Tuberculosis

BCG vaccines have been given to billions of people since 1921, more than any other vaccine. Despite such a lengthy track record, BCG vaccination has also generated at least as much controversy as any other form of immunisation. Most importantly, the capacity to protect individuals against tuberculosis is still debated, since randomised clinical trials have provided estimates ranging from 80% protection to no benefit. Traditionally, BCG vaccines have been considered among the safest in use. However, the true incidence of disease due to BCG strains (called “BCG-itis” or “BCG-osis”) is unknown.
With the concerns about BCG efficacy and safety have come calls for new vaccines against tuberculosis. Various new vaccine candidates have been developed and tested in animal models. Notably, of nearly 200 candidate vaccines tested to date, only one has provided better protection than BCG, a recombinant form of BCG itself.
The history of BCG begins with pathogenesis experiments by Calmette and Guerin in the first decade of the 20th century. To study tuberculosis in cattle, they worked with cultures of bovine tubercle bacilli (M. bovis), which explains why our present vaccines against M. tuberculosis are derived from closely related M. bovis. The importance of differences between M tuberculosis and M bovis in the derivation of a live, attenuated vaccine against human tuberculosis remains unknown.
For optimum oral infection of cattle and guineapigs, Calmette added a detergent, specifically bile, to the culture medium, to prevent the bacteria from clumping. Within a few months, an unusual colony type arose, which was less virulent to the guinea pigs. Calmette continued the process of growing these bacteria in the presence of bile, for 13 years, changing the nutrient medium every two weeks.
Beginning in 1921, BCG was administered to people to prevent tuberculosis. At this time, it was not possible to freeze-dry (lyophilise) BCG or put away a stock of the strain in a freezer. Therefore, BCG continued to be grown in much the same conditions that had resulted in its original attenuation until the lyophilisation of BCG-Pasteur after 1173 passages in 1961.
During these decades, the same poorly understood laboratory selective pressures that had created BCG in the first place were presumably still at work. Since Calmette first reported attenuation of virulence after 15 passages in vitro and reported further attenuation of virulence over the next 215 passages, was it possible that no further attenuation would happen during the subsequent 943 passages? Since neither the parent strain of M. bovis that gave rise to BCG nor the original BCG of 1921 are available for study, this question cannot be answered directly.
In 1924, BCG lots began to be distributed to various different countries for local preparation of vaccine. BCG was propagated at these laboratories in the same conditions as at the Pasteur Institute, with the same goals – namely to prevent BCG from reverting to virulence while preserving an acceptable degree of what was called “potency”. Over the course of a few decades, each of these BCG vaccine laboratories developed its own daughter strain of BCG, typically named after the laboratory director, the city, or the country.
Presently, all BCG strains are prepared as lyophilised stocks that are resuspended before inoculation. The proportion of BCG vaccine that is dead versus live varies greatly after reconstitution. Most lyophilised BCG vaccines are 90–95% dead bacteria, but BCG-Tokyo is a notable exception, estimated to consist of perhaps 25% live bacteria at vaccination. The importance of the proportion of viable bacteria in the vaccine has yet to be formally assessed; for instance, does giving more dead bacteria compensate?
In the rational design of an attenuated vaccine, one would presumably attempt to remove virulence factors while maintaining antigens. It is known today that several antigenic proteins are either absent from all BCG strains or absent / not expressed in BCG vaccines obtained after 1931. The loss of antigens from certain BCG strains is apparently contrary to what would be desired and suggests an important phenotype for further study.
The other important phenotype of BCG strains is their safety, and more specifically the rate of BCG dissemination. One such experiment involved the replacement of BCG-Prague with BCG-Russia in the former country of Czechoslovakia. Rates of disseminated BCG disease, including BCG osteitis were greater with the Russian strain. An epidemic of BCG osteitis was also reported in Sweden and Finland in the 1970s, but not due to a change of strain, rather because the Swedish strain of BCG was sent to Copenhagen for production of vaccine. In Sweden, BCG vaccination was halted. In Finland, BCG vaccination continued, with a change to another BCG strain.
Have BCG strains evolved over time? The answer is clearly yes. Does this matter? The answer depends on who is asked. A bacteriologist would be surprised if BCG has not changed considerably during a half-century of growth in the laboratory. For the person planning to administer BCG to an infant or the public-health official planning for the vaccination of millions of newborns, more information is needed. Is there a “most protective BCG”? Is there a “safest BCG”? Are these necessarily different? Unfortunately, answers to these questions cannot yet be given.
Regardless of whether the future involves specific BCG strains, a genetically altered BCG, or a completely new vaccine, one hopes that those currently providing BCG vaccines will be prepared to validate laboratory observations in the field, so that we are not again left with the uncertainty of vaccinating millions each year without a clear understanding of its risks and benefits.

The BCG vaccine has been given to 4 billion people since 1921, and to more than 90% of the children in the world today, however, it has done little to contain the current tuberculosis pandemic. Despite evidence of confirmed efficacy against childhood tuberculous meningitis and miliary tuberculosis, protection induced by BCG can wane within a decade.
Tuberculosis remains a disease of poverty that is inextricably associated with overcrowding and undernutrition. Our fundamental understanding of the pathogenesis of this disease is inadequate. Despite substantial progress in worldwide tuberculosis control, it is unclear why tuberculosis incidence is only falling at a rate of less than 1% per year. To eliminate tuber culosis as a public health problem by 2050, incidence must fall by an average of 16% yearly over the next 40 years.

The BCG vaccine has been used since 1921 to prevent tuberculosis (TB) and is considered to be the world’s most widely used vaccine. Yet, it is well established that the protective efficacy of BCG varies depending in which geographical location it is administered and we understand very little about why it protects when it does, or why it fails to protect when it does not. There is no simple correlate of BCG-induced protection against TB (meaning that if with other vaccinations it is possible to verify the presence of antibodies, with BCG it is impossible to determine whether it has or as not given any effect).
In man, BCG is still present in vaccination sites at 1 month after vaccination, but data on its longer-term survival are limited. There have been case reports of longer-term survival of BCG (i.e., where an HIV-infected individual developed disseminated BCG 30 years after vaccination).
Certain countries have never given BCG, in order to retain the use of the tuberculin skin test (or the newer IGRA tests) as a means of assessing infection or because the risk of infection is low.

The World Health Organization (WHO) estimates (2012) that approximately one-third of the world’s population are infected with the Mycobacterium. However, only approximately 10% of all individuals infected, most commonly those with lowered immunity, will ever develop active disease. Long before antibiotics were introduced, the typical treatment for TB involved increasing a patient’s immunity through improved nutrition, hygiene and rest (conservative therapies). All of these measures were used at sanatoria and helped to cause and maintain a decline in mortality due to TB throughout the 19th century. Antibiotics and other chemical therapies were introduced in the 1940s and 1950s. However, their use caused the development of drug-resistant bacteria. Some strains have even been observed to be extensively drug resistant and are very difficult and expensive to treat (estimated cost US$500,000–1,000,000 per patient for hospital-based care in high-income countries). In Peru, the incidence of TB has declined 3.7% per year since 1996, but the incidence of cases with drug resistant strains has increased by 4.5%. In Belarus, 35.3% of newly diagnosed TB patients and 76.5% of previously treated patients had multiple-drug resistant TB.
In this article the authors had analyzed the TB mortality rate in several countries and concluded that in Switzerland, 80% of the decline in TB mortality had occurred before the introduction of streptomycin, which had little effect on further mortality rate reduction. In England and Wales and New York, the declines were 90% and 88% complete, respectively, before anti-TB therapies. In Brazil and Japan antibiotics were effective in combination with conservative measures and public health interventions.
In Sierra Leone, the TB mortality rate had increased 3-fold in 20 years, despite availability of antibiotics, which are ineffective. The mortality rate in Japan had rapidly increased in the end of 19th to beginning of 20th centuries. This increase in mortality rate in Japan (and most probably in other countries before statistical data was being acquired) occurred during the initial heavy industrialization.

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. It was later determined that the BCG vaccine had been contaminated with variable amounts of fully virulent M. tuberculosis.
Three lessons that can be learned from the Lübeck disaster. 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, 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.

Active and passive smoking is associated with a doubling of the risk of tuberculosis. In past and present smokers, the risk of infection with the tuberculosis bacterium, the risk of developing tuberculosis, the risk of complications, and the risk of death from tuberculosis are increased.
The risk of recurrent tuberculosis was 2 times higher in those who smoked more than 10 cigarettes a day than non-smokers. In addition: [1] [2] [3] [4]

In people with reduced weight, the risk of tuberculosis was 12 times higher than in people with normal weight. In overweight people, the risk of tuberculosis was 3 times lower, and in obese people 5 times lower.
In the 1950s, it was found that people with vitamins A and C deficiency contracted tuberculosis more often, and the addition of vitamins and minerals reduced the incidence in the patients' families. Since then, no adequate research has been carried out on the effect of nutrients on tuberculosis risk.

The link between diabetes and tuberculosis was originally recognized by Avicenna, and we are rediscovering it today. Diabetics suffer from tuberculosis 3 times more often, HIV carriers – 20 times more often. The risk of tuberculosis is also increased by use of immunosuppressive drugs, such as corticosteroids. The association of drugs for rheumatological disorders treatment with tuberculosis is an emergent problem in developed countries.
The CDC reports that other risk factors for the disease are alcoholism, drug use, homelessness, and jail. In 2015, 470 people died from tuberculosis in the United States.

A meta-analysis of BCG efficacy. Protection in children not stringently tested was 59%. In older individuals the efficacy was lower. Protection was higher in trials further from the equator where environmental mycobacteria are less. Protection against meningeal and miliary tuberculosis was 90%.

The largest double blind randomized controlled trial that was carried out in Chingleput district of south India to evaluate the protective effect of BCG against bacillary forms of pulmonary tuberculosis. 281,161 persons were vaccinated with BCG or placebo by random allocation. Two strains of BCG were used, the French and Danish, with a high dose (0.1 mg/0.1 ml) and a low dose (0.01 mg/0.1 ml) in each strain. The entire population was followed up for 15 years.
BCG offered no overall protection in adults and a low level of overall protection (27%) in children, although there was no statistical significance.
In the first years after the trial start, the vaccinated contracted tuberculosis more often than the unvaccinated. Then, in the period of 5-12 years after the vaccination, the unvaccinated contracted tuberculosis with higher incidence. After 12 years, tuberculosis occurred with higher incidence in the vaccinated again. The same effect was seen in another BCG study in India. In the first 3 years, the vaccinated fell ill more often, and in the period of 3-9 years after vaccination the tuberculosis incidence rate in vaccinated became lower than in unvaccinated. In a British study, on the contrary, in the first 12 years the vaccinated contracted tuberculosis with lower incidence rate, and after 12 years the incidence rate went higher than in unvaccinated. Infants under one month of age were not tested in this study. [1]

A double-blind, randomized controlled trial to evaluate effectiveness of repeat BCG vaccination in northern Malawi (120,000 subjects). The vaccinated contracted leprosy with 49% lower incidence rate, but the tuberculosis incident rate was 69% higher than in unvaccinated.
Other studies in Malawi and Venezuela also found that BCG does not protect against tuberculosis, but protects against leprosy to some extent.
WHO reports that there is no evidence of the effectiveness of revaccination, and it does not recommend it.

A controlled trial of BCG vaccination was conducted in 1950 in the USA.
Throughout 14 years of observation, vaccination accounted for a reduction in tuberculosis of only 14%. Moreover, BCG vaccination had negative efficacy among the African-American population. It was concluded that the BCG efficacy was too low (and least effective among groups most in need of protection), and the protection was too short-term to justify the use of BCG in the US. Thus BCG has never been introduced into the US vaccination calendar.

In children vaccinated with BCG, all forms of tuberculosis are observed, and the disease progresses to the disseminated form in 16% of them. The authors conclude that the protective effect of BCG is possible only with an adequate nutrition and with improved socioeconomic conditions.
Also: 1]

The immunogenicity of tuberculosis vaccines is usually determined by the cytokine profile. In this study, it was found that the cytokine profile post BCG vaccination does not correlate with protection against tuberculosis in any way.

The incidence rate of recurrent tuberculosis in previously infected is 4 times higher than a first-time TB in those who had not previously contracted it. The authors conclude that the fact that the natural disease does not provide protection against recurrent infection may partly explain the ineffectiveness of BCG vaccination.

Sadly, we are no closer to eliminating or even controlling tuberculosis (TB) today than we were when Koch first identified the causative agent, Mycobacterium tuberculosis. Although a meta-analysis of all vaccination data available has yielded a theoretical efficacy rate of 50%, it has been estimated that only 5% of all vaccine-preventable deaths caused by TB could have been prevented by BCG. Thus, BCG is not a satisfactory vaccine. In case of TB, the vaccinologists are faced with a difficult hurdle – to design a vaccine that is superior to the pathogen with regard to the immune response evoked.
Given that T-cells are central to protection against TB, future vaccine design should focus on T-lymphocyte populations. Unfortunately, there is no precedent for this because all successful vaccines in use today work through antibodies rather than T-cells.
Imagine the following scenario: one of the heroes in the TB field proclaims he has developed a therapeutic vaccine for TB based on his success in curing the disease in experimental animals. Because of the reputation of the scientist, and to proceed as fast as possible, controlled clinical trials comprising almost 2000 TB patients are immediately initiated by a governmental agency and the results already provided after 6 months. Due to great economic interest, the product is licensed to a pharmaceutical company, making the investigator a millionaire. The story is true. It occurred between August 1890 when Robert Koch, the highly respected discoverer of the TB bacillus, proclaimed at the 10th International Congress of Medicine that he had found a remedy for TB, and February 1891 when the official report on the clinical trials was published. Unfortunately, the report was crushing, with only 2% cured. We cannot risk such a fiasco again and it is therefore appropriate to ask whether the task of developing a TB vaccine is too formidable, even today.

Long-standing paradigm that a healthy pregnancy implies a sterile uterus is already questioned. Recent studies have extended the observations that placenta is colonized by non-pathogenic bacteria (commensals) and have defined placental microbiome (placentobiome) with specific metabolic functions, which differs in term babies and those born prematurely.
The ability of bacteria to exist as a population of self-replicating forms with defective or entirely missing cell wall (L-forms) is an adaptive mechanism for survival and reproduction of bacteria under unfavorable conditions. It was established that filterable L-forms exist freely in the Bacille Calmette-Guérin (BCG) vaccine and are able to reproduce and to form colonies.
The authors of this study were able to isolate mycobacterial L-forms from the blood of newborn babies whose mothers had been BCG-vaccinated in their infancy. 85% of the obtained paired samples (term placenta and cord blood from one and the same neonate) were positive for mycobacterial L-forms. Placenta colonization with mycobacterial L-forms occurs by maternal blood-to-decidua transfer very early in gestation (1st trimester).
L-forms are able replicate within the L-form cycle or revert to walled bacteria. Recent experiments have shown that L-forms are an independent form of life that can multiply indefinitely as an alternative form of bacterial life. Little is known how long M. bovis BCG as a live strain can survive in the vaccinated persons. There are reports about detection and isolation of BCG bacilli from patients with AIDS many years after their vaccination.
Recently published data showed that conversion of bacteria to L-forms may often result in chronic infections, since L-forms remain slumbered for long periods in the tissues becoming sequestered in protective regions of the body.
Despite large amounts of literature published on L-forms, atypical bacterial forms have been neglected by clinicians for very long time because of difficulty to identify and prove them, even though L-forms can be the cause for latent, chronic and relapsing/recurrent infections, as well as for diseases of unknown infectious-allergic or autoimmune origin.

Patients with Crohn's disease are vaccinated with BCG 3.6 times more often than healthy individuals.

BCG vaccination is associated with a 27% reduction in the risk of leukemia.

Although when considering all types of cancer, BCG vaccination has been associated with an increased risk of cancer by 13%. More: [1] [2] [3]
After BCG vaccination was discontinued on the southern island of New Zealand, and uphold on the northern island, the death rate from non-Hodgkin's lymphoma increased on the northern island and decreased on the southern island, although it was the same before. The authors conclude that the proposals for using BCG against leukemia are unreasonable.

When the BCG vaccine was introduced in the 1920s, it was suggested that it occasionally had nonspecific beneficial effects on mortality beyond the specific protection against tuberculosis. Considering that BCG has since then become the most used vaccine in the world, surprisingly few studies have been undertaken into the effect of BCG on general mortality and morbidity.
Recent studies suggest that BCG has beneficial nontargeted effects on general infant morbidity and mortality in low-income countries, often with the most pronounced effect among girls.
No vaccine in the world has been introduced on the basis of tests that measure their effect on overall mortality and morbidity, except the tetanus vaccine for pregnant women.

Routine infant vaccines currently used in low income countries were not tested in randomized trials for their impact on overall child survival before their introduction. It has been assumed that the impact of a vaccine on mortality is proportional to the vaccine’s efficacy and the contribution of the target disease to overall mortality. The past 15 years of research on vaccines in low income countries, however, have shown that this assumption is not a tenable basis for vaccination policy, since vaccines have important non-specific effects. For example, measles and BCG vaccines have reported significant reductions in all-cause mortality, while Diphtheria-tetanus-pertussis (DTP) and high-titre measles vaccine has been associated with increased mortality, especially in girls.
The study was conducted in Guinea-Bissau to determine whether BCG revaccination at 19 months of age reduces overall child mortality. The trial was stopped prematurely because of a cluster of deaths in the BCG arm of the study. The hazard ratio for BCG revaccinated children compared with controls was 2.69.
The authors believed that this was not related to the BCG vaccinations itself, but to the DTP vaccine, which effect is somehow negatively altered by BCG, and to iron and vitamin A supplements that the children received during the experiment.

A number of observational studies suggest that many African females below the age of one year die each year from the nonspecific effects of DTP vaccination. In contrast, similar studies suggest that many African females and males may have their lives saved each year by the nonspecific immunological benefits of BCG vaccination.
From an immunological point of view, we hypothesise that the adverse effects of DTwP vaccine may occur because of the Th2-polarising effect of the aluminium phosphate adjuvant in the vaccine and because intramuscular administration of the vaccine may cause chronic inflammation at the site of injection. However, the Th1-polarising effect of BCG is likely to be beneficial.
Supplementation with vitamin A, iron, and zinc enhances both the detrimental nonspecific effects of DTP vaccination and the beneficial effects of BCG vaccination.

Study of the nonspecific effects of the vaccine in southern India (11,000 infants). Receipt of either one of BCG or DTP vaccines was associated with significant reductions of one‐half to two‐thirds of mortality hazards. However, the mortality rate was the same for those who received both BCG and DTP.
Girls who received both vaccines experienced 4.5 times higher mortality than those who received only one of the two vaccines.
The authors eliminated deaths in the first week, thinking they could not be due to non‐specific effects of BCG vaccine, and that the high mortality in that first week might cloud relevant associations.

The authors, inspired by the findings of BCG nonspecific effects in third world countries, decided to conduct a randomized BCG study in Denmark. Nonspecific effects were not found. Vaccinated children did not fall ill less than unvaccinated.

According to some studies, systemic infections such as measles, hepatitis A and tuberculosis infections prevent allergies and asthma. This is explained by the fact that some bacterial and viral infections shift the immune response towards Th1.
BCG vaccination, however, does not prevent allergies and asthma.

BCG is the most effective treatment for bladder cancer.

Adult guinea pigs were fed tuberculous sputum. 70% of those who were maintained on a diet partially deficient in vitamin C, developed ulcerative intestinal tuberculosis. In the remaining animals whose diet was supplemented by an adequate amount of vitamin C only 5% developed tuberculous ulcers in the intestines. In the authors opinion, an adequate supply of vitamin C (in the form of tomato juice or cabbage leaves) usually protects the guinea pig against ulcerative intestinal tuberculosis.

A protective effect of vitamin C against tuberculous infections in animals has been described repeatedly. Decreased resistance to tuberculous infection develops in animals fed a vitamin C deficient diet and, conversely, an increased susceptibility to acute scurvy is seen in infected animals.
TB patients excrete less vitamin C in the urine than healthy people, which probably means that the human body’s need for vitamin increases during infection.

The brain and the cerebrospinal fluid (CSF) contain high levels of vitamin C aimed to prevent oxidative injury. Oxidative stress is thought to be implicated in the pathogenesis of TBM (tuberculous meningitis) and other types of meningitis.
Concentration of total serum vitamin C in the TBM group was lower than in controls. Compared to controls, CSF and serum ascorbate were markedly decreased in TBM patients with complications in comparison to those without complications.

Vitamin C kills tuberculosis bacteria in vitro.

Combining vitamin C with tuberculosis medications leads to faster recovery in mice.

High doses of vitamin D were widely used to treat active TB in the preantibiotic era. In 1854, Hermann Brehmer, a Silesian botany student who was suffering from TB, traveled to the Himalayan mountains to pursue his botanical studies and cured his TB.
Low vitamin D levels have been associated with a 5-fold increased risk for progression to TB. More: [1] [2] [3]
A report on the clinical testing of the effects of two doses of vitamin D (600,000 IU) is provided here. The treatment led to an improvement in symptoms.
On the other hand, it was reported that vitamin D supplement demonstrated no overall effect on mortality in TB patients. However, a suboptimal dosage of 100,000 ME had been used. More: [1] [2] [3]

MVA85A is a new subunit vaccine designed as a parenteral booster to be given after BCG. In July 2009, researchers began a clinical trial of this vaccine in 2,800 infants in South Africa. The trial results published in 2013 showed no evidence of added protection.
Before the 2009 efficacy trial in South African babies, it had been tested in mice, guinea pigs, cattle, and monkeys and had also undergone early phase safety and immunogenicity trials in humans. However, in 2015 an independent systematic review of eight studies using 192 animals published between 2003 and 2010 concluded that the data did not provide evidence to support efficacy of MVA85A as a BCG booster. Two studies showed significant protection, but in these MVA85A was given differently from the way it was given in humans. One was in guinea pigs and MVA85A was further boosted with a recombinant fowlpox virus. The other was a mouse experiment when both BCG and MVA85A were given intranasally rather than intradermally.
In a UK study in rhesus macaque monkeys, four of the six macaques given BCG alone survived to the end of the experiment. Worryingly, however, only one of the six macaques that received BCG plus MVA85A survived. This study raised the possibility that MVA85A was unsafe and actually impairing the effectiveness of BCG. All this was known to researchers for a year and a half before the start of tests on infants. Nevertheless, the researchers had suppressed this information when they presented the results at the TB conference in Vancouver in 2007, in funding applications and in applications for conducting human trials. They also failed to communicate it to the parents whose babies participated in the vaccine testing.
Peter Beverley, at that time a principal research fellow at Oxford University, was warried about the absence of the data and repeatedly expressed his concerns about the macaque study. In response, the Oxford University shut down Beverley's laboratory. It also refused to provide the trial protocols to the BMJ.
(Mind you, all this happened in Oxford – the most prestigious university in the world. One can only guess what are the practices in other universities and in the pharmaceutical companies' labs).

The rapid progress of the tuberculous endemy in the 1860s corresponds to the period of industrialization, urbanization and pauperism existing in Europe at that time. Initially, the two professions principally at risk were the lacemakers and the laundresses.
Koch described the bacillus in 1882 and the tuberculin was presented as the first immunotherapeutic product against TB in 1890. The vaccinal treatment with tuberculin ended with the death of 55 of the first 1769 patients treated.
A second candidate for TB vaccine was M. chelonae, live bacillus of Friedmann, which natural pathogenicity for mammals was weak. However the raise of antisemitism and of nationalism resulted in a lawsuit against Friedmann in 1937, the suppression of manufacture of the product in Italy at the demand of Hitler, the burning of the Friedman Institute in Leipzig and a French legal interdiction to use this vaccine, in favor of live attenuated M. bovis.
Children having developed a tuberculous cervical lymphadenitis after drinking milk contaminated with M. bovis appeared protected against more serious forms of pulmonary TB and thus became the third candidate for the TB vaccine. Calmette proceeded to attenuate the bovine bacillus by repeated subculture in vitro for 13 years. This live vaccine provoked a general lymphatic disease in the guinea-pig that was claimed to heal spontaneously within 3 weeks. On the basis of this observation, the vaccine was administered per os to human newborns, despite the fact that the BCG itself was shown to multiply during months in various organs of the guinea pig.
Calmette refused to evaluate the consequences of this last observation. To monkeys at risk, the vaccine lent no protection at all, but Calmette refused to examine either the monkeys or the results. In children, the protective efficacy of the vaccine was wildly exaggerated: the occasional occurrence of meningitis cases in vaccinees was explained by contaminations with M. tuberculosis, which indeed occurred once and served as an explanation for all the cases.
The flaws in the experimental designs set up to prove the efficacy of the BCG, and the misuse of the statistics exploiting the results came to full light when Sweden discontinued the universal coverage of its population and analysed the effects of this measure: the adverse effects were tenfold superior to those commonly reported.
The chairman of UNICEF’s Subcommittee on Medical Projects was the brother of an influencial French politician who needed reconstruction money, pacific heroes and heroic achievements for a country that had emerged in discomfiture from World War II. The Pasteur Institute, BCG and Calmette fulfilled his expectations, and UNICEF offered $3 million to the WHO to endorse the vaccine. The WHO accepted the bribe and popularized the vaccine.
The undisputable epidemiological evidence of vaccine inefficacy shown by a regression of the endemy in non-covered countries at a rate similar to that observed in vaccinated populations was met with procrastination. No heed was given to the disastrous South-India trial (see paragraph 10 above). The claim that the BCG was totally innocuous paralysed the faculty of analysis concerning the BCGitis cases observed after vaccination.

139 children in Papua New Guinea with bacteriological or histological proof of active tuberculosis were given the Mantoux tuberculin test. Only half of the children had positive results (induration of at least 5 mm). Of the children under 2 years, 25 (71%) showed no reaction whatsoever. In non-tropical countries, the Mantoux test seems to show more accurate results.

The Mantoux test contains polysorbate 80 and phenol.
The CDC reports that BCG can cause a false-positive Mantoux reaction, and therefore it is better for the vaccinated to have a blood test (T-spot / quantiferon) to determine if the infection is present.

The methods to differentiate between active and latent tuberculosis have not changed over the past 88 years. Photofluorography, Mantoux test and sputum examination remain the cornerstones of diagnosis.
The sensitivity of Mantoux and T-spot to determine active infection is only 70-90%. Test that are not able to identify the most infected people leave much to be desired.

Of the Western European countries, BCG is still officially included in the national immunization schedule only in Ireland. However, in practice the vaccine stocks ran out in 2015, and since then BCG and Ireland have not been used.

Tuberculosis incidence as a function of GDP in different countries. The higher the per capita income, the lower the incidence.

The TB mortality rate in England decreased by 90% before the antibiotics were introduced. The same is true for the USA. Prior to vaccine research, mortality decreased by 98%.