A Touch of France / “The Savior of Children”—Albert Calmette and the BCG vaccine






Antituberculosis stamp created in 1934, extolling the BCG vaccination and Calmette,
“The Savior of Children.” The first antituberculosis stamp was issued in Denmark in 1904. France followed
suit in 1927. In France, these stamps played a special educational role, and booklets of stamps were
handed out by schoolteachers to schoolchildren who sold them to the public. The proceeds went
towards the fight against tuberculosis. Themes and slogans changed until 1967,
the last year such stamps were produced.

© Comité National contre les Maladies Respiratoires.


“The Savior of Children” Albert Calmette and the BCG vaccine


by A. Perrot, France






Annick PERROT,
Honorary curator of the Pasteur Museum, Paris
FRANCE



Growing up in Nice, in southern France, Albert Calmette (1863-1933) gazed across the bay and dreamt of voyages to faraway lands, of sailing o’er the bounding main. Dreams he realized on joining the French navy, not as a mariner, as in his boyhood musings, but a ship’s surgeon. He sailed the China Seas, traveled on assignment to Gabon, and voyaged to Saint Pierre and Miquelon in the Atlantic Ocean near Canada, where, self-taught, he began his microbiological research. On his return to France, in 1890, Calmette took classes at the Pasteur Institute given by Émile Roux, with whom over the years he forged a lasting friendship. On the recommendation of Louis Pasteur, Calmette was sent to Saigon (now Ho Chi Minh City) to set up a laboratory for the preparation of vaccines against rabies and smallpox. In one year, half a million people were vaccinated against smallpox. It was in Saigon that Calmette oversaw the building of the first Pasteur Institute outside France; the second one, also in Vietnam, was founded in Nha Trang by Calmette’s colleague and great friend, Alexandre Yersin (today there are 32 Pasteur Institutes throughout the world). He worked on anti–snake venom serum there and later, back in Paris, developed antivenom serotherapy. Confident in Calmette’s organizational skills, Pasteur entrusted him with setting up and directing a Pasteur Institute in Lille. Calmette turned it into a model of its kind that played a major part in the industrial and agricultural development of Northern France and in the improvement of public health and social hygiene, and above all, in the fight against tuberculosis. With Camille Guérin, Calmette studied the tuberculosis bacillus and developed what came to be known as the BCG vaccine, which has prevented hundreds of millions of premature deaths ever since.

Medicographia. 2015;37:94-103 (see French abstract on page 103)



Ascourge since antiquity, tuberculosis is blind to merely mortal distinctions of rank, wealth, and kudos. From Egyptian pharaohs to crossing sweepers, from nabobs to panhandlers, over millennia it killed millions. In recent times, tuberculosis was, for more than half a century until the rise of drug-resistant strains in the 1980s, thwarted by the BCG vaccine. B for Bacillus, C for Calmette, G for Guérin. Bacillus—Mycobacterium tuberculosis—the foe, needs no introduction. Guérin (Camille) we will come to shortly. Here, though, our story is that of Albert Calmette.



Albert Calmette in his laboratory, around 1920-1925.

Photo Ph. Henri Manuel. © Institut Pasteur – Musée Pasteur.



Albert, his father exulted, was born “to the booming of cannon saluting the seizure of Mexico City” (instigated by Emperor Napoleon III of France). The year was 1863, the place Nice, in southern France. Albert was the third son, and the last, because before he reached two his mother was dead. Albert’s father then embarked with his children on an itinerant life, following the demands of his career as a high-ranking regional civil servant. Albert grew up at a time when France was building its overseas empire, and his curiosity plunged him into adventure novels and explorers’ tales. Exoticism kindled his taste for discovery, and by the age of 13 Albert had made his choice. A life on the high seas.

A vocation sadly that proved short-lived, curtailed by a severe bout of typhoid fever contracted during his preparatory classes for entry to naval school. By the time his long convalescence was over, the naval school’s doors were closed to him— Albert was already too old. Yet still he dreamed of seeing the world. So instead, he turned to medicine and in October 1881 entered the naval medical school in Brest. Two years later, he was appointed physician assistant in the French navy and enthusiastically wrote to his father: “Now the future is mine.”

His immediate future lay in the China Seas. In November 1883, he boarded the battleship Victorieuse and later the Triomphante in Admiral Courbet’s squadron, which lay at anchor in Halong Bay (meaning, in Vietnamese, “descending dragon bay”), with its myriad islets and grottoes in a karst landscape (now a UNESCO World Heritage Site). The French naval division was on a war footing. Calmette had arrived at a decisive moment of French expansion in the Far East.

China, hostile to the extension to Tonkin of the French protectorate of Annam, was encouraging acts of piracy to which the French responded with an iron fist. Tension was high. Anticipating trouble, the Triomphante cruised along the coast, berthing at various ports, where Calmette had his first glimpse of the vast panorama of Chinese life. Captivated, he observed, studied, and noted. Everything. At Hong Kong, he met the Scottish physician Patrick Manson, who had discovered a developmental phase of filaria in mosquitos. Under the microscope, Calmette saw the various stages of the life cycle of the nematode worm that was the cause of elephantiasis.

Tensions between France and China continued to mount and the failure of diplomatic negotiations triggered the Sino-French War (August 1884 to April 1885). From his first-aid post, Calmette saw action at the Battles of Fuzhou, on 23 August 1884 (a victory for the French), and Tamsui on 8 October 1884 (a victory for the Chinese), the occupation of Keelung, and the capture of the Pescadore Islands. When the signing of a peace protocol ended hostilities, Calmette was recalled to France. Before leaving, he visited Saigon, which he said was “the most agreeable town I’ve seen in the Far East,” adding wistfully “I shall perhaps never return.” Little did he know that Saigon was to play a major part in his career. Back in France, Calmette completed his medical studies, extending Manson’s observations in a doctoral thesis on the “Etiology and pathology of tropical diseases caused by filariae in human blood.”

And then a new departure, this time for Africa, Gabon, where he was to serve aboard the floating hospital the Alceste in Libreville harbor. The year was 1886, and Savorgnan de Brazza, the Italian-born, naturalized French navy officer and explorer, was deploying his legendary energy in preparing an expedition. Calmette’s brother Gaston, the future director of the newspaper Le Figaro, introduced him to this mythical figure. Calmette was sorely tempted to accept the explorer’s offers, but he had recently become engaged to Emilie de la Salle and was loathe to leave her for an extended period of uncertain adventuring.





French (top) and Chinese (bottom) rendering of the naval battle of Fuzhou, on 23 August 1884, during the Sino-French War,
eyewitnessed by Albert Calmette. © Musée de l’Image/H. Rouyer – © 华声轮胎/bbs.voc.com.cn. All rights reserved.




Newlyweds: Albert Calmette donning his naval officer uniform and
his wife Emilie, in 1889. © Institut Pasteur – Musée Pasteur.



Aboard the Alceste, which was reserved for the hospitalization of whites, and ashore, Calmette worked double shifts in tending to the halt and sick, and also spent time studying local diseases like sleeping sickness (African trypanosomiasis) and blackwater fever. He was shocked by the gulf between the goals he and others were striving for—economic development, protection of indigenous peoples and of Europeans— and the scarcity of means. While other doctors, faced with unknown diseases, made do with treating and bandaging, Calmette saw and acted on the need for improved hygiene and living conditions, for preventive medicine, convinced that the civilizing work claimed by the colonialists depended on the development of health protection among the local populations. This was prescient, since discoveries at the Pasteur Institute would soon extend to exotic diseases.

Calmette left Libreville in November 1887 and, after a testing 35-day voyage aboard the Ariège, arrived back in France, where he married Emilie de la Salle in February of the following year. Young and frail, Emilie over the years to come braved, with Albert, journeys to exotic lands of icy wastes or sweltering heat. Their first port of call was Saint Pierre and Miquelon, in April 1888, an odd destination for the newlyweds, a frozen and deserted archipelago buffeted by violent storms or smothered in fog, where cod fishing was the only resource.

At the Naval Hospital, Calmette had his work cut out. Often unwell (he had caught malaria in Africa), he provided medical care for a local population of 6000, which doubled during the fishing season. He cared for the inhabitants in their homes, the length and breadth of the town, and beyond, delivering babies, medicating, performing surgical interventions— everything from amputations to cataracts. He was unfazed by these numerous initiatives and responsibilities: “It was hard going, but oh so worthwhile in my youthful inexperience!” And on top of all this, he still found the time to fit in two English lessons a week and half an hour of fencing every morning. In the evenings, after a demanding day attending to patients, he studied and marveled at microbiology by reading the Annales de l’Institut Pasteur (created in 1887 by the chemist and microbiologist Émile Duclaux), which he had been receiving since his time in Africa. With an oil immersion objective and an incubator sent from France, he set about his research: “without working, enjoying myself, I gathered together a small collection of preparations of all kinds of microbes.”

To hand there was an intriguing conundrum to be solved: salted cod heaped up in the holds of ships were turning bright red. The contaminated flesh was unfit for sale and so the local economy was ailing. To study this “rouge de la morue” (“cod red”), Calmette isolated the microbe, reproduced the spoilage experimentally, proved that the microbe was in the salt from Atlantic saltworks of Cadiz and Lisbon, and showed that sodium sulfite has a preventive action.

In the meantime Félix Le Dantec, one of Calmette’s colleagues in the navy health corps, preempted him by publishing identical results in 1891, without, however, mentioning transmission by salt. Calmette was only 26 years old and self-taught, yet already he had accomplished laboratory work of great relevance to public health and with an industrial application, as long advocated by Pasteur. Even before he entered the Pasteur Institute, Calmette was well and truly of the same stripe as the great man himself.

The French Colonial Medical Service was created in 1890, and Calmette had no hesitation in joining. His aim was to work on tropical diseases, and in preparation he wished to take a 3-month microbiology course at the Pasteur Institute. Yet word of the course’s repute had spread internationally and no places were left. Calmette, though, came to the attention of Émile Roux, one of Pasteur’s closest disciples, who appreciated his work on “cod red,” his enthusiasm, scientific rigor, and technique, and reserved for him a bench in a small laboratory. Roux’s lab assistant Alexandre Yersin had just left, having succumbed to the call of distant horizons in the Far East. And so Calmette joined the course which, he later said, “opened up attractive vistas towards which I shall strive.” This was the beginning of a mutual esteem and friendship between Roux and Calmette that lasted their whole lives.



Children surround Albert Calmette during a smallpox vaccination session in Saigon in 1891. © Institut Pasteur – Musée Pasteur.


When the Colonial Medical Service needed someone to set up a laboratory for the preparation of vaccines against smallpox and rabies in Indochina, it looked to the Pasteur Institute. Thus it was that Pasteur summoned Calmette and explained the mission. “Think it over and let me have an answer soon.” To Pasteur’s great surprise, the young and eager doctor accepted forthwith: “There’s nothing to think over. I’ll leave whenever you wish.”

In February 1891, Albert and Emilie arrived in Saigon, and Calmette set up his laboratory in two rooms at the military hospital. Great was the contrast after Saint Pierre and Miquelon. Despite its muggy climate, Saigon appealed to them—the hospitality of the small French colony, the facilities provided, their house with the supreme luxury of running water and a bathroom, plus a garden.

The first problem Calmette faced was storage of his antirabies vaccine, which contained attenuated virus taken from the spinal cord of rabid rabbits. Throughout the long sea voyage, Calmette had maintained the virus by passing it from rabid rabbit to healthy rabbit, but now his lagomorph population was running low. So Calmette implemented one of Roux’s discoveries: storage in glycerol of rabbit spinal cord containing attenuated virus. Before long, people bitten by “mad dogs” were sent for treatment to Calmette in Saigon, from all over Indochina, but also Singapore, Siam, Java, Hong Kong, and Shanghai.

Calmette also adapted Edward Jenner’s method of vaccination against smallpox, which was endemic and widespread in Indochina. Before the French occupation, smallpox was responsible for 90% of infant deaths, and those that survived were badly scarred, and many were blind, to the point that some villages kept a nearby “hamlet of the blind.” Calmette inoculated the skin of local water buffalos with vaccinia virus and collected vaccine lymph. This method was quickly adopted over a large area, including the Indonesian peninsula and southern China, and 500 000 people were vaccinated against smallpox in just two years.

Calmette pursued his interest in snakebite envenoming and, in his first paper on the subject, recounted how a source of venom was found. “A village in the environs of Bac-Lieu (Cochin- China) was invaded, in October 1891, at the time of the great rains, by a swarm of venomous snakes belonging to the species Naja tripudians or cobra capel. These animals, driven into the native huts by the flood, bit 40 individuals of whom four, as reported to us, died almost immediately. An Annamite was able to capture and enclose in a barrel 19 of these cobras and the administrator of the region, M. Séville, kindly sent them to the laboratory. Fourteen arrived alive. We killed 11 of them immediately to remove their venom glands.” Calmette extracted venom from the glands with glycerol and used the solution to prepare anti–snake venom serum.



Naja tripudians (spectacled cobra), an aggressive snake associated
with a high rate of lethal snakebites. Color engraving, 1872.

© Wellcome Library, London.




The Lille Pasteur Institute, founded by Albert Calmette and
Émile Roux in 1899.

© Institut Pasteur.



Calmette also contributed greatly to the local economy, by investigating the so-called “Chinese yeast” used to ferment rice and so produce an alcohol beverage. He doubled the yield of rice alcohol by means of a fungus which he named Amylomyces rouxii in honor of his teacher and friend Émile Roux. In this, the heyday of the opium trade, he also showed that another fungus, Aspergillus niger, shortened the time needed to ferment opium from one year to 30 days.

And his interests did not stop there. He returned to ideas first formulated in Gabon and began research work on other diseases widespread in Indochina: cholera, dysentery, and filariasis.

Not content with that, Calmette set up the first Pasteur Institute outside France (today, the Pasteur Institute in Ho Chi Minh City). The second, north of Saigon, was the work of Alexandre Yersin, with whom Calmette struck up a real and lasting friendship when they first met in 1891, as Yersin was setting out on an expedition to the Annamite Mountains.

This was the dawn of the Pasteurian epic, which in a few years saw Pasteur’s followers reproduce around the world the model put in place by Calmette, often, like him, in precarious conditions, but always with great adaptability. Researchers, but also hands-on strategists, and military and civilian doctors, all trained in the methods of Pasteur, driven by what amounted almost to fervor. Today, 32 Pasteur Institutes across five continents continue the good work: public health services for local populations, research, and teaching, the only worldwide network of its kind.

After two and a half years in Saigon, Calmette, weakened by dysentery, was recalled to France. At just 30 years old he was appointed a Knight of the Legion of Honor. Keen to continue his research, he wanted to return to the Pasteur Institute where the working atmosphere had so impressed him. Alas, regu- lations forbade a colonial physician from taking a position outside the colonial office, so instead Calmette accepted a position of secretary to the board of health, where he was given a free hand to conduct his personal research in the morning. For two years he resumed his studies of antivenom serotherapy and worked with Amédée Borrel and Yersin on the preparation of antiplague serum.



Camille Guérin (standing) and Albert Calmette (sitting), in their
BCG laboratory, at the Pasteur Institute in 1931. BCG stands for
“bacille de Calmette et Guérin.” © Institut Pasteur – Musée Pasteur.



Pasteur and Roux then entrusted him with the task of creating a Pasteur Institute in Lille, in the north of France, at the request of the board of health and the city council, which, for this new center of serotherapy, public health, social hygiene, and research, wanted “Mr Roux’s students.” Calmette signed a 10-year contract, but stayed on for a quarter of a century. Inaugurated in 1899, the institute met the needs of physicians and hygienists, but also local industrialists, following Pasteur’s advice that pure science, at its noblest, cannot advance a single step without sooner or later using its precious results for the good of industrial applications.

Calmette turned to problems of public health and hygiene, and started by developing biological treatments to clean up waste water using trickling filters (also known as biofilters).

He worked too on hookworm (miner’s anemia), and on his new calling, the study of tuberculosis. Although the disease causing bacillus (Mycobacterium tuberculosis) had been identified in 1882 by Robert Koch, no treatment had yet been produced to stem the progress of the contagion.

The situation was especially bad in industrial towns, where workers lived in overcrowded, unhealthy conditions. In Lille, for example, a city of 220 000, some 6000 among the poverty- stricken had tuberculosis, which killed 1000 to 1200 of them every year. In affected households, infant mortality was 43%. More generally, in early 20th-century France, “consumption” killed 100 000 to 150 000 people each year, nearly one quarter of all deaths. Calmette thereafter single-mindedly pursued the scientific and social fight against tuberculosis until the end of his days.

His first priorities in Lille were to focus on the environment and living conditions, to provide the townspeople with safeguards, and to educate them. He set up the first tuberculosis clinic, the Émile Roux Preventorium (for patients infected by a form of tuberculosis not yet active) in 1901, the Ligue du Nord contre la Tuberculose, which raised public awareness and collected funds, a family sanatorium, a school of nursing and hygiene, and an annex for a nonprofit organization that protected children from infected households by sending them to foster homes in the country.

With these treatment and educational networks in place, Calmette focused on the prevention of tuberculosis. The odyssey began in 1900, with at his side Camille Guérin, his research colleague since the early days in Lille. By 1908 they had shown that successive cultures of bovine bacilli (Mycobacterium bovis), on medium containing cooked potato and glycerinated bile, lose their virulence progressively through successive subcultures.



Various types of tuberculosis bacteria cultures: human, bovine,
biliary, and aviary tuberculosis on glycerinated potato medium (I
to IV); human, bovines and aviary tuberculosis on glycerinated
agar-agar (V to VII). Drawing illustrating Calmette’s work, by Demoulin,
1920. © Institut Pasteur – Musée Pasteur.




Oral administration of the BCG vaccine
to a newborn child by Albert Calmette
on 6 June 1931.

© Institut Pasteur – Musée Pasteur.



The Great War and the German occupation of Lille in 1914 interrupted this promising research. During those dark years, Calmette somehow managed to continue making sera for serotherapy and vaccines, in spite of having to cope with the hardships and restrictions imposed by the war and not least the ordeal of having his wife Emilie being taken hostage in 1918 together with a group of twenty-five prominent women from Lille, and deported and interned for seven months in a war prisoner camp in Holzminden, in Lower Saxony.

The war over, Roux called upon Calmette to become an assistant director of the Pasteur Institute in Paris and to run the bacteriology course there, following the death of the previous incumbent Ilya Metchnikov, who had shared the 1908 Nobel Prize in Physiology or Medicine with Paul Ehrlich for his work on immunity. Calmette and Guérin resumed their experiments on tuberculosis and after 13 years of unflagging work, using cultures from 230 passages in the bile/potato medium, they at last had an effective means of vaccination using live attenuated bacillus, thereafter known as Bacillus Calmette-Guérin (BCG). Satisfied that the BCG vaccine was safe, they vaccinated 120 newborn infants of tuberculous mothers with three oral doses of their BCG culture. Thus began the era of vaccination against tuberculosis.



Cartons of BCG vaccine doses being packed for dispatch throughout the world, at the Pasteur Institute, in 1935.

© Institut Pasteur – Musée Pasteur.



But in 1930, as recognition for his work flowed in from all sides, disaster struck. Terrible news arrived from Lübeck in northern Germany. Seventy-six of 250 children vaccinated with BCG prepared using a strain sent by Calmette in 1929 died of tuberculosis. At the resulting trial, which opened in October 1931, it slowly emerged that the tragedy was not attributable to a recovery of the virulence of BCG, but rather to mistakes perpetrated at the Lübeck laboratory that prepared the vaccine.

Calmette was deeply affected by the Lübeck disaster, which, along with physical exhaustion from years of work and struggle, worsened the heart condition that had afflicted him for some time. Now 70 years old, Calmette was still paying frequent calls on his ailing friend Émile Roux, but declining health forced him to his bed on 24 October 1933, and he died on the morning of 29 October, five days before Roux.

Two years before he died aged 70 in October 1933, Albert Calmette wrote a letter to his children and grandchildren in which he expressed the wish: “I hope that it will be given to me to work until my eyes are closing to the light and that I will fall asleep my soul in peace, conscious of having done that which I have been able.” The wish was granted, and since his death Calmette’s main contribution to humanity—the live BCG vaccine—has protected millions of people around the world and, together with antibiotics and improved hygiene, has helped turn the tide against tuberculosis. In its tribute, the Pasteur Institute said of Calmette: “…his death deprives science of one of its most illustrious servants.”