Diphtheria: A hundred years ago, the first toxoid vaccine

Diphtheria is a serious infection that starts in the throat and can go on to affect other organs and the central nervous system. It is characterized by the formation of a gray "pseudomembrane" of dead cells at the back of the throat. Diphtheria can also cause croup, with patients developing a barking cough as they experience respiratory distress. In mid-19th-century France, diphtheria affected nearly 30,000 people each year and killed half of all children infected with the disease.

Using bacterial toxins to create their own antidote

In 1888, Institut Pasteur scientists Emile Roux and Alexandre Yersin discovered that the bacterium that causes diphtheria, Corynebacterium diphtheriae, is capable of secreting a toxin thought to be responsible for the disease. The diphtheria toxin, as it was named, was the first bacterial toxin to be identified.

Portraits of Emile Roux (left, around 1894) and Alexandre Yersin (right, around 1908). Copyright: Institut Pasteur

Seropathy, which involved inoculating animals with increasing doses of a toxin, emerged in the 1890s. The animals would protect themselves from the toxin by secreting increasing quantities of a specific neutralizing substance known as an antitoxin.

During their experiments, Emile Roux and his associates observed that this substance could be produced in horses and then extracted in large quantities without causing trauma. They decided to inoculate dozens of children at risk of diphtheria with the serum. Twice as many of the inoculated children survived as had been expected. The experiment was a success and marked the beginning of serotherapy. At the Budapest Congress in 1894, Emile Roux was hailed as a hero, a "savior of children." But Roux's associates – Alexandre Yersin of course, as well as Louis Martin and Auguste Chaillou – also played a crucial part with their research and support.

Gaston Ramon, inventor of the diphtheria vaccine

Thirty years later, the Institut Pasteur scientist Gaston Ramon began researching toxoids, bacterial toxins treated by formaldehyde and heat to suppress their pathogenicity.

In 1923, he observed that a precipitate had formed in a recipient containing a toxin and its antitoxin. This was flocculation, a measurable phenomenon used to quantify the neutralization of a toxin by its antitoxin. Gaston Ramon concluded that inoculating a living being with a toxoid would provide immunity from the associated toxin. On December 10, he reported his findings to the French Academy of Sciences.

Canada was one of the first countries to administer toxoids on a large scale. In 1924, under the supervision of Gaston Ramon, the University of Toronto's Connaught Laboratories began producing the diphtheria antitoxin. It was soon made available to the entire Canadian population.

The same year, Gaston Ramon conceptualized the notion of adjuvants, substances that strengthen the immune response when administered together with treatment. His invention of combined vaccines was also a remarkable achievement as it enabled people to be simultaneously immunized against diphtheria and tetanus with the forerunner of today's DTP (diphtheria, tetanus, polio) vaccine. As a result of this and other research, the 1920s saw the development of vaccines for tuberculosis (1921), diphtheria (1923), tetanus and whooping cough (1926), all of which were also fatal diseases.

Gaston Ramon (1886-1963) in his laboratory at the Institut Pasteur in Marnes-la-Coquette, working on diphtheria around 1935-1940. Copyright: Institut Pasteur

In France, the tetanus vaccine was administered to all horses in the army from 1933 onwards. Following the success of that campaign, the vaccine became compulsory in the French army three years later. The diphtheria vaccine became compulsory in children under the age of 18 months from 1938 onwards, leading to a decline in the incidence of diphtheria throughout France until it had virtually disappeared by the 1990s.