristics. CONCLUSIONS: BCG vaccination at birth did not reduce the risk of hospitalisation for somatic acquired disease until 15...

  1. THE ABELL 85 BCG: A NUCLEATED, CORELESS GALAXY

    Energy Technology Data Exchange (ETDEWEB)

    Madrid, Juan P. [Gemini Observatory, Southern Operations Center, Colina El Pino s/n, La Serena (Chile); Donzelli, Carlos J. [Instituto de Astronomía Teórica y Experimental, CONICET-UNC, Laprida 922, Córdoba (Argentina)

    2016-03-01

    New high-resolution r-band imaging of the brightest cluster galaxy (BCG) in Abell 85 (Holm 15A) was obtained using the Gemini Multi Object Spectrograph. These data were taken with the aim of deriving an accurate surface brightness profile of the BCG of Abell 85, in particular, its central region. The new Gemini data show clear evidence of a previously unreported nuclear emission that is evident as a distinct light excess in the central kiloparsec of the surface brightness profile. We find that the light profile is never flat nor does it present a downward trend toward the center of the galaxy. That is, the new Gemini data show a different physical reality from the featureless, “evacuated core” recently claimed for the Abell 85 BCG. After trying different models, we find that the surface brightness profile of the BCG of Abell 85 is best fit by a double Sérsic model.

  2. Cytochemical and biological properties of Mycobacterium bovis BCG.

    Science.gov (United States)

    Slosárek, M

    1977-01-01

    It was the aim of the present communication to find a simple test for a reliable discrimination of Mycobacterium bovis BCG from Mycobacterium tuberculosis. A total of 26 BCG strains, out of them 10 Czechoslovak strains (2 lyophilized cultures of BCG of different batch, 6 strains isolated from abscesses of children after BCG-vaccination and 2 strains from fatal cases after BCG-vaccination) and 16 strains obtained from foreign laboratories, were used. Of the tested characteristics a combination of 3 tests, sensitivity to 1 microgram of 2-thiophene carbonylhydrazide (TCH), activity of 3 acylamidases (urease, nicotinamidase and pyrazinamidase) and a quantitative nitrate test, was found to be most advantageous. The Czechoslovak strains of Mycobacterium bovis BCG were fully sensitive to TCH, of the 3 acylamidases mentioned above only urease was positive and nitrate was reduced only little or not at all. On the other hand, strains of Mycobacterium tuberculosis were always resistant to TCH, had positive urease, nicotinamidase and pyrazinamidase and reduced nitrate very intensively.

  3. Improving Mycobacterium bovis bacillus Calmette-Guèrin as a vaccine delivery vector for viral antigens by incorporation of glycolipid activators of NKT cells.

    Directory of Open Access Journals (Sweden)

    Manjunatha M Venkataswamy

    Full Text Available Recombinant Mycobacterium bovis bacillus Calmette-Guèrin (rBCG has been explored as a vector for vaccines against HIV because of its ability to induce long lasting humoral and cell mediated immune responses. To maximize the potential for rBCG vaccines to induce effective immunity against HIV, various strategies are being employed to improve its ability to prime CD8+ T cells, which play an important role in the control of HIV infections. In this study we adopted a previously described approach of incorporating glycolipids that activate CD1d-restricted natural killer T (NKT cells to enhance priming of CD8+ T cells by rBCG strains expressing an SIV Gag antigen (rBCG-SIV gag. We found that the incorporation of the synthetic NKT activating glycolipid α-galactosylceramide (α-GC into rBCG-SIV gag significantly enhanced CD8+ T cell responses against an immunodominant Gag epitope, compared to responses primed by unmodified rBCG-SIV gag. The abilities of structural analogues of α-GC to enhance CD8+ T cell responses to rBCG were compared in both wild type and partially humanized mice that express human CD1d molecules in place of mouse CD1d. These studies identified an α-GC analogue known as 7DW8-5, which has previously been used successfully as an adjuvant in non-human primates, as a promising compound for enhancing immunogenicity of antigens delivered by rBCG.vectors. Our findings support the incorporation of synthetic glycolipid activators of NKT cells as a novel approach to enhance the immunogenicity of rBCG-vectored antigens for induction of CD8+ T cell responses. The glycolipid adjuvant 7DW8-5 may be a promising candidate for advancing to non-human primate and human clinical studies for the development of HIV vaccines based on rBCG vectors.

  4. Improving Mycobacterium bovis bacillus Calmette-Guèrin as a vaccine delivery vector for viral antigens by incorporation of glycolipid activators of NKT cells.

    Science.gov (United States)

    Venkataswamy, Manjunatha M; Ng, Tony W; Kharkwal, Shalu S; Carreño, Leandro J; Johnson, Alison J; Kunnath-Velayudhan, Shajo; Liu, Zheng; Bittman, Robert; Jervis, Peter J; Cox, Liam R; Besra, Gurdyal S; Wen, Xiangshu; Yuan, Weiming; Tsuji, Moriya; Li, Xiangming; Ho, David D; Chan, John; Lee, Sunhee; Frothingham, Richard; Haynes, Barton F; Panas, Michael W; Gillard, Geoffrey O; Sixsmith, Jaimie D; Korioth-Schmitz, Birgit; Schmitz, Joern E; Larsen, Michelle H; Jacobs, William R; Porcelli, Steven A

    2014-01-01

    Recombinant Mycobacterium bovis bacillus Calmette-Guèrin (rBCG) has been explored as a vector for vaccines against HIV because of its ability to induce long lasting humoral and cell mediated immune responses. To maximize the potential for rBCG vaccines to induce effective immunity against HIV, various strategies are being employed to improve its ability to prime CD8+ T cells, which play an important role in the control of HIV infections. In this study we adopted a previously described approach of incorporating glycolipids that activate CD1d-restricted natural killer T (NKT) cells to enhance priming of CD8+ T cells by rBCG strains expressing an SIV Gag antigen (rBCG-SIV gag). We found that the incorporation of the synthetic NKT activating glycolipid α-galactosylceramide (α-GC) into rBCG-SIV gag significantly enhanced CD8+ T cell responses against an immunodominant Gag epitope, compared to responses primed by unmodified rBCG-SIV gag. The abilities of structural analogues of α-GC to enhance CD8+ T cell responses to rBCG were compared in both wild type and partially humanized mice that express human CD1d molecules in place of mouse CD1d. These studies identified an α-GC analogue known as 7DW8-5, which has previously been used successfully as an adjuvant in non-human primates, as a promising compound for enhancing immunogenicity of antigens delivered by rBCG.vectors. Our findings support the incorporation of synthetic glycolipid activators of NKT cells as a novel approach to enhance the immunogenicity of rBCG-vectored antigens for induction of CD8+ T cell responses. The glycolipid adjuvant 7DW8-5 may be a promising candidate for advancing to non-human primate and human clinical studies for the development of HIV vaccines based on rBCG vectors.

  5. Human T cell responses induced by vaccination with Mycobacterium bovis bacillus Calmette-Guérin

    DEFF Research Database (Denmark)

    Ravn, P; Boesen, H; Pedersen, B K

    1997-01-01

    Many aspects of the widely used bacillus Calmette-Guérin (BCG) vaccine against tuberculosis are still the subject of controversy. There is a huge variation in efficacy from one clinical trial to another and no relationship between vaccine-induced skin test conversion and subsequent protection. We...... have studied in vitro cell-mediated immune responses primed by BCG vaccination in 22 healthy Danish donors with different levels of in vitro purified protein derivative (PPD) reactivity before vaccination. The study demonstrated a markedly different development of reactivity to mycobacterial Ags...... depending on the prevaccination sensitivity to PPD. Previously sensitized donors mounted a potent and highly accelerated recall response within the first week of BCG vaccination. Nonsensitized donors, in contrast, exhibited a gradually increasing responsiveness to mycobacterial Ags, reaching maximal levels...

  6. Effects of P-MAPA Immunomodulator on Toll-Like Receptors and p53: Potential Therapeutic Strategies for Infectious Diseases and Cancer

    Directory of Open Access Journals (Sweden)

    Fávaro Wagner J

    2012-06-01

    Full Text Available Abstract Background Compounds that can act as agonists for toll-like receptors (TLRs may be promising candidates for the development of drugs against infectious diseases and cancer. The present study aimed to characterize the immunomodulatory effects of P-MAPA on TLRs in vitro and in vivo, as well as to investigate its potential as adjuvant therapy in infectious diseases and cancer. Methods For these purposes, the activity of P-MAPA on TLRs was assayed in vitro through NF-κB activation in HEK293 cells expressing a given TLR, and using an in vivo animal model for bladder cancer (BC. The antimicrobial activity of P-MAPA was tested against Mycobacterium tuberculosis (TB in vitro in an MIC assay, and in vivo using an aerosol infection model of murine tuberculosis. Antitumor effects of P-MAPA were tested in an animal model with experimentally induced BC. Moxifloxacin (MXF and Bacillus Calmette-Guerin (BCG were used as positive controls in the animal models. Results The results showed that P-MAPA, administered alone or in combination with MXF, induced significant responses in vivo against TB. In contrast, the compound did not show antimicrobial activity in vitro. P-MAPA showed a significant stimulatory effect on human TLR2 and TLR4 in vitro. In BC, TLR2, TLR4 and p53 protein levels were significantly higher in the P-MAPA group than in the BCG group. The most common histopathological changes in each group were papillary carcinoma in BC group, low-grade intraepithelial neoplasia in BCG group and simple hyperplasia in P-MAPA group. Concerning the toxicological analysis performed during BC treatment, P-MAPA did not show evidence for hepatotoxicity and nephrotoxicity. Conclusions In conclusion, P-MAPA acted as TLR ligand in vitro and improved the immunological status in BC, increasing TLR2 and TLR4 protein levels. P-MAPA immunotherapy was more effective in restoring p53 and TLRs reactivities and showed significantly greater antitumor activity than BCG

  7. Systemic BCG-Osis as a Rare Side Effect of Intravesical BCG Treatment for Superficial Bladder Cancer

    Directory of Open Access Journals (Sweden)

    S. Lukacs

    2013-01-01

    Full Text Available Intravesical Bacilli Calmette-Guérin (BCG immunotherapy is a commonly used treatment for superficial bladder cancer. Although the treatment is well tolerated in 95% of cases, life-threatening side effects including BCG sepsis can occur. This report describes the case of an 82-year-old man with a background of lung disease. He developed septic shock and type two respiratory failure after receiving the sixth installation of intravesical BCG (TICE strain immunotherapy for recurrent bladder Transitional Cell Carcinoma in situ. Despite the early initiation of broad spectrum antibiotics (tazocin and gentamicin, he remained pyrexial. There was a rapid deterioration, and on the second day of his admission, he developed type two respiratory failure secondary to Acute Respiratory Distress Syndrome (ARDS prompting transfer to Intensive Care for Bilevel Positive Airway Pressure (BiPAP Ventilation. The blood cultures taken before the induction of antibiotics results were negative. Increasing clinical suspicion of systemic BCG-osis prompted the initiation of antituberculosis therapy (ethambutol, isoniazid rifampicin and steroids. Following six days of BiPAP and anti-tuberculosis therapy in ITU, his condition started to improve. Following a prolonged hospital stay he was discharged on long term ethambutol therapy. BCG-osis is a well-known though rare side effect of intravesical BCG therapy. We would like to highlight the importance of having a low threshold for starting anti-TB treatment.

  8. Persistence of the immune response induced by BCG vaccination

    Directory of Open Access Journals (Sweden)

    Blitz Rose

    2008-01-01

    Full Text Available Abstract Background Although BCG vaccination is recommended in most countries of the world, little is known of the persistence of BCG-induced immune responses. As novel TB vaccines may be given to boost the immunity induced by neonatal BCG vaccination, evidence concerning the persistence of the BCG vaccine-induced response would help inform decisions about when such boosting would be most effective. Methods A randomised control study of UK adolescents was carried out to investigate persistence of BCG immune responses. Adolescents were tested for interferon-gamma (IFN-γ response to Mycobacterium tuberculosis purified protein derivative (M.tb PPD in a whole blood assay before, 3 months, 12 months (n = 148 and 3 years (n = 19 after receiving teenage BCG vaccination or 14 years after receiving infant BCG vaccination (n = 16. Results A gradual reduction in magnitude of response was evident from 3 months to 1 year and from 1 year to 3 years following teenage vaccination, but responses 3 years after vaccination were still on average 6 times higher than before vaccination among vaccinees. Some individuals (11/86; 13% failed to make a detectable antigen-specific response three months after vaccination, or lost the response after 1 (11/86; 13% or 3 (3/19; 16% years. IFN-γ response to Ag85 was measured in a subgroup of adolescents and appeared to be better maintained with no decline from 3 to 12 months. A smaller group of adolescents were tested 14 years after receiving infant BCG vaccination and 13/16 (81% made a detectable IFN-γ response to M.tb PPD 14 years after infant vaccination as compared to 6/16 (38% matched unvaccinated controls (p = 0.012; teenagers vaccinated in infancy were 19 times more likely to make an IFN-γ response of > 500 pg/ml than unvaccinated teenagers. Conclusion BCG vaccination in infancy and adolescence induces immunological memory to mycobacterial antigens that is still present and measurable for at least 14 years in the

  9. Different transcriptional profiles of human monocyte-derived dendritic cells infected with distinct strains of Mycobacterium tuberculosis and Mycobacterium bovis bacillus Calmette-Guérin.

    Science.gov (United States)

    Sanarico, Nunzia; Colone, Alessia; Grassi, Manuela; Speranza, Viviana; Giovannini, Daniela; Ciaramella, Antonio; Colizzi, Vittorio; Mariani, Francesca

    2011-01-01

    In order to analyze dendritic cells (DCs) activation following infection with different mycobacterial strains, we studied the expression profiles of 165 genes of human monocyte-derived DCs infected with H37Rv, a virulent Mycobacterium tuberculosis (MTB) laboratory strain, CMT97, a clinical MTB isolate, Mycobacterium bovis bacillus Calmette-Guérin (BCG), Aventis Pasteur, and BCG Japan, both employed as vaccine against tuberculosis. The analysis of the gene expression reveals that, despite a set of genes similarly modulated, DCs response resulted strain dependent. In particular, H37Rv significantly upregulated EBI3 expression compared with BCG Japan, while it was the only strain that failed to release a significant IL-10 amount. Of note, BCG Japan showed a marked increase in CCR7 and TNF-α expression regarding both MTB strains and it resulted the only strain failing in exponential intracellular growth. Our results suggest that DCs display the ability to elicit a tailored strain-specific immune response.

  10. Bull's eye dermatoscopy pattern at bacillus Calmette-Guérin inoculation site correlates with systemic involvements in patients with Kawasaki disease.

    Science.gov (United States)

    Tseng, Han-Chi; Ho, Ji-Chen; Guo, Mindy Ming-Huey; Lo, Mao-Hung; Hsieh, Kai-Sheng; Tsai, Wen-Chien; Kuo, Ho-Chang; Lee, Chih-Hung

    2016-09-01

    For the past decades, although the rash at the bacillus Calmette-Guérin (BCG) inoculation site has been recognized as a diagnostic clue in Kawasaki disease, the present study is the first known one attempting to characterize BCG inoculation by dermatoscopy in Kawasaki disease and correlate the grade of BCG reaction with systemic involvement. Thirty-four patients diagnosed with Kawasaki disease by pediatric specialists were enrolled. We performed detailed history taking, laboratory examination, physical examination and dermatoscopy examinations. Based on the BCG reaction pattern by dermatoscopy, we were able to characterize three patterns: (A) Bull's eye pattern in 18 patients; (B) faint homogenous erythema in nine; and (C) central white patch in seven. Patients from group A exhibited the highest elevation of blood aspartate aminotransferase levels (P Kawasaki disease. © 2016 Japanese Dermatological Association.

  11. A Case of Acquired Rifampin Resistance in Mycobacterium bovis Bacillus Calmette-Guérin-Induced Cystitis: Necessity for Treatment Guidelines

    Directory of Open Access Journals (Sweden)

    Joyce N Wolfe

    2006-01-01

    Full Text Available A case of presumed bacillus Calmette-Guérin (BCG cystitis in an elderly female patient following direct intravesical BCG instillation treatment for papillary transitional cell carcinoma is reported. The organism cultured from urine samples was eventually identified as a rifampin-resistant Mycobacterium bovis BCG isolate. Because the patient had received rifampin monotherapy during the course of treatment for presumed BCG disease, the clinical picture favoured acquired rifampin resistance. Sequencing of the target gene for rifampin (rpoB confirmed a known mutation responsible for conferring high levels of resistance to both rifampin and rifabutin (Ser531Tyr. To the authors' knowledge, this is the first reported case of M bovis BCG disease in a non-HIV patient where the organism had acquired drug resistance to rifampin, and the second reported case of M bovis BCG that had acquired drug resistance. The present case demonstrates the necessity to re-evaluate appropriate guidelines for the effective treatment of BCG disease.

  12. Association Between Number of Endoscopic Resections and Utilization of Bacillus Calmette-Guérin Therapy for Patients With High-Grade, Non-Muscle-Invasive Bladder Cancer.

    Science.gov (United States)

    Lenis, Andrew T; Donin, Nicholas M; Litwin, Mark S; Saigal, Christopher S; Lai, Julie; Hanley, Jan M; Konety, Badrinath R; Chamie, Karim

    2017-02-01

    Bacillus Calmette-Guérin (BCG) is the reference standard treatment for patients with high-grade, non-muscle-invasive bladder cancer (NMIBC). We previously described noncompliance with guidelines for BCG use in patients with high-risk disease. In the current study, we sought to characterize how the number of endoscopic resections of bladder tumors affects BCG utilization using population-level data. We queried a Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to evaluate claims records of 4776 patients diagnosed with high-grade NMIBC between 1992 and 2002 and followed until 2007, who survived for at least 2 years and who did not undergo definitive treatment with cystectomy, radiotherapy, or systemic chemotherapy. We stratified patients on the basis of the number of endoscopic resections of bladder tumors. We used chi-square analysis to compare number of resections to BCG utilization and multinomial logistic regression analysis to quantify BCG utilization by patient and tumor characteristics. Utilization of BCG increases with increasing endoscopic resections from 40% at diagnosis to 72% after 6 resections. The cumulative rate of at least an induction course of BCG plateaus after 3 resections. Lower BCG utilization was associated with advanced age (≥ 80 years), while increased utilization was associated with being married, higher disease stage (Tis and T1) and grade (undifferentiated), and increasing endoscopic resections. A significant fraction of patients with NMIBC do not receive induction BCG despite its proven benefit in minimizing recurrences. Most patients receive BCG only after multiple endoscopic resections. Strategies focused on earlier adoption of BCG to prevent recurrences instead of reacting to recurrences may limit progression and improve survival. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. BCG and Adverse Events in the Context of Leprosy

    Directory of Open Access Journals (Sweden)

    Renate Richardus

    2018-04-01

    Full Text Available BackgroundNotwithstanding its beneficial immunoprophylactic outcomes regarding leprosy and childhood TB, BCG vaccination may cause adverse events, particularly of the skin. However, this local hyper-immune reactivity cannot be predicted before vaccination, nor is its association with protection against leprosy known. In this study we investigated the occurrence of adverse events after BCG (revaccination in contacts of leprosy patients and analyzed whether the concomitant systemic anti-mycobacterial immunity was associated with these skin manifestations.MethodsWithin a randomized controlled BCG vaccination trial in Bangladesh, 14,828 contacts of newly diagnosed leprosy patients received BCG vaccination between 2012 and 2017 and were examined for adverse events 8 to 12 weeks post-vaccination. From a selection of vaccinated contacts, venous blood was obtained at follow-up examination and stimulated with Mycobacterium leprae (M. leprae antigens in overnight whole-blood assays (WBA. M. leprae phenolic glycolipid-I-specific antibodies and 32 cytokines were determined in WBAs of 13 individuals with and 13 individuals without adverse events after vaccination.ResultsOut of the 14,828 contacts who received BCG vaccination, 50 (0.34% presented with adverse events, mainly (80% consisting of skin ulcers. Based on the presence of BCG scars, 30 of these contacts (60% had received BCG in this study as a booster vaccination. Similar to the pathological T-cell immunity observed for tuberculoid leprosy patients, contacts with adverse events at the site of BCG vaccination showed elevated IFN-γ levels in response to M. leprae-specific proteins in WBA. However, decreased levels of sCD40L in serum and GRO (CXCL1 in response to M. leprae simultaneously indicated less T-cell regulation in these individuals, potentially causing uncontrolled T-cell immunity damaging the skin.ConclusionSkin complications after BCG vaccination present surrogate markers for protective

  14. Production of BCG alginate-PLL microcapsules by emulsification/internal gelation.

    Science.gov (United States)

    Esquisabel, A; Hernández, R M; Igartua, M; Gascón, A R; Calvo, B; Pedraz, J L

    1997-01-01

    A biocompatible emulsification method for microencapsulation of live cells and enzymes within a calcium alginate matrix applied to Bacillus Calmette-Guérin (BCG) has been developed. Small-diameter alginate beads (microcapsules) were formed via internal gelation of an alginate solution emulsified within vegetable oil. Five different oils (sesame, sweet almond, perhydrosqualene, camomile and jojoba) were used. The rheological analysis of the oils showed a Newtonian behaviour, with viscosities = 30.0, 37.7, 51.2, 59.3 and 67.1 mPa.s for perhydrosqualene, jojoba, camomile, sesame and sweet almond oil respectively. The particle size of the microcapsules obtained ranged from 30.3 microns for the microcapsules prepared with sweet almond oil to 57.0 microns for those made with perhydrosqualene. The mean particle diameter obtained was found to be dependent on the viscosity of the oil employed, according to the equation: phi (micron) = 76.6-0.628 eta (mPa.s) (r2 = 0.943). The encapsulated BCG was identified by the Difco TB stain set K, followed by observation under optical microscopy. Freeze-drying of the microcapsules was carried out to ensure their stability during storage. Two batches of microcapsules (those prepared with sesame and jojoba oil) and four types of cryoprotectors (glucose, trehalose, mannitol and sorbitol), at three concentration levels (5, 10 and 20% w/v) were studied. The parameters evaluated were particle size, physical appearance, reconstitution of lyophilizates and microscopical evaluation. For both batches of microcapsules the best results were obtained with trehalose 5%, showing particle sizes of 42.1 microns in the case of the microcapsules prepared with sesame oil, and of 45.3 microns for those prepared with jojoba.

  15. Influence of multi-year Bacillus thuringiensis subsp. israelensis on the abundance of B. cereus group populations in Swedish riparian wetland soils

    DEFF Research Database (Denmark)

    Hendriksen, Niels Bohse; Schneider, Salome; Tajrin, Tania

    Bacillus thuringiensis subsp. israelensis (Bti) is a soil-born bacterium affiliated to the B. cereus group (Bcg, a group including the pathogens B. cereus, B. thuringiensis, and B. anthracis) and used in biocontrol products against nematoceran larvae. However, knowledge is limited on how long...

  16. Comparative Proteomic Profiling of Mycobacterium bovis and BCG Vaccine Strains

    KAUST Repository

    Gao, Ge

    2013-09-01

    BCG is the only licensed human vaccine currently available against TB. Derived from a virulent strain of M. bovis, the vaccine was thought to have struck a balance between reduced virulence and preserved immunogenicity. Nowadays, BCG vaccine strains used in different countries and vaccination programs show clear variations in their genomes and immune protective properties. The aim of this study was to characterize the proteomic profile on Mycobacterium bovis and five BCG strains Pasteur, Tokyo, Danish, Phipps and Birkhaug by Tandem Mass Tag® (TMT®)-labeling quantitative proteomic approach. In total, 420 proteins were identified and 377 of them were quantitated for their relative abundance. We reported the number and relationship of differential expressed proteins in BCG strains compared to M. bovis and investigated their functions by bioinformatics analysis. Several interesting up-regulated and down-regulated protein targets were found. The identified proteins and their quantitative expression profiles provide a basis for further understanding of the cellular biology of M. bovis and BCG vaccine strains, and hopefully would assist in the design of better anti-TB vaccine and drugs.

  17. Deletion of zmp1 improves Mycobacterium bovis BCG-mediated protection in a guinea pig model of tuberculosis.

    Science.gov (United States)

    Sander, Peter; Clark, Simon; Petrera, Agnese; Vilaplana, Cristina; Meuli, Michael; Selchow, Petra; Zelmer, Andrea; Mohanan, Deepa; Andreu, Nuria; Rayner, Emma; Dal Molin, Michael; Bancroft, Gregory J; Johansen, Pål; Cardona, Pere-Joan; Williams, Ann; Böttger, Erik C

    2015-03-10

    Having demonstrated previously that deletion of zinc metalloprotease zmp1 in Mycobacterium bovis BCG increased immunogenicity of BCG vaccines, we here investigated the protective efficacy of BCG zmp1 deletion mutants in a guinea pig model of tuberculosis infection. zmp1 deletion mutants of BCG provided enhanced protection by reducing the bacterial load of tubercle bacilli in the lungs of infected guinea pigs. The increased efficacy of BCG due to zmp1 deletion was demonstrated in both BCG Pasteur and BCG Denmark indicating that the improved protection by zmp1 deletion is independent from the BCG sub-strain. In addition, unmarked BCG Δzmp1 mutant strains showed a better safety profile in a CB-17 SCID mouse survival model than the parental BCG strains. Together, these results support the further development of BCG Δzmp1 for use in clinical trials. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Post-Vaccination disseminated BCG infection in an 8-month-old infant

    Directory of Open Access Journals (Sweden)

    fariba Tarhani

    2004-06-01

    Conclusions: Although the BCG vaccine has been in use since 1921 and its protective effect for disseminated, meningial and pulmonary tuberculosis is clear, controversy continues around its use. The most serious complication of BCG vaccine is a disseminated BCG infection that may lead to death.

  19. BCG lowers plasma cholesterol levels and delays atherosclerotic lesion progression in mice

    NARCIS (Netherlands)

    van Dam, Andrea D.; Bekkering, Siroon; Crasborn, Malou; van Beek, Lianne; van den Berg, Susan M.; Vrieling, Frank; Joosten, Simone A.; van Harmelen, Vanessa; de Winther, Menno P. J.; Lütjohann, Dieter; Lutgens, Esther; Boon, Mariëtte R.; Riksen, Niels P.; Rensen, Patrick C. N.; Berbée, Jimmy F. P.

    2016-01-01

    Bacille-Calmette-Guérin (BCG), prepared from attenuated live Mycobacterium bovis, modulates atherosclerosis development as currently explained by immunomodulatory mechanisms. However, whether BCG is pro- or anti-atherogenic remains inconclusive as the effect of BCG on cholesterol metabolism, the

  20. Inhibition of natural killer cell-mediated cytotoxicity by lipids extracted from Mycobacterium bovis BCG

    NARCIS (Netherlands)

    Roozemond, R. C.; Halperin, M.; Das, P. K.

    1985-01-01

    Several studies have demonstrated an augmentation of natural killer (NK) cell-mediated cytotoxicity by various adjuvants including BCG. Inhibitory effects of BCG have also been reported, particularly for relatively high doses. Because the cell wall of Mycobacterium bovis BCG contains a high

  1. Multi-stage subunit vaccines against Mycobacterium tuberculosis: an alternative to the BCG vaccine or a BCG-prime boost?

    Science.gov (United States)

    Khademi, Farzad; Derakhshan, Mohammad; Yousefi-Avarvand, Arshid; Tafaghodi, Mohsen; Soleimanpour, Saman

    2018-01-01

    More than two billion people are latently infected with Mycobacterium tuberculosis. Most tuberculosis (TB)-subunit vaccines currently in various stages of clinical trials are designed for prevention of active TB, but not to prevent reactivation of latent TB-infection. Thus, there is an urgent need for an effective multi-stage vaccine based on early-expressed and latently-expressed antigens that prevents both acute and latent infections. Areas covered: Here, we reviewed the published pre-clinical and clinical studies of multi-stage subunit vaccines against TB, and the protective capacities of the vaccines were compared with BCG, either alone or in combination with different vaccine delivery systems/adjuvants. The results revealed that multi-stage subunit vaccines induced a wide variety of immune-responses to all forms of TB, including CD8 + T-cell-mediated cytolytic and IFN-γ responses comparable to those induced by the BCG. They could potentially be used as a booster vaccine to improve the efficacy of the BCG. Expert commentary: Multi-stage TB-vaccines could boost BCG-primed immunity, decrease bacterial loads and provide efficient protection against progressive TB-infection, especially in the latent phase. These types of vaccines administered before and after TB-infection can act as pre-exposure, post-exposure and even therapeutic vaccines. In the near future, these vaccines could provide a new generation of prime-vaccines or BCG prime-boosters.

  2. Bacillus thuringiensis

    Science.gov (United States)

    Hollensteiner, Jacqueline; Wemheuer, Franziska; Harting, Rebekka; Kolarzyk, Anna M; Diaz Valerio, Stefani M; Poehlein, Anja; Brzuszkiewicz, Elzbieta B; Nesemann, Kai; Braus-Stromeyer, Susanna A; Braus, Gerhard H; Daniel, Rolf; Liesegang, Heiko

    2016-01-01

    Verticillium wilt causes severe yield losses in a broad range of economically important crops worldwide. As many soil fumigants have a severe environmental impact, new biocontrol strategies are needed. Members of the genus Bacillus are known as plant growth-promoting bacteria (PGPB) as well as biocontrol agents of pests and diseases. In this study, we isolated 267 Bacillus strains from root-associated soil of field-grown tomato plants. We evaluated the antifungal potential of 20 phenotypically diverse strains according to their antagonistic activity against the two phytopathogenic fungi Verticillium dahliae and Verticillium longisporum . In addition, the 20 strains were sequenced and phylogenetically characterized by multi-locus sequence typing (MLST) resulting in 7 different Bacillus thuringiensis and 13 Bacillus weihenstephanensis strains. All B. thuringiensis isolates inhibited in vitro the tomato pathogen V. dahliae JR2, but had only low efficacy against the tomato-foreign pathogen V. longisporum 43. All B. weihenstephanensis isolates exhibited no fungicidal activity whereas three B. weihenstephanensis isolates showed antagonistic effects on both phytopathogens. These strains had a rhizoid colony morphology, which has not been described for B. weihenstephanensis strains previously. Genome analysis of all isolates revealed putative genes encoding fungicidal substances and resulted in identification of 304 secondary metabolite gene clusters including 101 non-ribosomal polypeptide synthetases and 203 ribosomal-synthesized and post-translationally modified peptides. All genomes encoded genes for the synthesis of the antifungal siderophore bacillibactin. In the genome of one B. thuringiensis strain, a gene cluster for zwittermicin A was detected. Isolates which either exhibited an inhibitory or an interfering effect on the growth of the phytopathogens carried one or two genes encoding putative mycolitic chitinases, which might contribute to antifungal activities

  3. Immunotherapy with BCG cell wall plus irradiated tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Mizukuro, Tomoyuki (Kyoto Prefectural Univ. of Medicine (Japan))

    1983-04-01

    Two different fibrosarcomas (MCB-I, MCB-II) were induced by methylcholcholanthrene in syngeneic Balb/C mice were used. The tumor cells irradiated with 5,000 to 30,000 rads did not growth in mice on 30 days after inoculation. The viable tumor cells were challenged intradermally to mice on 7 days after inoculation of the tumor cells irradiated with 5,000 to 30,000 rads. The challenged tumor cells were all rejected at 30 days after inoculation. Mice were challenged with 5 x 10/sup 5/ viable tumor cells on 7 days after inoculation of 10/sup 3/ to 10/sup 8/ irradiated tumor cells. Mice pretreated with 10/sup 5/ or 10/sup 6/ irradiated tumor cells rejected the tumor cells completely. The viable tumor cells were challenged to mice on 7 days after inoculation of BCG-CW emulsion plus 10/sup 6/ irradiated tumor cells. 0, 50, 100, 200, and 400 mu g of BCG-CW emulsion were mixed in 10/sup 6/ irradiated tumor cells. Optimal dosage of BCG-CW emulsion was 50 or 100 mu g. BCG-CW emulsion plus irradiated tumor cells were injected subcutaneously to the mice after tumor cells inoculation. Three injections of the vaccine significantly suppressed the tumor outgrowth, but not one or two injections in no-treated mice. However, in the mice pretreated with BCG-CW emulsion, the tumor growth was significantly suppressed by one or two injections of the vaccine. Especially, the three injections of the vaccine significantly suppressed the tumor growth and the 25% of the mice were completely cured. The effect of the vaccine was almost the same grade by contralateral or ipsilateral treatment. The irradiated MCB-II tumor cells plus BCG-CW emulsion were not effective to the MCB-1 tumor bearing mice, suggesting the anti-tumor effect of this vaccine was immunologically specific.

  4. Microbial Disease Spectrum Linked to a Novel IL-12Rβ1 N-Terminal Signal Peptide Stop-Gain Homozygous Mutation with Paradoxical Receptor Cell-Surface Expression

    Science.gov (United States)

    Louvain de Souza, Thais; de Souza Campos Fernandes, Regina C.; Azevedo da Silva, Juliana; Gomes Alves Júnior, Vladimir; Gomes Coelho, Adelia; Souza Faria, Afonso C.; Moreira Salomão Simão, Nabia M.; Souto Filho, João T.; Deswarte, Caroline; Boisson-Dupuis, Stéphanie; Torgerson, Dara; Casanova, Jean-Laurent; Bustamante, Jacinta; Medina-Acosta, Enrique

    2017-01-01

    Patients with Mendelian Susceptibility to Mycobacterial Diseases (MSMD) exhibit variable vulnerability to infections by mycobacteria and other intramacrophagic bacteria (e.g., Salmonella and Klebsiella) and fungi (e.g., Histoplasma, Candida, Paracoccidioides, Coccidioides, and Cryptococcus). The hallmark of MSMD is the inherited impaired production of interferon gamma (IFN-γ) or the lack of response to it. Mutations in the interleukin (IL)-12 receptor subunit beta 1 (IL12RB1) gene accounts for 38% of cases of MSMD. Most IL12RB1 pathogenic allele mutations, including ten known stop-gain variants, cause IL-12Rβ1 complete deficiency (immunodeficiency-30, IMD30) by knocking out receptor cell-surface expression. IL12RB1 loss-of-function genotypes impair both IL-12 and IL-23 responses. Here, we assess the health effects of a rare, novel IL12RB1 stop-gain homozygous genotype with paradoxical IL-12Rβ1 cell-surface expression. We appraise four MSMD children from three unrelated Brazilian kindreds by clinical consultation, medical records, and genetic and immunologic studies. The clinical spectrum narrowed down to Bacillus Calmette-Guerin (BCG) vaccine-related suppurative adenitis in all patients with one death, and recrudescence in two, histoplasmosis, and recurrence in one patient, extraintestinal salmonellosis in one child, and cutaneous vasculitis in another. In three patients, we established the homozygous Trp7Ter predicted loss-of-function inherited genotype and inferred it from the heterozygote parents of the fourth case. The Trp7Ter mutation maps to the predicted IL-12Rβ1 N-terminal signal peptide sequence. BCG- or phytohemagglutinin-blasts from the three patients have reduced cell-surface expression of IL-12Rβ1 with impaired production of IFN-γ and IL-17A. Screening of 227 unrelated healthy subjects from the same geographic region revealed one heterozygous genotype (allele frequency 0.0022) vs. one in over 841,883 public genome/exomes. We also show that the

  5. Impact of the BCG vaccination policy on tuberculous meningitis in children under 6 years in metropolitan France between 2000 and 2011.

    Science.gov (United States)

    Van Bui, T; Lévy-Bruhl, D; Che, D; Antoine, D; Jarlier, V; Robert, J

    2015-03-19

    In France, Bacillus Calmette–Guérin (BCG) vaccination by multipuncture device was withdrawn in 2006. In 2007, universal mandatory BCG vaccination was replaced by vaccination of high-risk children. To evaluate the impact of these changes on tuberculous meningitis (TBM) epidemiology, data on culture-positive and culture-negative (or unknown microbiological result) TBM in ≤5 years olds were collected from 2000–2011. Ten culture-positive and 17 culture-negative TBM cases were identified, with an annual incidence rate ranging from 0.16 to 0.66 cases per 10 million inhabitants. The average annual numbers of TBM cases were 2.7 and 1.8 from 2000–2005 and 2006–2011, respectively. In Ile-de-France where all children are considered at risk, the overall incidence rates were 1.14 and 0.29 per million for the two periods. In other regions where only at-risk children are vaccinated since 2007, rates were 0.30 and 0.47, respectively. None of these differences were significant. Annual incidence rates for each one year age group cohort were comparable before and after changes. Childhood TBM remains rare in France. No increase in incidence was observed after changes in BCG vaccination strategy. Ongoing surveillance should be maintained, as a slight increase in TBM in the coming years remains possible, in the context of suboptimal vaccination coverage of high-risk children.

  6. Genomic and proteomic analyses of Mycobacterium bovis BCG Mexico 1931 reveal a diverse immunogenic repertoire against tuberculosis infection.

    Science.gov (United States)

    Orduña, Patricia; Cevallos, Miguel A; de León, Samuel Ponce; Arvizu, Adriana; Hernández-González, Ismael L; Mendoza-Hernández, Guillermo; López-Vidal, Yolanda

    2011-10-08

    Studies of Mycobacterium bovis BCG strains used in different countries and vaccination programs show clear variations in the genomes and immune protective properties of BCG strains. The aim of this study was to characterise the genomic and immune proteomic profile of the BCG 1931 strain used in Mexico. BCG Mexico 1931 has a circular chromosome of 4,350,386 bp with a G+C content and numbers of genes and pseudogenes similar to those of BCG Tokyo and BCG Pasteur. BCG Mexico 1931 lacks Region of Difference 1 (RD1), RD2 and N-RD18 and one copy of IS6110, indicating that BCG Mexico 1931 belongs to DU2 group IV within the BCG vaccine genealogy. In addition, this strain contains three new RDs, which are 53 (RDMex01), 655 (RDMex02) and 2,847 bp (REDMex03) long, and 55 single-nucleotide polymorphisms representing non-synonymous mutations compared to BCG Pasteur and BCG Tokyo. In a comparative proteomic analysis, the BCG Mexico 1931, Danish, Phipps and Tokyo strains showed 812, 794, 791 and 701 protein spots, respectively. The same analysis showed that BCG Mexico 1931 shares 62% of its protein spots with the BCG Danish strain, 61% with the BCG Phipps strain and only 48% with the BCG Tokyo strain. Thirty-nine reactive spots were detected in BCG Mexico 1931 using sera from subjects with active tuberculosis infections and positive tuberculin skin tests. BCG Mexico 1931 has a smaller genome than the BCG Pasteur and BCG Tokyo strains. Two specific deletions in BCG Mexico 1931 are described (RDMex02 and RDMex03). The loss of RDMex02 (fadD23) is associated with enhanced macrophage binding and RDMex03 contains genes that may be involved in regulatory pathways. We also describe new antigenic proteins for the first time.

  7. Genomic and proteomic analyses of Mycobacterium bovis BCG Mexico 1931 reveal a diverse immunogenic repertoire against tuberculosis infection

    Directory of Open Access Journals (Sweden)

    López-Vidal Yolanda

    2011-10-01

    Full Text Available Abstract Background Studies of Mycobacterium bovis BCG strains used in different countries and vaccination programs show clear variations in the genomes and immune protective properties of BCG strains. The aim of this study was to characterise the genomic and immune proteomic profile of the BCG 1931 strain used in Mexico. Results BCG Mexico 1931 has a circular chromosome of 4,350,386 bp with a G+C content and numbers of genes and pseudogenes similar to those of BCG Tokyo and BCG Pasteur. BCG Mexico 1931 lacks Region of Difference 1 (RD1, RD2 and N-RD18 and one copy of IS6110, indicating that BCG Mexico 1931 belongs to DU2 group IV within the BCG vaccine genealogy. In addition, this strain contains three new RDs, which are 53 (RDMex01, 655 (RDMex02 and 2,847 bp (REDMex03 long, and 55 single-nucleotide polymorphisms representing non-synonymous mutations compared to BCG Pasteur and BCG Tokyo. In a comparative proteomic analysis, the BCG Mexico 1931, Danish, Phipps and Tokyo strains showed 812, 794, 791 and 701 protein spots, respectively. The same analysis showed that BCG Mexico 1931 shares 62% of its protein spots with the BCG Danish strain, 61% with the BCG Phipps strain and only 48% with the BCG Tokyo strain. Thirty-nine reactive spots were detected in BCG Mexico 1931 using sera from subjects with active tuberculosis infections and positive tuberculin skin tests. Conclusions BCG Mexico 1931 has a smaller genome than the BCG Pasteur and BCG Tokyo strains. Two specific deletions in BCG Mexico 1931 are described (RDMex02 and RDMex03. The loss of RDMex02 (fadD23 is associated with enhanced macrophage binding and RDMex03 contains genes that may be involved in regulatory pathways. We also describe new antigenic proteins for the first time.

  8. Ipr1 modified BCG as a novel vaccine induces stronger immunity than BCG against tuberculosis infection in mice.

    Science.gov (United States)

    Wang, Yuwei; Yang, Chun; He, Yonglin; Zhan, Xingxing; Xu, Lei

    2016-08-01

    Tuberculosis is a major challenge to global public health. However, the Bacille Calmette‑Guérin (BCG), the only vaccine available against tuberculosis, has been questioned for the low protective effect. The present study used the mouse gene intracellular pathogen resistance I (Ipr1) gene to alter the current BCG vaccine and evaluated its immunity effect against tuberculosis. This study also investigated the intrinsic relationships of Ipr1 and innate immunity. The reformed BCG (BCGi) carrying the Ipr1 gene was constructed. The mice were intranasally challenged with the M. tuberculosis H37Rv strain after vaccination with BCGi. Protection efficacy of the vaccine was assessed by the organ coefficient, bacterial load and pathological changes in the lung. The differential expression of 113 immune‑related genes between BCGi and BCG groups were detected by an oligo microarray. According to the results of organ coefficient, bacterial load and pathological changes in the organization, BCGi had been shown to have stronger protective effects against M. tuberculosis than BCG. The oligo microarray and reverse transcription‑quantitative polymerase chain reaction further revealed that the Ipr1 gene could upregulate the expression of 13 genes, including a >3‑fold increase in Toll‑like receptor (TLR)4 and 10‑fold increase in surfactant protein D (sftpd). The two genes not only participate in innate immunity against pathogens, but also are closely interrelated. Ipr1 could activate the TLR4 and sftpd signaling pathway and improve the innate immunity against tuberculosis, therefore Ipr1 modified BCG may be a candidate vaccine against M. tuberculosis.

  9. Mycobacterium bovis BCG vaccine induces non-specific immune responses in Japanese flounder against Nocardia seriolae.

    Science.gov (United States)

    Kato, Goshi; Kondo, Hidehiro; Aoki, Takashi; Hirono, Ikuo

    2012-08-01

    Nocardiosis caused by Nocardia seriolae has been causing severe loss of fish production, so that an effective vaccine is urgently needed. Mycobacterium bovis BCG (BCG) is a live attenuated vaccine for tuberculosis, which is effective against various infectious diseases including nocardiosis in mammals. In this study, the protective efficacy of BCG against N. seriolae was evaluated in Japanese flounder Paralichthys olivaceus and antigen-specific immune responses induced in BCG vaccinated fish were investigated. Cumulative mortality of BCG-vaccinated fish was 21.4% whereas that of PBS-injected fish was 56.7% in N. seriolae challenge. However, gene expression level of IFN-γ was only slightly up-regulated in BCG-vaccinated fish after injection of N. seriolae antigen. In order to reveal non-specific immune responses induced by BCG vaccination, transcriptome of the kidney after BCG vaccination was investigated using oligo DNA microarray. Gene expression levels of antimicrobial peptides such as C-type and G-type lysozyme were significantly up-regulated after BCG vaccination. Consistently, BCG vaccination appeared to increase the bacteriolysis activity of the serum against Micrococcus luteus and N. seriolae. These results suggest that BCG-vaccinated Japanese flounder fight N. seriolae infection mainly by non-specific immune responses such as by the production of bacteriolytic lysozymes. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Bacille Calmette-Guérin (BCG) vaccination at birth and antibody responses to childhood vaccines

    DEFF Research Database (Denmark)

    Nissen, Thomas Nørrelykke; Birk, Nina Marie; Smits, Gaby

    2017-01-01

    Introduction BCG vaccination has been associated with beneficial non-specific effects on child health. Some immunological studies have reported heterologous effects of vaccines on antibody responses to heterologous vaccines. Within a randomised clinical trial of Bacille Calmette-Guérin (BCG......) vaccination at birth, The Danish Calmette Study, we investigated the effect of BCG at birth on the antibody response to the three routine vaccines against DiTeKiPol/Act-Hib and Prevenar 13 in a subgroup of participants. Methods Within 7 days after birth, children were randomised 1:1 to BCG vaccination...... included children (178 BCG; 122 controls), almost all children (>96%) had antibody responses above the protective levels. Overall BCG vaccination at birth did not affect the antibody level. When stratifying by ‘age at randomisation’ we found a possible inducing effect of BCG on antibodies against B...

  11. BCG vaccination status of children with tuberculous meningitis and ...

    African Journals Online (AJOL)

    From 1985 to 1992, 193 children with tuberculous meningitis (TBM) with a median age of 26 months were admitted to the Department of Paediatrics and Child Health, Tygerberg Hospital. Of these children 143 (74%) were documented to have received BCG, either by reference to 'Road to Health' cards or by contact with ...

  12. BCG vaccination status of children with tuberculous meningitis and ...

    African Journals Online (AJOL)

    From 1985 to 1992, 193 children with tuberculous meningitis (TBM) with a median age of 26 months were admitted to the Department of Paediatrics and Child. Health, Tygerberg Hospital. Of these children 143 (74%) were documented to have received BCG, either by reference to 'Road to Health' cards or by contact with.

  13. Surgical management of BCG vaccine-induced regional axillary ...

    African Journals Online (AJOL)

    The age of the patient and mode of presentation, imaging findings, and results of tuberculin skin testing (Mantoux test) ... Primary surgical treatment (incisional drainage or biopsy) is therefore not considered an ideal form of management in BCG lymphadenitis because of the high fistulisation and poor wound healing, ...

  14. Diffuse bony involvement in disseminated BCG disease in a patient ...

    African Journals Online (AJOL)

    BCG (bacille Calmette-Guérin) vaccination is carried out worldwide to prevent tuberculosis. It is considered to be very effective and has an excellent safety profile, but complications do occur. These may range from erythema and abscess at the site of inoculation to extensive disseminated disease including regional and ...

  15. BCG vaccination at birth and early childhood hospitalisation

    DEFF Research Database (Denmark)

    Stensballe, Lone Graff; Sørup, Signe; Aaby, Peter

    2017-01-01

    vaccination at birth would reduce early childhood hospitalisation in Denmark, a high-income setting. METHODS: Pregnant women planning to give birth at three Danish hospitals were invited to participate. After parental consent, newborn children were allocated to BCG or no intervention within 7 days of age....... Randomisation was stratified by prematurity. The primary study outcome was number of all-cause hospitalisations analysed as repeated events. Hospitalisations were identified using The Danish National Patient Register. Data were analysed by Cox proportional hazards models in intention-to-treat and per...... compared with 1003 hospitalisations among 2133 control children (mean 0.47), resulting in a HR comparing BCG versus no BCG of 1.05 (95% CI 0.93 to 1.18) (intention-to-treat analysis). The effect of BCG was the same in children born at term (1.05 (0.92 to 1.18)) and prematurely (1.07 (0.63 to 1.81), p=0...

  16. Synergistic Cytotoxic Effects of Ganoderma lucidum and Bacillus Calmette Guérin on Premalignant Urothelial HUC-PC Cells and Its Regulation on Proinflammatory Cytokine Secretion

    Directory of Open Access Journals (Sweden)

    John Wai-man Yuen

    2012-01-01

    Full Text Available Bacillus Calmette-Guérin (BCG is conventionally used as an adjuvant immunotherapy to reduce the recurrence of bladder cancer. To address the issues of efficacy and safety, an ethanol extract of Ganoderma lucidum (GLe was evaluated for its interaction with BCG. In a model of premalignant human uroepithelial cells (HUC-PC, GLe exerted immediate cytotoxic effects while BCG showed a delayed response, given that both were immunological active in inducing the secretion of interleukin (IL-6, IL-8, and monocyte chemotactic protein-1 (MCP-1. Synergistic cytotoxic effects were observed when cells were either coincubated with both drugs or firstly preincubated with GLe. Synergism between GLe and BCG was demonstrated to achieve a complete cytostasis in 24 hours, and such effects were progressed in the subsequent 5 days. However, the pretreatment of GLe resulted in suppression of IL-6, IL-8, and MCP-1 secretions without affecting the cytotoxicity. Given that numerous proinflammatory cytokines are associated with the high side effects toll of BCG, results herein suggested the potential implications of GL to supplement the BCG immunotherapy in bladder cancer, for better efficacy and reducing side effects.

  17. The impact of re-transurethral resection on clinical outcomes in a large multicentre cohort of patients with T1 high-grade/Grade 3 bladder cancer treated with bacille Calmette-Guerin

    NARCIS (Netherlands)

    Gontero, P.; Sylvester, R.; Pisano, F.; Joniau, S.; Oderda, M.; Serretta, V.; Larre, S.; Stasi, S. Di; Rhijn, B. Van; Witjes, A.J.; Grotenhuis, A.J.; Colombo, R.; Briganti, A.; Babjuk, M.; Soukup, V.; Malmstrom, P.U.; Irani, J.; Malats, N.; Baniel, J.; Mano, R.; Cai, T.; Cha, E.K.; Ardelt, P.; Vakarakis, J.; Bartoletti, R.; Dalbagni, G.; Shariat, S.F.; Xylinas, E.; Karnes, R.J.; Palou, J.

    2016-01-01

    OBJECTIVES: To determine if a re-transurethral resection (TUR), in the presence or absence of muscle at the first TUR in patients with T1-high grade (HG)/Grade 3 (G3) bladder cancer, makes a difference in recurrence, progression, cancer specific (CSS) and overall survival (OS). PATIENTS AND METHODS:

  18. Stable expression of Mycobacterium bovis antigen 85B in auxotrophic M. bovis bacillus Calmette-Guérin

    Directory of Open Access Journals (Sweden)

    Caroline Rizzi

    Full Text Available BACKGROUND Bovine tuberculosis (TB is a zoonotic disease caused by Mycobacterium bovis, responsible for causing major losses in livestock. A cost effective alternative to control the disease could be herd vaccination. The bacillus Calmette-Guérin (BCG vaccine has a limited efficacy against bovine TB, but can improved by over-expression of protective antigens. The M. bovis antigen 85B demonstrates ability to induce protective immune response against bovine TB in animal models. However, current systems for the construction of recombinant BCG expressing multiple copies of the gene result in strains of low genetic stability that rapidly lose the plasmid in vivo. Employing antibiotic resistance as selective markers, these systems also compromise vaccine safety. We previously reported the construction of a stable BCG expression system using auxotrophic complementation as a selectable marker. OBJECTIVES The fundamental aim of this study was to construct strains of M. bovis BCG Pasteur and the auxotrophic M. bovis BCG ΔleuD expressing Ag85B and determine their stability in vivo. METHODS Employing the auxotrophic system, we constructed rBCG strains that expressed M. bovis Ag85B and compared their stability with a conventional BCG strain in mice. Stability was measured in terms of bacterial growth on the selective medium and retention of antigen expression. FINDINGS The auxotrophic complementation system was highly stable after 18 weeks, even during in vivo growth, as the selective pressure and expression of antigen were maintained comparing to the conventional vector. MAIN CONCLUSION The Ag85B continuous expression within the host may generate a stronger and long-lasting immune response compared to conventional systems.

  19. Coexisting Bacillus Calmette-Guérin-Induced Lupus Vulgaris Involving the Vaccination Site and Lichen Scrofulosorum in an Immunocompetent Boy.

    Science.gov (United States)

    Angoori, Gnaneshwar Rao

    2016-09-01

    The coexistence of Bacillus Calmette-Guérin (BCG)-induced lupus vulgaris involving the site of vaccination with lichen scrofulosorum is rare. Herein we report a 3-year-old boy who presented with lupus vulgaris at the vaccination site 3 weeks after neonatal BCG vaccination followed by the development of lichen scrofulosorum approximately 2.5 years later. Characteristic clinical morphology, typical histopathology, and positive DNA polymerase chain reaction for Mycobacterium bovis confirmed the clinical diagnosis. © 2016 Wiley Periodicals, Inc.

  20. Improving Mycobacterium bovis Bacillus Calmette-Guèrin as a Vaccine Delivery Vector for Viral Antigens by Incorporation of Glycolipid Activators of NKT Cells

    OpenAIRE

    Venkataswamy, Manjunatha M.; Ng, Tony W.; Kharkwal, Shalu S.; Carreño, Leandro J.; Johnson, Alison J.; Kunnath-Velayudhan, Shajo; Liu, Zheng; Bittman, Robert; Jervis, Peter J.; Cox, Liam R.; Besra, Gurdyal S.; Wen, Xiangshu; Yuan, Weiming; Tsuji, Moriya; Li, Xiangming

    2014-01-01

    Recombinant Mycobacterium bovis bacillus Calmette-Guèrin (rBCG) has been explored as a vector for vaccines against HIV because of its ability to induce long lasting humoral and cell mediated immune responses. To maximize the potential for rBCG vaccines to induce effective immunity against HIV, various strategies are being employed to improve its ability to prime CD8+ T cells, which play an important role in the control of HIV infections. In this study we adopted a previously described approac...

  1. Loss of Lipid Virulence Factors Reduces the Efficacy of the BCG Vaccine

    Science.gov (United States)

    Tran, Vanessa; Ahn, Sang Kyun; Ng, Mark; Li, Ming; Liu, Jun

    2016-01-01

    Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is the only vaccine available for tuberculosis (TB) control. BCG comprises a number of substrains that exhibit genetic and biochemical differences. Whether and how these differences affect BCG efficacy remain unknown. Compared to other BCG strains, BCG-Japan, -Moreau, and -Glaxo are defective in the production of phthiocerol dimycocerosates (PDIMs) and phenolic glycolipids (PGLs), two lipid virulence factors. To determine if the loss of PDIMs/PGLs affects BCG efficacy, we constructed a PDIM/PGL-deficient strain of BCG-Pasteur by deleting fadD28, and compared virulence, immunogenicity, and protective efficacy in animal models. SCID mouse infection experiments showed that ∆fadD28 was more attenuated than wild type (WT). The ∆fadD28 and WT strains induced equivalent levels of antigen specific IFN-γ by CD4+ and CD8+ T cells; however, ∆fadD28 was less effective against Mycobacterium tuberculosis challenge in both BALB/c mice and guinea pigs. These results indicate that the loss of PIDMs/PGLs reduces the virulence and protective efficacy of BCG. Since the loss of PDIMs/PGLs occurs naturally in a subset of BCG strains, it also suggests that these strains may have been over-attenuated, which compromises their effectiveness. Our finding has important implications for current BCG programs and future vaccine development. PMID:27357109

  2. BCG-loaded chitosan microparticles: interaction with macrophages and preliminary in vivo studies.

    Science.gov (United States)

    Caetano, Liliana Aranha; Figueiredo, Lara; Almeida, António J; Gonçalves, L M D

    2017-03-01

    The aim of this study was to develop a novel BCG-loaded chitosan vaccine with high association efficiency which can afford efficient interaction with APC and elicit local and Th1-type-specific immune response after intranasal administration. Chitosan-suspended BCG and BCG-loaded chitosan-alginate microparticles were prepared by ionotropic gelation. Interaction with APC was evaluated by fluorescence microscopy using rBCG-GFP. Specific immune responses were evaluated following intranasal immunisation of mice. Cellular uptake was approximately two-fold higher for chitosan-suspended BCG. A single dose of BCG-loaded microparticles or chitosan-suspended BCG by intranasal route improved Th1-type response compared with subcutaneous BCG. Chitosan-suspended BCG originated the highest mucosal response in the lungs by intranasal route. These positive results indicate that the proposed approach of whole live BCG microencapsulation in chitosan-alginate for intranasal immunisation was successful in allowing efficient interaction with APC, while improving the cellular immune response, which is of interest for local immunisation against tuberculosis.

  3. Bacillus amyloliquefaciens

    Science.gov (United States)

    Qin, Yuxuan; Shang, Qingmao; Zhang, Ying; Li, Pinglan; Chai, Yunrong

    2017-01-01

    Vegetable plug seedling has become the most important way to produce vegetable seedlings in China. This seedling method can significantly improve the quality and yield of vegetables compared to conventional methods. In the process of plug seedling, chemical fertilizers or pesticides are often used to improve the yield of the seedlings albeit with increasing concerns. Meanwhile, little is known about the impact of beneficial bacteria on the rhizosphere microbiota and the growth conditions of vegetables during plug seedling. In this study, we applied a culture-independent next-generation sequencing-based approach and investigated the impact of a plant beneficial bacterium, Bacillus amyloliquefaciens L-S60, on the composition and dynamics of rhizosphere microbiota and the growth conditions of cucumbers during plug seedling. Our results showed that application of L-S60 significantly altered the structure of the bacterial community associated with the cucumber seedling; presence of beneficial rhizosphere species such as Bacillus, Rhodanobacter, Paenibacillus, Pseudomonas, Nonomuraea , and Agrobacterium was higher upon L-S60 treatment than in the control group. We also measured the impact of L-S60 application on the physiological properties of the cucumber seedlings as well as the availability of main mineral elements in the seedling at different time points during the plug seedling. Results from those measurements indicated that L-S60 application promoted growth conditions of cucumber seedlings and that more available mineral elements were detected in the cucumber seedlings from the L-S60 treated group than from the control group. The findings in this study provided evidence for the beneficial effects of plant growth-promoting rhizosphere bacteria on the bacterial community composition and growth conditions of the vegetables during plug seedling.

  4. Bacillus Calmette-Guérin vaccination at birth: Effects on early childhood infections, growth, and development.

    Science.gov (United States)

    Kjærgaard, Jesper

    2016-11-01

    The Bacillus Calmette-Guérin vaccine (BCG), which is used to protect against tuberculosis, has been associated with a variety of other effects since it was developed almost 100 years ago. Most notably, observational studies and randomized clinical trials from low-income countries indicate that it protects against unrelated infections, i.e. a so-called non-specific effect. The Danish Calmette Study was conducted to study these effects in a high-income population. The immune response to BCG is not fully understood but involves a pro-inflammatory profiling of the immune system, also when exposed to unrelated pathogens. Immune changes have been implicated in changes in both child growth and child development and for that reason we also studied these outcomes. We randomized 4262 children at birth to receive BCG vaccination at birth or to a no-intervention control group. We had pre-specified subgroup analyses of child sex, prematurity, and maternal BCG vaccination. The statistical analysis plan was finalized prior to unblinding of the data. Follow-up for the outcomes reported in this thesis consisted of telephone interviews and clinical examination at age 3 and 13 months, as well as online developmental questionnaires distributed to the parents at 12 months and additionally to the parents of premature children at age 6 and 22 months. The outcomes of this thesis were number of parent reported infections, child growth and body composition, and child psychomotor development. Overall, there was no effect of BCG on either incidence of infections, growth, body composition or psychomotor development. A subgroup analysis of children of mothers who were BCG vaccinated showed a reduced incidence of infections from 0 to 3 months among BCG vaccinated children (incidence rate ratio = 0.62, CI: 0.39 to 0.98), but there was no effect from 3 to 13 months. Previous research has shown that maternal exposure to BCG or mycobacteria can alter the effect of BCG in the offspring, and thus the

  5. Rodent malaria: BCG-induced protection and immunosuppression. [Mice, gamma radiation, Plasmodium berghei

    Energy Technology Data Exchange (ETDEWEB)

    Smrkovski, L.L.; Strickland, G.T.

    1978-10-01

    One dose of 10/sup 7/ viable units of Mycobacterium bovis, strain BCG, protected a significant number of Swiss mice from a primary challenge with 10/sup 4/ thoracic sporozoites of Plasmodium berghei. Immunization with irradiated sporozoites induced greater protection than that observed in BCG-treated animals. Mice treated with BCG and surviving a primary sporozoite challenge were not protected from rechallenge, whereas mice immunized with irradiated sporozoites and surviving initial challenge of sporozoites were solidly immune to further challenge. Immunizing mice with BCG and irradiated sporozoites simulataneously resulted in a synergistic effect of increased protection against a primary challenge of sporozoites only if the two immunogens were administered on the same day and if the mice were challenged 1 to 3 days later. Mice given BCG and irradiated sporozoites and surviving a primary challenge of sporozoites were unable to survive rechallenge. BCG given to mice previously immunized with irradiated sporozoites suppressed their protective immunity against sporozoite challenge.

  6. Searching for the Recoiling Black Hole in BCG2261

    Science.gov (United States)

    Gultekin, Kayhan

    2017-09-01

    We propose a 100 ksec observation of the core of BCG 2261 to test for the presence of a recoiling SMBH. Binary SMBHs are thought to scour out cores in the host galaxy before coalescence of the black holes, which can lead to large recoils. Despite the importance of the connection between binary BHs, strong gravity, and galaxy evolution, it has never been conclusively observed. Without confirmation, we don't know if binary SMBHs can create stellar cores achieve high recoil velocities. We can produce the first direct observational proof of a recoiling SMBH in BCG 2261, the strongest candidate to date to host a recoiling SMBH and an extreme stellar core. With a detection, we will finally have definitive observational evidence connecting core formation, gravitational waves, and binary BHs.

  7. Oral polio vaccine influences the immune response to BCG vaccination. A natural experiment.

    Science.gov (United States)

    Sartono, Erliyani; Lisse, Ida M; Terveer, Elisabeth M; van de Sande, Paula J M; Whittle, Hilton; Fisker, Ane B; Roth, Adam; Aaby, Peter; Yazdanbakhsh, Maria; Benn, Christine S

    2010-05-21

    Oral polio vaccine (OPV) is recommended to be given at birth together with BCG vaccine. While we were conducting two trials including low-birth-weight (LBW) and normal-birth-weight (NBW) infants in Guinea-Bissau, OPV was not available during some periods and therefore some infants did not receive OPV at birth, but only BCG. We investigated the effect of OPV given simultaneously with BCG at birth on the immune response to BCG vaccine. We compared the in vitro and the in vivo response to PPD in the infants who received OPV and BCG with that of infants who received BCG only. At age 6 weeks, the in vitro cytokine response to purified protein derivate (PPD) of M. Tuberculosis was reduced in LBW and NBW infants who had received OPV with BCG. In a pooled analysis receiving OPV with BCG at birth was associated with significantly lower IL-13 (p = 0.041) and IFN-gamma (p = 0.004) and a tendency for lower IL-10 (p = 0.054) in response to PPD. Furthermore, OPV was associated with reduced in vivo response to PPD at age 2 months, the prevalence ratio (PR) of having a PPD reaction being 0.75 (0.58-0.98), p = 0.033, and with a tendency for reduced likelihood of having a BCG scar (0.95 (0.91-1.00), p = 0.057)). Among children with a scar, OPV was associated with reduced scar size, the regression coefficient being -0.24 (-0.43-0.05), p = 0.012. This study is the first to address the consequences for the immune response to BCG of simultaneous administration with OPV. Worryingly, the results indicate that the common practice in low-income countries of administering OPV together with BCG at birth may down-regulate the response to BCG vaccine.

  8. Oral polio vaccine influences the immune response to BCG vaccination. A natural experiment.

    Directory of Open Access Journals (Sweden)

    Erliyani Sartono

    Full Text Available BACKGROUND: Oral polio vaccine (OPV is recommended to be given at birth together with BCG vaccine. While we were conducting two trials including low-birth-weight (LBW and normal-birth-weight (NBW infants in Guinea-Bissau, OPV was not available during some periods and therefore some infants did not receive OPV at birth, but only BCG. We investigated the effect of OPV given simultaneously with BCG at birth on the immune response to BCG vaccine. METHODS AND FINDINGS: We compared the in vitro and the in vivo response to PPD in the infants who received OPV and BCG with that of infants who received BCG only. At age 6 weeks, the in vitro cytokine response to purified protein derivate (PPD of M. Tuberculosis was reduced in LBW and NBW infants who had received OPV with BCG. In a pooled analysis receiving OPV with BCG at birth was associated with significantly lower IL-13 (p = 0.041 and IFN-gamma (p = 0.004 and a tendency for lower IL-10 (p = 0.054 in response to PPD. Furthermore, OPV was associated with reduced in vivo response to PPD at age 2 months, the prevalence ratio (PR of having a PPD reaction being 0.75 (0.58-0.98, p = 0.033, and with a tendency for reduced likelihood of having a BCG scar (0.95 (0.91-1.00, p = 0.057. Among children with a scar, OPV was associated with reduced scar size, the regression coefficient being -0.24 (-0.43-0.05, p = 0.012. CONCLUSIONS: This study is the first to address the consequences for the immune response to BCG of simultaneous administration with OPV. Worryingly, the results indicate that the common practice in low-income countries of administering OPV together with BCG at birth may down-regulate the response to BCG vaccine.

  9. Immunotherapy with irradiated tumour cells and BCG in experimental osteosarcoma

    International Nuclear Information System (INIS)

    Larsson, S.-E.; Lorentzon, R.; Boquist, L.

    1981-01-01

    The effects of immunotherapy with irradiated tumour cells and BCG were studied in a non-metastasizing variety of the Dunn osteosarcoma transplantable in mice. Experimental animals which had been preimmunized with three injections of 0.7 to 1.4 x 10 6 irradiated tumour cells each 1 to 3 weeks before administration of 1 x 10 6 living tumour cells, showed a tumour incidence of 23 per cent. This was significantly (P<0.005) lower than the 92 per cent tumour incidence in the control animals. Non-specific immunotherapy with BCG given subcutaneously at a dose of 1.0 mg of dry-weight bacterial mass three times at 3-weeks intervals was found to have no protective effect against the osteosarcoma. The tumour incidence was 90 per cent for BCG-treated and 94 per cent for control animals. The osteosarcomas were studied light and electron microscopically and also with regard to the histochemical alkaline phosphatase activity. No structural difference was found between the tumours of the various groups. The demonstrated immunotherapeutic response is in contrast o the low degree of immunogenicity of the osteosarcoma, which we will report elsewhere. (author)

  10. Features of General Reactive Potential of the Body in Infants with BCG lymphadenitis

    Directory of Open Access Journals (Sweden)

    A.I. Bobrovitskaia

    2014-11-01

    Conclusions. When using BCG vaccine of Russian production, there is far less significant overload of blood flow by products of intoxication and inflammation, more pronounced body’s ability to respond to antigenic stimulus generalization and no risk of infection, especially in infants, compared with Danish BCG vaccine. For vaccination of infants against tuberculosis, it is advisable to use more refined, with high immunogenicity and less reactogenic BCG vaccine of Russian production. Despite the presence of complications when using BCG vaccine, protection of the body from the development of generalized forms of tuberculosis in young children is possible by vaccination in the neonatal period.

  11. Low Dose BCG Infection as a Model for Macrophage Activation Maintaining Cell Viability

    Directory of Open Access Journals (Sweden)

    Leslie Chávez-Galán

    2016-01-01

    Full Text Available Mycobacterium bovis BCG, the current vaccine against tuberculosis, is ingested by macrophages promoting the development of effector functions including cell death and microbicidal mechanisms. Despite accumulating reports on M. tuberculosis, mechanisms of BCG/macrophage interaction remain relatively undefined. In vivo, few bacilli are sufficient to establish a mycobacterial infection; however, in vitro studies systematically use high mycobacterium doses. In this study, we analyze macrophage/BCG interactions and microenvironment upon infection with low BCG doses and propose an in vitro model to study cell activation without affecting viability. We show that RAW macrophages infected with BCG at MOI 1 activated higher and sustained levels of proinflammatory cytokines and transcription factors while MOI 0.1 was more efficient for early stimulation of IL-1β, MCP-1, and KC. Both BCG infection doses induced iNOS and NO in a dose-dependent manner and maintained nuclear and mitochondrial structures. Microenvironment generated by MOI 1 induced macrophage proliferation but not MOI 0.1 infection. In conclusion, BCG infection at low dose is an efficient in vitro model to study macrophage/BCG interactions that maintains macrophage viability and mitochondrial structures. This represents a novel model that can be applied to BCG research fields including mycobacterial infections, cancer immunotherapy, and prevention of autoimmunity and allergies.

  12. Active suppression of in vitro reactivity of spleen cells after BCG treatment

    International Nuclear Information System (INIS)

    Orbach-Arbouys, S.; Poupon, M.F.

    1978-01-01

    It was found that spleen cells from mice injected i.v. with large doses of BCG responded to PHA stimulation less intensely than did normal spleen cells. It was shown that nylon wool column purified BCG treated T cells also had a low PHA reactivity. Unfractionated spleen cells, adherent cells or T-enriched populations from BCG treated mice, when added to normal T cells lowered their PHA reactivity. When the same BCG treated cell populations were added to tumor cells in vitro, they inhibited their growth. (author)

  13. Neonatal BCG vaccination influences cytokine responses to Toll-like receptor ligands and heterologous antigens.

    Science.gov (United States)

    Freyne, B; Donath, S; Germano, S; Gardiner, K; Casalaz, D; Robins-Browne, R M; Amenyogbe, N; Messina, N L; Netea, M G; Flanagan, K L; Kollmann, T; Curtis, N

    2018-02-03

    Bacille Calmette-Guérin (BCG) vaccination is associated with a reduction in all-cause infant mortality in high-mortality settings. The underlying mechanisms remain uncertain but long-term modulation of the innate immune response (trained immunity) may be involved. Whole blood, collected 7 days post randomisation from 212 neonates enrolled in a randomised trial of neonatal BCG vaccination, was stimulated with killed pathogens and Toll-like receptor (TLR) ligands to interrogate cytokine responses. BCG-vaccinated infants had increased production of IL-6 in unstimulated samples and decreased production of IL-1ra, IL-6, and IL-10 and the chemokines MIP-1α, MIP-1β, MCP-1 following stimulation with peptidoglycan (TLR2) and R848 (TLR7/8). BCG-vaccinated infants also had decreased MCP-1 responses following stimulation with heterologous pathogens. Sex and maternal BCG vaccination status interacted with neonatal BCG vaccination. Neonatal BCG vaccination influences cytokine responses to TLR ligands and heterologous pathogens. This effect is characterised by decreased anti-inflammatory cytokine and chemokine responses in the context of higher levels of IL-6 in unstimulated samples. This supports the hypothesis that BCG vaccination modulates the innate immune system. Further research is warranted to determine if there is an association between these findings and the beneficial non-specific (heterologous) effects of BCG vaccine on all-cause mortality.

  14. BCG revaccination does not protect against leprosy in the Brazilian Amazon: a cluster randomised trial.

    Directory of Open Access Journals (Sweden)

    Sérgio S Cunha

    2008-02-01

    Full Text Available Although BCG has been found to impart protection against leprosy in many populations, the utility of repeat or booster BCG vaccinations is still unclear. When a policy of giving a second BCG dose to school children in Brazil was introduced, a trial was conducted to assess its impact against tuberculosis, and a leprosy component was then undertaken in parallel.to estimate the protection against leprosy imparted by a second dose of BCG given to schoolchildren.This is a cluster randomised community trial, with 6 years and 8 months of follow-up.City of Manaus, Amazon region, a leprosy-endemic area in Brazil.99,770 school children with neonatal BCG (aged 7-14 years at baseline, of whom 42,662 were in the intervention arm (revaccination.BCG given by intradermal injection.Leprosy (all clinical forms.The incidence rate ratio of leprosy in the intervention over the control arm within the follow-up, in schoolchildren with neonatal BCG, controlled for potential confounders and adjusted for clustering, was 0.99 (95% confidence interval: 0.68 to 1.45.There was no evidence of protection conferred by the second dose of BCG vaccination in school children against leprosy during the trial follow-up. These results point to a need to consider the effectiveness of the current policy of BCG vaccination of contacts of leprosy cases in Brazilian Amazon region.

  15. Vacina BCG contra tuberculose: efeito protetor e políticas de vacinação BCG vaccine against tuberculosis: its protective effect and vaccination policies

    Directory of Open Access Journals (Sweden)

    Susan M Pereira

    2007-09-01

    Full Text Available OBJETIVO: A vacina BCG é utilizada desde 1921, embora ainda apresente controvérsias e aspectos não esclarecidos. O objetivo do artigo foi analisar aspectos relacionados ao efeito protetor da primeira e segunda doses da vacina BCG e as políticas de vacinação adotadas. MÉTODOS: Foi realizada revisão sistemática da literatura publicada em inglês e espanhol, abrangendo o período compreendido entre 1948 e 2006, na base PubMed. Os principais descritores utilizados foram BCG vaccine, BCG efficacy, BCG e tuberculosis. Os estudos foram agrupados por tipo de desenho, apresentando-se separadamente os principais resultados de ensaios clínicos, estudos de caso-controle e metanálises. RESULTADOS: O efeito protetor da primeira dose da vacina BCG contra a tuberculose na forma miliar ou na meningite é elevado. No entanto, os resultados são discordantes em relação à forma pulmonar, variando de ausência de efeito a níveis próximos a 80%. Estão sendo conduzidas pesquisas sobre novas vacinas candidatas a substituir a BCG ou serem utilizadas como reforço. CONCLUSÕES: Há evidências de que a segunda dose da BCG não aumenta o seu efeito protetor. Apesar de seus limites e da expectativa futura de nova vacina para tuberculose, a vacina BCG mantém-se como importante instrumento no controle dos efeitos danosos da doença, sobretudo em países com taxas de incidência médias e elevadas.OBJECTIVE: The BCG vaccine has been in use since 1921, but still arouses controversy and uncertainties. The objective was to analyze the protective effect of the BCG vaccine in its first and second doses and the accompanying vaccination policies. METHODS: A systematic review of the literature in both English and Spanish was carried out, covering the period 1948 to 2006, using the PubMed database. The main search terms used included BCG vaccine, BCG efficacy, BCG and tuberculosis. The studies were grouped by design, with the main results from the clinic tests, case

  16. Mycobacterium bovis Bacillus Calmette-Guérin-Induced Macrophage Cytotoxicity against Bladder Cancer Cells

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    Yi Luo

    2010-01-01

    Full Text Available Many details of the molecular and cellular mechanisms involved in Mycobacterium bovis bacillus Calmette-Guérin (BCG immunotherapy of bladder cancer have been discovered in the past decades. However, information on a potential role for macrophage cytotoxicity as an effector mechanism is limited. Macrophages play pivotal roles in the host innate immunity and serve as a first line of defense in mycobacterial infection. In addition to their function as professional antigen-presenting cells, the tumoricidal activity of macrophages has also been studied with considerable interest. Studies have shown that activated macrophages are potent in killing malignant cells of various tissue origins. This review summarizes the current understanding of the BCG-induced macrophage cytotoxicity toward bladder cancer cells with an intention to inspire investigation on this important but underdeveloped research field.

  17. Tuberculin reactivity in a population of schoolchildren with high BCG vaccination coverage

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    Bierrenbach Ana L.

    2003-01-01

    Full Text Available OBJECTIVE: To investigate the influence of BCG vaccination or revaccination on tuberculin skin test reactivity, in order to guide the correct interpretation of this test in a setting of high neonatal BCG vaccination coverage and an increasing BCG revaccination coverage at school age. METHODS: We conducted tuberculin skin testing and BCG scar reading in 1148 children aged 7-14 years old in the city of Salvador, Bahia, Brazil. We measured the positive effect of the presence of one or two BCG scars on the proportion of tuberculin skin test results above different cut-off levels (induration sizes of > 5 mm, > 10 mm, and > 15 mm and also using several ranges of induration size (0, 1-4, 5-9, 10-14, and > 15 mm. We also measured the effects that age, gender, and the school where the child was enrolled had on these proportions. RESULTS: The proportion of tuberculin results > 10 mm was 14.2% (95% confidence interval (CI = 8.0%-20.3% for children with no BCG scar, 21.3% (95% CI = 18.5%-24.1% for children with one BCG scar, and 45.0% (95% CI = 32.0%-58.0% for children with two BCG scars. There was evidence for an increasing positive effect of the presence of one and two BCG scars on the proportion of results > 5 mm and > 10 mm. Similarly, there was evidence for an increasing positive effect of the presence of one and two scars on the proportion of tuberculin skin test results in the ranges of 5-9 mm and of 10-14 mm. The BCG scar effect on the proportion of results > 5 mm and > 10 mm did not vary with age. There was no evidence for BCG effect on the results > 15 mm. CONCLUSIONS: In Brazilian schoolchildren, BCG-induced tuberculin reactivity is indistinguishable, for results under 15 mm, from reactivity induced by Mycobacterium tuberculosis infection. BCG revaccination at school age increases the degree of BCG-induced tuberculin reactivity found among schoolchildren. This information should be taken into account in tuberculin skin test surveys intended to

  18. Bacillus subtilis

    Science.gov (United States)

    Wang, Xiaoqing; Hu, Weiwei; Zhu, Liqi; Yang, Qian

    2017-04-28

    Intestinal epithelial cells are the targets for transmissible gastroenteritis (TGE) virus (TGEV) infection. It is urgent to develop a novel candidate against TGEV entry. Bacillus subtilis is a probiotic with excellent anti-microorganism properties and one of its secretions, surfactin, has been regarded as a versatile weapon for most plant pathogens, especially for the enveloped virus. We demonstrate for the first time that B. subtilis OKB105 and its surfactin can effectively inhibit one animal coronavirus, TGEV, entering the intestinal porcine epithelial cell line (IPEC-J2). Then, several different experiments were performed to seek the might mechanisms. The plaque assays showed that surfactant could reduce the plaque generation of TGEV in a dose-dependent manner. Meanwhile, after incubation with TGEV for 1.5 h, B. subtilis could attach TGEV particles to their surface so that the number of virus to bind to the host cells was declined. Furthermore, our data showed that the inhibition of B. subtilis was closely related to the competition with TGEV for the viral entry receptors, including epidermal growth factor receptor (EGFR) and aminopeptidase N (APN) protein. In addition, Western blotting and apoptosis analysis indicated that B. subtilis could enhance the resistance of IPEC-J2 cells by up-regulating the expression of toll-like receptor (TLR)-6 and reducing the percentage of apoptotic cells. Taken together, our results suggest that B. subtilis OKB105 and its surfactin can antagonize TGEV entry in vitro and may serve as promising new candidates for TGEV prevention. © 2017 The Author(s).

  19. Oral Polio Vaccine Influences the Immune Response to BCG Vaccination. A Natural Experiment

    DEFF Research Database (Denmark)

    Sartono, E.; Lisse, I.M.; Terveer, E.M.

    2010-01-01

    not receive OPV at birth, but only BCG. We investigated the effect of OPV given simultaneously with BCG at birth on the immune response to BCG vaccine. Methods and Findings: We compared the in vitro and the in vivo response to PPD in the infants who received OPV and BCG with that of infants who received BCG...... scar (0.95 (0.91-1.00), p = 0.057)). Among children with a scar, OPV was associated with reduced scar size, the regression coefficient being -0.24 (-0.43-0.05), p = 0.012. Conclusions: This study is the first to address the consequences for the immune response to BCG of simultaneous administration...... only. At age 6 weeks, the in vitro cytokine response to purified protein derivate (PPD) of M. Tuberculosis was reduced in LBW and NBW infants who had received OPV with BCG. In a pooled analysis receiving OPV with BCG at birth was associated with significantly lower IL-13 (p = 0.041) and IFN-gamma (p...

  20. Determinants of BCG scarification among children in rural Guinea-Bissau

    DEFF Research Database (Denmark)

    Funch, Katarina M; Thysen, Sanne M; Rodrigues, Amabelia

    2018-01-01

    : Bandim Health Project (BHP) runs a Health and Demographic Surveillance System site in rural Guinea-Bissau. BHP provides BCG at monthly visits. We studied determinants for not developing a BCG scar using binomial regression models to obtain relative risks (RR). RESULTS: From May 2012 until October 2014...

  1. IL-18 Does not Increase Allergic Airway Disease in Mice When Produced by BCG

    Directory of Open Access Journals (Sweden)

    L. Amniai

    2007-01-01

    These data show that IL-18 did not increase allergic airway responses in the context of the mycobacterial infection, and suggest that BCG-IL-18 and BCG are able to prevent the development of local Th2 responses and therefore inhibit allergen-induced airway responses even after restimulation.

  2. Clinical manifestations of leprosy after BCG vaccination: An observational study in Bangladesh

    NARCIS (Netherlands)

    R. Richardus (Renate); C.R. Butlin (C. Ruth); K. Alam (Khorshed); K. Kundu (Kallyan); A. Geluk (Annemieke); J.H. Richardus (Jan Hendrik)

    2015-01-01

    textabstractBackground: Although BCG is used as a vaccine against tuberculosis, it also protects against leprosy. Previous evaluation over 18 years of an intervention of two doses BCG for 3536 household contacts of leprosy patients showed that 28 (23%) out of 122 contacts diagnosed with leprosy,

  3. Surgical Complications of Bacille Calmette-Guérin (BCG) Infection in ...

    African Journals Online (AJOL)

    Aim. Bacille Calmette-Guérin (BCG) immunisation is well established as part of the South African national expanded programme for immunisation (EPI). The World Health Organization (WHO) currently recommends that BCG be given to all asymptomatic infants irrespective of HIV exposure at birth but does not recommend ...

  4. Surgical Complications of Bacille Calmette-Guérin (BCG) Infection in ...

    African Journals Online (AJOL)

    Surgical Complications of Bacille Calmette-Guérin (BCG) Infection in HIV infected children. J Karpelowsky, A Alexander, SD Peek, A Millar, H Rode. Abstract. Aim. Bacille Calmette-Guérin (BCG) immunisation is well established as part of the South African national expanded programme for immunisation (EPI). The World ...

  5. Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau

    DEFF Research Database (Denmark)

    Roth, A.E.; Benn, Christine Stabell; Ravn, H.

    2010-01-01

    -up. Compared with controls, the BCG revaccinated children had a hazard ratio of 1.20 (95% confidence interval 0.77 to 1.89). Two hundred and fifty children were admitted to hospital for the first time between enrolment and the end of the study, with an incidence rate ratio for BCG revaccinated children versus...

  6. Bacillus coagulans

    Science.gov (United States)

    Aulitto, Martina; Fusco, Salvatore; Bartolucci, Simonetta; Franzén, Carl Johan; Contursi, Patrizia

    2017-01-01

    The transition from a petroleum-based economy towards more sustainable bioprocesses for the production of fuels and chemicals (circular economy) is necessary to alleviate the impact of anthropic activities on the global ecosystem. Lignocellulosic biomass-derived sugars are suitable alternative feedstocks that can be fermented or biochemically converted to value-added products. An example is lactic acid, which is an essential chemical for the production of polylactic acid, a biodegradable bioplastic. However, lactic acid is still mainly produced by Lactobacillus species via fermentation of starch-containing materials, the use of which competes with the supply of food and feed. A thermophilic and cellulolytic lactic acid producer was isolated from bean processing waste and was identified as a new strain of Bacillus coagulans , named MA-13. This bacterium fermented lignocellulose-derived sugars to lactic acid at 55 °C and pH 5.5. Moreover, it was found to be a robust strain able to tolerate high concentrations of hydrolysate obtained from wheat straw pre-treated by acid-catalysed (pre-)hydrolysis and steam explosion, especially when cultivated in controlled bioreactor conditions. Indeed, unlike what was observed in microscale cultivations (complete growth inhibition at hydrolysate concentrations above 50%), B. coagulans MA-13 was able to grow and ferment in 95% hydrolysate-containing bioreactor fermentations. This bacterium was also found to secrete soluble thermophilic cellulases, which could be produced at low temperature (37 °C), still retaining an optimal operational activity at 50 °C. The above-mentioned features make B. coagulans MA-13 an appealing starting point for future development of a consolidated bioprocess for production of lactic acid from lignocellulosic biomass, after further strain development by genetic and evolutionary engineering. Its optimal temperature and pH of growth match with the operational conditions of fungal enzymes hitherto

  7. Some characteristics of BCG-RIV lot no. 602, prepared to be used for immunostimulation in cancer therapy

    NARCIS (Netherlands)

    Steerenberg PA; de Jong WH; Kruizinga W; Ruitenberg EJ; Tiesjema RH; Kreeftenberg JG; Groothuis DG; Smid P; van Noorle Jansen LM

    1985-01-01

    In dit rapport worden verschillende eigenschappen van BCG batch 602, die gebruikt wordt voor immunotherapie bij kanker, onderzocht. Het bleek dat deze batch BCG dezelfde eigenschappen bezat als de voorafgaande BCG batches. Onderzocht werden de potentie van specifieke en a-specifieke

  8. Some characteristics of BCG-RIVM lot no. 605, prepared to be used for immunostimulation in cancer therapy

    NARCIS (Netherlands)

    Steerenberg PA; de Jong WH; Kruizinga W; Ruitenberg EJ; Tiesjema RH; Kreeftenberg JG; Groothuis DG; Smid P; van Noorle Jansen LM

    1986-01-01

    Het rapport behandelt de karakterisatie, toxiciteit en de effectiviteit van een nieuw geproduceerde batch BCG (BCG-RIVM, lot no. 605), bestemd voor immunotherapie bij de behandeling naar kanker. Uit dit onderzoek blijkt dat deze batch BCG dezelfde eigenschappen heeft als voorgaande

  9. Some characteristics of BCG-RIVM lot no 606, prepared to be used for immunostimulation in cancer therapy

    NARCIS (Netherlands)

    Steerenberg PA; de Jong WH; Kruizinga W; Ruitenberg EJ; Tiesjema RH; Kreeftenberg JG; Groothuis DG; Smid P; van Noorle Jansen LM

    1986-01-01

    Het rapport behandelt de karakterisatie, toxiciteit en de effectiviteit van een nieuw geproduceerde batch BCG (BCG-RIVM lot no. 606), bestemd voor immunotherapie bij de behandeling van kanker. Uit dit onderzoek blijkt dat deze batch BCG dezelfde eigenschappen heeft als voorgaande

  10. Uptake of newly introduced universal BCG vaccination in newborns.

    LENUS (Irish Health Repository)

    Braima, O

    2012-01-31

    Universal neonatal BCG vaccination was discontinued in Cork in 1972. Following an outbreak of TB in 2 creches in the HSE South, a universal BCG vaccination program was re-introduced in October 2008. The aim of this study was to determine the vaccination process (in-hospital and community) and the in-hospital uptake of the vaccine. Following informed parental consent, babies of birth weight > 2.5 Kg were eligible for in-hospital vaccination if they were not: febrile, jaundiced on phototherapy, on antibiotics and if not born to HIV- positive mothers. Parents of babies not vaccinated in-hospital were asked to book an appointment in either of the 2 Cork community clinics. The immunisation nurse collected data on BCG vaccination, prospectively. This study examined vaccination uptakes in-hospital and community over a 6 month period (October 2008 to March 2009). There were 4018 deliveries during the study period. In-hospital consent was declined in only 16 babies (<1%) while the in-hospital vaccination uptake was 80% of total liv births. Although 635 newborns were admitted to the NICU, only 46 (8%) were vaccinated while in the NICU. At least 48% of planned community vaccination has been achieved to date. In conclusion, in-hospital consent was almost universal and vaccination uptake was satisfactory. NICU exclusion criteria accounted for a significant proportion of non-vaccination in-hospital. These criteria need to be readdressed considering that all premature babies are given other routine newborn vaccines at 2 months of age, regardless of weight.

  11. Uptake of newly introduced universal BCG vaccination in newborns.

    LENUS (Irish Health Repository)

    Braima, O

    2010-06-01

    Universal neonatal BCG vaccination was discontinued in Cork in 1972. Following an outbreak of TB in 2 creches in the HSE South, a universal BCG vaccination program was re-introduced in October 2008. The aim of this study was to determine the vaccination process (in-hospital and community) and the in-hospital uptake of the vaccine. Following informed parental consent, babies of birth weight > 2.5 Kg were eligible for in-hospital vaccination if they were not: febrile, jaundiced on phototherapy, on antibiotics and if not born to HIV- positive mothers. Parents of babies not vaccinated in-hospital were asked to book an appointment in either of the 2 Cork community clinics. The immunisation nurse collected data on BCG vaccination, prospectively. This study examined vaccination uptakes in-hospital and community over a 6 month period (October 2008 to March 2009). There were 4018 deliveries during the study period. In-hospital consent was declined in only 16 babies (<1%) while the in-hospital vaccination uptake was 80% of total liv births. Although 635 newborns were admitted to the NICU, only 46 (8%) were vaccinated while in the NICU. At least 48% of planned community vaccination has been achieved to date. In conclusion, in-hospital consent was almost universal and vaccination uptake was satisfactory. NICU exclusion criteria accounted for a significant proportion of non-vaccination in-hospital. These criteria need to be readdressed considering that all premature babies are given other routine newborn vaccines at 2 months of age, regardless of weight.

  12. Biochemical characterization of the maltokinase from Mycobacterium bovis BCG

    Directory of Open Access Journals (Sweden)

    Lamosa Pedro

    2010-05-01

    Full Text Available Abstract Background Maltose-1-phosphate was detected in Mycobacterium bovis BCG extracts in the 1960's but a maltose-1-phosphate synthetase (maltokinase, Mak was only much later purified from Actinoplanes missouriensis, allowing the identification of the mak gene. Recently, this metabolite was proposed to be the intermediate in a pathway linking trehalose with the synthesis of glycogen in M. smegmatis. Although the M. tuberculosis H37Rv mak gene (Rv0127 was considered essential for growth, no mycobacterial Mak has, to date, been characterized. Results The sequence of the Mak from M. bovis BCG was identical to that from M. tuberculosis strains (99-100% amino acid identity. The enzyme was dependent on maltose and ATP, although GTP and UTP could be used to produce maltose-1-phosphate, which we identified by TLC and characterized by NMR. The Km for maltose was 2.52 ± 0.40 mM and 0.74 ± 0.12 mM for ATP; the Vmax was 21.05 ± 0.89 μmol/min.mg-1. Divalent cations were required for activity and Mg2+ was the best activator. The enzyme was a monomer in solution, had maximal activity at 60°C, between pH 7 and 9 (at 37°C and was unstable on ice and upon freeze/thawing. The addition of 50 mM NaCl markedly enhanced Mak stability. Conclusions The unknown role of maltokinases in mycobacterial metabolism and the lack of biochemical data led us to express the mak gene from M. bovis BCG for biochemical characterization. This is the first mycobacterial Mak to be characterized and its properties represent essential knowledge towards deeper understanding of mycobacterial physiology. Since Mak may be a potential drug target in M. tuberculosis, its high-level production and purification in bioactive form provide important tools for further functional and structural studies.

  13. Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial

    DEFF Research Database (Denmark)

    Biering-Sørensen, Sofie; Aaby, Peter; Lund, Najaaraq

    2017-01-01

    Background. BCG vaccine may reduce overall mortality by increasing resistance to nontuberculosis infections. In 2 randomized trials in Guinea-Bissau of early BCG-Denmark (Statens Serum Institut) given to low-weight (LW) neonates (... ratios (MRRs). We had prespecified an analysis censoring follow-up at oral poliovirus vaccine campaigns. Results. Early administration of BCG-Denmark was associated with a nonsignificant reduction in neonatal mortality rate (MRR, 0.70; 95% confidence interval [CI], .47–1.04) and a 34% reduction (0.......66; .44–1.00) when censoring for oral poliovirus vaccine campaigns. There was no reduction in mortality rate for noninfectious diseases, but a 43% reduction in infectious disease mortality rate (MRR, 0.57; 95% CI, .35–.93). A meta-analysis of 3 BCG trials showed that early BCG-Denmark reduced mortality...

  14. Another vaccine, another story: BCG vaccination against tuberculosis in India, 1948 to 1960.

    Science.gov (United States)

    Brimnes, Niels

    2011-02-01

    Through an examination of mass BCG vaccination against tuberculosis in India between 1948 and 1960 this article draws attention to the diversity of the history of vaccination. The features of vaccination campaigns often differed from those of the celebrated campaign to eradicate smallpox. Due to differences between smallpox and tuberculosis as well as between the vaccines developed against them, an analysis of BCG mass vaccination against tuberculosis seems particularly well suited for this purpose. Three points of difference are identified. First, in non-Western contexts BCG vaccination procedures were modified to a greater extent than vaccination against smallpox. Second, tuberculosis lacked the drama and urgency of smallpox and BCG vaccination campaigns suffered more from recruitment problems than did the more "heroic" smallpox eradication campaign. Third, the BCG vaccine was contested in medical circles and was much better suited than the vaccine against smallpox as a vehicle for the articulation of concerns about post-colonial modernization.

  15. Recombinant BCG vaccines: molecular features and their influence in the expression of foreign genes.

    Science.gov (United States)

    Oliveira, Thaís Larré; Rizzi, Caroline; Dellagostin, Odir Antônio

    2017-09-01

    Recombinant Mycobacterium bovis BCG vaccines (rBCG) were first developed in the 1990s as a means of expressing antigens from multiple pathogens. This review examines the key structural factors of recombinant M. bovis that influence the expression of the heterologous antigens and the generation of genetic and functional stability in rBCG, which are crucial for inducing strong and lasting immune responses. The fundamental aim of this paper is to provide an overview of factors that affect the expression of recombinant proteins in BCG and the generation of the immune response against the target antigens, including mycobacterial promoters, location of foreign antigens, and stability of the vectors. The reporter systems that have been employed for evaluation of these molecular features in BCG are also reviewed here.

  16. BCG-induced trained immunity in NK cells: Role for non-specific protection to infection.

    Science.gov (United States)

    Kleinnijenhuis, Johanneke; Quintin, Jessica; Preijers, Frank; Joosten, Leo A B; Jacobs, Cor; Xavier, Ramnik J; van der Meer, Jos W M; van Crevel, Reinout; Netea, Mihai G

    2014-12-01

    Adaptive features of innate immunity, also termed 'trained immunity', have recently been shown to characterize monocytes of BCG vaccinated healthy volunteers. Trained immunity leads to increased cytokine production in response to non-related pathogens via epigenetic reprogramming of monocytes. Recently, memory-like properties were also observed in NK cells during viral infections, but it is unknown if memory properties of NK cells contribute to trained immunity due to BCG vaccination. BCG vaccination of healthy volunteers increased proinflammatory cytokine production following ex vivo stimulation of NK cells with mycobacteria and other unrelated pathogens up until at least three months after vaccination. In addition, in a murine model of disseminated candidiasis, BCG vaccination led to an increased survival in SCID mice, which was partially dependent on NK cells. These findings suggest that NK cells may contribute to the non-specific (heterologous) beneficial effects of BCG vaccination. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Genomic analysis of a Mycobacterium bovis bacillus [corrected] Calmette-Guérin strain isolated from an adult patient with pulmonary tuberculosis..

    Directory of Open Access Journals (Sweden)

    Xuming Li

    Full Text Available For years, bacillus Calmette-Guérin (BCG has served as the unique vaccine against tuberculosis and has generally been regarded as safe. However, a clinical strain labeled 3281 that was isolated from a TB patient was identified to be BCG. Via the combination of next-generation sequencing (NGS and comparative genomic analysis, unique 3281 genetic characteristics were revealed. A region containing the dnaA and dnaN genes that is closely related to the initial chromosome replication was found to repeat three times on the BCG Pasteur-specific tandem duplication region DU1. Due to the minimum number of epitopes in BCG strains, 3281 was inferred to have a high possibility for immune evasion. Additionally, variations in the virulence genes and predictions for potential virulence factors were analyzed. Overall, we report a pathogen that has never previously been thought to be pathogenic and initial insights that are focused on the genetic characteristics of virulent BCG.

  18. Deconvolution of the Response to Bacillus Calmette–Guérin Reveals NF-κB-Induced Cytokines As Autocrine Mediators of Innate Immunity

    Directory of Open Access Journals (Sweden)

    Aurélie Bisiaux

    2017-07-01

    Full Text Available Bacillus Calmette–Guérin (BCG is used as a vaccine and diagnostic test for tuberculosis, as well as immunotherapy in the treatment of bladder cancer. While clinically useful, the response to mycobacterial stimulation is complex and the induced protein signature remains poorly defined. We characterized the cell types directly engaged by BCG, as well as the induced cytokine loops that transmit signal(s to bystander cells. Standardized whole-blood stimulations and mechanistic studies on single and purified cell populations identified distinct patterns of activation in monocytes as compared to neutrophils and invariant lymphocyte populations. Deconvoluting the role of Toll-like receptor 2/4 and Dectin-1/2 in the inflammatory response to BCG, we revealed Dectin-1/2 as dominant in neutrophils as compared to monocytes, which equally engaged both pathways. Furthermore, we quantified the role of NF-κB and NADPH/reactive oxygen species (ROS-dependent cytokines, which triggered a JAK1/2-dependent amplification loop and accounted for 40–50% of the induced response to BCG. In sum, this study provides new insight into the molecular and cellular pathways involved in the response to BCG, establishing the basis for a new generation of immunodiagnostic tools.

  19. Pre-Clinical Development of BCG.HIVACAT, an Antibiotic-Free Selection Strain, for HIV-TB Pediatric Vaccine Vectored by Lysine Auxotroph of BCG

    Science.gov (United States)

    Saubi, Narcís; Mbewe-Mvula, Alice; Gea-Mallorqui, Ester; Rosario, Maximillian; Gatell, Josep Maria; Hanke, Tomáš; Joseph, Joan

    2012-01-01

    In the past, we proposed to develop a heterologous recombinant BCG prime-recombinant modified vaccinia virus Ankara (MVA) boost dual pediatric vaccine platform against transmission of breast milk HIV-1 and Mycobacterium tuberculosis (Mtb). In this study, we assembled an E. coli-mycobacterial shuttle plasmid pJH222.HIVACAT expressing HIV-1 clade A immunogen HIVA. This shuttle vector employs an antibiotic resistance-free mechanism based on Operator-Repressor Titration (ORT) system for plasmid selection and maintenance in E. coli and lysine complementation in mycobacteria. This shuttle plasmid was electroporated into parental lysine auxotroph (safer) strain of BCG to generate vaccine BCG.HIVACAT. All procedures complied with Good Laboratory Practices (GLPs). We demonstrated that the episomal plasmid pJH222.HIVACAT was stable in vivo over a 20-week period, and genetically and phenotypically characterized the BCG.HIVACAT vaccine strain. The BCG.HIVACAT vaccine in combination with MVA.HIVA induced HIV-1- and Mtb-specific interferon γ-producing T-cell responses in newborn and adult BALB/c mice. On the other hand, when adult mice were primed with BCG.HIVACAT and boosted with MVA.HIVA.85A, HIV-1-specific CD8+ T-cells producing IFN-γ, TNF-α, IL-2 and CD107a were induced. To assess the biosafety profile of BCG.HIVACAT-MVA.HIVA regimen, body mass loss of newborn mice was monitored regularly throughout the vaccination experiment and no difference was observed between the vaccinated and naïve groups of animals. Thus, we demonstrated T-cell immunogenicity of a novel, safer, GLP-compatible BCG-vectored vaccine using prototype immunogen HIVA. Second generation immunogens derived from HIV-1 as well as other major pediatric pathogens can be constructed in a similar fashion to prime protective responses soon after birth. PMID:22927933

  20. Code system BCG for gamma-ray skyshine calculation

    International Nuclear Information System (INIS)

    Ryufuku, Hiroshi; Numakunai, Takao; Miyasaka, Shun-ichi; Minami, Kazuyoshi.

    1979-03-01

    A code system BCG has been developed for calculating conveniently and efficiently gamma-ray skyshine doses using the transport calculation codes ANISN and DOT and the point-kernel calculation codes G-33 and SPAN. To simplify the input forms to the system, the forms for these codes are unified, twelve geometric patterns are introduced to give material regions, and standard data are available as a library. To treat complex arrangements of source and shield, it is further possible to use successively the code such that the results from one code may be used as input data to the same or other code. (author)

  1. Toxicity of Tolyltriazole to Bacillus Microorganisms.

    Science.gov (United States)

    2000-03-01

    Bacillus coagulans Microbacterium lacticum Jupiter Bacillus thuringiensis Bacillus thuringiensis Bacillus cereus Bacillus Bacillus thuringiensis...TOXICITY OF TOLYLTRIAZOLE TO BACILLUS MICROORGANISMS THESIS Christopher J. Leonard, First Lieutenant, USAF AFIT/GEE/ENV/OOM-12 Approved for...AND DATES COVERED Master’s Thesis 4. TITLE AND SUBTITLE TOXICITY OF TOLYLTRIAZOLE TO BACILLUS MICROORGANISMS 6. AUTHOR(S) Christopher J

  2. Immunomodulatory effects of recombinant BCG expressing pertussis toxin on TNF-alpha and IL-10 in a bladder cancer model

    Directory of Open Access Journals (Sweden)

    Ramos Kátia L

    2008-11-01

    Full Text Available Abstract Background Since successful treatment of superficial bladder cancer with BCG requires proper induction of Th1 immunity, we have developed a rBCG-S1PT strain that induced a stronger cellular immune response than BCG. This preclinical study was designed to compare the modulatory effects of BCG and rBCG-S1PT on bladder TNF-α and IL-10 expression and to evaluate antitumour activity. Methods For Experiment I, the MB49 bladder cancer cell line was used in C57BL/6 mice. Chemical cauterization of the bladder was performed to promote intravesical tumor implantation. Mice were treated by intravesical instillation with BCG, rBCG-S1PT or PBS once a week for four weeks. After 35 days the bladders were removed and weighed. TNF-〈 and IL-10 cytokine responses were measured by qPCR. Experiment II was performed in the same manner as Experiment I, except the animals were not challenged with MB49 tumor cells. Results: rBCG-S1PT immunotherapy resulted in bladder weight reduction, compared to the BCG and control group. There were increases in TNF-α in the BCG-treated group, as well as increases in TNF-α and IL-10 mRNA in the rBCG-S1PT group. Conclusion These data indicate a significant reduction of bladder tumor volume for the rBCG group, compared to the BCG and PBS groups. This suggests that rBCG could be a useful substitute for wild-type BCG and that the potential modulation between TNF-α and IL-10 cytokine productions may have therapeutic value.

  3. Lack of a Negative Effect of BCG-Vaccination on Child Psychomotor Development: Results from the Danish Calmette Study - A Randomised Clinical Trial.

    Science.gov (United States)

    Kjærgaard, Jesper; Stensballe, Lone Graff; Birk, Nina Marie; Nissen, Thomas Nørrelykke; Foss, Kim Thestrup; Thøstesen, Lisbeth Marianne; Pihl, Gitte Thybo; Andersen, Andreas; Kofoed, Poul-Erik; Pryds, Ole; Greisen, Gorm

    2016-01-01

    To assess the non-specific effect of Bacillus Calmette-Guérin (BCG) vaccination at birth on psychomotor development. This is a pre-specified secondary outcome from a randomised, clinical trial. Maternity units and paediatric wards at three university hospitals in Denmark. Children born at gestational age (GA) 32 weeks and above. All women planning to give birth at the three sites were invited during the recruitment period. Out of 4262 randomised children, 144 were premature (GA Psychomotor development measured using Ages and Stages Questionnaire (ASQ) completed by the parents at 12 months. Additionally, parents of premature children (gestational age psychomotor development was excluded in term children. ClinicalTrials.gov NCT01694108.

  4. Cosmological Constraints from the SDSS maxBCG Cluster Catalog

    Energy Technology Data Exchange (ETDEWEB)

    Rozo, Eduardo; /CCAPP; Wechsler, Risa H.; /KIPAC, Menlo Park /SLAC; Rykoff, Eli S.; /UC, Santa Barbara; Annis, James T.; /Fermilab; Becker, Matthew R.; /Chicago U. /KICP, Chicago; Evrard, August E.; /Michigan U. /Michigan U., MCTP; Frieman, Joshua A.; /Fermilab /KICP, Chicago /Chicago U.; Hansen, Sarah M.; /UC, Santa Cruz; Hao, Jia; /Michigan U.; Johnston, David E.; /Northwestern U.; Koester, Benjamin P.; /KICP, Chicago /Chicago U.; McKay, Timothy A.; /Michigan U. /Michigan U., MCTP; Sheldon, Erin S.; /Brookhaven; Weinberg, David H.; /CCAPP /Ohio State U.

    2009-08-03

    We use the abundance and weak lensing mass measurements of the SDSS maxBCG cluster catalog to simultaneously constrain cosmology and the richness-mass relation of the clusters. Assuming a flat {Lambda}CDM cosmology, we find {sigma}{sub 8}({Omega}{sub m}/0.25){sup 0.41} = 0.832 {+-} 0.033 after marginalization over all systematics. In common with previous studies, our error budget is dominated by systematic uncertainties, the primary two being the absolute mass scale of the weak lensing masses of the maxBCG clusters, and uncertainty in the scatter of the richness-mass relation. Our constraints are fully consistent with the WMAP five-year data, and in a joint analysis we find {sigma}{sub 8} = 0.807 {+-} 0.020 and {Omega}{sub m} = 0.265 {+-} 0.016, an improvement of nearly a factor of two relative to WMAP5 alone. Our results are also in excellent agreement with and comparable in precision to the latest cosmological constraints from X-ray cluster abundances. The remarkable consistency among these results demonstrates that cluster abundance constraints are not only tight but also robust, and highlight the power of optically-selected cluster samples to produce precision constraints on cosmological parameters.

  5. Predictive Biomarkers of Bacillus Calmette-Guérin Immunotherapy Response in Bladder Cancer: Where Are We Now?

    Directory of Open Access Journals (Sweden)

    Luís Lima

    2012-01-01

    Full Text Available The most effective therapeutic option for managing nonmuscle invasive bladder cancer (NMIBC, over the last 30 years, consists of intravesical instillations with the attenuated strain Bacillus Calmette-Guérin (the BCG vaccine. This has been performed as an adjuvant therapeutic to transurethral resection of bladder tumour (TURBT and mostly directed towards patients with high-grade tumours, T1 tumours, and in situ carcinomas. However, from 20% to 40% of the patients do not respond and frequently present tumour progression. Since BCG effectiveness is unpredictable, it is important to find consistent biomarkers that can aid either in the prediction of the outcome and/or side effects development. Accordingly, we conducted a systematic critical review to identify the most preeminent predictive molecular markers associated with BCG response. To the best of our knowledge, this is the first review exclusively focusing on predictive biomarkers for BCG treatment outcome. Using a specific query, 1324 abstracts were gathered, then inclusion/exclusion criteria were applied, and finally 87 manuscripts were included. Several molecules, including CD68 and genetic polymorphisms, have been identified as promising surrogate biomarkers. Combinatory analysis of the candidate predictive markers is a crucial step to create a predictive profile of treatment response.

  6. Revaccination of Guinea Pigs With the Live Attenuated Mycobacterium tuberculosis Vaccine MTBVAC Improves BCG's Protection Against Tuberculosis.

    Science.gov (United States)

    Clark, Simon; Lanni, Faye; Marinova, Dessislava; Rayner, Emma; Martin, Carlos; Williams, Ann

    2017-09-01

    The need for an effective vaccine against human tuberculosis has driven the development of different candidates and vaccination strategies. Novel live attenuated vaccines are being developed that promise greater safety and efficacy than BCG against tuberculosis. We combined BCG with the vaccine MTBVAC to evaluate whether the efficacy of either vaccine would be affected upon revaccination. In a well-established guinea pig model of aerosol infection with Mycobacterium tuberculosis, BCG and MTBVAC delivered via various prime-boost combinations or alone were compared. Efficacy was determined by a reduction in bacterial load 4 weeks after challenge. Efficacy data suggests MTBVAC-associated immunity is longer lasting than that of BCG when given as a single dose. Long and short intervals between BCG prime and MTBVAC boost resulted in improved efficacy in lungs, compared with BCG given alone. A shorter interval between MTBVAC prime and BCG boost resulted in improved efficacy in lungs, compared with BCG given alone. A longer interval resulted in protection equivalent to that of BCG given alone. These data indicate that, rather than boosting the waning efficacy of BCG, a vaccination schedule involving a combination of the 2 vaccines yielded stronger immunity to M. tuberculosis infection. This work supports development of MTBVAC use as a revaccination strategy to improve on the effects of BCG in vaccinated people living in tuberculosis-endemic countries. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  7. Early BCG vaccine to low-birth-weight infants and the effects on growth in the first year of life

    DEFF Research Database (Denmark)

    Biering-Sørensen, Sofie; Andersen, Andreas; Ravn, Henrik

    2015-01-01

    BACKGROUND: Randomised trials have shown that early Bacille Calmette-Guérin (BCG) vaccine reduces overall neonatal and infant mortality. However, no study has examined how BCG affects growth. We investigated the effect on infant growth of early BCG vaccine given to low-birth-weight (LBW) infants...... A supplementation (VAS) or placebo. Anthropometric measurements were obtained 2, 6, and 12 months after enrolment. RESULTS: Overall there was no effect of early BCG on growth in the first year of life. The effect of early BCG on weight and mid-upper-arm circumference at 2 months tended to be beneficial among girls...... but not among boys (interaction between "early BCG" and sex: weight p = 0.03 and MUAC p = 0.04). This beneficial effect among girls was particularly seen among the largest infants weighing 2.0 kg or more at inclusion. CONCLUSION: Though BCG vaccination is not recommended to be given to LBW infants at birth...

  8. Long-term in vitro and in vivo effects of γ-irradiated BCG on innate and adaptive immunity

    DEFF Research Database (Denmark)

    Arts, Rob J W; Blok, Bastiaan A; Aaby, Peter

    2015-01-01

    but not in immunocompromised hosts, as it is a live, attenuated vaccine. Therefore, we assessed whether killed γBCG has similar potentiating effects. In an in vitro model of trained immunity, human monocytes were incubated with γBCG for 24 h and restimulated after 6 d. Cytokine production and the role of pattern recognition...... were less strong than those induced by live BCG. γBCG vaccination in volunteers had only minimal effects on innate immunity, whereas a significant increase in heterologous Th1/Th17 immunity was observed. Our results indicate that γBCG induces long-term training of innate immunity in vitro. In vivo, γ......BCG vaccination is associated with a reduced mortality from nonmycobacterial infections. This is likely to be mediated by a combination of innate-immune memory ("trained immunity") and heterologous effects on adaptive immunity. As such, BCG could be used to boost host immunity...

  9. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: Interim results.

    Science.gov (United States)

    Packiam, Vignesh T; Lamm, Donald L; Barocas, Daniel A; Trainer, Andrew; Fand, Benjamin; Davis, Ronald L; Clark, William; Kroeger, Michael; Dumbadze, Igor; Chamie, Karim; Kader, A Karim; Curran, Dominic; Gutheil, John; Kuan, Arthur; Yeung, Alex W; Steinberg, Gary D

    2017-07-26

    CG0070 is a replication-competent oncolytic adenovirus that targets bladder tumor cells through their defective retinoblastoma pathway. Prior reports of intravesical CG0070 have shown promising activity in patients with high-grade non-muscle invasive bladder cancer (NMIBC) who previously did not respond to bacillus Calmette-Guérin (BCG). However, limited accrual has hindered analysis of efficacy, particularly for pathologic subsets. We evaluated interim results of a phase II trial for intravesical CG0070 in patients with BCG-unresponsive NMIBC who refused cystectomy. At interim analysis (April 2017), 45 patients with residual high-grade Ta, T1, or carcinoma-in-situ (CIS) ± Ta/T1 had evaluable 6-month follow-up in this phase II single-arm multicenter trial (NCT02365818). All patients received at least 2 prior courses of intravesical therapy for CIS, with at least 1 being a course of BCG. Patients had either failed BCG induction therapy within 6 months or had been successfully treated with BCG with subsequent recurrence. Complete response (CR) at 6 months was defined as absence of disease on cytology, cystoscopy, and random biopsies. Of 45 patients, there were 24 pure CIS, 8 CIS + Ta, 4 CIS + T1, 6 Ta, 3 T1. Overall 6-month CR (95% CI) was 47% (32%-62%). Considering 6-month CR for pathologic subsets, pure CIS was 58% (37%-78%), CIS ± Ta/T1 50% (33%-67%), and pure Ta/T1 33% (8%-70%). At 6 months, the single patient that progressed to muscle-invasive disease had Ta and T1 tumors at baseline. No patients with pure T1 had 6-month CR. Treatment-related adverse events (AEs) at 6 months were most commonly urinary bladder spasms (36%), hematuria (28%), dysuria (25%), and urgency (22%). Immunologic treatment-related AEs included flu-like symptoms (12%) and fatigue (6%). Grade III treatment-related AEs included dysuria (3%) and hypotension (1.5%). There were no Grade IV/V treatment-related AEs. This phase II study demonstrates that intravesical CG0070 yielded an overall 47

  10. Tuberculosis vaccine strain Mycobacterium bovis BCG Russia is a natural recA mutant

    Directory of Open Access Journals (Sweden)

    Böttger Erik C

    2008-07-01

    Full Text Available Abstract Background The current tuberculosis vaccine is a live vaccine derived from Mycobacterium bovis and attenuated by serial in vitro passaging. All vaccine substrains in use stem from one source, strain Bacille Calmette-Guérin. However, they differ in regions of genomic deletions, antigen expression levels, immunogenicity, and protective efficacy. Results As a RecA phenotype increases genetic stability and may contribute restricting the ongoing evolution of the various BCG substrains while maintaining their protective efficacy, we aimed to inactivate recA by allelic replacement in BCG vaccine strains representing different phylogenetic lineages (Pasteur, Frappier, Denmark, Russia. Homologous gene replacement was achieved successfully in three out of four strains. However, only illegitimate recombination was observed in BCG substrain Russia. Sequence analyses of recA revealed that a single nucleotide insertion in the 5' part of recA led to a translational frameshift with an early stop codon making BCG Russia a natural recA mutant. At the protein level BCG Russia failed to express RecA. Conclusion According to phylogenetic analyses BCG Russia is an ancient vaccine strain most closely related to the parental M. bovis. We hypothesize that recA inactivation in BCG Russia occurred early and is in part responsible for its high degree of genomic stability, resulting in a substrain that has less genetic alterations than other vaccine substrains with respect to M. bovis AF2122/97 wild-type.

  11. Vaccination with a BCG strain overexpressing Ag85B protects cattle against Mycobacterium bovis challenge.

    Directory of Open Access Journals (Sweden)

    Caroline Rizzi

    Full Text Available Mycobacterium bovis is the causative agent of tuberculosis in cattle but also infects other animals, including humans. Previous studies in cattle have demonstrated that the protection induced by BCG is not complete. In order to improve the protection efficacy of BCG, in this study we overexpressed Ag85B in a BCG Pasteur strain, by using an expression system based on the use of an auxotrophic strain for the leucine amino acid, and complementation with leuD. We found that vaccination of cattle with BCG overexpressing Ag85B induced higher production of IL-17 and IL-4 mRNA upon purified protein derivative (PPDB stimulation of peripheral blood mononuclear cells (PBMCs than vaccination with BCG. Moreover, the IL-17 mRNA expression after vaccination negatively correlated with disease severity resulting from a subsequent challenge with M. bovis, suggesting that this cytokine is a potential biomarker of cattle protection against bovine tuberculosis. Importantly, vaccination with the recombinant BCG vaccine protected cattle better than the wild-type BCG Pasteur.

  12. Preclinical Development of an In Vivo BCG Challenge Model for Testing Candidate TB Vaccine Efficacy

    Science.gov (United States)

    Minassian, Angela M.; Ronan, Edward O.; Poyntz, Hazel; Hill, Adrian V. S.; McShane, Helen

    2011-01-01

    There is an urgent need for an immunological correlate of protection against tuberculosis (TB) with which to evaluate candidate TB vaccines in clinical trials. Development of a human challenge model of Mycobacterium tuberculosis (M.tb) could facilitate the detection of such correlate(s). Here we propose a novel in vivo Bacille Calmette-Guérin (BCG) challenge model using BCG immunization as a surrogate for M.tb infection. Culture and quantitative PCR methods have been developed to quantify BCG in the skin, using the mouse ear as a surrogate for human skin. Candidate TB vaccines have been evaluated for their ability to protect against a BCG skin challenge, using this model, and the results indicate that protection against a BCG skin challenge is predictive of BCG vaccine efficacy against aerosol M.tb challenge. Translation of these findings to a human BCG challenge model could enable more rapid assessment and down selection of candidate TB vaccines and ultimately the identification of an immune correlate of protection. PMID:21629699

  13. Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau.

    Science.gov (United States)

    Roth, Adam Edvin; Benn, Christine Stabell; Ravn, Henrik; Rodrigues, Amabelia; Lisse, Ida Maria; Yazdanbakhsh, Maria; Whittle, Hilton; Aaby, Peter

    2010-03-15

    To determine whether BCG revaccination at 19 months of age reduces overall child mortality. Randomised trial, with follow-up to age 5. A health project in Bissau, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area with 90 000 inhabitants. 2871 children aged 19 months to 5 years with low or no reactivity to tuberculin and who were not severely sick on the day of enrollment. BCG vaccination or no vaccination (control). Hazard ratios for mortality. 77 children died during follow-up. Compared with controls, the BCG revaccinated children had a hazard ratio of 1.20 (95% confidence interval 0.77 to 1.89). Two hundred and fifty children were admitted to hospital for the first time between enrollment and the end of the study, with an incidence rate ratio for BCG revaccinated children versus controls of 1.04 (0.81 to 1.33). The trial was stopped prematurely because of a cluster of deaths in the BCG arm of the study. This increase in mortality occurred at a time when many children had received missing vaccinations or vitamin A or iron supplementation; the hazard ratio for BCG revaccinated children compared with controls was 2.69 (1.05 to 6.88) in the period after these campaigns. Throughout the trial, the effect of BCG revaccination on mortality was significantly different (P=0.006) in children who had received diphtheria-tetanus-pertussis (DTP) booster vaccination before enrollment (hazard ratio 0.36, 0.13 to 0.99) and children who had not received the booster before enrollment (1.78, 1.04 to 3.04). There was no overall beneficial effect of being revaccinated with BCG. The effect of BCG revaccination on mortality might depend on other health interventions. Trial registration Clinical Trials ICA4-CT-2002-10053-REVAC.

  14. Bladder preservation using chemoradiation therapy for locally invasive bladder cancer

    International Nuclear Information System (INIS)

    Abe, Toyofumi; Yoshioka, Toshiaki; Sato, Mototaka; Mori, Naoki; Sekii, Ken-Ichiro; Itatani, Hiroaki

    2011-01-01

    We investigated the long-term results and molecular markers of outcome with selective organ preservation in invasive bladder cancer using chemoradiation therapy. We examined locally invasive bladder cancer in 32 patients (30 men, 2 women; mean age at treatment 68.1 years) who underwent bladder-sparing protocols in the Department of Urology at Sumitomo Hospital between 2000 and 2005. The clinical stage was T2, T3, and T4 in 13, 16, and 3 patients, respectively. Our protocol includes aggressive transurethral resection of the bladder tumor (TURBT) and 46 Gy radiotherapy (2 Gy/fraction, 5 fractions/week) to the pelvis with concurrent cisplatin chemotherapy (20 mg/body/day, 5 days/week, the first and fourth week, intravenously). The initial evaluation included magnetic resonance imaging (MRI), urine cytology, and cystoscopy with a biopsy. During follow-up, if the patients developed superficial recurrence, they was treated with TURBT and intravesical Bacillus Calmette-Guerin (BCG), while patients with invasive recurrence were advised to undergo a salvage cystectomy. We examined the association between the expression of the Bcl-2 family in pretreatment TUR specimens and patient outcome. The mean follow-up was 54.6 months. The first assessment after the induction chemoradiotherapy showed that bladder preservation was achieved in 27 patients (84.4%). The actuarial local control rate with an intact bladder was 56.3% (18 patients) at 3 years. The 1-, 3-, and 5-year cancer-specific survival rate was 90.6, 84.0, and 66.9%, respectively. The 5-year cancer-specific survival rate was 75.0, 67.2, and 33.3% in T2, T3, and T4, respectively. Bcl-x positivity was significantly associated with a poor cancer-specific survival rate (log-rank test, p=0.038). Chemoradiation therapy for invasive bladder cancer can achieve survival rates similar to those in patients treated with radical cystectomy, with successful bladder preservation. Our results suggest that the expression of Bcl-x is a

  15. Risk factors for community-acquired pneumonia among adults in Kenya: a case-control study.

    Science.gov (United States)

    Muthumbi, Esther; Lowe, Brett S; Muyodi, Cyprian; Getambu, Esther; Gleeson, Fergus; Scott, J Anthony G

    2017-01-01

    Pneumonia is a leading cause of morbidity and mortality among adults worldwide; however, the risk factors for community-acquired pneumonia in Africa are not well characterized. The authors recruited 281 cases of community-acquired pneumonia and 1202 hospital controls among patients aged ≥15 years who attended Kilifi District Hospital/Coast Provincial General Hospital in Kenya between 1994 and 6. Cases were admissions with an acute illness with ≥2 respiratory signs and evidence of consolidation on a chest radiograph. Controls were patients without signs of pneumonia, frequency matched by age, sex and hospital. Risk factors related to socio-demographic factors, drug use, clinical history, contact patterns and exposures to indoor air pollution were investigated by questionnaire, anthropometric measurements and laboratory assays. Associations were evaluated using a hierarchical logistic regression model. Pneumonia was associated with human immunodeficiency virus (HIV) infection (Odds Ratio [OR] 2.06, 95% CI 1.44-3.08), anemia (OR 1.91, 1.31-2.74), splenomegaly (OR 2.04, 95% CI 1.14-3.41), recent history of pneumonia (OR 4.65, 95% CI 1.66-12.5), history of pneumonia >2 years previously (OR 17.13, 95% CI 5.01-60.26), coryza in the 2 weeks preceding hospitalization (OR 2.09, 95% CI 1.44-3.03), current smoking (2.19, 95% CI 1.39-3.70), use of khat (OR 3.44, 95% CI 1.72-7.15), use of snuff (OR 2.67, 95% CI 1.35-5.49) and contact with several animal species. Presence of a Bacillus Calmette-Guerin (BCG) scar was associated with protection (OR 0.51, 95% CI 0.32-0.82). The risk factors varied significantly by sex. Pneumonia in Kenyan adults was associated with global risk factors, such as HIV and smoking, but also with specific local factors like drug use and contact with animals. Intervention strategies should account for sex-specific differences in risk factors.

  16. The Use of Genomics in Microbiology: From Vaccines to Drug Resistance

    KAUST Repository

    Hill-Cawthorne, Grant A.

    2015-05-01

    Since 2004 sequencing has undergone a revolutionary change with the advent of first the 454 sequencer, followed by the introduction of the Solexa/Illumina chemistries. This has led to the ability to sequence the whole genomes of a large number of microorganisms in a short space of time. Microbiology’s last revolution was in the introduction of PCR, which allowed for faster detection of pathogens, particularly viruses. With whole genome sequencing (WGS) many of the time-consuming steps carried out by a reference laboratory can be skipped. These include organism detection, speciation, antimicrobial susceptibility testing, typing and molecular epidemiology – all carried out in a single sequencing run followed by bioinformatics analysis. So far the merits of WGS in microbiology have only been demonstrated in highly specialised scientific laboratories in high-income countries. However, with continuingly decreasing costs and increasing throughput, many public health laboratories are now acquiring sequencers and their use will inevitably spread to middle-income countries. In this thesis I explore the use of WGS in three specific areas and include details on how to develop and assess bioinformatics pipelines. First, I shall demonstrate that WGS can be used to assess highly divergent regions within microorganisms by using the example of the weaknesses in current approaches to the molecular detection of methicillin-resistant Staphylococcus aureus isolates. In particular, I shall highlight how current molecular tests have limitations in detecting drug resistance when the regions of the genome conferring resistance have significant mutations. Second, I will examine how WGS can provide insights into the biology of the current vaccine against tuberculosis, Bacillus Calmette Guerin (BCG), particularly how the continued passage of the seedlot for this vaccine has led to very different versions being used around the globe. Finally, I will demonstrate how WGS can be used to

  17. Co-administration of BCG and Diphtheria-tetanus-pertussis (DTP) Vaccinations May Reduce Infant Mortality More Than the WHO-schedule of BCG First and Then DTP. A Re-analysis of Demographic Surveillance Data From Rural Bangladesh.

    Science.gov (United States)

    Aaby, Peter; Andersen, Andreas; Ravn, Henrik; Zaman, K

    2017-08-01

    WHO recommends BCG at birth and diphtheria-tetanus-pertussis (DTP)-containing vaccine at 6, 10 and 14weeks of age. However, BCG and DTP are often co-administered in low-income countries. The health implications have not been examined. We reanalysed data from Matlab, Bangladesh, to examine the influence of co-administration on mortality; 37,894 children born 1986-1999 were followed with registration of vaccinations and survival. Using Cox models, survival was analysed from 6weeks to 9months of age when measles vaccine is given; 712 children died in this age group. We calculated mortality rate ratios (MRR) for children starting the vaccination schedule with BCG-first, BCG+DTP1-first or DTP1-first. Only 17% followed the WHO-schedule with BCG-first. Mortality was 16/1000 person-years for children who initiated the vaccination schedule with BCG+DTP1 but 32/1000 and 20/1000 for children who received BCG-first or DTP-first, respectively. Compared with BCG+DTP1-first and adjusting for background factors, the BCG-first-schedule was associated with 2-fold higher mortality (MRR=1.94 (1.42-2.63)). DTP1 administered after BCG-first was associated with higher mortality than receiving DTP1 with BCG (MRR=1.78 (1.03-3.03)). Co-administration of BCG and DTP may further reduce mortality. Since all observational studies support this trend, co-administration of BCG and DTP should be tested in randomised trials. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  18. [Mass spectrometry identification of secreted proteins from Bacillus firmus and analysis of its secretive sequences].

    Science.gov (United States)

    Liu, Sun; Song, Xiaoling; Huang, Jie

    2011-07-01

    Bacillus firmus was a common probiotics bacteria in nature and widely used in the shrimp aquaculture. In order to construct expression vectors for secretive proteins, we identified several major secretive proteins of Bacillus firmus by mass spectrometry and analyzed their gene sequences to find signal peptide sequences. The secreted proteins of Bacillus firmus were extracted and separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The 3 highly expressed protein bands in the SDS-PAGE were identified by mass spectrometry Matrix Assisted Laser Desorption Ionization (MALDI)-Time of Flight (TOF)/Time of Flight (TOF) and the sequences were downloaded from National Center for Biotechnology Information (NCBI) database. Then Polymerase Chain Reaction (PCR) primers were designed according to the downloaded sequences and specific DNA bands were amplified sequenced and bioinformatics analyzed. The proteins were identified as the putative chitinase, enterotoxin A and protein BCG9842 of Bacillus firmus. Three signal peptides were conformed by using the online software SignaIP 3.0, namely bf-43, bf-37 and bf-16. The cellular localization of the secreted sequences were analyzed by PSORT. And we found that bf-43 located in the outer membrane of cells, bf-37 and bf-16 located in the extracellular cell. 3 major secreted proteins of Bacillus firmus have been identified. 3 possible signal peptides were obtained and will be useful for the construction of expression vectors for secretive proteins.

  19. Vaccination against M. tuberculosis – what next after BCG?

    Directory of Open Access Journals (Sweden)

    Marek Fol

    2011-01-01

    Full Text Available Tuberculosis (TB still remains a huge global health problem. An increase in TB has been observed in many parts of the world, especially in poor and densely populated sub-Saharan Africa and Asia. Tuberculosis affects not only the developing countries but also the relatively wealthy regions of Europe, particularly Eastern Europe, where drug-resistant mycobacterial strains are increasingly reported.Control of tuberculosis expansion is very difficult. It requires the long-term use of anti-mycobacterial drugs. Additionally, the HIV epidemic and the phenomenon of multi-drug resistance are assumed to be responsible for the increase in TB cases. Therefore the most reasonable form of anti-TB protection seems to be effective vaccination.At the beginning of the twentieth century the BCG vaccine was introduced into general use as the first and so far the only immune protector against tuberculosis. Now it is known that this vaccine is not powerful enough and induces protection at a relatively low level. Hence ongoing research on the development of a more powerful anti-mycobacterial vaccine is still needed. Many of the new formulations are in phase II or III of clinical trials and the results are promising. The search for new vaccines involves several strategies: modified virulence-attenuated [i]Mycobacterium tuberculosis[/i] strains, recombination of attenuated M. bovis BCG bacilli, immunogenic mycobacterial proteins and DNA encoding selected proteins as well as unrelated microorganisms used as carriers of mycobacterial antigens. The wide range of concepts is extremely important because new vaccines should serve for immunization of the broadest possible population, not only healthy individuals but also those who are immunocompromised.

  20. Oral vaccination with lipid-formulated BCG induces a long-lived, multifunctional CD4(+ T cell memory immune response.

    Directory of Open Access Journals (Sweden)

    Lindsay R Ancelet

    Full Text Available Oral delivery of BCG in a lipid formulation (Liporale™-BCG targets delivery of viable bacilli to the mesenteric lymph nodes and confers protection against an aerosol Mycobacterium tuberculosis challenge. The magnitude, quality and duration of the effector and memory immune response induced by Liporale™-BCG vaccination is unknown. Therefore, we compared the effector and memory CD4(+ T cell response in the spleen and lungs of mice vaccinated with Liporale™-BCG to the response induced by subcutaneous BCG vaccination. Liporale™-BCG vaccination induced a long-lived CD4(+ T cell response, evident by the detection of effector CD4(+ T cells in the lungs and a significant increase in the number of Ag85B tetramer-specific CD4(+ T cells in the spleen up to 30 weeks post vaccination. Moreover, following polyclonal stimulation, Liporale™-BCG vaccination, but not s.c. BCG vaccination, induced a significant increase in both the percentage of CD4(+ T cells in the lungs capable of producing IFNγ and the number of multifunctional CD4(+ T cells in the lungs at 30 weeks post vaccination. These results demonstrate that orally delivered Liporale™-BCG vaccine induces a long-lived multifunctional immune response, and could therefore represent a practical and effective means of delivering novel BCG-based TB vaccines.

  1. Long-term in vitro and in vivo effects of γ-irradiated BCG on innate and adaptive immunity.

    Science.gov (United States)

    Arts, Rob J W; Blok, Bastiaan A; Aaby, Peter; Joosten, Leo A B; de Jong, Dirk; van der Meer, Jos W M; Benn, Christine Stabell; van Crevel, Reinout; Netea, Mihai G

    2015-12-01

    BCG vaccination is associated with a reduced mortality from nonmycobacterial infections. This is likely to be mediated by a combination of innate-immune memory ("trained immunity") and heterologous effects on adaptive immunity. As such, BCG could be used to boost host immunity but not in immunocompromised hosts, as it is a live, attenuated vaccine. Therefore, we assessed whether killed γBCG has similar potentiating effects. In an in vitro model of trained immunity, human monocytes were incubated with γBCG for 24 h and restimulated after 6 d. Cytokine production and the role of pattern recognition receptors and histone methylation markers were assessed. The in vivo effects of γBCG vaccination were studied in a proof-of-principle trial in 15 healthy volunteers. γBCG induced trained immunity in vitro via the NOD2 receptor pathway and up-regulation of H3K4me3 histone methylation. However, these effects were less strong than those induced by live BCG. γBCG vaccination in volunteers had only minimal effects on innate immunity, whereas a significant increase in heterologous Th1/Th17 immunity was observed. Our results indicate that γBCG induces long-term training of innate immunity in vitro. In vivo, γBCG induces mainly heterologous effects on the adaptive-immune system, whereas effects on innate cytokine production are limited. © Society for Leukocyte Biology.

  2. Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau

    DEFF Research Database (Denmark)

    Roth, A.E.; Benn, Christine Stabell; Ravn, H.

    2010-01-01

    Objective To determine whether BCG revaccination at 19 months of age reduces overall child mortality. Design Randomised trial, with follow-up to age 5. Setting A health project in Bissau, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area with 90 000...... ratio 0.36, 0.13 to 0.99) and children who had not received the booster before enrolment (1.78, 1.04 to 3.04). Conclusions There was no overall beneficial effect of being revaccinated with BCG. The effect of BCG revaccination on mortality might depend on other health interventions...... children compared with controls was 2.69 (1.05 to 6.88) in the period after these campaigns. Throughout the trial, the effect of BCG revaccination on mortality was significantly different (P=0.006) in children who had received diphtheria-tetanus-pertussis (DTP) booster vaccination before enrolment (hazard...

  3. Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates

    DEFF Research Database (Denmark)

    Benn, Christine Stabell; Fisker, Ane Baerent; Napirna, Bitiguida Mutna

    2010-01-01

    OBJECTIVE: To investigate the effect of vitamin A supplementation and BCG vaccination at birth in low birthweight neonates. DESIGN: Randomised, placebo controlled, two by two factorial trial. SETTING: Bissau, Guinea-Bissau. PARTICIPANTS: 1717 low birthweight neonates born at the national hospital...... months of age for infants who received vitamin A supplementation compared with those who received placebo. RESULTS: No interaction was observed between vitamin A supplementation and BCG vaccine allocation (P=0.73). Vitamin A supplementation at birth was not significantly associated with mortality......: the MRR of vitamin A supplementation compared with placebo, controlled for randomisation to "early BCG" versus "no early BCG" was 1.08 (95% CI 0.79 to 1.47). Stratification by sex revealed a significant interaction between vitamin A supplementation and sex (P=0.046), the MRR of vitamin A supplementation...

  4. Vitamin A supplementation and BCG vaccination at birth may affect atopy in childhood

    DEFF Research Database (Denmark)

    Kiraly, N; Benn, Christine Stabell; Biering-Sørensen, S

    2013-01-01

    Recent evidence suggests that immunogenic interventions such as vaccines and micronutrients may affect atopic sensitization and atopic disease. We aimed to determine whether neonatal BCG vaccination, vitamin A supplementation and other vaccinations affect atopy in childhood....

  5. Using BCG as a framework for setting goals and communicating progress toward those goals

    Science.gov (United States)

    This 5 minute Lightning Talk will discuss the benefits of stakeholder-supported quantitative targets in measuring progress, and will describe the Biological Condition Gradient (BCG) as one way to develop these quantitative targets.

  6. Noncontiguous finished genome sequences and description of Bacillus massiliglaciei, Bacillus mediterraneensis, Bacillus massilinigeriensis, Bacillus phocaeensis and Bacillus tuaregi, five new species identified by culturomics

    OpenAIRE

    Cadoret, F.; Alou, M.T.; Afouda, P.; Traore, I.S.; Br?chard, L.; Michelle, C.; Di Pinto, F.; Andrieu, C.; Delerce, J.; Levasseur, A.; Fournier, P.-E.; Raoult, D.

    2017-01-01

    Microbial culturomics, which investigates microbial diversity by combining diversified culture conditions, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and 16S rDNA identification, allowed to identify five new species within the Bacillus genus. Bacillus massiliglaciei strain Marseille-P2600T, Bacillus mediterraneensis strain Marseille-P2384T, Bacillus massilinigeriensis strain Marseille-P2366T, Bacillus tuaregi strain Marseille-P2489T and Bacillus phocaeensis s...

  7. Recombinant BCG Expressing Mycobacterium ulcerans Ag85A Imparts Enhanced Protection against Experimental Buruli ulcer.

    Science.gov (United States)

    Hart, Bryan E; Hale, Laura P; Lee, Sunhee

    2015-09-01

    Buruli ulcer, an emerging tropical disease caused by Mycobacterium ulcerans (MU), is characterized by disfiguring skin necrosis and high morbidity. Relatively little is understood about the mode of transmission, pathogenesis, or host immune responses to MU infection. Due to significant reduction in quality of life for patients with extensive tissue scarring, and that a disproportionately high percentage of those affected are disadvantaged children, a Buruli ulcer vaccine would be greatly beneficial to the worldwide community. Previous studies have shown that mice inoculated with either M. bovis bacille Calmette-Guérin (BCG) or a DNA vaccine encoding the M. ulcerans mycolyl transferase, Ag85A (MU-Ag85A), are transiently protected against pathology caused by intradermal challenge with MU. Building upon this principle, we have generated quality-controlled, live-recombinant strains of BCG and M. smegmatis which express the immunodominant MU Ag85A. Priming with rBCG MU-Ag85A followed by an M. smegmatis MU-Ag85A boost strongly induced murine antigen-specific CD4+ T cells and elicited functional IFNγ-producing splenocytes which recognized MU-Ag85A peptide and whole M. ulcerans better than a BCG prime-boost vaccination. Strikingly, mice vaccinated with a single subcutaneous dose of BCG MU-Ag85A or prime-boost displayed significantly enhanced survival, reduced tissue pathology, and lower bacterial load compared to mice vaccinated with BCG. Importantly, this level of superior protection against experimental Buruli ulcer compared to BCG has not previously been achieved. These results suggest that use of BCG as a recombinant vehicle expressing MU antigens represents an effective Buruli ulcer vaccine strategy and warrants further antigen discovery to improve vaccine efficacy.

  8. Mycobacterium bovis BCG: the importance of an accurate identification in the diagnostic routine

    Directory of Open Access Journals (Sweden)

    Antonella Grottola

    2010-09-01

    Full Text Available M. bovis BCG is used clinically in the immunotherapy treatment of superficial bladder cancer to prevent progression to invasive disease, leading in some cases to a severe localized inflammation or disseminated infections. For this reason, an accurate and early identification of this particular microorganism is clinically relevant.We describe a case-report of bladder cancer with a urine culture-positive for mycobacteria initially diagnosed as MTB complex infection and later identified as BCG disease by molecular methods.

  9. Removal of BCG artefact from concurrent fMRI-EEG recordings based on EMD and PCA.

    Science.gov (United States)

    Javed, Ehtasham; Faye, Ibrahima; Malik, Aamir Saeed; Abdullah, Jafri Malin

    2017-11-01

    Simultaneous electroencephalography (EEG) and functional magnetic resonance image (fMRI) acquisitions provide better insight into brain dynamics. Some artefacts due to simultaneous acquisition pose a threat to the quality of the data. One such problematic artefact is the ballistocardiogram (BCG) artefact. We developed a hybrid algorithm that combines features of empirical mode decomposition (EMD) with principal component analysis (PCA) to reduce the BCG artefact. The algorithm does not require extra electrocardiogram (ECG) or electrooculogram (EOG) recordings to extract the BCG artefact. The method was tested with both simulated and real EEG data of 11 participants. From the simulated data, the similarity index between the extracted BCG and the simulated BCG showed the effectiveness of the