INT J TUBERC LUNG DIS 9(9):944–945 FOUNDERS OF OUR KNOWLEDGE © 2005 The Union

Leon Charles Albert Calmette and BCG vaccine

T. M. Daniel Department of Medicine, Center for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio, USA

ALBERT CALMETTE is known throughout the world today because his name is attached to the widely used vaccine against tuberculosis (TB). With his associate, Camille Guérin, he developed bacille Calmette-Guérin (BCG), for which he deserves credit. He was, how- ever, more than simply the person who attenuated Mycobacterium bovis to produce the vaccine. Calmette was born on 12 July 1863 in Nice, France.1 At age 10, he moved with his family to Brest, where he suffered typhoid during an outbreak that swept through the lycée in which he was enrolled. Un- able to join the French navy as a regular mariner be- cause of his typhoid history, he entered the Naval Medical College of Brest in 1881. He earned the title of ‘aide-médecin’ in 1883 and was sent to South-East Asia. There he met Patrick Munson and made obser- vations on lymphatic filariasis under Munson’s tute- lage. Returning to France, he completed his medical studies in Paris in 1886; the title of his thesis was Figure Albert Calmette. Drawing by Robert Conley. ‘Etude critique sur la pathogénie des maladies tropi- cales attribuées à la filaire du sang humain’. Calmette was then sent to the Congo, where he tuted studies of Koch’s tuberculin treatment of TB. spent 2 years before returning to France in 1888. In He quickly concluded that tuberculin therapy pro- that year he married Emilie de la Salle. After 18 months duced more harm than benefit. He nevertheless went on a French island off the coast of Newfoundland on to try tuberculin for the treatment of leprosy, again studying a disease of cod fish, Calmette obtained an with disastrous results. French troops in the region appointment in the French Colonial Medical Service. were plagued with recurrent dysentery, and Calmette He secured a position at the Institut Pasteur in Paris, conducted a number of studies trying to establish a where he studied the new science of bacteriology with bacterial etiology. He focused on a Pseudomonas spe- Émile Roux. cies that he isolated from the blood and colonic ulcers In 1891, on the recommendation of Pasteur, Cal- of persons who had succumbed to diarrheal disease. mette was sent to Saigon, in what was then French He conducted meticulous animal studies, but was un- Indochina, as the founding director of a newly opened able to satisfy himself that the organism was the cause Institut Pasteur in that city.2,3 Calmette was well pre- of tropical dysentery. Calmette was more successful pared for this position. He had already developed a in dealing with rabies and venomous snake bites. He draft plan for a tropical research laboratory, and the established a laboratory for the production of Pas- official documents establishing the laboratory drew teur’s rabies vaccine using rabbit spinal cords, and he heavily upon his draft. developed an antisnake venom serum. Shortly after his arrival in Saigon, Calmette insti- Disabled by dysentery, Calmette returned to Paris and the Institut Pasteur in 1893. There he continued his work on snake venom, developing a polyvalent KEY WORDS: Albert Calmette; BCG; tuberculosis antivenom. He himself was bitten while handling a

Correspondence to: Prof Thomas M Daniel, Department of Medicine, Center for Global Health and Diseases, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-7286, USA. Tel: (ϩ1) 216-368-6321. Fax: (ϩ1) 216-368- 4825. e-mail: [email protected] [A version in French of this article is available from the Editorial Office in Paris and from the Union website www.iuatld.org] Acquisition of drug resistance in MDR-TB 945 snake and was treated with his serum. He recovered, become deputy director of the Institut Pasteur. Guérin but lost the tip of his right index finger. joined him there, and they continued their work with Recognition and fame came to Calmette. He was BCG. Two years later they were ready to give their made a Chevalier of the Légion d’Honneur in 1893. vaccine to a human. They collaborated with Drs Ben- He was elected to the French Academy of Science in jamin Weill-Hallé and Raymond Turpin at the Hôpi- 1907 and to the Academy of Medicine in 1919. In tal Charité in Paris, and in July 1921, they gave 6 mg 1920 he presided over the first meeting of the Inter- of BCG orally to a 3-day-old infant whose mother national Union Against Tuberculosis. had died of pulmonary TB (PTB) the day following When the city of Lille raised money to establish a the birth. The baby was to be placed in the care of its new branch of the Institut Pasteur in 1895, Calmette grandmother, who had smear-positive PTB. Addi- was chosen as its director. He recognized TB as the tional doses of BCG were given on the fifth and seventh city’s major health problem; the TB death rate was day of the infant’s life. When examined at 6 months, approximately 300/100 000 population/year. Calmette the child was well and showed no signs of TB, despite decided that his work in the new institute would fo- being almost constantly exposed to its grandmother. cus on this disease. He opened a TB clinic in 1891, the Cautiously, Calmette and his colleagues gave BCG first such clinic in France, and France’s first public TB to additional children, including his own grandchil- hospital in 1905. He had not completely abandoned dren. By 1928 more than 100 000 doses had been the tropical world, however, and in 1912 he pub- given and the vaccine had become accepted. In the lished an analysis of tuberculin reactivity in several spring of 1930 in what Calmette called ‘le catastrophe French colonies based on data received from those de Lübeck’, 251 young children were mistakenly areas.4 given virulent cultures of M. tuberculosis instead of Calmette was joined by Guérin in 1897, and to- BCG. Sixty-seven died of TB. Others were less seri- gether they began the work that would lead to BCG.5,6 ously afflicted, but only 72 remained healthy. Cal- They obtained a culture of M. bovis from Edmond mette himself led the investigation of the incident.7 Nocard in Paris; he had isolated the organism from Despite exoneration of the vaccine, this incident dra- the udder of a tuberculous cow in 1902. Frustrated by matically slowed acceptance of BCG. Not until the clumping of organisms in their liquid medium cultures, vaccination campaigns led by Johannes Holm in post- they added ox bile to their culture medium in 1908. World War II Europe was BCG again widely accepted. Not only did this promote more dispersed growth, Calmette never recovered his optimism and cheer- but for the first time a substantial decrease in the vir- ful disposition after the Lübeck disaster. He continued ulence of the organism for guinea pigs was noted in to work at the Institut Pasteur, and became increas- subsequent passages. More than 200 passages in cul- ingly preoccupied with the rise of German Naziism. tures and laboratory animals followed, and in 1913 He died on 29 October 1933 at the age of 70. they were ready to inject the now attenuated M. bovis into cows for evaluation as a protective vaccine. War erupted in Europe, and German armies swept References across northern France, laying siege to Lille. After 10 1 Sakula A. BCG: who were Calmette and Guérin? Thorax 1983; days of nearly constant artillery shelling, the city fell 38: 806–812. to the invaders. Nine cows had been vaccinated and 2 Gelinas J A. Albert Calmette. The Saigon years 1891–1893: a then challenged with virulent M. bovis. The Germans historical review. Mil Med 1973; 138: 730–733. requisitioned the animals for slaughter to feed their 3 Guénel A. The creation of the first overseas Pasteur Institute, or the beginning of Albert Calmette’s Pastorian career. Med Hist soldiers, but with the collusion of veterinarians of the 1999; 43: 1–25. invading forces, Calmette and Guérin were able to 4 Calmette A. Enquète sur l’épidémiologie de la tuberculose dan autopsy the animals. None had TB. As the war con- les colonies françaises. Ann Inst Pasteur 1912; 26: 497–514. tinued, the Germans began taking civilian hostages. 5 Daniel T M. Captain of death: the story of tuberculosis. Roch- On 12 January 1918, Calmette’s wife was sent to ester, NY: University of Rochester Press, 1997. 6 Moore D F. The history and development of the BCG. Practi- be interned in Germany until 1919, after the end of tioner 1983; 227: 1–3. the war. 7 Calmette A. Épilogue de la catastrophe de Lübeck. Presse Méd In June 1919, Calmette was recalled to Paris to 1931; 39: 17–18.