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Background: Bacille Calmette-Guérin (BCG) vaccination can potentially reduce the rate of respiratory infections in vulnerable populations. This study evaluates the safety and efficacy of VPM1002 (a genetically modified BCG) as prophylaxis against severe respiratory tract infections including coronavirus disease 2019 (COVID-19) in an elderly population., Methods: In this phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trial, healthy elderly volunteers (N = 2064) were enrolled, randomized (1:1) to receive either VPM1002 or placebo, and followed up remotely for 240 days. The primary outcome was the mean number of days with severe respiratory infections at hospital and/or at home. Secondary endpoints included the incidence of self-reported fever, number of hospital and intensive care unit (ICU) admissions, and number of adverse events., Results: A total of 31 participants in the VPM1002 group reported at least 1 day with severe respiratory disease and a mean number of days with severe respiratory disease of 9.39 ± 9.28 while in the placebo group; 38 participants reported a mean of 14.29 ± 16.25 days with severe respiratory disease. The incidence of self-reported fever was lower in the VPM1002 group (odds ratio, 0.46 [95% confidence interval, .28-.74]; P = .001), and consistent trends to fewer hospitalization and ICU admissions due to COVID-19 were observed after VPM1002 vaccination. Local reactions typical for BCG were observed in the VPM1002-vaccinated group, which were mostly of mild intensity., Conclusions: Vaccination with VPM1002 is well tolerated and seems to have a prophylactic effect against severe respiratory disease in the elderly., Clinical Trials Registration: NCT04435379., Competing Interests: Potential conflicts of interest. H. S. and U. S. are employed by SIIPL, which manufactures VPM1002. L. G., A. M. B., S. B., M. M., and G. P. P. are employed by VPM, which developed the vaccine. S. H. E. K. and L. G. are coinventors and named patent holders for VPM1002, which is licensed to Vakzine Projekt Management, Hannover, Germany, and sublicensed to Serum Institute of India Pvt Ltd. S. H. E. K. is also coholder of a patent licensed to Serum Institute of India Pvt Ltd; reports consulting fees (honorarium) from Memo Therapeutics AG, Switzerland, LTS Lohmann Therapie-Systeme AG, Germany, kENUP Foundation, Malta, and TUI AG, Germany; honorarium from IPSEN for speaker activities (information event for IPSEN employees) and from Gilead for speaker activity; and a role as Chair of Board for Schering Foundation. S. B. reports royalties or licenses related to a patent planned issued or pending (TB vaccine VPM1002) as an employee of VPM, the patent holder. M. G. N. is a scientific founder of TTxD and Lemba. M. G. N. also reports unrestricted research grants from GSK, ViiV Healthcare, Ono Pharma, and TTxD, all awarded to institution; patents for nanobiologics inducing or inhibiting trained immunity; participation on a scientific advisory board for TTxD; and stock in TTxD. G. P. P. reports royalties or licences and patents planned, issued, or pending for TB vaccine VPM1002, as an employee of VPM, the patent holder. H. S. reports license held by Serum Institute of India Pvt Ltd. L. G. reports royalties or licences and patents planned, issued, or pending related to employment with VPM, the patent holder of TB vaccine VPM1002. C. S. reports participation in the blinded part of the data and safety monitoring board as principal investigator of the present trial (no advisory board). All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Bovine ocular squamous cell carcinoma (BOSCC) also called cancer eye, represents the most economically important neoplasm in large animals. Hereditary factors, environmental factors, lack of eyelid pigmentation, age and dietary habits have all been reported to play a role in the etiopathogenesis of bovine ocular squamous cell carcinoma. In group I, six animals with small, localized eye cancer where vision was not affected were included and subjected to intralesional injection of Bacillus Calmette- Guerin (BCG) vaccine at 0, 14, 35, and 56 days interval. In group II (six animals), surgical excision and Mitomycin C 0.04% topically on alternate weeks for two months as adjunctive therapy. All the animals recovered completely with no recurrence for a follow up period of one year., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: This case study describes a multidisciplinary initiative to promote the safe use, preparation, and administration of bacillus Calmette-Guérin (BCG) in patients with bladder cancer that is in compliance with United States Pharmacopeia chapter 800., Summary: After an evaluation of a hospital's medication-use process for the preparation and administration of BCG identified inconsistencies with guideline-based procedures for the safe handling and manipulation of hazardous drug products, a revised medication-use process promoting the inclusion of pharmacy services was developed by pharmacy and urology clinic leaders. Implementation of the enhanced medication-use process included (1) the shift of BCG vaccine preparation from urology clinic nurses to a pharmacy equipped with the appropriate engineering controls for the safe preparation of hazardous product, (2) greater involvement by pharmacists in BCG order justification and verification, and (3) a process that ensured just-in-time preparation and delivery of medication for enhanced patient satisfaction. After initial process changes resulted in increased turnaround time from preparation to administration, a study on time to preparation, delivery, and administration was conducted and resulted in complete reduction of turnaround times and increased patient satisfaction., Conclusion: Through a multidisciplinary initiative involving pharmacists, physicians, nurses, and leadership, a new process to promote the safe preparation and administration of the tuberculosis vaccine Mycobacterium bovis BCG was developed and implemented. The results of a post-implementation time study indicated that a standardized approach to scheduling, preparing, and administering BCG was effective in managing the operations of BCG through having high clinic and patient satisfaction., (© American Society of Health-System Pharmacists 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A global BCG vaccine shortage began in 2013 which impacted availability for infant vaccinations, as well as preclinical studies and clinical trials of new TB vaccines. Stakeholders met in 2015 at McGill University in Montreal to discuss the shortage and potential mitigation strategies. Manufacturing BCG through a more tractable liquid fermentation process instead of the traditional pellicle growth method was considered a potentially viable strategy. This pilot program compared pellicle-grown and shake flask-grown BCG strains (as a first step towards modeling fermenter-produced BCG vaccine) in selected quality control assays, as well as mouse and guinea pig protection studies. Conventional pellicle-grown, lyophilized BCG WHO Reference Reagents (Danish, Moreau, Russian, Tokyo strains) were obtained from the National Institute for Biological Standards and Control (NIBSC), UK. Strains were grown in shake flasks and glycerol stocks prepared. Shake flask-grown BCG culture preparations generally met the requirements of quality control testing at NIBSC. In mouse and guinea pig protection studies there were no significant differences in lung colony forming units (CFUs) between shake flask-grown and pellicle-grown preparations, with the exception of BCG Russian, where the shake flask-grown preparation protected better in mice (P = 0.0042), but the pellicle-grown preparation protected better in guinea pigs (P = 0.0015). Producing BCG vaccines by a more tractable liquid growth process could be a viable solution to the global BCG shortage., (Copyright © 2018. Published by Elsevier Ltd.)

The S1602 Intergroup trial is a randomized phase III clinical trial that aims to test two important hypotheses: (1) priming with intradermal bacillus Calmette-Guérin (BCG) vaccine prior to standard intravesical BCG improves response to BCG in terms of recurrence-free survival and (2) Tokyo-172 BCG strain is non-inferior to TICE BCG in terms of time to high-grade recurrence. The study was approved by the Cancer Therapy Evaluation Program of the National Cancer Institute and activated in spring 2017. Here, we provide a synopsis of the study background, design, and update of the clinical trial., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: Bacille Calmette-Guérin (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 delayed BCG, the manufacturer of the BCG vaccine experienced a period with relatively slow growth rate of the BCG. We investigated the association between growth rate of BCG when manufacturing the vaccine and its capability to induce immune responses in vivo and in vitro., Methods: 1633 neonates were randomised to BCG at birth and examined for scar at 12 months; a subgroup was tested for PPD response at 2 and 6 months. The BCG batches from the Slow growth period were compared with the precedent and subsequent Normal growth batches with regard to prevalence and size of BCG scar and PPD response. We also tested the effect of batches on in vitro cytokine responses., Results: At 12 months, the Slow growth batches were associated with higher BCG scar prevalence (98.2%) than the precedent batches (92.3%, p=0.01) but the prevalence remained high after return to normal growth (98.8%, p=0.52). The Slow growth batches were associated with larger scar size (5.0mm) than precedent (4.4mm, p<0.01) and subsequent batches (4.8mm, p=0.03). Compared with Normal growth batches, the Slow growth batches were associated with a higher prevalence of positive PPD responses, and among PPD positive children, a larger PPD reaction (geometric mean ratio: 1.40 (1.20-1.63)) at 2 months. In response to secondary heterologous stimulation, monocytes primed with Slow growth batches induced higher IL-6 (p=0.03) and TNF-α responses (p=0.03) compared with Normal growth batches., Conclusion: The study indicates that variations in the production of BCG vaccine may influence important immunological effects of the vaccine., Trial Registration: clinicaltrials.gov (NCT00625482)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

As the latest addition to the sub-strain specific WHO Reference Reagents of BCG vaccine, an international collaborative study was completed to evaluate the suitability of a candidate BCG Moreau-RJ sub-strain as a WHO Reference Reagent of BCG vaccine. This follows the recent replacement of the WHO 1st International Reference Preparation for BCG vaccine, by three sub-strain specific WHO Reference Reagents of BCG vaccine (Danish 1331, Tokyo 172-1 and Russian BCG-I) in order to complete the coverage of most predominant sub-strains used for BCG vaccine production and distribution for use worldwide. The study used cultural viable count and modified ATP assays to quantify the preparation and multiplex PCR to confirm the identity of the sub-strain. The establishment of this WHO Reference Reagent of BCG vaccine of Moreau-RJ sub-strain was approved by the WHO Expert Committee on Biological Standardization meeting in October 2012. This preparation is available for distribution by NIBSC-MHRA, UK. The data from real-time stability monitoring demonstrated that these Reference Reagents of BCG vaccine are very stable in storage condition at -20°C. They serve as the valuable source of BCG Reference Reagents for use as comparators (1) for viability assays (such as cultural viable count and modified ATP assays); (2) for in vivo assays (such as the absence of virulent mycobacteria, dermal reactivity and protection assays) in the evaluation of candidate TB vaccines in non-clinical models; (3) for identity assays using molecular biology techniques., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Vaccination of badgers by the subcutaneous, mucosal and oral routes with the Pasteur strain of Mycobacterium bovis bacille Calmette-Guérin (BCG) has resulted in significant protection against experimental infection with virulent M. bovis. However, as the BCG Danish strain is the only commercially licensed BCG vaccine for use in humans in the European Union it is the vaccine of choice for delivery to badger populations. As all oral vaccination studies in badgers were previously conducted using the BCG Pasteur strain, this study compared protection in badgers following oral vaccination with the Pasteur and the Danish strains. Groups of badgers were vaccinated orally with 10(8) colony forming units (CFU) BCG Danish 1331 (n = 7 badgers) or 10(8) CFU BCG Pasteur 1173P2 (n = 6). Another group (n = 8) served as non-vaccinated controls. At 12 weeks post-vaccination, the animals were challenged by the endobronchial route with 6 × 10(3) CFU M. bovis, and at 15 weeks post-infection, all of the badgers were euthanased. Vaccination with either BCG strain provided protection against challenge compared with controls. The vaccinated badgers had significantly fewer sites with gross pathology and significantly lower gross pathological severity scores, fewer sites with histological lesions and fewer sites of infection, significantly lower bacterial counts in the thoracic lymph node, and lower bacterial counts in the lungs than the control group. No differences were observed between either of the vaccine groups by any of the pathology and bacteriology measures. The ELISPOT analysis, measuring production of badger interferon - gamma (IFN-γ), was also similar across the vaccinated groups., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The current World Health Organization Requirements for BCG vaccine are in need of revision to address the diversity of sub-strains used for production, potential improvements of quality control assays for lot release, and the establishment of sub-strain specific Reference Reagents. A consultation meeting was organized to discuss issues regarding the standardization and evaluation of BCG vaccines in the forum of regulators, BCG vaccine manufacturers, developers of selected new live tuberculosis (TB) vaccines and researchers. The development of new recombinant BCG and live attenuated TB vaccines and the characterisation of different BCG sub-strains using state-of-the-art technologies were also reviewed. The objective of the meeting was to revise and update the current recommendations focused on the scope, terminology, manufacturing issues, and the incorporation of new reference reagents and new quality control tests., (Copyright © 2010. Published by Elsevier Ltd.. All rights reserved.)

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.

Background: The inverse correlation of mycobacterial infection with asthma prevalence and the inhibitory effects of vaccination with Bacille Calmette-Guérin (BCG) on airway hyperreactivity in asthma models suggest modulation of dendritic cell (DC) and T cell functions by mycobacterial compounds., Methods: To delineate these immunological effects, the immunogenicity of BCG Copenhagen, BCG Chicago and BCG Pasteur was compared in a mouse model. Bone marrow-derived dendritic cells (BMDCs) from BALB/c mice were stimulated with ovalbumin (OVA) with or without BCG. BMDCs were phenotypically characterized by flow cytometry, and we used ELISA to measure the cytokine production of BMDCs as well as of co-cultivated allergen-specific T cells in response to OVA-pulsed. Immunomodulatory effects of BCG were studied in a model of allergic airway inflammation by adoptive transfer of allergen-pulsed BMDCs., Results: Immunomodulation with BCG induced production of IL-10 and IL-12 by BMDCs. Co-cultured allergen-specific T cells produced less IL-5, IL-13 and IFN-gamma but more IL-10. Also the number of FoxP3(+) regulatory T cells was enhanced. Strongest effects were seen with BCG Chicago and BCG Pasteur. In vivo, administration of BCG modulated OVA-pulsed BMDCs then reduced eosinophilic airway inflammation but enhanced infiltration with granulocytes. Airway hyperreactivity and mucus production were reduced and more FoxP3(+) T cells were observed., Conclusion: BCG-induced suppression of Th2-type allergic airway inflammation was associated with enhancement of regulatory T cell function but also of Th1-associated neutrophilic airway inflammation. These findings raise concerns regarding the safety profile of BCG as a potential tool for prevention and therapy of allergic airway disease., (Copyright 2009 S. Karger AG, Basel.)

Background: One strategy for improving anti-tuberculosis (TB) vaccination involves the use of recombinant bacille Calmette-Guérin (rBCG) overexpressing protective TB antigens. rBCG30, which overexpresses the Mycobacterium tuberculosis secreted antigen Ag85b, was the first rBCG shown to induce significantly greater protection against TB in animals than parental BCG., Methods: We report here the first double-blind phase 1 trial of rBCG30 in 35 adults randomized to receive either rBCG30 or parental Tice BCG intradermally. Clinical reactogenicity was assessed, and state-of-the-art immunological assays were used to study Ag85b-specific immune responses induced by both vaccines., Results: Similar clinical reactogenicity occurred with both vaccines. rBCG30 induced significantly increased Ag85b-specific T cell lymphoproliferation, interferon (IFN)-gamma secretion, IFN-gamma enzyme-linked immunospot responses, and direct ex vivo intracellular IFN-gamma responses. Additional flow cytometry studies measuring carboxyfluorescein succinimidyl ester dilution and intracellular cytokine production demonstrated that rBCG30 significantly enhanced the population of Ag85b-specific CD4(+) and CD8(+) T cells capable of concurrent expansion and effector function. More importantly, rBCG30 significantly increased the number of Ag85b-specific T cells capable of inhibiting intracellular mycobacteria., Conclusions: These results provide proof of principal that rBCG can safely enhance human TB immunity and support further development of rBCG overexpressing Ag85b for TB vaccination.

Using the example of the anti-tuberculosis vaccine BCG during the 1920s and 1930s, this article asks how a labile laboratory-modified bacteria was transformed into a genuine standard vaccine packaged and commercialized as a pharmaceutical product. At the center of the analysis lies the notion of standardization inquiring why and how a local laboratory process with standard operating procedures (SOPs) reached its limits and was transformed when the product faced international distribution. Moving from Paul Ehrlich's initial technological notion of Wertbestimmung referring to a practice physiologically testing the effects of ill-defined antitoxins, the concept of standardization is extended to pharmaceutical and economical meanings implying quality control for biological therapeutic agents produced by a variety of industrial entrepreneurs. Following the request for product uniformity, two ways to maintain levels of compatibility and commonality are depicted opposing SOPs and end-product control. Furthermore, standardization is understood as a spiral, never ending process where progressive transformation of the vaccine in its production and medical uses periodically recreated the necessity of standardization. Developments analyzed are thus understood as a stabilization process aligning laboratory settings, products, and practices with medical theories and practices through technical, bureaucratic, and organizational systems. A paradox of the analysis is that standardization as a historical phenomenon and moment in the history of drug development was initially linked to a problem of under-determination of what was to be standardized and to a knowledge gap before it could become a central concept for quality control.

Bacillus Calmette and Guérin (BCG) was introduced to Japan in 1924 by Kiyoshi Shiga and has been propagated for research purposes ever since propagation is accomplished using a glycerin-bile-potato mixture in the same manner used by Calmette and Guérin. To prepare a stable and safe freeze-dried BCG vaccine, several joint research projects were organized in 1949. At the National Institute of Infectious Diseases (formerly the National Institute of Health), the 172nd passage of BCG from the first culture was freeze-dried in 1961 and was used as the origin of the Japanese BCG strain, Tokyo-172. The Tokyo-172 was registered as an International Reference Strain in 1965 by the World Health Organization. In 1967, a multiple puncture method for BCG vaccination using a plastic cylinder implanted with nine fine needles at one end was introduced to Japan; thereafter, percutaneous administration replaced intradermal injection. The efficacy and adverse reactions of BCG vaccines as well as recent knowledge on the genetic characterization of BCG is also discussed.

Meta-analyses of clinical trials are increasingly seeking to go beyond estimating the effect of a treatment and may also aim to investigate the effect of other covariates and how they alter treatment effectiveness. This requires the estimation of treatment-covariate interactions. Meta-regression can be used to estimate such interactions using published data, but it is known to lack statistical power, and is prone to bias.The use of individual patient data can improve estimation of such interactions, among other benefits, but it can be difficult and time-consuming to collect and analyse. This paper derives, under certain conditions, the power of meta-regression and IPD methods to detect treatment-covariate interactions. These power formulae are shown to depend on heterogeneity in the covariate distributions across studies. This allows the derivation of simple tests, based on heterogeneity statistics, for comparing the statistical power of the analysis methods., (Copyright 2006 John Wiley & Sons, Ltd.)

Background: The study was undertaken to estimate the effectiveness of BCG vaccination in relation to scar size in the prevention of tuberculosis and leprosy., Methods: The present study was designed as hospital-based pair-matched case-control study and was carried out at Government Medical College Hospital, Nagpur, Maharashtra, India. It included 877 cases of tuberculosis and 292 cases of leprosy (diagnosed by WHO criteria), born onwards 1962. Each case was pair-matched with one control for age, sex and socio-economic status. BCG vaccination status was assessed by examination for the presence of BCG scar, immunisation records if available and information from subjects/parents of children. Subjects uncertain about BCG vaccination were not included. The diameter of the BCG scar was measured both across and along the arm in millimeters using a plastic ruler. The average was then calculated., Results: A significant protective association between BCG vaccination and tuberculosis (OR=0.38, 95% CI 0.31-0.47) and leprosy (OR = 0.38, 95% CI 0.26-0.55) was observed. The overall vaccine effectiveness (VE) was 62% (95% CI 53-69) against tuberculosis and 62% (95% CI 45- against leprosy. Vaccine effectiveness against tuberculosis and leprosy was non-significantly greater in the group who had BCG scar size < or =5 mm as compared to subjects who had BCG scar size > 5 mm. Thus there was no clear association between BCG scar size and its effectiveness., Conclusion: The current study did not identify any significant association between BCG scar size and its effectiveness against tuberculosis or leprosy.

BCG remains the only possible prophylactic intervention against Buruli ulcer (BU). Estimating its public health impact on BU control is an important issue. We conducted a case-control study to investigate the vaccine effectiveness of routine BCG vaccine against BU in southern Benin. From August 2002 to August 2003, BCG vaccination status was obtained for 279 clinically diagnosed BU cases and 988 age- and sex-matched neighborhood controls. BCG coverage, which was estimated by the presence of a scar or a vaccination record, was 64.5% in cases and 67.2% in controls. There was no evidence of a protective effect of routine BCG vaccination against BU in southern Benin (vaccine effectiveness adjusted for socioeconomic status = 12%, 95% confidence interval = -24% to 37%).

Objectives: To review the protective efficacy of the first and second doses of BCG vaccine and to assess its major indications and contraindications., Sources of Data: A systematic review of the literature was made by searching PubMed and selecting studies carried out in the last 50 years. The studies were grouped according to their design (clinical trials, case-control studies, and meta-analyses) and the results were presented separately for each type of study. Other relevant topics such as BCG and HIV/AIDS, use of tuberculin skin test, issues related to vaccine scars and to the development of new vaccines were also reviewed., Summary of the Findings: BCG vaccine has been used since 1921. However, the data concerning its use are variable and inconsistent. The protective efficacy of the first dose of BCG vaccine against miliary tuberculosis or tuberculous meningitis is remarkably important. Nevertheless, results regarding pulmonary tuberculosis have been inconsistent, either showing no efficacy or a protective efficacy rate around 80%. There is some evidence that a second dose of BCG vaccine does not increase its protective efficacy. Studies have shown that BCG vaccine protects against leprosy. The development of new vaccines to replace BCG in the future has been investigated., Conclusions: Despite the hope that a new vaccine against tuberculosis will be available in the future, BCG vaccine, in spite of its deficiencies, is today and will be for many years to come an important tool in controlling the harmful effects of tuberculosis, especially in countries where this disease has moderate to high levels of incidence.

Current global control efforts targeting tuberculosis (TB) include the treatment of latent TB infection, case detection and treatment with directly observed therapy short-course (DOTS), and BCG (bacille Calmette-Guérin) vaccination. However, BCG has been found to decrease only childhood TB morbidity and mortality but has a very limited effect in the transmission dynamics of the infection. These limitations of BCG are the driving force for the development of new TB vaccines. New TB vaccine candidates have entered clinical evaluation and many more are in the pipeline to undergo clinical testing. New vaccine candidates may offer better protection than that afforded by currently available BCG vaccines. Furthermore, combined vaccination schedules against TB seem to be a promising strategy in the new millennium.

Vaccination against bovine tuberculosis is likely to become an important disease control strategy in developing countries, which cannot afford a test and slaughter control programme, or in countries which have a wildlife reservoir of Mycobacterium bovis infection. In the past decade, considerable progress has been made in the development and evaluation of tuberculosis vaccines for cattle and for a range of wildlife maintenance hosts including possums, badgers, deer and African buffaloes. Experimental challenge systems have been established for the different target species and the resulting disease process has mimicked that seen in the field. In cattle, neonatal vaccination with BCG appeared to be more effective than vaccination of 6-month-old calves and in most situations no other vaccine has been shown to be better than BCG. However, prime-boost strategies involving combinations of BCG with a protein or DNA vaccine, to improve on BCG vaccination alone, have produced very encouraging results. Differential diagnostic tests have been developed using mycobacterial antigens that are only present in virulent M. bovis to differentiate between BCG-vaccinated and M. bovis-infected cattle. BCG vaccine has been shown to reduce the spread of tuberculous lesions in a range of wildlife species and a prototype oral bait delivery system has been developed. Prospects for the development of improved vaccines against bovine tuberculosis are promising and vaccination approaches could become very valuable in the control and eradication of bovine tuberculosis.

The development of a new and improved vaccine against tuberculosis has in the last 10 years been accelerated tremendously from the completed Mycobacterium tuberculosis genome and the progress in molecular biology. This has resulted in the identification of a large number of antigens with potential in tuberculosis vaccines. The next phase of this work has now started--putting the most relevant molecules back together as fusion molecules and cocktails. This requires carefully monitoring of aspects as immunodominance, recognition in different populations as well as the influence of different adjuvants and delivery systems. The most advanced of these vaccines such as the fusion between ESAT6 and Ag85B have been evaluated in a range of animal models including non-human primates and are now entering into clinical trials. For these vaccines to be successfully implemented in future vaccination programmes it is necessary to understand the immunological background for the failure of BCG and optimize the vaccines for their ability to boost the immuno-response primed by BCG.

The anti-tuberculosis BCG (Bacille Calmette-Guérin) vaccine was conceived and developed between 1905 and 1921 at Pasteur Institutes in France. Between 1921 and A. Calmette's death in 1933, the vaccine went through a first period of national and international production and distribution for its use in humans. In France these activities were exclusively carried out by Calmette and his collaborators at the Pasteur Institute in Paris. Initially improvised production in a small room in the cellar gave way in 1931 to the construction of the spacious and magnificent 'New laboratories for research on tuberculosis and the preparation of the BCG' within the premises of the Pasteur Institute. Presentation and image-building of the vaccine in France insisted on the fact that the BCG was not a commercial specialty but distributed free of charge. The technical monopoly of its production nevertheless lay with the Paris Pasteur Institute and standardization of scientific proof of safety, efficacy and stability was dominated by that Institute in France. In contrast, the international production and distribution of the vaccine was entrusted and transferred, free of charge, to trustworthy laboratories outside France. Multiplication of producers and users led to an increased need for standardization. For this process the analysis distinguishes between the standardization of scientific proof concerning safety, efficacy and stability of the vaccine and standardization of its medical uses. Whereas standardization was rather successful in the inter-war period in France, the international efforts remained rather unsuccessful. Only after world war II under Scandinavian leadership and in the context of mass vaccination programs supported by the WHO and UNICEF was the international standardization effectively implemented and succeeded at least to some extend.

This tutorial on advanced statistical methods for meta-analysis can be seen as a sequel to the recent Tutorial in Biostatistics on meta-analysis by Normand, which focused on elementary methods. Within the framework of the general linear mixed model using approximate likelihood, we discuss methods to analyse univariate as well as bivariate treatment effects in meta-analyses as well as meta-regression methods. Several extensions of the models are discussed, like exact likelihood, non-normal mixtures and multiple endpoints. We end with a discussion about the use of Bayesian methods in meta-analysis. All methods are illustrated by a meta-analysis concerning the efficacy of BCG vaccine against tuberculosis. All analyses that use approximate likelihood can be carried out by standard software. We demonstrate how the models can be fitted using SAS Proc Mixed., (Copyright 2002 John Wiley & Sons, Ltd.)

Based on the review of Polish and world literature on adverse reactions after BCG immunization--causes of complications and clinical management has been described.

Tuberculosis remains one of the top three infectious disease killers. Treatment is long and expensive and drug resistant strains of Mycobacterium tuberculosis are already on the rise. The current vaccine, BCG, is ineffective in parts of the world where the disease is most widespread and therefore the search for a novel, more effective vaccine is paramount. In this review we discuss the current state of vaccine research, including the identification of candidate antigens and the current methods used for their evaluation.

A more effective vaccine will be essential if the global tuberculosis (TB) pandemic is ever to be controlled. A large number of new tuberculosis vaccines have been developed, representing the whole range of modern strategies for vaccine formulation and delivery. There is currently no alternative to testing these new vaccines in experimental animals challenged with virulent Mycobacteriurn tuberculosis in order to assess their protective efficacy. Although such testing is being carried out in several animal species (mice, guinea pigs, rabbits), all rational models include pulmonary challenge with a low dose of virulent mycobacteria. The quantitative measures for TB vaccines include increased survival, amelioration of clinical signs and symptoms (e.g. prevention of weight loss), decreased lesion size, reduction in bacillary loads in the lungs, and prevention of extrapulmonary dissemination and hematogenous reseeding of the lung. Although the ultimate objective of vaccination in humans is to prevent transmission to susceptible contacts, no such measurement is being used in animal studies of new vaccines. The validation of an immunological "correlate of protection" is urgently needed. Candidates for such a correlate include antigen-specific interferon-gamma production by T cells of the memory phenotype (CD45RB(high) or mycobacterial killing by macrophages co-cultured with immune T cells. Additional animal models must be developed for vaccines designed to prevent endogenous reactivation or exogenous reinfection, or to be used as a adjunct to chemotherapy.

The development of novel vaccines for the prevention of tuberculosis is an area of intense interest for scientific researchers, public health agencies, and pharmaceutical manufacturers. Development of effective new vaccines directed against tuberculosis for use in target populations will require close cooperation among several different international organizations, including regulatory agencies responsible for evaluating the safety and effectiveness of new biologics for human use.

Attempts to eradicate tuberculosis from cattle and farmed deer in some countries have been frustrated by the existence of wildlife reservoirs of Mycobacterium bovis infection. Possum control programmes in New Zealand using poisons have shown clearly that the brushtail possum is an important source of infection for cattle and farmed deer, and the sum of evidence strongly suggests that badgers serve as a source of infection for cattle in the UK. Bovine tuberculosis can only be eradicated from these countries by controlling M. bovis infection in both wildlife and domestic animals. The most promising options for control of M. bovis infection in wildlife in the longer term include the development of a tuberculosis vaccine for wildlife and a strategy for biological control of possums. The aim of this review is to address the problems and approaches involved in the control of wildlife tuberculosis from an immunological perspective.

In order to validate two new lots of Mérieux BCG vaccine (Mérieux seed derived from strain 1072), a calibration study was performed to compare their safety and immunogenicity to a full dose of the WHO-reference BCG vaccine (Tokyo strain 172) as well as the WHO-reference vaccine given at 1/10 of its normal concentration, in an open, randomized, four-arm, multicenter study in Senegal. A total of 1041 healthy Senegalese children aged 8-10 years were screened for participation in this study, of whom 548 had a negative Mantoux test and complied with inclusion and exclusion criteria. These children were randomly allocated a single dose of one of the following vaccines: full-dose Mérieux BCG vaccine (lot E0650); full-dose Mérieux BCG vaccine (lot E0624); full-dose WHO-reference vaccine (Tokyo strain 172); or 1/10 dose WHO-reference vaccine. A follow-up examination, including a tuberculin test, was performed 10-12 weeks after BCG vaccination for 465 (85%) children: 236 Mérieux BCG vaccine (117 lot E0650; 119 lot E0624); 115 full-dose WHO; 114 1/10 dose WHO. The percentage of subjects with a positive tuberculin test after vaccination was significantly lower (P < 0.001) in the 1/10 dose group (81.5%) compared to the other three groups (> 96%). The mean induration diameter was significantly smaller in subjects who received the low-dose of WHO vaccine compared to the others, according to analyses considering all subjects vaccinated, as well as only those subjects with a positive tuberculin test after vaccination. More children in the low-dose group did not have a vaccination scar, and the mean diameter of scars was smaller in this group. The rate of tuberculin reactions, the classification of reactions (Palmer and Edwards), and the characteristics of the vaccinal lesion were similar for the Mérieux BCG vaccines and the full-dose WHO-reference vaccine. All vaccines were safe, as evidenced by the absence of adenitis or suppurative adenitis during the course of the study. Results from this trial show that the two lots of Mérieux BCG vaccine behave equally as well as the full-dose WHO-reference BCG vaccine. The WHO-reference vaccine, given at 1/10 of its normal concentration was significantly less immunogenic, according to all parameters evaluated.

All the vaccines supplied for the large scale comparative leprosy vaccine trial of ICRC bacilli, M.w, BCG plus killed M. leprae (candidate vaccines), BCG and normal saline (control arms) at CJIL Field Unit, Chennai were tested for quality control by the suppliers following the procedures laid down in the WHO protocol for killed M. leprae. Quality control for BCG was carried out at BCG vaccine laboratory as per protocol. Toxicity and sterility tests were done on all the vaccine batches/lots received. As part of the quality control, bacterial count, and protein estimation were also done. Studies showed that the bacterial content and protein concentration were comparable with the original preparations. Vaccines were free from micro-organisms, toxic materials and safe for human use. Thus the quality of all vaccine preparations was satisfactory.

The reemergence of tuberculosis, including the impact of HIV infection and multidrug-resistant tuberculosis, have renewed interest in the bacille Calmette-Guérin (BCG) vaccine. During the past 7 decades, numerous studies have shown variable efficacy of BCG vaccination, ranging from 0% to 80%. The BCG vaccine is more likely to prevent disseminated forms of tuberculosis in children than pulmonary tuberculosis in adolescents or adults. Bacille Calmette-Guérin vaccination is recommended in asymptomatic children with or at risk for HIV infection, but it rarely may cause disseminated BCG infection and should not be used in persons with symptomatic HIV infection or AIDS. In healthcare workers with exposure to Mycobacterium tuberculosis, including multidrug-resistant tuberculosis, BCG vaccination generally is not recommended. Revaccination with BCG does not confer more benefit than initial vaccination, and repeat vaccinations should be discontinued. With recent advances in technology and a better understanding of the immunopathogenesis of tuberculosis, efforts to develop a more potent and specific vaccine need to be pursued. If a more effective vaccine against tuberculosis is developed, vaccination can be expected to have an additional impact on global tuberculosis control in conjunction with current strategies of case detection, treatment of disease, and preventive therapy.

Aquired resistance against tuberculosis depends on the survival, multiplication and persistence of BCG in the host organs. Therefore, the viability and stabilisation during storage of BCG vaccine constitute a major attribute for good immunogenicity. Different factors which influence BCG viability have been studied. Among the more important ones it was found that a very large number of viable bacilli are killed when vaccine is manufactured in the conventional way by ball milling the surface-grown bacillary mass. The dispersed deep-grow BCG offers the advantage that all bacilli are live in the fresh suspension before stabilisation procedures are applied. Two procedures of stabilisation have been used, freezing and freeze-drying. Preservation by resuspending BCG in different cryoprotective solutions has been followed by storage at low temperatures. Complete survival is obtained when this vaccine was frozen in glycerol solutions and stored for many years at -70 degrees C. Freeze-drying killed more than 50% of the live bacilli in the fresh suspension; the remaining freeze-dried live bacilli were preserved at -30 degrees C for 20 years or at 4 degrees C for at least one year. They also resist exposure to 37 degrees C for one month. Nevertheless, most of the BCG bacilli in freeze-dried vaccines are dead. In conclusion the best BCG viability is obtained with young dispersed-grown bacilli by both freezing and freeze-drying. Freezing is a good method of stabilisation for research purposes or cancer immunotherapy, and freeze-drying for BCG vaccination campaings in tuberculosis prevention. However, BCG stabilisation still needs improvement.