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History of BCG vaccine – Calmette, Guerin, Lubeck

The history of the BCG vaccine starts with Albert Calmette and Camille Guerin. They were two French scientists who from 1905 had been working on developing a vaccine against TB. BCG is an abbreviation of Bacillus Calmette-Guerin, meaning the bacilli of Calmette and Guerin.

Between 1905 and 1918, Calmette and Guerin carried out research into the mechanisms of tuberculosis infection. They demonstrated that small doses of injected and weakened animal bacilli could be used as a protective vaccine against TB, in cattle and various species of monkey. So they then cultured the bacillus, and found that successive culturing weakened the bacillus.

Albert Calmette the French scientist who helped develop the BCG vaccine

Albert Calmette

Calmette and Guerin tried to produce ever more weakened strains of the bacillus by successive sub culturing every three weeks. The research had to stop during the first world war, but was resumed in 1918. By 1921 the tubercle bacillus had been sub cultured 230 times, and it was so weakened that it was believed that it could confer immunity without causing disease in humans.1Calmette A, “L’ninfection bacillaire et la tuberculose chez l’homme et chez les animaux , 1922 2Calmette A, “Preventive vaccination against tuberculosis with BCG”, Proc Roy Soc Med, 1931; 24: 85-94www.ncbi.nlm.nih.gov/pmc/articles/PMC2182232/

The first use of the BCG vaccine in humans

The BCG vaccine was first used in humans in 1921 when it was given to a child in Paris by Dr Weil-Hale. The baby’s mother, who had tuberculosis, had died just after the baby was born, and the baby was due to be brought up by its grandmother who also had tuberculosis. The baby was given 6 mg. of BCG orally, and was said to have developed into a perfectly normal boy. During the next three years (up to July 1924) a further 317 infants were also vaccinated.3Calmette A, “Preventive vaccination against tuberculosis with BCG”, Proc Roy Soc Med, 1931; 24: 85-94 www.ncbi.nlm.nih.gov/pmc/articles/PMC2182232/

The effectiveness and safety of the BCG vaccine

In 1927 and 1928 there were a number of publications from Calmette reporting on the BCG vaccination of children between 1924 and 1927, as well as between 1921 and 1927. Calmette said that between 1921 and 1927 969 children had been vaccinated, of whom 303 had mothers with TB, and the remainder had close contact with the disease. Of these children only 3.9% died of either tuberculosis or of other unspecified causes, and the comparable rate for unvaccinated children was 32.6%.4Calmette A, “La Vaccination Preventive contra la Tuberculosis”, Masson et Cie, Paris, 1927)
There was significant criticism in the medical press of Calmette’s figures. This included criticism of the enormous rate of mortality from TB that was said by Calmette to normally apply to the children of those with TB, as well as children exposed to massive infection.5Greenwood M, “Professor Calmette’s statistical study of B.C.G. vaccination”, BMJ, 1928, 793-795www.ncbi.nlm.nih.gov/pmc/articles/ This was to be just the start of what was to be a long running debate about the effectiveness of the BCG vaccine. Despite this, at the Conference of the League of Nations in Paris in 1928, the vaccine was recognized as safe and its use was encouraged.

Calmette’s main fear at this time was about the safety of the vaccine, and whether the weakened BCG bacilli, having lived for a certain time in an organism, could once again become virulent.6Calmette A, “Preventive vaccination against tuberculosis with BCG”, Proc Roy Soc Med, 1931; 24: 85-94 www.ncbi.nlm.nih.gov/pmc/articles/PMC2182232/

The Lubeck disaster

The history of the BCG vaccine nearly came to an end in 1930 when the Lubeck disaster occurred. This also cast doubts on the safety of BCG. In the German city of Lubeck 252 infants were given BCG that came originally from the Pasteur Institute in Paris, but it was prepared for administration in the TB laboratory in Lubeck.

Seventy two of the children developed TB and died within a year as a result of the disease. A subsequent investigation carried out by German TB experts, revealed that the vaccine had become contaminated with the distinct virulent human strain during its preparation at a local laboratory. Two people who had worked in the local laboratory were sent to prison in 1932 for “bodily injury due to negligence.”7“Appeal Taken from the Decision in the Lubeck Case”, JAMA, 1932; 98(15):1316-1317 http://jama.ama-assn.org/content/98/15/1316.extract

Although the BCG vaccine itself was eventually exonerated as the cause of the Lubeck disaster, its use declined for several years afterwards. Particularly in England a number of people felt that:

“Calmette’s views as to the freedom from danger of this method of treatment have not been universally accepted. Fears have been expressed that a virulent strain of bacilli, when injected into the human body, might regain its virulence.”

Dr G. B. Dixon, Chief Tuberculosis Officer, City of Birmingham8Dixon, G “Pulmonary tuberculosis in childhood”, BMJ, 1931, 694-697www.ncbi.nlm.nih.gov/pmc/articles/PMC2314871/

These fears though were to prove unfounded, and eventually, with a resurgence of TB during the second world war, the BCG vaccine was again used on a massive scale and public confidence in its safety was restored.

The BCG vaccine – different strains

The BCG vaccine was disseminated throughout the world in the late 1920s, and then each country maintained its own supply. At these other laboratories BCG was propagated in the same conditions as at the Pasteur Institute, and with the same aims. These aims were to prevent BCG from reverting to the virulent form, whilst preserving its potency, and hence its effectiveness. Over the course of the next few decades each of these laboratories developed its own sub strains, or “daughter strain” of BCG. These became called by the laboratory, country or person’s name with which they were associated, for example the Moscow and Gothenburg strains.9Behr, M “BCG – different strains, different vaccines?”, The Lancet Infectious Diseases, 2002, 86www.thelancet.com/journals/laninf/article

The effectiveness of the BCG vaccine

There have been a number of controversies concerning the prevention of TB, and one of these has been concerning the efficacy or effectiveness of the BCG vaccine. In various clinical trials the estimates of effectiveness have ranged from 80% protection to no benefit, and the reasons for these differences are still not clearly understood.((Kernodle, D “Decrease in the Effectiveness of Bacille Calmette-Guerin Vaccine against Pulmonary Tuberculosis”, Clin Infect Dis, 2010, 177 cid.oxfordjournals.org/content/51/2/177.full The history of the BCG vaccine is still not over.

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1. Calmette A, “L’ninfection bacillaire et la tuberculose chez l’homme et chez les animaux , 1922
2. Calmette A, “Preventive vaccination against tuberculosis with BCG”, Proc Roy Soc Med, 1931; 24: 85-94www.ncbi.nlm.nih.gov/pmc/articles/PMC2182232/
3. Calmette A, “Preventive vaccination against tuberculosis with BCG”, Proc Roy Soc Med, 1931; 24: 85-94 www.ncbi.nlm.nih.gov/pmc/articles/PMC2182232/
4. Calmette A, “La Vaccination Preventive contra la Tuberculosis”, Masson et Cie, Paris, 1927)
There was significant criticism in the medical press of Calmette’s figures. This included criticism of the enormous rate of mortality from TB that was said by Calmette to normally apply to the children of those with TB, as well as children exposed to massive infection.((Greenwood M, “Professor Calmette’s statistical study of B.C.G. vaccination”, BMJ, 1928, 793-795www.ncbi.nlm.nih.gov/pmc/articles/
5. Greenwood M, “Professor Calmette’s statistical study of B.C.G. vaccination”, BMJ, 1928, 793-795www.ncbi.nlm.nih.gov/pmc/articles/ This was to be just the start of what was to be a long running debate about the effectiveness of the BCG vaccine. Despite this, at the Conference of the League of Nations in Paris in 1928, the vaccine was recognized as safe and its use was encouraged.

Calmette’s main fear at this time was about the safety of the vaccine, and whether the weakened BCG bacilli, having lived for a certain time in an organism, could once again become virulent.((Calmette A, “Preventive vaccination against tuberculosis with BCG”, Proc Roy Soc Med, 1931; 24: 85-94 www.ncbi.nlm.nih.gov/pmc/articles/PMC2182232/

6. Calmette A, “Preventive vaccination against tuberculosis with BCG”, Proc Roy Soc Med, 1931; 24: 85-94 www.ncbi.nlm.nih.gov/pmc/articles/PMC2182232/

The Lubeck disaster

The history of the BCG vaccine nearly came to an end in 1930 when the Lubeck disaster occurred. This also cast doubts on the safety of BCG. In the German city of Lubeck 252 infants were given BCG that came originally from the Pasteur Institute in Paris, but it was prepared for administration in the TB laboratory in Lubeck.

Seventy two of the children developed TB and died within a year as a result of the disease. A subsequent investigation carried out by German TB experts, revealed that the vaccine had become contaminated with the distinct virulent human strain during its preparation at a local laboratory. Two people who had worked in the local laboratory were sent to prison in 1932 for “bodily injury due to negligence.”((“Appeal Taken from the Decision in the Lubeck Case”, JAMA, 1932; 98(15):1316-1317 http://jama.ama-assn.org/content/98/15/1316.extract

7. “Appeal Taken from the Decision in the Lubeck Case”, JAMA, 1932; 98(15):1316-1317 http://jama.ama-assn.org/content/98/15/1316.extract

Although the BCG vaccine itself was eventually exonerated as the cause of the Lubeck disaster, its use declined for several years afterwards. Particularly in England a number of people felt that:

“Calmette’s views as to the freedom from danger of this method of treatment have not been universally accepted. Fears have been expressed that a virulent strain of bacilli, when injected into the human body, might regain its virulence.”

Dr G. B. Dixon, Chief Tuberculosis Officer, City of Birmingham((Dixon, G “Pulmonary tuberculosis in childhood”, BMJ, 1931, 694-697www.ncbi.nlm.nih.gov/pmc/articles/PMC2314871/

8. Dixon, G “Pulmonary tuberculosis in childhood”, BMJ, 1931, 694-697www.ncbi.nlm.nih.gov/pmc/articles/PMC2314871/

These fears though were to prove unfounded, and eventually, with a resurgence of TB during the second world war, the BCG vaccine was again used on a massive scale and public confidence in its safety was restored.

The BCG vaccine – different strains

The BCG vaccine was disseminated throughout the world in the late 1920s, and then each country maintained its own supply. At these other laboratories BCG was propagated in the same conditions as at the Pasteur Institute, and with the same aims. These aims were to prevent BCG from reverting to the virulent form, whilst preserving its potency, and hence its effectiveness. Over the course of the next few decades each of these laboratories developed its own sub strains, or “daughter strain” of BCG. These became called by the laboratory, country or person’s name with which they were associated, for example the Moscow and Gothenburg strains.((Behr, M “BCG – different strains, different vaccines?”, The Lancet Infectious Diseases, 2002, 86www.thelancet.com/journals/laninf/article

9. Behr, M “BCG – different strains, different vaccines?”, The Lancet Infectious Diseases, 2002, 86www.thelancet.com/journals/laninf/article

The effectiveness of the BCG vaccine

There have been a number of controversies concerning the prevention of TB, and one of these has been concerning the efficacy or effectiveness of the BCG vaccine. In various clinical trials the estimates of effectiveness have ranged from 80% protection to no benefit, and the reasons for these differences are still not clearly understood.((Kernodle, D “Decrease in the Effectiveness of Bacille Calmette-Guerin Vaccine against Pulmonary Tuberculosis”, Clin Infect Dis, 2010, 177 cid.oxfordjournals.org/content/51/2/177.full