Complications of Intravesical BCG Immunotherapy for Bladder Cancer.

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

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.

BCG-induced protection: effects on innate immune memory.

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.

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.

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.

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.

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.

[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.

[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.

Oral bacillus Calmette-Guérin vaccine against tuberculosis: why not?

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.

[When the scientific career favors the scholarly diffusion of innovation: doctor Max Fourestier]. / Quand la carrière scientifique d'un médecin favorise la diffusion d'innovations scolaires: l'exemple du docteur Max Fourestier.

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: celebrating the 150th anniversary of his birth]. / Albert Calmette : à propos du 150e anniversaire de sa naissance.

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.

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.

[Albert Calmette (1863-1933). Description of the BCG vaccine inventor's stay in Gabon]. / Albert Calmette (1863-1933) quand l'inventeur du BCG était au Gabon.

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.

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.

History of bacillus Calmette-Guerin and bladder cancer: an immunotherapy success story.

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.

BCG vaccination and WHO's global strategy for tuberculosis control 1948-1983.

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.