In the early 20th century, French bacteriologists Albert Calmette and Camille Guérin at the Pasteur Institute in Lille set out to develop a vaccine to protect against tuberculosis, a potentially severe lung infection that has been responsible for more human deaths than any other pathogen in history. It would take more than a decade of painstaking work before they had a TB vaccine ready to test in humans, but it would be worth the investment. Despite its shortcomings, that vaccine remains the primary tool for preventing the disease 100 years later.
Inspired by English physician and scientist Edward Jenner, who developed the world’s first vaccine after discovering that inoculation with cowpox was protective against deadly smallpox infection, Calmette and Guérin turned to Mycobacterium bovis, a bacterium that infects cows and is closely related to the human pathogen M. tuberculosis. Because M. bovis itself can cause disease in humans, the duo began culturing the bacterium, and soon noticed that adding ox bile to glycerol-soaked potato slices used to grow the bacteria somehow lowered the microbes’ virulence. Starting in 1908, Calmette and Guérin passaged the bacteria to fresh potato slices every three weeks or so—more than 200 times—testing it on animals including guinea pigs, rabbits, cows, monkeys, and horses along the way to monitor its waning deadliness. Even in the throes of World War I, when Germans occupied Lille, the price of potatoes skyrocketed, and ox bile became difficult to get, they kept going.
“It was all empirical,” says Andreas Kupz, a microbiologist at James Cook University in Australia. “At the time there was obviously no genetic modification. . . . All they did was to play around with it.”
Eleven years later, they had bacteria in their cultures that no longer generated disease in a variety of animal models, from guinea pigs to cows. Two years after that, the experimental vaccine, dubbed Bacille Bilié Calmette-Guérin, later shortened to Bacille Calmette-Guérin (BCG), was deemed ready for humans. On July 18, 1921, at the Charité Hospital in Paris, doctors gave an oral dose of BCG to an infant whose mother had died of tuberculosis only hours after giving birth.
“No one knows exactly who made a decision and why . . . but they gave this newborn the BCG vaccine—experimental vaccine, at the time—and that was kind of the beginning,” Kupz says. Despite having been exposed not only by his mother, but by his grandmother, who had clinical tuberculosis, the child never developed any signs of the disease.
As more and more babies received the vaccine, Calmette and Guérin gained confidence in its safety. Their initial report published in 1924 spurred the Pasteur Institute to begin mass production, and a subsequent publication tracking 114,000 vaccinations confirmed that BCG recipients suffered no adverse effects. At the same time, Calmette and Guérin documented a drop in childhood deaths from tuberculosis among those who had been vaccinated. Other countries quickly adopted the vaccination for their own infants.
Despite its widespread use, BCG has its shortcomings. It is not 100 percent protective, for example, and the protection it does provide in childhood often wanes in young adulthood. To this day, no one really knows why, largely because research on BCG dropped off as tuberculosis was all but eliminated from the West thanks to improved hygiene in addition to vaccination. As a result, “TB is still a large problem in the developing world,” says Kupz, who is now working to update the BCG vaccine. Killing nearly 1.5 million people in 2019, it stood as the leading global cause of death from an infectious pathogen, according to the World Health Organization.