Brief History: The century situation of BCG vaccine

Brief History: The century situation of BCG vaccine. Will humans still be vaccinated against the COVID-19 vaccine in a hundred years? Let’s first understand the century situation of BCG vaccine.

Let’s first do a thought experiment. Suppose you have traveled through the time tunnel, and one day 100 years later, you find that humans at that time need to be vaccinated as soon as they are born. You are curious to know what kind of vaccine it is. Someone told you it is called “Covid-19 vaccine”. When you find out that you are still vaccinated with the COVID-19 vaccine that has been vaccinated 100 years ago, will you be surprised: “How can this infectious disease have not been controlled for a century? After 100 years of scientific development, why can’t humans be conquered? What about this infectious disease?”

So I’m sorry to tell you that if the perspective is pushed back a century from now, people at that time might have similar thoughts. At the beginning of the twentieth century, tuberculosis was a disease that seriously threatened human health. In 1921, the BCG vaccine formally came out to prevent human tuberculosis. People at the time were full of confidence and expected that tuberculosis would soon become history. But a century later, we are still vaccinated with BCG vaccine, and tuberculosis is still an important infectious disease threatening human health worldwide. Today we will introduce in detail the birth of BCG and the situation in the next century.

Why tuberculosis became a white plague?

Current research has found that tuberculosis may have existed in humans in sporadic form as early as 8,000 BC. When the human society gradually developed into a relatively stable agricultural society, the colony made tuberculosis disease a popular infectious disease. Archaeology found that there were spinal deformities caused by bone tuberculosis in ancient Egyptian mummies around 3000 BC.

From the Middle Ages in Europe, to the Renaissance, to the 19th century after the Industrial Revolution, the burden of human tuberculosis increased sharply, and its prevalence in Europe reached its peak in the late 19th century. At the beginning of the industrial revolution, the spread of tuberculosis reminded people of the plague, the “black death” that ravaged Europe, and was called the “white plague” because of the thin and pale faces of tuberculosis patients.

At that time, tuberculosis was the deadliest infectious health problem, accounting for 15% of human deaths among all socioeconomic groups. The prevalence and industrialization of tuberculosis in Europe in the 19th century are inseparable. Industrialization has led to the density of humans in cities, and the increase in population density and poor sanitation have promoted the epidemic and spread of tuberculosis in cities.

Colonization followed industrialization, which in turn led to the spread of the disease from Europe to the Americas and Asia.

Koch’s contribution

German scientist Robert Koch had been engaged in bacterial culture and staining research for 6 years before discovering the pathogenic bacteria of tuberculosis, and he had conducted groundbreaking research on the bacteriology of anthrax, which was recognized by the scientific community. After 8 months and countless failures, Koch announced on March 24, 1882 that he had discovered the pathogen that caused tuberculosis.

Because of this, the World Health Organization has designated March 24 every year as World Tuberculosis Day since 1995.

Koch conducted a detailed and in-depth study of the biological characteristics of the bacteria that cause tuberculosis, which greatly expanded the technical and microbiological knowledge of tuberculosis. Koch used tuberculosis as a model to describe the standard of bacterial causality, which was later called the Koch hypothesis. This standard quickly became the cornerstone of the rapidly evolving microbiology.

Tuberculin

In addition to his pioneering work in the etiology of tuberculosis, Koch also discovered a substance called “tuberculin” in 1890. He initially claimed that this substance had proven successful in the prevention and treatment of tuberculosis in guinea pigs. However, the results of animal experiments do not always work in humans.

In order to prove its preventive effect on tuberculosis, a clinical trial using “tuberculin” for tuberculosis treatment was carried out in a Berlin hospital. The results of the study were disappointing. Although infected patients usually show obvious skin reactions to the intradermal inoculation of tuberculin, it has no therapeutic effect on tuberculosis. The skin reaction observed by Koch (later called the “Koch phenomenon”) is actually a delayed-type hypersensitivity reaction.

Although tuberculin does not play a preventive role as a vaccine, the Koch phenomenon has become the basis of a skin test to diagnose whether tuberculosis has ever been infected. It is now called the OT test (old tuberculin test).

Kalmet and Gailing

Despite the mistakes related to the tuberculin incident, some major bacteriological research groups in the world at that time were still working towards the ultimate goal of developing a vaccine that can prevent tuberculosis.

Albert Kalmet (1863-1933) served as a doctor in the French Navy in the Far East, the North Atlantic and French West Africa, and then accepted the post of director of the first branch of the Pasteur Institute, which was located in the French colony at the time Saigon in Indochina.

Kalmet worked in Saigon for two years, during which he presided over the smallpox vaccination for half a million locals; developed buffalo as a source of vaccinia virus production; successfully implemented a rabies vaccination program; and investigated outbreaks of cholera and dysentery . However, his most important scientific contribution in Saigon involved his research on cobra venom and its attenuation, which led to the successful development of the first effective anti-venom protein.

In 1895, Kalmet was selected as the head of the second European Pasteur Institute in Lille, France. There, he started experimental and clinical research on tuberculosis and devoted the rest of his career to it.

Recognizing that new research requires animal expertise, Kalmet enrolled the young veterinarian Camille Guelling (1872-1961) into the institute in 1897. Since then, Kalmet and Gailing began a 36-year collaboration on tuberculosis vaccine research.

Following the example of Jenner, two French scientists invented the BCG vaccine

Do you remember that Jenner used vaccinia virus inoculation to prevent the spread of smallpox? Since the tuberculin discovered by Koch failed to prevent or treat tuberculosis, Kalmet and Gaeling decided not to use bacterial components as vaccines, but wanted to learn from Jenner’s successful experience in those years and use non-pathogenic to humans. , Mycobacteria from animal sources (including cattle and horses, etc.) are used as raw materials for vaccine manufacturing.

In 1904, Kalmet and Geling began to study Mycobacterium bovis isolated from cattle with tuberculous mastitis. They used a special medium developed by themselves to continuously subculture Mycobacterium bovis at 21-day intervals.

The virulence of the Mycobacterium bovis strain is fixed when it is first isolated, and only 0.0001 mg can kill the guinea pig within 40-60 days of inoculation to the guinea pig. They found that the virulence of the new medium increased slightly after the first year of passage, but the successive passages in the following years caused the virulence of Mycobacterium bovis to gradually decrease. By the 39th generation, this strain can no longer kill animals.

On December 28, 1908, Kalmet and Gaeling submitted a paper entitled “A new species of Mycobacterium bovis, maintaining its antigenicity while attenuating its virulence” to the Paris Academy of Sciences. Announcing that they have obtained a “new strain of tuberculosis”, which can be used as a vaccine to prevent tuberculosis. And this Mycobacterium bovis, which was attenuated by Kalmet and Guellin, was named after two people, called Bacille-Calmette-Guérin (Bacille means bacteria), and the vaccine made by this bacteria is called Bacille-Calmette-Guérin (Bacille means bacteria). It is BCG (BCG vaccine).

Promotion of BCG and accidents

The main reason why Kalmet and Gaeling’s early research work on BCG took a long time to develop into clinical application was that the First World War broke out soon after the German army occupied Lille, making their The research was interrupted.

In 1919, Kalmet had to return to Paris from Lille to serve as assistant dean of the Pasteur Institute. Gaelin stayed in Lille to continue the treatment of tuberculosis. After five years, they finally met in Paris, and they continued their fruitful cooperation for 14 years.

Once the safety and effectiveness of the BCG vaccine were proven in animals, the vaccine began to be used in humans. In the early twentieth century, tuberculosis was still a major public health problem, and once the symptoms of tuberculosis appeared, the mortality rate was extremely high. Therefore, the prospect of potential vaccines is considered vital to health.

Unlike the current vaccine experiments that were first carried out in adults, the initial human vaccination was carried out in children. The first baby is a newborn, and one of his family members has a patient with tuberculosis. In 1921, Dr. Benjamin Weil-Hallé used a small spoon to give a small amount of BCG vaccine to newborns. From 1921 to 2021, this historic scene has been a whole century since.

After proving that the first 30 vaccinated babies did not suffer from tuberculosis due to contact with their family members, they can be safely protected. The use of BCG vaccination spread rapidly throughout France and even Europe. Between 1921 and 1926, more than 50,000 children were vaccinated.

Kalmet’s paper reported that the TB death rate among vaccinated TB contacts was 1.8%, while the TB death rate among unvaccinated Paris children was higher than 25%. At the League of Nations meeting held in Paris in 1928, the vaccine was considered safe, had a certain degree of protection, or could prevent severe tuberculosis.

BCG accident

Soon after the BCG vaccine was universally recognized at the conference, a disaster occurred and its safety was seriously questioned. In 1929, in the German port city of Lübeck, after 252 babies received the BCG vaccine made from the Pasteur Institute in Paris, most of the children were infected with tuberculosis, and 72 people died of the disease within a year.

A subsequent investigation by German tuberculosis experts revealed that the vaccine was contaminated with the Kiel strain of human tuberculosis when it was prepared in a local laboratory in Germany.

At first, BCG was condemned as the cause of the Lübeck disaster. Both Kalmet and Gailing were questioned and criticized by the public, and the use of BCG declined in the following years. It was not until the Second World War that the BCG vaccine was used on a large scale again due to the epidemic of tuberculosis, and the public gradually regained confidence in its safety.

Kalmet was frustrated by the long-term litigation related to the Lübeck incident and died in 1933. Gelin has been working on BCG vaccines at the Pasteur Institute until he retires. The contribution of Kalmet and Gailing to tuberculosis is indelible.

Does BCG really work?

The role of BCG in preventing tuberculosis has been the subject of constant debate. Early evaluation of the protective effect of BCG on children showed that the mortality rate of unvaccinated subjects was 25%, while the mortality rate of vaccinated subjects was less than 2%.

However, some people think that using child mortality to represent the effectiveness of vaccines is not a good indicator of observation. Therefore, recent studies have regarded tuberculosis infection instead of death as the end point. However, the protective effect of BCG vaccine varies greatly in different studies. From 80% of American Indians and British children to 14% in the southeastern United States. Therefore, it is difficult to evaluate the impact of vaccines on global tuberculosis control in one sentence.

Why is there such a big difference in research in different places? Different methodological, epidemiological and immunological factors may have caused inconsistent results in the study. Factors such as the rate of environmental mycobacterial infection in the study subjects may confuse the assessment of the immune response. Epidemiological factors include the duration of cohort follow-up; the heterogeneous genetic background of the vaccinated population; their living conditions; and even the influence of the local climate on the viability of the vaccine may interfere with the evaluation of the efficacy of the BCG vaccine.

It can be known from this that even if it is the same vaccine, its protective efficacy may be quite different in different regions and different populations (the COVID-19 vaccine may also have the same situation).

However, the consensus is that BCG can prevent about 80% of miliary tuberculosis and tuberculous meningitis in children, and 50% of pulmonary tuberculosis in adults.

BCG needs new alternatives

BCG has different effects in preventing different forms of tuberculosis in different populations. It is now clear that it is not effective for endogenous reactivation of tuberculosis infection.

For example, if Xiao Ming had been infected with tuberculosis when he was a child, but did not show symptoms, he is in a latent infection state at this time. And when one day in the future, possibly decades later, when tuberculosis may be active under certain circumstances, Xiao Ming will also develop symptoms of tuberculosis. Then the role of BCG vaccine is mainly reflected in the fact that if Xiaoming has never been infected with tuberculosis, then BCG can help prevent tuberculosis, but if he has been infected with tuberculosis, then whether it has been onset (that is, whether it is in latent tuberculosis or active tuberculosis stage). When Xiaoming is vaccinated with BCG, BCG will not produce any protective effect.

For this reason, BCG vaccine cannot play a role in protecting previously infected adults from the disease or preventing the spread of tuberculosis.

In view of the limited protection of BCG, modern vaccinologists have worked hard to develop new methods for tuberculosis vaccines. The elucidation of the complete genome sequence of Mycobacterium tuberculosis may further deepen the understanding of its biological characteristics and propose new methods for vaccines. Such strategies can include subunit vaccines, live attenuated mycobacterial mutants, attenuated viral recombinants and DNA constructs.

Globally, tuberculosis is still the leading cause of death. A large part of the world’s population is infected, and their chances of getting treatment are very low. Every year, there are about 10 million new cases of tuberculosis worldwide; every day, about 4,500 people lose their lives due to tuberculosis. Due to the increasing prevalence of individuals with immunodeficiency, people with higher tuberculosis morbidity and mortality, and the emergence of multidrug resistance of mycobacteria, the impact of the disease has expanded.

Although BCG is certainly not the ultimate solution to tuberculosis, it is still a relatively cheap, safe, and available vaccine. It is still the only vaccine that can effectively prevent human tuberculosis.

How far are we from the new tuberculosis vaccine

Although the tuberculosis bacillus and the new coronavirus, although one is a bacterium and the other is a virus, they are similar in that they are also transmitted through the respiratory tract, which also seriously endangers human health and life.

Although the BCG vaccine was born a century ago, it is not perfect and can only prevent limited tuberculosis. Even so, because mankind has not found a better alternative, it is still a planned vaccination in many countries in the world, including our country, and babies need to be vaccinated as soon as they are born. Mankind urgently needs a more efficient and safe vaccine to prevent tuberculosis infection, so as not to allow the white plague to continue to spread.

The COVID-19 virus may face a similar situation. Although we now have a variety of vaccines, no matter what kind of vaccine is currently considered to be perfect. We must not be complacent and stand still, because the COVID-19 virus is constantly evolving, and only by constantly innovating and improving can mankind achieve “you change and I change, you are faster and I am faster”. Perhaps only in this way will it be possible for humans in a hundred years to no longer need to be vaccinated against the coronavirus.

(source:internet, reference only)

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