Albert Calmette and Camille Guérin cultured an avirulent strain of bovine tuberculosis bacilli for use as a vaccine against tuberculosis in humans.
Tuberculosis, often called consumption, is a deadly contagious disease of humans and other mammals, including primates and cattle. The disease is caused by the bacterium Mycobacterium tuberculosis, first identified by the eminent German physician Robert Koch in 1882. The bacterium can be transmitted from person to person through physical contact or droplet infection (for example, through sneezing). The bacterium can survive in moist or dried sputum for up to six weeks.
Once inside the body, the tuberculosis bacterium, called the tubercle bacillus because of its rod shape, invades lung tissue. Amoeba-like immune system cells called phagocytes attack and engulf the tubercle bacilli, destroying some of the bacteria. Other tubercle bacilli, however, destroy the phagocytes and reproduce to form new bacilli. Bacilli activity eventually damages and inflames large lung regions, causing difficulty in breathing and failure of the body to deliver sufficient oxygen to various tissues. The tubercle bacilli can also spread to other body tissues, where further complications develop. Without treatment, the disease progresses, disabling and eventually killing the victim. Today, tuberculosis normally is treated with a combination of antibiotics and other drugs.
During the late 1800’s, microbiologists, principal among them Louis Pasteur and Koch, established the germ theory of disease,
Albert Calmette.
Koch developed his approach for identifying bacterial pathogens (disease producers) with simple equipment, primarily microscopy. He identified numerous other bacterial agents of disease and classified hundreds of microorganisms (for example, bacteria, protists, fungi), both pathogens and nonpathogens. In 1882, he identified Mycobacterium tuberculosis as the causative agent of tuberculosis in humans from phlegm and lung abscesses of diseased victims. Koch reported his discovery to the Physiological Society of Berlin in March, 1882. In subsequent years, he made additional contributions to microbiology, although he continued to place special emphasis on tuberculosis. In 1890, he discovered that a chemical released from tubercle bacilli elicits a hypersensitive (allergic) reaction in individuals previously exposed to or suffering from tuberculosis. This chemical, called tuberculin, was isolated from culture extracts in which tubercle bacilli were being grown.
When small amounts of tuberculin are injected into a person subcutaneously (beneath the skin), a small inflamed patch develops if the person has been exposed to or is suffering from tuberculosis. This occurs because the infected person’s body produces antibodies against foreign objects such as tubercle bacilli and foreign chemicals (for example, tuberculin) released from tubercle bacilli. Injection of tuberculin into an uninfected person yields a negative response (that is, no inflammation) because the person’s immune system has never been stimulated to produce antibodies against any aspect of tuberculosis.
Tuberculin does not injure tested patients because it is only an extract derived from tubercle bacilli. It is targeted by the immune systems of infected individuals because it is a foreign object. Therefore, Koch’s discovery of the tuberculin skin test was extremely valuable to medicine because it gave doctors a diagnostic tool for identifying unknowing victims and carriers of the disease, thereby limiting its further spread.
The first vaccine to prevent tuberculosis was developed in 1921 by two French microbiologists, Albert Calmette and Camille Guérin. Calmette was a student of the eminent French microbiologist Louis Pasteur at the Pasteur Institute in Paris. Guérin was a veterinarian who joined Calmette’s laboratory in Lille, France, in 1897. Calmette and Guérin focused their research on the microbiology of infectious diseases, especially tuberculosis. In 1906, they discovered that individuals who had been exposed to tuberculosis or who had mild infections developed resistance to the disease. They found that resistance to tuberculosis was caused by the body’s immune response to tubercle bacilli located within the body. They also discovered that tubercle bacilli grown in culture over many generations become progressively weaker and avirulent—that is, they lose their ability to cause disease.
From 1906 through 1921, Calmette and Guérin cultured tubercle bacilli from cattle (Mycobacterium bovis). With proper nutrients and temperature, bacteria can reproduce through binary fission (that is, one bacterium splits into two bacteria) in as little time as thirty minutes. Calmette and Guérin cultivated thousands of generations of tubercle bacilli in a bile-derived food medium over fifteen years, periodically testing the bacteria for virulence (their ability to cause disease) by injecting them into cattle. After many generations, the tubercle bacilli lost their virulence. Nevertheless, these avirulent tubercle bacilli still stimulated the production of antibodies by the cow immune system. Calmette and Guérin had successfully bred a strain of avirulent tubercle bacilli that could not cause tuberculosis in cows but could stimulate immunity against the disease, thereby making the cows immune to virulent tubercle bacilli. Cows that had been vaccinated with the avirulent tubercle bacilli did not develop tuberculosis when they later were injected with virulent tubercle bacilli. They had been immunized against tuberculosis.
There was considerable concern over whether the avirulent tubercle bacillus strain was harmless to humans. Calmette and Guérin continued cultivating weaker versions of the avirulent tubercle bacillus strain that retained antibody-stimulating capacity. By 1921, they had isolated an avirulent antibody-stimulating tubercle bacillus strain that was harmless to humans, a strain they called Bacillus Calmette-Guérin (BCG). In 1922, they began using BCG to vaccinate newborn children against tuberculosis at the Charité Hospital in Paris. The immunized children exhibited no ill effects from the vaccination.
Calmette and Guérin’s vaccine was so successful in controlling the spread of tuberculosis in France that it attained widespread use in Europe and Asia beginning in the 1930’s. Furthermore, Calmette devised a skin test for detecting tuberculosis that was very similar to Koch’s tuberculin test. Unfortunately, Calmette did not live long enough to see very widespread use of the BCG vaccine.
Most bacterial vaccines involve the use of antitoxin or heat/chemical-treated bacteria. BCG is one of the few vaccines that use specially bred live bacteria. Its use sparked some controversy in the United States and England, where the medical community questioned its effectiveness and postponed BCG immunizations until the late 1950’s. Researchers at the University of Illinois conducted extensive testing of the vaccine, and it was eventually adopted in the United States despite ongoing questions among physicians regarding its effectiveness.
Calmette and Guérin’s development of the BCG vaccine against tuberculosis saved thousands of lives across Canada, Europe, and Asia from the 1920’s to the 1940’s and worldwide from the 1950’s onward. Tuberculosis affects primarily newborns, children, and Caucasian males forty years of age and above, although non-Caucasians have a higher mortality rate from the disease. The disease is more common among impoverished individuals and alcoholics. BCG played a very important role in saving many such persons.
Whereas the BCG vaccine was derived from bovine tuberculosis, it is equally effective in inducing antibody production in humans against human tuberculosis because of the two bacterial species’ structural similarities. The human immune system produces antibodies that attack either species of tubercle bacilli. The two bacterial species are shaped similarly and produce nearly identical proteins on which human antibodies are targeted. Therefore, the BCG vaccine is interspecies-specific. The procedure is somewhat similar to English physician Edward Jenner’s 1796 historic treatment of human smallpox using matter from cowpox sores on infected cattle.
A person cannot contract tuberculosis from a BCG injection because this particular bacterial strain cannot damage lung tissue—it is avirulent. Once inside the body, however, its shape and the proteins it produces stimulate human immune system cells called lymphocytes to produce and release special proteins called immunoglobulins (antibodies). The antibodies bind to the BCG bacteria and associated BCG proteins, followed by phagocytic engulfment of the bacteria. Some lymphocytes multiply to become “memory” cells so that the body will have a large supply of anti-BCG antibodies. If the vaccinated person is exposed to virulent tubercle bacilli, then these memory cells will release these anti-BCG antibodies to inactivate the bacteria; the exposed person will not contract tuberculosis.
The avirulent, antibody-stimulating BCG vaccine was controversial in the United States because of its inadvertent conflict with the tuberculin skin test. The tuberculin skin test is designed to identify people suffering from tuberculosis so that they can be treated. Like somebody with tuberculosis, a BCG-vaccinated person will have a positive tuberculin skin test. If a physician is unaware that a patient has had a BCG vaccination and uses the tuberculin skin test on that patient, the doctor will presume that the patient has tuberculosis. Despite this possible confusion, the BCG vaccine has been invaluable in curbing the worldwide spread of tuberculosis. It has not eradicated the disease, however.
With worldwide acceptance of the BCG vaccine in the late 1950’s, medical science obtained a complete set of weapons for battling tuberculosis, a disease that remained prevalent in less developed countries as of the early twenty-first century. Infected individuals can be identified through the tuberculin skin test, which has become a part of most routine physical examinations. Individuals who contract tuberculosis can be treated with a variety of drugs and antibiotics. BCG vaccinations can be given to people in high-risk groups and to health care workers. Together, these approaches have held tuberculosis in check, at least in the developed countries of North America and Europe.
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Tortora, Gerard J., Berdell R. Funke, and Christine L. Case. Microbiology: An Introduction. 8th ed. Redwood City, Calif.: Benjamin/Cummings, 2003. Excellent introductory microbiology textbook for allied health care majors offers a thorough but uncomplicated presentation of the subject. Well written, well organized, and beautifully illustrated. Describes various bacterial, viral, and protozoan pathogens of the respiratory tract, including the Mycobacteria.
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