Comparison of the BCG vaccine produced in Poland and BCG vaccines produced from BCG substrains of various origin.
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Animals↗
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[Testing post-vaccination and post-infection hypersensitivity with the use of tuberculin PPD-S BCG Polska. I. Use of tuberculin PPD-S BCG in children vaccinated with BCG vaccine].
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Adolescent↗
Phenotypic difference between Bcg(r) and Bcg(s) macrophages is related to differences in protein-kinase-C-dependent signalling.
Mice of diverse genetic backgrounds may be classified as being either resistant or susceptible to infection with Mycobacteria. These phenotypes appear to be determined by a single gene on chromosome 1, the Bcg gene, and are expressed at the level of the macrophage in vitro. When compared to macrophages from mice of the susceptible phenotype (Bcg[s]), macrophages from mice of the resistant phenotype (Bcg[r]) show enhanced functional properties including increased expression of MHC class II molecules, increased nitric oxide production, and greater capacity to inhibit the growth of several intracellular pathogens. The bacteriostatic activity of B10R and B10S macrophages correlated with the amount of nitric oxide produced by the macrophages. Since protein kinase C (PKC) has been shown to be involved in the induction of a range of macrophage functional activities, experiments were conducted to examine the possibility that phenotypic differences between Bcg(r) and Bcg(s) macrophages may be related to differences in PKC-dependent signalling. Macrophage cell lines were derived from mice congenic at the Bcg locus that are either resistant (B10R) or susceptible (B10S) to infection with Mycobacteria. In the basal state, PKC-specific activity was significantly increased in the cytosolic fractions of B10R cells when compared to B10S cells. Following phorbol myristate acetate (PMA) treatment and following the stimulation with Mycobacteria bovis BCG, PKC-specific activity increased significantly in membrane fractions of both B10R and B10S cells, but the absolute level was significantly greater in particulate fractions from B10R macrophages. Furthermore, B10R cells had a superior ability to phosphorylate endogenous substrates compared to B10S macrophages. Scatchard analysis of phorbol ester receptors revealed no differences between B10R and B10S cells. In contrast, the sensitivity of partially purified PKC from B10S cells to activation in vitro by diacylglycerol was decreased by approximately 50% when compared to enzyme from B10R cells. Western-blotting analysis using antibodies specific for PKC isoforms (alpha, beta, delta, epsilon, zeta and eta) showed similar levels of PKC isoforms present in B10R and B10S cells. To examine whether differences in PKC activity of B10R and B10S cells had functional consequences, the induction of c-fos gene expression was compared in the two cell lines. In response either to infection with M. bovis BCG or to stimulation with PMA, c-fos mRNA levels in B10R macrophages were increased 2-4-fold in comparison to B10S macrophages. Since we have previously found that the bacteriostatic activity of B10R and B10S macrophages correlated with the amount of nitric oxide produced by the macrophages, we have tested if the enhancement of PKC activity in these macrophages affects their ability to produce nitric oxide. We have found that interferon-gamma-(IFNgamma)-induced secretion of nitric oxide by B10R macrophages could be augmented a few fold by the activation of PKC whereas, in B10S macrophages stimulated with IFNgamma, nitric oxide release could be augmented by only about 10-20%. These results indicate that the differences in PKC activity between B10R and B10S macrophages may contribute to altered responsiveness to IFNgamma that results in different production of effector molecules crucial for bacteriostatic activity against M. bovis BCG.
Animals↗
Safety and efficacy of living BCG or BCG cell walls (CW) in the treatment of guinea pig hepatoma.
Guinea pigs with established intradermal tumors and microscopic lymph node metastases were treated by intralesional injection of graded doses of living BCG or BCG CW. The lowest dose of living BCG used produced a significant cure rate and no grossly evident toxicity. An intermediate and the highest dose of living BCG used cured some animals but others lost weight and a significant number died as a result of the treatment. Histologic examination of animals with significant weight loss showed fatty degeneration of the liver, granulomatous hepatitis and histiocytic infiltration of the spleen. None of the doses of BCG CW used was toxic and they were at least as effective as living BCG in intralesional treatment. In some experiments in which treatment was delayed it was found that the extent of disease required to render treatment ineffective was about the same for living BCG and for BCG CW.
Animals↗
Effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: the BCG-REVAC cluster-randomised trial.
BACKGROUND: Many countries offer a second BCG vaccination to prevent tuberculosis, although there is little evidence of whether this confers additional protection. BCG vaccination is routine in Brazil but BCG revaccination procedures vary by state. We studied revaccination efficacy in two Brazilian cities with tuberculosis prevalence representative of Brazil. METHODS: We did a cluster-randomised trial of the protection against tuberculosis from BCG revaccination in school-aged children who had had one BCG vaccination as infants. 767 schools in the cities of Salvador and Manaus, Brazil, participated; schools were the unit of randomisation. The study was open label with no placebo. Cases of tuberculosis were identified through record linkage to the Tuberculosis Control Programme. Revaccination status was masked during linkage and validation of cases. The incidence of tuberculosis was the primary outcome. Analysis was by intention to treat. FINDINGS: 386 schools (176,846 children) were assigned BCG revaccination and 365 (171,293 children) no revaccination. 42,053 children in the vaccine group and 47,006 in the control group were absent from school on the day of the visit and were excluded. 31,163 and 27,146, respectively were also excluded because they had no BCG scar, two or more scars, or a doubtful scar on assessment. The crude incidence of tuberculosis in the intervention group was 29.3 per 100,000 person years and in the control group 30.2 per 100,000 person-years (crude-rate ratio 0.97; 95% CI 0.76-1.28). The efficacy of BCG revaccination was 9% (-16 to 29%). INTERPRETATION: Revaccination given to children aged 7-14 years in this setting does not provide substantial additional protection and should not be recommended. Follow-up is ongoing and needed to assess the effect of other factors on revaccination efficacy: time since vaccination, age at vaccination, and high or low prevalence of environmental mycobacteria.
Adolescent↗
Alternating mitomycin C and BCG instillations versus BCG alone in treatment of carcinoma in situ of the urinary bladder: a nordic study.
OBJECTIVES: To evaluate whether, in patients with carcinoma in situ (CIS) of the urinary bladder, alternating instillation therapy with mitomycin C (MMC) and bacillus Calmette-Guerin (BCG) was more effective and less toxic than conventional BCG monotherapy. METHODS: Patients were stratified prospectively for primary, secondary, and concomitant CIS and randomized to one of two regimens. Patients in the alternating group received six weekly intravesical instillations of MMC 40 mg, followed by alternating monthly instillations of BCG 120 mg and MMC for one year. In the monotherapy group, only BCG was instilled on the same schedule. RESULTS: Of 323 enrolled patients, 304 were eligible for analysis. After an overall median follow-up of 56 months, the Kaplan-Meier disease-free estimate for BCG monotherapy was significantly better than that for alternating therapy (p=0.03; log rank test). Risk for progression appeared lower in the BCG monotherapy group (p=0.07), but no differences existed in survival. Besides the regimen, CIS category also predicted outcome to some extent. BCG monotherapy caused significantly more local side-effects and premature cessation of instillation treatment than did the alternating therapy. However, no differences were observed in the number of serious side-effects. CONCLUSION: One-year BCG monotherapy was more effective than the alternating therapy for reducing recurrence and compared well with the best regimens reported from substantially smaller series. The alternating therapy was better tolerated.
Adjuvants, Immunologic↗
Mycobacterium bovis BCG-induced human T-cell clones from BCG-vaccinated healthy subjects: antigen specificity and lymphokine production.
A total of 121 human T-cell clones were raised from nine Mycobacterium bovis BCG-vaccinated healthy individuals. Three clones were autoreactive, 74 responded to BCG in the presence of antigen-presenting cells, and the others required in addition exogenous interleukin 2. Only one clone was CD8+ CD4-, and the rest were CD4+ CD8-. Testing with a panel of mycobacteria suggested that the clones were recognizing epitopes of varied specificity. Out of 44 clones tested, 15 were specific to BCG and Mycobacterium tuberculosis, 22 showed limited cross-reactivity, and 8 were broadly cross-reactive. None of the 22 BCG responder clones could differentiate between Danish, French, Prague, and Moreau strains of BCG. BCG and M. tuberculosis H37Rv also paralleled very closely; however, 6 of 18 BCG- and M. tuberculosis H37Rv-responding clones did not proliferate to Mycobacterium africanum. BCG- and M. tuberculosis H37Rv-specific as well as cross-reactive T-cell clones could be induced to produce interleukin 2, gamma interferon, and granulocyte-macrophage colony-stimulating factor activity.
BCG Vaccine↗
Protective immunization of monkeys with BCG or BCG plus heat-killed Mycobacterium leprae: clinical results.
Rhesus and sooty mangabey monkeys (RM and SMM) were vaccinated and boosted with BCG or BCG + low dose (LD) or high dose (HD) heat-killed Mycobacterium leprae (HKML). One group was not vaccinated. Except for a group of controls, all monkeys were challenged with live M. leprae. All animals were studied longitudinally to determine antileprosy protective efficacy. BCG reduced the numbers of RM with histopathologically-diagnosed leprosy by 70% and slowed and ameliorated the appearance of symptoms. BCG + LDHKML reduced the number of RM with leprosy by 89% and BCG + HDHKML by 78%. BCG did not protect SMM from developing leprosy, but disease progress was slowed; disease in SMM was exacerbated by the addition of HKML to the vaccine. RM, as a species, are prone to paucibacillary (PB) forms of leprosy, whereas SMM are prone to multibacillary (MB) forms. Thus, BCG vaccination offers significant protection from clinical disease and slows/ameliorates the rate of progression/degree of disease at the PB end and appears to at least ameliorate symptoms at the MB end of the leprosy spectrum. BCG + HKML protects at the PB end and exacerbates disease progress at the MB end of the leprosy spectrum.
Animals↗
[Nonspecific immune stimulation with BCG in Herpes simplex recidivans. Follow-up 5 to 10 years after BCG vaccination].
The efficacy of a single intracutaneous BCG injection in prevention of recurrent herpes simplex (HS) was investigated in Tine-test-negative people. Most patients had a recurrence rate of HS of at least once per month. Between 1976 and 1983 109 patients were BCG-vaccinated (BCG sec Berna). Tine-test was negative in all subjects and converted to positive in 106 out of 109 patients after vaccination. Patients suffered from HS for many years and thus acted as their own controls comparing them before and after BCG. After vaccination all patients remained herpes-free for at least 4-6 months. In a separate study a follow-up up to 10 years was done. This showed a decreasing effect of BCG over the years with still 21 (19%) completely herpes-free patients after 3 years. 10 patients (9%) even had been free of herpes for more than 6 years. Reduction of frequency and duration of HS after BCG was statistically significant (p less than 0.01). Since the BCG vaccination can be assumed to be virtually without risk, a Tine-test followed by BCG vaccination should be considered as treatment of choice in patients with recurrent HS for prevention of recurrences.
Adolescent↗
[Comparative evaluation of the effectiveness of vaccination of newborn infants with BCG and BCG-M vaccines].
A comparative effectiveness of the newborn BCG- and BCG-M vaccination was analysed as to the indices of primary infection, morbidity and its structure. The rate of postvaccination complications in 1,645,360 children, aged under 3 years, and living in the areas with different epidemiological situations for tuberculosis was studied too. 2,142,292 and 799486 healthy newborns were BCG- and BCG-M-vaccinated, respectively. The studies were carried out in Moscow, Kiev, Vilnius++ and Tashkent. The obtained results indicate that the number of complications in the form of regional lymphadenitis induced by BCG-M vaccine is 5 times less frequent than those caused by BCG. Under favourable epidemiological conditions, the primary infection and morbidity are alike, while under unfavourable ones the former is higher, particularly in infants in their first year as compared to the BCG-vaccinated. On the basis of the available data BCG-M can be recommended for the vaccination of all the newborns living in the areas with a favourable epidemiological situation for tuberculosis, thus increasing the newborn vaccination coverage and bringing the morbidity down.
BCG Vaccine↗
[Possible applications of living BCG and the BCG cell wall in immunotherapy].
BCG, Bacillus Calmette-Guerin, has an immunostimulant capacity and antitumor activity against both experimental and human tumors. Its mechanism of action has not yet been well clarified; maybe it involves one or more immune cell populations: in fact BCG has been reported to loose its activity in immunosuppressed animals. A limiting factor for systemic use of living BCG is its high toxicity: therefore BCG-derivatives have been introduced in both the experimental and the clinical fields. For experimental use one of the most interesting of these products is BCG-cell wall: when used in laboratory animals it demonstrated an efficient dose-dependent antitumor activity and lack of toxicity. On the contrary living BCG was notably toxic and ineffective when used in high doses. An interesting approach in antineoplastic therapy is the use of BCG with tumor cells as a vaccine against micrometastases remaining after surgery, chemotherapy or radiotherapy. A vaccine containing BCG-cell wall and tumor cells (either living or x-irradiated) gave very encouraging experimental results for a possible clinical use in the treatment of tumor metastases.
BCG Vaccine↗
Studies on the morphology of colonies of bacilli of BCG-Poland substrain. I. The influence of iron on the type of BCG-Poland colonies.
The influence of iron concentration in Sauton's medium solidified with agar on the type of colonies of BCG-Poland substrains, BCG-Rio de Janeiro, BCG-France, BCG-Denmark and BCG-Japan substrains has been examined. Of all the studied BCG substrains only the BCG-Poland substrain formed rough (R) and smooth (S) colonies. In the investigated substrains rough colonies became smaller with the decrease of iron concentration but they retained their characteristic surface roughness. The smooth colonies which in the same conditions appeared only in BCG-Poland substrain did not display such dependency on iron concentration. When the incubation period was prolonged secondary rough colonies appeared among the smooth ones, regardless of the iron concentration in the medium.
BCG Vaccine↗
Effects of isoniazid (INH) on the BCG-induced local immune response after intravesical BCG therapy for superficial bladder cancer.
Because recent investigations showed that the use of isoniazid (INH) severely impaired the local immune reaction to intravesical bacillus Calmette-Guérin (BCG) in the bladder of guinea pigs, in this study the effect of INH in man has been investigated. Patients were treated with BCG with or without oral INH. The concentration of free INH in most urine samples of patients treated with BCG/INH was much higher (mean 38.0 +/- 60.9 micrograms INH/ml) than the minimal inhibitory concentration (MIC; 0.1 microgram INH/ml), suggesting at least a bacteriostatic potential of the INH present. However, in vitro studies showed that these urinary concentrations of INH did not kill BCG organisms effectively, even at a concentration of 150 micrograms/ml for 24 h. After the fifth and sixth BCG instillations a significant increase in the concentration of cytokines (IL2, IL6, IL8 and TNFa), IgG and IgA antibodies to BCG and the number of leukocytes in urine was observed. The leukocytes mainly consisted of granulocytes, besides monocytes/macrophages and, in lower amounts, T- and B-lymphocytes and natural killer (NK) cells. The absolute number of granulocytes and the concentration of IgG antibodies after BCG instillation were significantly suppressed by INH, whereas INH appeared to have no effect on the urinary cytokine and IgA antibody concentrations or the total number and phenotype of the leukocytes present. In conclusion, the results of this study indicate that INH does not impair the local immunological stimulation after BCG instillation in man as severely as was observed in the guinea pig and it may be expected that INH does not impair the antitumor efficacy of BCG.
Administration, Intravesical↗
Clinical experience with BCG alone versus BCG plus epirubicin.
BACKGROUND: Bacillus Calmette-Guérin (BCG) and epirubicin have both been shown to be effective in the treatment of superficial bladder cancer. We studied whether the alternating combination of these agents could improve the efficacy with tolerable side-effects in the treatment of high-risk superficial bladder tumors. METHODS: Forty-one patients with high-risk superficial bladder transitional carcinoma were included in this study. Twenty-one patients were randomized into the BCG group and 20 patients were treated with sequential BCG and epirubicin. The patients were followed for 9-24 months (mean 18 months). Recurrence rates, median time to the first recurrence, progression rate and complications were compared. RESULTS: Fifteen percent of the patients in the BCG and epirubicin group and 19% of the patients in the BCG alone group developed tumor recurrence. Tumor progression was observed in 4.7% and 10% in the BCG/epirubicin group and the BCG alone group, respectively. Median time to first recurrence was 11 months for the BCG/epirubicin group and 16 months for the BCG group (P > 0.05). Three patients in the BCG/epirubicin treatment group developed serious side-effects, which necessitated antituberculosis treatment. CONCLUSION: Because the efficacy of combination was no better than the standard treatment and the alternating combination seemed to be related to a higher incidence of side-effects, this study albeit small, does not recommend combination therapy of BCG and epirubicin in high risk patients with superficial bladder cancer.
Antibiotics, Antineoplastic↗
Induction of alpha and beta interferons during the hyporeactive state of gamma interferon by Mycobacterium bovis BCG cell wall fraction in Mycobacterium bovis BCG-sensitized mice.
Characterization of interferon (IFN) induced by a second challenge with specific antigen was investigated during the development of hyporeactivity established after challenge of Mycobacterium bovis BCG-sensitized mice with BCG cell wall fraction (BCG-CW). When BCG-sensitized mice were challenged with BCG-CW, IFN-gamma was detected in the circulation 4 h later and rapidly disappeared. After IFN-gamma disappeared from their blood, mice became completely hyporeactive to the second challenge with BCG-CW for 1 day, and thereafter they recovered from this hyporeactive state. However, we always observed that IFN induced at first by the second challenge with BCG-CW during the hyporeactive state was type I IFN-alpha/beta, but thereafter was entirely IFN-gamma. Induction of IFN-alpha/beta by the specific antigen during restoration from the hyporeactive state in BCG-sensitized mice is discussed.
Animals↗
Possible mechanism of the preventive effect of BCG against diabetes mellitus in NOD mouse. I. Generation of suppressor macrophages in spleen cells of BCG-vaccinated mice.
With the aim of clarifying the mechanism of the suppressive action of BCG against insulitis and overt diabetes in NOD mice, we studied the effects of BCG on spleen cell populations and on the in vitro immune responses of spleen cells. The spleen cells of BCG-vaccinated mice showed much lower responsiveness to various mitogens such as Con A, PHA, PWM, and LPS than those of saline-treated mice. Low responsiveness to alloantigens was also observed. Flow cytometric analysis of the spleen cells revealed that Mac-1+ and Mac-2+ cells had increased while T and B cells had decreased in the BCG-vaccinated mice compared with the saline-treated mice at the time when the maximum level of inhibition of mitogen responses of BCG-vaccinated mice was observed. This suggests that the decreased in vitro immune response was due to the increase in macrophages which suppress lymphocyte functions. Support for this interpretation comes from the following two findings: (1) the restoration of mitogen responses of spleen cells when macrophages were eliminated by plastic adhesion or FACS sorting and (2) resuppression of PHA and Con A responses of plastic-nonadherent spleen cells by addition of adherent cells or flow cytometrically sorted Mac-1+ cells obtained from BCG-vaccinated mice. These results indicate the generation of suppressor macrophages after BCG vaccination and suggest that these macrophages prevent the autoimmune pathogenesis leading to diabetes in NOD mice.
Animals↗
Role of Th1 and Th2 cytokines in BCG-induced IFN-gamma production: cytokine promotion and simulation of BCG effect.
Induction of a T-helper-type 1 (Th1) immune response is indispensable for successful treatment of superficial bladder cancer with BCG. In this study possible involvement of various cytokines in BCG action as well as their potential roles in enhancing and mimicking BCG effect were explored. In immunocompetent cell cultures, IFN-gamma, a major Th1 cytokine, appears to be a late responsive cytokine to BCG stimulation. Its induction requires involvement of various endogenously produced Th1 and Th2 cytokines. Functional abolishment of any one of these cytokines (IL-2, IL-6, IL-12, IL-18, GMCSF, TNF-alpha, or IFN-alpha, except IL-10) by neutralizing antibodies leads to reduced IFN-gamma production (19-82% inhibition in mouse and 44-77% inhibition in human systems, respectively). In mice cytokines IL-2, IL-12, IL-18, and GMCSF are observed to synergize with BCG for IFN-gamma production, whereas in human cytokines IL-2, IL-12, TNF-alpha, and IFN-alpha exhibit similar synergistic effects. Rational combinations of these Th1-stimulating cytokines (IL-12 plus IL-18 in mice and IL-2 plus IL-12 in humans, respectively) dramatically up-regulate IFN-gamma production that is incomparably superior to BCG for induction of this cytokine. These results suggest that combined Th1-stimulating cytokines and combinations of BCG plus selected Th1-stimulating cytokines are rational candidates for further study in the treatment of bladder cancer patients.
Adjuvants, Immunologic↗
Distant metastasis facilitated by BCG: spread of tumour cells injected in the BCG-primed site.
Tumour metastasis in BCG-pretreated mice was studied using a methylcholanthrene-induced fibrosarcoma in C3H/He mice. When tumour cells were injected into the BCG-primed site, distant metastasis occurred in the lungs and the popliteal lymph node, through this tumour did not metastasize in normal mice. Such metastases were increased in proportion to the number of tumour cells injected into the BCG-primed site, and developed soon after tumour challenge. Concomitant immunity developed well in the mice bearing such metastases, but did not inhibit metastatic growth. Experiments using 125I-labelled SRBC or tumour cells revealed that such cells egressed rapidly from the BCG-primed site. When the tumour was inoculated into the contralateral foot to the BCG-primed site, the incidence and the number of metastases was reduced. Furthermore, BCG infection induced an increase of platelet count. I.v. injection of this tumour induced marked thrombocytopenia in normal mice. Administration of pentoxifylline, a methylxanthine derivative before tumour challenge reduced such metastases. These findings suggest that the changes in peripheral blood, such as increased platelet count and increased release of tumour cells from the injection site, facilitated distant metastasis in BCG-pretreated mice.
Animals↗