100 years of Mycobacterium bovis bacille Calmette-Guérin.

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.

100 years of Bacillus Calmette-Guérin immunotherapy: from cattle to COVID-19.

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.

[BCG: an almost 100-year-old vaccine]. / BCG: een bijna 100 jaar oud vaccin.

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.

Complications of Intravesical BCG Immunotherapy for Bladder Cancer.

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

Vacunación frente a tuberculosis / Vaccination against tuberculosis

La vacunación con BCG (bacilo Calmette-Guérin) está incluida en el calendario de inmunización al nacimiento en países con alta incidencia de tuberculosis, con una cobertura global cercana al 90%. BCG tiene casi cien años de antigüedad y está basada en una cepa atenuada de Mycobacterium bovis, proporcionando protección contra las formas diseminadas de la enfermedad pero confiriendo una protección muy limitada contra las formas pulmonares de tuberculosis, responsables de su transmisión. Diferentes vacunas profilácticas contra la tuberculosis se encuentran hoy en desarrollo clínico para reemplazar a BCG o para mejorar la protección en individuos ya vacunados con BCG. MTBVAC es la primera y única vacuna candidata basada en una cepa de Mycobacterium tuberculosis atenuada en evaluación clínica. Los planes de desarrollo clínico del MTBVAC se dirigen en primer lugar a la prevención de la tuberculosis en recién nacidos, para reemplazar a BCG, y en segundo lugar en adolescentes y adultos

BCG (Bacille Calmette-Guérin) vaccination is included in the immunization schedule for tuberculosis endemic countries with a global coverage at birth close to 90% worldwide. BCG was attenuated from Mycobacterium bovis almost a century ago, and provides a strong protection against disseminated forms of the disease, though very limited against pulmonary forms of tuberculosis, responsible for transmission. Novel prophylactic tuberculosis vaccines are in clinical development either to replace BCG or to improve its protection against respiratory forms of the disease. There are limitations understanding the immunological responses involved and the precise type of long-lived immunity that new vaccines need to induce. MTBVAC is the first and only tuberculosis vaccine candidate based on live-attenuated Mycobacterium tuberculosis in clinical evaluation. MTBVAC clinical development plans to target tuberculosis prevention in newborns, as a BCG replacement strategy, and as secondary objective to be tested in adolescents and adults previous vaccinated with BCG

Bacillus Calmette-Guérin strain differences as the basis for immunotherapies against bladder cancer.

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.

Evolution and Strain Variation in BCG.

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 practice of BCG vaccination in 1930 s' China].

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.

BCG: A throwback from the stone age of vaccines opened the path for bladder cancer immunotherapy.

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.

[Strategies for BCG vaccination 1947 - 94]. / Strategier for BCG-vaksinasjon 1947 - 94.

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.

Ancient Disease, Modern Epidemiology: A Century of Progress in Understanding and Fighting Tuberculosis.

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.

Tuberculosis in Newborns: The Lessons of the "Lübeck Disaster" (1929-1933).

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.

[Tuberculosis 110 years after the Nobel Prize awarded to Koch]. / La tuberculosis a 110 años del Premio Nobel de Koch.

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.

BCG 1948 – 2014: la misma cepa? / BCG 1948 – 2014: is the same strain yet?

Tuberculosis remains a public health problem and its control is a global health priority. One of the most successful tools to control infectious diseases has been the use of vaccines. Bacille Calmette-Guérin is one of the oldest available vaccines used today, the only licensed against tuberculosis. It has been administered to billions of people, as part of national immunization programs around the world. Immunological mechanisms by which it induces protection are not fully understood, but a role in the innate immune system maturation and the activation of T CD4 + and CD8 +, have been considered. Its effectiveness in terms of pulmonary tuberculosis is variable and controversial but highly cost - efficient to control tuberculous meningitis and miliary dissemination. However, it has not been enough to solve the global problem of tuberculosis, especially in countries with high rates, so that scientific development aiming at getting a new vaccine remains active.

La tuberculosis sigue siendo un problema de salud pública mundial y su control es una prioridad de salud global. Una de las herramientas más exitosas que se han utilizado para controlar enfermedades infecciosas ha sido el uso de vacunas. El bacilo de Calmette-Guérin es una de las vacunas más antiguas disponibles utilizadas en la actualidad, la única licenciada contra tuberculosis. Ha sido administrada en miles de millones de personas, siendo parte de distintos programas de vacunación nacionales en el mundo. Los mecanismos inmunológicos por los cuales induce protección aún no son completamente comprendidos, planteándose un rol sobre la maduración del sistema inmune innato y activación de células T CD4+ y CD8+. Su eficacia respecto de tuberculosis pulmonar es variable y controvertida, pero altamente costo eficiente para controlar meningitis tuberculosa y diseminación miliar, sin embargo no ha sido suficiente para resolver el problema global de la tuberculosis, especialmente en los países con endemias más altas, por lo que el desarrollo científico en miras de obtener una nueva vacuna se mantiene vigente.

[DEYCKE PASHA AND THE LÜBECK DISASTER].

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.