Science

The history of BCG, the most widely used vaccine in the world and 100% made in France

Riddle: what do potatoes and beef bile have in common? Answer: tuberculosis. These two ingredients have indeed served for 13 years as culture media for the tuberculosis bacillus for the development of the final vaccine, BCG (bacillus of Calmette and Guérin), which will soon celebrate its centenary.

The BCG vaccine has since been administered to nearly three billion people

July 18, 1921, everything was happening in Paris, at the Charité hospital, which has now disappeared, in the current Campus Saint-Germain-des-Prés of the University of Paris, at 45 rue des Saints- Fathers. For the curious who think of looking up, a plaque hung on the wall in the hall, testimony of the first administration of BCG to a newborn condemned to develop the disease, his mother and his two grandparents then contaminated by the bacillus tuberculosis patient having expressed their refusal to separate from the child. Absolute success for the infant who will grow up safely and the beginning of the BCG adventure for millions of others around the world.

These three letters definitively passed down to posterity are the fruit of the work of two French Pasteur researchers, a doctor, Dr Albert Calmette (1863-1933), and a veterinarian, Camille Guérin (1872-1961), both determined to do battle. with one of the greatest plagues of the time, phthisis (or white plague), in short, tuberculosis.

As a reminder, at the start of the 20th century, it was estimated that this extremely contagious and complex disease, pulmonary but also extrapulmonary (see box below), was responsible for around 150,000 deaths per year, only in France.

Tuberculosis, a complex disease

The disease, which is only contagious by air in its pulmonary form, is complex because it can affect many organs other than the lung (lymph nodes, bones, meninges, kidneys). It actually evolves in several stages. After contact with the tubercle bacillus, one third of people develop primary tuberculosis infection. In 90% of cases, the bacteria remain at rest in the body: it is latent tuberculosis infection, without symptoms and not contagious. But in 10% of cases, after a few months or years, the bacteria develop and disseminate in the body through the bronchi, blood or lymph. This is called “disease tuberculosis” or “active tuberculosis”.

Of all the vaccines available today, BCG remains the most widely used across the planet and has since been administered to nearly three billion people. 100% made in France, it is still used to this day, its administration having been made compulsory in 1950 and suspended in 2007. If it has obviously saved millions of lives, we must keep in mind that the killer bacteria, the bacillus de Koch (BK, named after the German doctor who isolated him in 1882) remains today, a hundred years after the discovery of BCG, still responsible worldwide for a million and a half deaths and nearly 10 million new cases, two-thirds of them in eight countries in Asia and Africa.

Yes, you read that correctly, 1,500,000 people still die each year from tuberculosis, despite the existence of a vaccine (which mainly protects children from severe forms but less well adults) and the development of different treatments. antibiotics to be followed for several months, sometimes even years, in case of resistant forms. Because the bacillus has adapted, to the chagrin of researchers who are still striving to find new vaccines, develop tests to improve diagnosis and develop shorter and less toxic treatments.

“Tuberculosis is above all a disease of poverty”

So many advances which, to materialize, would require financial investments far greater than those available to the teams. “We need to better understand the very specific immunity of this bacterium, which is much more complex than that of SARS-CoV-2”, underlined Olivier Neyrolles, director ofInstitute of Pharmacology and Structural Biology (CNRS / University of Toulouse) and CNRS 2021 silver medal at an online conference on June 17 entitled “A tremendous success, but not enough” (available in replay). “But the sums allocated to the development of new anti-tuberculosis vaccines have nothing to do with the billions invested since the start of the pandemic for anti-Covid vaccines, recalls the researcher. Tuberculosis is first and foremost a disease of poverty, a perfect correlation between countries’ gross domestic product and the incidence of the disease. “

Pgo back and time travel. If BCG was born in 1921, it was following a meeting twenty years earlier between two very different men initially working on smallpox. One is a doctor, Albert Calmette, an adventurer who has already stayed in China, worked in the Congo. The other is a provincial veterinarian, Camille Guérin, who has never left his native Poitou but who was marked, at the age of 10, by the death of his father, struck by BK. The fate will beset again on his family a few years later, in 1918, when he will also lose his wife, carried away by tuberculous meningitis.

In the laboratories of the Instituts Pasteur in Paris and Lille, where the two men are working hard, one goal: to develop the anti-tuberculosis vaccine so much hoped for. Thirteen years of trial and error will be necessary, as many repeated and meticulous manipulations, successive cultures of the bacillus on slices of potatoes macerated in glycerinated beef bile, before obtaining a live attenuated bacillus, the form usable for the vaccine. .

In 1909, at the fifteenth passage, the bacterium is no longer virulent in cattle but still is in horses. It was not until 1921 that the two men moved on to human experimentation with the Parisian newborn. However, the sky will not be completely serene for BCG. If the first years go smoothly, the vaccine being administered to hundreds of children with very good tolerance, in 1930, a thunderclap from Lübeck (Germany) will break the honeymoon. In this city across the Rhine, 242 children are vaccinated but 68 die of tuberculosis. Insofar as the strains supplied to Germany came from Paris, suspicion immediately fell on the two inventors of BCG who would then receive numerous letters of insult, which Guérin would intercept so that Calmette was unaware of them and did not be unaffected by these unfair accusations. The investigation will finally prove accidental contamination of the vaccine by virulent tuberculosis bacilli and exonerate BCG.

Calmette and Guérin will refuse to file a patent for their vaccine

Today, it is near Châtellerault, in Vouneuil-sur-Vienne, in the family home of Camille Guérin, that the great-grandson of the veterinarian, Sylvain Thénault-Guérin, has been leading for more than twenty years, with the same stubbornness and determination as his ancestor, a mission: to maintain the memory of the works of his famous ancestor.

In the family house, surrounded by a park with trees older than the vaccine, are piled up photos, drawings, handwritten letters, press articles … The descendant of Camille Guérin, a real man-orchestra, who created his association , always has a project in mind: organize an exhibition to celebrate the vaccine (it’s done), plan the various commemorations-memories according to the calendar (soon July), participate in a documentary film on the history of BCG (done), write a book (in progress), work with researchers from the Institut Pasteur de Lille for a scientific conference scheduled for next fall… nothing is stopping him.

Among the treasures of his family museum, period newspapers, a filmed and sound archive of Camille Guérin in front of his bench. A few moving minutes where we hear the voice of the researcher evoking (finally) the obtaining of “a good, harmless little bacillus”. Important detail, Calmette and Guérin will refuse to file a patent so that the vaccine is freely accessible to all researchers and today, a few laboratories around the world continue to produce it. So, see you on July 18 under the plaque in the hall of the Saints-Fathers faculty?

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