Search

Mycobacterium bovis bacille Calmette-Guérin (BCG), an experimental vaccine designed to protect cattle from bovine tuberculosis, was administered for the first time to a newborn baby in Paris in 1921. Over the past century, BCG has saved tens of millions of lives and has been given to more humans than any other vaccine. It remains the sole tuberculosis vaccine licensed for use in humans. BCG provides long-lasting strong protection against miliary and meningeal tuberculosis in children, but it is less effective for the prevention of pulmonary tuberculosis, especially in adults. Evidence mainly from the past two decades suggests that BCG has non-specific benefits against non-tuberculous infections in newborn babies and in older adults, and offers immunotherapeutic benefit in certain malignancies such as non-muscle invasive bladder cancer. However, as a live attenuated vaccine, BCG can cause localised or disseminated infections in immunocompromised hosts, which can also occur following intravesical installation of BCG for the treatment of bladder cancer. The legacy of BCG includes fundamental discoveries about tuberculosis-specific and non-specific immunity and the demonstration that tuberculosis is a vaccine-preventable disease, providing a foundation for new vaccines to hasten tuberculosis elimination., Competing Interests: Declaration of interests SHEK is coinventor of the tuberculosis vaccine VPM1002 and coholder of a patent licensed to Serum Institute of India, Pune, India. MGN is coholder of patents on trained immunity licensed to Trained Therapeutix Discovery. CL reports personal fees from Chiesi, Gilead, Janssen, Novartis, Oxford Immunotec, and Insmed, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Bacillus Calmette-Guérin (BCG) is the most widely used vaccine worldwide and has been used to prevent tuberculosis for a century. BCG also stimulates an anti-tumour immune response, which urologists have harnessed for the treatment of non-muscle-invasive bladder cancer. A growing body of evidence indicates that BCG offers protection against various non-mycobacterial and viral infections. The non-specific effects of BCG occur via the induction of trained immunity and form the basis for the hypothesis that BCG vaccination could be used to protect against the severity of coronavirus disease 2019 (COVID-19). This Perspective article highlights key milestones in the 100-year history of BCG and projects its potential role in the COVID-19 pandemic., (© 2021. Springer Nature Limited.)

There has been a vaccine against tuberculosis (TB) since 1921. This vaccine contains Bacillus Calmette-Guérin (BCG), a live attenuated strain of the tubercle bacterium Mycobacterium bovis. The vaccine is fairly effective in children, but protection is poor in adults. Protection lasts about 15 years. The vaccine is safe for immunocompetent people, provided it is administered intracutaneously and at the correct dose. This article looks back at the development of the tuberculin skin test and BCG vaccine, and their use in the Netherlands.

An earlier incorrect version appeared online. This article was corrected on December 14, 2018.

In the past 40 years, intravesical immunotherapy with Mycobacterium bovis bacillus Calmette-Guérin has been carried out as the most effective treatment for preventing local recurrences and tumor progression of non-muscle-invasive bladder cancer. Bacillus Calmette-Guérin is a family of vaccines derived in 1921 by the in vitro attenuation of Mycobacterium bovis. Subsequently, bacillus Calmette-Guérin seed lots were spread around the world, and both phenotypic and genotypic differences among the strains have been compiled. In recent genomic comparisons, the evolution of the different bacillus Calmette-Guérin substrains has begun to emerge. However, some of these genetic alterations in bacillus Calmette-Guérin strains have yet to be shown to affect the therapeutic effects and/or adverse effects. There are thus ongoing research efforts to assess the effects of these genetic alterations on the properties of bacillus Calmette-Guérin strains, with the ultimate goal of identifying an ideal bacillus Calmette-Guérin strain for treatment of non-muscle-invasive bladder cancer and providing clues for the improvement of bacillus Calmette-Guérin strains. The present review provides a history of bacillus Calmette-Guérin immunotherapy, and discusses the genetic differences among bacillus Calmette-Guérin strains, the different clinical outcomes afforded by bacillus Calmette-Guérin strains and possible future developments., (© 2018 The Japanese Urological Association.)

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.

Introduction: It is 40 years since the initial documentation of the efficacy of bacille Calmette-Guérin (BCG) in the management of non-muscle invasive bladder cancer (NMIBC) and probably an opportune a time as any to retrace the origins of this development and to reflect on the progress that has occurred on the use of immune modifiers in the treatment of NMIBC., Materials and Methods: A PubMed search for publications on the history of BCG was conducted, and those related to the development of the vaccine for protection against tuberculosis as well as those published in the last 40 years related to its use for treatment for NMIBC were selected for review. A manual search was also carried out for recent articles on immunotherapy for NMIBC failing to respond to BCG. Publications were selected for their usefulness in exemplifying the development of BCG as an antineoplastic agent, elucidating its mechanisms of action of BCG or introducing significant modifications in treatment regimens resulting in enhancement of its efficacy. Alternative innovative immunotherapeutic approaches were chosen to illustrate current trends in the management of this disease., Results: Well thought-out modifications of the original protocol resulted in enhanced efficacy of the vaccine, which currently ranks as the best-known and most-used and investigated agent for high risk NMIBC. Despite its efficacy, a considerable number (30%-40%) of these tumors fail to respond to BCG. In addition, as a live bacterium it carries the potential for serious adverse effects and some patients are unable to tolerate it. These shortcomings have created the need for new agents. These range from other mycobacteria and viruses to monoclonal antibodies alone or in combination with other agents currently at various stages of development., Conclusion: After 4 decades of use, BCG remains the most effective agent against high risk NMIBC, but it still holds substantial drawbacks. The enduring use of immunotherapy for NMIBC has created a propitious environment to search for better alternatives. There are an increasing number of promising in vitro, animal and early human clinical trials to anticipate a significant therapeutic alternative in the foreseeable future.

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.

The tuberculosis reform of 1947 stipulated a clear responsibility of the state to combat tuberculosis. This entailed sanctions directed at individuals, as well as compulsory vaccination. Universal vaccination was to be achieved through extensive information work that emphasised the responsibility of the individual. The decline in the disease, the dawning of human rights thinking and the decline of professional boards in public administration help to explain the downgrading of compulsory vaccination over time.

A century's worth of efforts to better understand the epidemiology of tuberculosis (TB) and to develop new vaccines, drugs, preventive interventions, and case-finding approaches have provided important insights and helped to advance the field of epidemiology as a whole. Wade Hampton Frost developed methods for cohort analysis that formed the early basis for adjustment of confounding variables. The streptomycin trial in the United Kingdom in the 1940s introduced random allocation for participants to either the treatment or control group, ensuring blinded treatment assignment and comparable treatment groups, which is now a key element in randomized clinical trials. Research into the bacille Calmette-Guérin vaccine demonstrated the importance of comparative analyses, potential difficulties in generalizability to populations not under study, and the role of meta-analysis for discrepant data-approaches now strongly recommended prior to implementing any novel public health intervention. George Comstock's work on preventive therapy for TB demonstrated the use of epidemiologic methods to evaluate interventions on a population level. Finally, studies from the Consortium to Respond Effectively to the AIDS/TB Epidemic focused on the evaluation of real-world effectiveness and of targeting of high-risk subpopulations. In this article, we discuss how TB research in each of these domains has helped to advance epidemiologic thinking and methodology over the past 100 years., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In an accident later known as the Lübeck disaster, 251 neonates were orally given three doses of the new Bacille Calmette-Guérin (BCG) antituberculosis (TB) vaccine contaminated with Mycobacterium tuberculosis. A total of 173 infants developed clinical or radiological signs of TB but survived the infection, while 72 died from TB. While some blamed the accident on BCG itself by postulating reversion to full virulence, such a possibility was conclusively disproven. Rather, by combining clinical, microbiological, and epidemiological data, the chief public health investigator Dr. A. Moegling concluded that the BCG vaccine had been contaminated with variable amounts of fully virulent M. tuberculosis. Here, we summarize the conclusions drawn by Moegling and point out three lessons that can be learned. First, while mortality was high (approximately 29%), the majority of neonates inoculated with M. tuberculosis eventually overcame TB disease. This shows the high constitutional resistance of humans to the bacillus. Second, four semiquantitative levels of contamination were deduced by Moegling from the available data. While at low levels of M. tuberculosis there was a large spread of clinical phenotypes reflecting a good degree of innate resistance to TB, at the highest dose, the majority of neonates were highly susceptible to TB. This shows the dominating role of dose for innate resistance to TB. Third, two infants inoculated with the lowest dose nevertheless died of TB, and their median time from inoculation to death was substantially shorter than for those who died after inoculation with higher doses. This suggests that infants who developed disease after low dose inoculation are those who are most susceptible to the disease. We discuss some implications of these lessons for current study of genetic susceptibility to TB.

The Nobel Prize in Physiology or Medicine was awarded in 1905 to Robert Koch "for his investigations and discoveries in relation to tuberculosis (TB)". He discovered the causal agent of TB, described the four principles that since then have guided research in communicable diseases and also prepared the old tuberculin, a bacillary extract that failed as a healing element but allowed the early diagnosis of TB infection and promoted the understanding of cellular immunity. After his death, the most conspicuous achievements against TB were the BCG vaccine, and the discovery of streptomycin, the antibiotic that launched the era of the effective treatment of TB. Drug-resistance soon appeared. In Argentina, studies on drug resistance began in the 60s. In the 70s, shortened anti-TB drug schemes were introduced consisting in two-month treatment with four drugs, followed by four months with two drugs. The incidence of TB decreased worldwide, but the immune depression associated with awarded together with the misuse of anti-TB drugs allowed the emergence of multidrug resistance and extensive resistance, with the emergence of nosocomial outbreaks worldwide, including Argentina. New rapid diagnostic methods based on molecular biology were developed and also new drugs, but the treatment of multidrug resistant and extensively resistant TB is still difficult and expensive. TB research has marked several milestones in medical sciences, including the monumental Koch postulates, the tuberculin skin test that laid the basis for understanding cell-mediated immunity, the first design of randomized clinical trials and the use of combined multi-drug treatments.

Dr. Georg Deycke, known as Deycke Pasha in Turkey, came to Istanbul in 1898 with Prof. Robert Rieder in order to reorganize the Imperial Medical School. Prof Rieder es- tablished a new training hospital named as The Giilhane Clinics and Dr. Deycke worked there until 1904 as the vice director. After Rieder left Turkey, he became the director to the hospital and served until the end of his contract in 1907. So after that time we know very less of his life and works. As well as its almost unknown that he was responsible for the BCG inoculation misfortune in Lübeck in 1930. Oral tuberculosis vaccine (BCG) was developed by Calmette and Gu6rin in 1921 after thirteen-year old preliminary work. Until 1928, before the BCG vaccination was begun in Germany, 150,000 children had been inoculated abroad. In 1929, Dr. Altstaedt, the director of the public health authorities in Lübeck, and Dr. George Deycke, the director of the gene- ral hospital in Lübeck, decided to introduce the inoculation at newborn children in Lübeck. At the beginning of August 1929, the original BCG culture, obtained from the Pasteur Insti- tute of Paris, was used to produce vaccine in the laboratory of the general hospital under the patronage of Dr. Deycke. The vaccination was begun in February 1930 and in the following two months 256 newborn children (about 84% of all newborn children) in Lübeck were inoculated orally against tuberculosis. In April 17th the first child died of tuberculosis and after it was followed by three more deaths Dr. Deycke stopped the inoculation. The large number of the inoculated children became ill and finally 75 of them died of tuberculosis. Dr. Deycke and those who assisted him were put on trial on October 12, 1931. A scientific committee was ordered to investigate what caused such a catastrophe. On February 6th 1932, after 76 days of inquiries and trials, Dr. Deycke was found guilty of negligent killing and negligent bodily injury and sentenced two years in prison. In this paper, both the life and the works of Deycke Pasha after the year 1907, and the details of Lübeck Disaster and the lessons learned from it will be discussed in detail.

The Bacille Calmette-Guerin (BCG) vaccine is the only vaccine proved to be effective against tuberculosis and it remains the most commonly used vaccine worldwide. In addition to its effects on mycobacterial diseases, an increasing body of epidemiological evidence accumulated since its introduction in 1921 shows that BCG also exerts beneficial non-specific effects ranging from protection against non-mycobacterial diseases, decreased incidence of allergic diseases, and treatment of certain malignancies. The biological substrate of these effects is mediated partly by heterologous effects on adaptive immunity, but also on the potentiation of innate immune responses through epigenetic mechanisms, a process termed 'trained immunity'. The process of trained immunity may also play a role in the beneficial effects of BCG against tuberculosis and Mycobacterium tuberculosis infection, and this could have important consequences for our quest for improving vaccination strategies., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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.

In 1992, the hospital of Nanterre assumed Max Fourestier's surname, as this great doctor was in office there between 1948 and 1973. Max Fourestier's biography and career emphasize that he embarked on three specific professional fields : specialty medicine, social medicine and school medicine. At the time, Max Fourestier was developing his universal endoscope in his department in Nanterre, achieving an extensive experience of massive BCG vaccination in a tuberculosis clinic in Montreuil, called "social hygiene" and, finally, carrying out a lot of school innovations to achieve an equal division of time between school work and sport practices. He also implemented snow classes in public schools in 1953 or napping classes,forest classes and snow classes in infant schools in 1959. In short, this presentation reveals that the inherent process of Max Fourestier's school innovation reputation lies in the scientific will of its creator, which allows him to convey his teaching ideas at the international level. Finally, in addition to the inventory of the physician's various innovations, the major challenge of this presentation is to reveal the intertwining and strong connections of Max Fourestier's medical and school commitments. In 1992, the hospital of Nanterre assumed Max Fourestier's surname, as this great doctor was in office there between 1948 and 1973. Max Fourestier's biography and career emphasize that he embarked on three specific professional fields: specialty medicine, social medicine and school medicine. At the time, Max Fourestier was developing his universal endoscope in his department in Nanterre, achieving an extensive experience of massive BCG vaccination in a tuberculosis clinic in Montreuil, called "social hygiene" and,finally, carrying out a lot of school innovations to achieve an equal division of time between school work and sport practices. He also implemented snow classes in public schools in 1953 or napping classes, forest classes and snow classes in infant schools in 1959. In short, this presentation reveals that the inherent process of Max Fourestier's school innovation reputation lies in the scientific will of its creator, which allows him to convey his teaching ideas at the international level. Finally, in addition to the inventory of the physician's various innovations, the major challenge of this presentation is to reveal the intertwining and strong connections of Max Fourestier's medical and school commitments.

Albert Calmette (1863-1933) left a major legacy, ranging from basic research to practical medical applications. His initial work focused on antivenimous serum therapy, as well as the creation of Pasteur Institutes outside France. But his greatest achievement is the discovery of the BCG vaccine, in conjunction with Camille Guerin. This was a major advance at a time when tuberculosis was a veritable scourge, responsible for the deaths of thousands of children each year. He also pioneered early TB control in the field. The validity of BCG vaccination was not called into question despite the Lubeck drama, that he bravely affronted in 1931.

By 1926, two French physicians working in Indochina, R. Pons and L. Chastel, have suggested to treat leprosy by subcutaneous injections of bacillus Calmette-Guerin. This treatment appeared efficient since the lepromatous lesions quickly regressed and the Hansen bacillus disappeared from the nasal mucus. These results were quickly confirmed by other authors. They were all more appreciated than, at this time, the Chaulmoogra oil and its products, the only available drugs, were poorly efficient against the disease. Nevertheless, although not a panacea, the BCG therapy allowed to relieve these unfortunate patients until the beginning of the 1950's when an effective treatment by sulfones was at length available.

The purpose of this article is to describe Albert Calmette's stay in Gabon from October 1886 to November 1887. During his year in Africa, this illustrious French navy physician who was to invent the BCG vaccine against tuberculosis was keenly interested in malaria and sleeping sickness.

The history of tuberculosis as a worldwide fatal illness traces back to antiquity, a well-known disease in ancient civilizations. However, its causative agent remained unidentified until the last decades of the 19th century, when discovered by Robert Koch. In due course, preparation of the BCG vaccine, application of the Mantoux intradermal diagnostic tuberculosis test and administration of proper antituberculosis medications eventually controlled tuberculosis. However, despite these significant advancements tuberculosis remained uneradicated, particularly in developing countries after the emergence of both multidrug-resistant tuberculosis and HIV co-infection. Presented here, is a brief review of the history of tuberculosis in the world as well as its historical background in Iran, mainly during the 19th and 20th centuries.

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.

Mass vaccination with BCG against tuberculosis has been one of the major health interventions of WHO since the Second World War. This article traces the history of the controversial BCG vaccine from its adoption by WHO in 1948 up to 1983. In 1948, there was no clear scientific evidence to support the vaccine, and its adoption by WHO seems to have been urged by the existence of the UNICEF funded 'International Tuberculosis Campaign' and a fear of a threatening global epidemic. Moreover, BCG fitted well with the post Second World War perception of public health interventions. The vaccine was not systematically reviewed by WHO until 1959, and this review appears to have been biased in favour of the vaccine. In 1979 the results from the South Indian Chingleput trial, which showed no protective effect of BCG against pulmonary tuberculosis in adults, prompted WHO to change the arguments for recommending the vaccine. Since 1983 BCG has been recommended with specific reference to its protective effect against severe forms of childhood tuberculosis. The story of the BCG vaccine and WHO is a story of medical uncertainty, institutional inertia, strategic obduracy, and not least, hope.

From the time it emerged as an epidemic in the last decades of the nineteenth century until it had become their number-one health problem in the 1950s, multiple explanations for the etiology of tuberculosis (TB) among American Indians competed for prominence. None was more debated than racial susceptibility-and none held on with such tenacity. Various race-based explanations -Indians' inherent racial susceptibility, virgin soil theory, and degree of Indian blood-had great explanatory power. These explanations faded from view by the 1950s as a result of epidemiological research begun in the 1930s-research that for the first time filled in many of the pieces of the Indian TB puzzle and allowed TB specialists to know the unknown: who and where the disease struck and why. Combining case finding, X rays, sputum tests-all the modern methods of tracking a TB epidemic-the Bureau of Indian Affairs (BIA) was finally able to understand the Indian TB epidemic. But they also wanted to control it. To this end, the BIA and the Phipps Institute, under the direction of Esmond Long and Joseph Aronson, joined together to begin the first controlled trial of the BCG vaccine.

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.

Purpose: We review how the bacillus Calmette-Guerin vaccine evolved to become standard therapy for superficial bladder cancer., Materials and Methods: We reviewed the historical literature describing the origin of the bacillus Calmette-Guerin vaccine as an anticancer agent and its singular success as the most effective immunotherapy used against a human neoplasm., Results: The association between tuberculosis and cancer, and the demonstration that bacillus Calmette-Guerin invoked immunological reactivity, inhibiting tumor growth in experimental animal models, led to clinical trials showing that intravesical bacillus Calmette-Guerin eradicated and prevented recurrence of superficial bladder tumors., Conclusions: For the last 3 decades bacillus Calmette-Guerin therapy has remained the most effective local therapy for superficial bladder cancer, an outstanding example of successful translational medicine in urology.

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.

Early in his medical career, Albert Calmette showed a remarkable aptitude for bacteriology and, in 1891, he opened the first daughter Pasteur Institute in Saigon, French Indochina at the request of Louis Pasteur. In 1894, at the Pasteur Institute in Paris, Calmette succeeded in developing an antiserum to cobra venom and so initiated antivenomous serotherapy. In 1895 Calmette was asked to found a second daughter, Pasteur Institute in Lille. Soon he was joined by the young veterinarian, Camille Guérin, and so began a unique partnership, the two men striving to free people from the dreadful scourge of tuberculosis. Investigating the intestinal route of tuberculous infection, Calmette and Guérin began to grow Mycobacterium tuberculosis bovis in a beef bile-glycerine medium. With continuous replanting of the culture in this medium (from 70 to 235 times), an attenuated bacillus of fixed properties was discovered; this Calmette called Bacille-Calmette-Guérin (BCG). Exhaustive testing of BCG showed its safety and effectiveness in protecting young animals against tuberculosis. In 1924 vaccination of newborn infants with BCG began in France and spread worldwide.

Between 1947 and 1951 the Scandinavian-led International Tuberculosis Campaign tested more than 37 million children and adolescents for tuberculosis, and vaccinated more than 16 million with BCG vaccine. The campaign was an early example of an international health program, and it was generally seen as the largest medical campaign to date. It was born, however, as a Danish effort to create goodwill in war-ravaged Europe, and was extended outside Europe only because UNICEF in 1948 unexpectedly donated US $2 million specifically for BCG vaccination in areas outside Europe. As the campaign transformed from postwar relief to an international health program it was forced to make adaptations to different demographic, social, and cultural contexts. This created a tension between a scientific ideal of uniformity, on the one hand, and pragmatic flexibility on the other. Looking at the campaign in India, which was the most important non-European country in the campaign, this article analyzes three issues in more detail: the development of a simplified vaccination technique; the employment of lay-vaccinators; and whether the campaign in India was conceived as a short-term demonstration or a more extensive mass-vaccination effort.

Tuberculosis has claimed its victims throughout much of known human history. It reached epidemic proportions in Europe and North America during the 18th and 19th centuries, earning the sobriquet, "Captain Among these Men of Death." Then it began to decline. Understanding of the pathogenesis of tuberculosis began with the work of Théophile Laennec at the beginning of the 19th century and was further advanced by the demonstration of the transmissibility of Mycobacterium tuberculosis infection by Jean-Antoine Villemin in 1865 and the identification of the tubercle bacillus as the etiologic agent by Robert Koch in 1882. Clemens von Pirquet developed the tuberculin skin test in 1907 and 3 years later used it to demonstrate latent tuberculous infection in asymptomatic children. In the late 19th and early 20th centuries sanatoria developed for the treatment of patients with tuberculosis. The rest provided there was supplemented with pulmonary collapse procedures designed to rest infected parts of lungs and to close cavities. Public Health measures to combat the spread of tuberculosis emerged following the discovery of its bacterial cause. BCG vaccination was widely employed following World War I. The modern era of tuberculosis treatment and control was heralded by the discovery of streptomycin in 1944 and isoniazid in 1952.

Even though the BCG vaccine is one of the most used vaccines in the world, tuberculosis is still a major problem worldwide. Research aimed at developing new vaccines against tuberculosis has become more goal-directed during the last 10-15 years, and there are now several vaccine candidates in clinical study phases I and II, that should be in phase III in 2010. It will then still take several years before we know whether a new vaccine will reduce the occurrence of tuberculosis. There are several promising vaccine candidates, but there is uncertainty whether they will be successful in reducing tuberculosis, as we do not have sufficient knowledge about protective immunity in tuberculosis. Today's vaccine candidates have been developed to protect against a few laboratory strains of the bacteria and will not protect against all strains. Estimations show that an effective vaccine against latent tuberculosis will give a rapid and considerable reduction in tuberculosis. The current vaccine candidates are however developed to protect against primary tuberculosis and not against reactivated latent tuberculosis. It is important to ensure an optimal experimental basis for new tuberculosis vaccines and to compare them so the best can be selected.

Five years after the National Health minister launched the vaccination program against hepatitis B in 1994, French public health experts are not satisfied by the coverage rate among young people. Is this stagnation related to the controversial way the program was initially managed and to the debate that has raged on the link between the vaccine and multiple sclerosis? Is the popular reaction of distrust specific to the vaccine or does it reveal a growing concern towards the whole vaccinal enterprise? More generally, is it the end of the almost unconditional French acceptance of vaccines? A historical retrospective on the history of vaccination in the country of Louis Pasteur.

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.

The vaccine Bacillus of Calmette Guérin (BCG) was originally developed in France as an oral vaccine against tuberculosis. The oral use of this vaccine was replaced by the parenteral route in almost all countries after the Lubeck disaster. In contrast, Brazil retained the oral delivery of the vaccine until the mid-seventies when it was replaced by the intradermal route. This change in route of delivery was mainly secondary to pressure by medical practitioners based on the poor responses of oral immunized subjects to purified protein derivative (PPD) skin tests. Even after the change of route of delivery, Ataulpho de Paiva Foundation continued making the oral vaccine. Currently, BCG Moreau has been described as one of the most immunogenic and with fewer side effects than other BCGs. The genomics, proteomics and vaccine trials for oral BCG Moreau Rio de Janeiro are currently under investigation. In this review, we intend to describe the history of BCG Moreau Rio de Janeiro in Brazil.

From 1924 onwards, mandatory tuberculin testing (von Pirquet's method) was introduced for student nurses on entry to the Ullevaal Hospital School of Nursing, Oslo. The chief physician of the hospital's Department IX, Olaf Scheel, was responsible for this measure. In 1927, his deputy Johannes Heimbeck showed that about half of the students were not infected at the time of entry, a conclusion that was in fundamental conflict with the prevailing view that nearly all tuberculous infection occurred in childhood. Virtually all tuberculin-negative student nurses, however, became infected during their 3-year training. These findings changed our understanding of the pathogenesis of tuberculosis. BCG vaccination had recently been introduced by Calmette. From 1927 onwards Heimbeck offered BCG vaccination to tuberculin-negative student nurses, while Scheel undertook a similar project among medical students. The two projects continued until respectively 1936 and 1939. Long-term follow-up of both groups demonstrated a protective effect of about 80% in those accepting vaccination. Calmette had given the vaccine per os to new-born babies. Heimbeck and Scheel pioneered giving the vaccine via injection and to adults. These projects have been criticised for being based on voluntary inclusion and not being conducted as randomised control trials. The results were so convincing, however, that they led to the launch of the Norwegian BCG programme shortly after World War II. Scheel and Heimbeck' efforts were also of great importance for the use of the BCG vaccine in other countries.