BCG The only tuberculosis Vaccine

October 3, 2008 by dadmin

The vaccine known as BCG, or Bacille Calmette-Guérin, is officially defined as a living culture of an attenuated form of Mycobacterium bovis, an organism similar to Mycobacterium tuberculosis which is the leading cause of tuberculosis in humans. The vaccine was developed at the turn of the 20th century as part of an attempt to halt the spread of tuberculosis in European industrial cities. This was, and remains, a significant disease that caused a great deal of human misery but, at that time, it was also becoming a significant factor in slowing the economic revolution then being experienced by the Europeans.

Little was known about the cause of the disease up to the last quarter of the 19th century but tuberculosis had become known as the “White Plague” and was a major cause of premature death in the working classes. However, it was by no means confined to the poor and there was little that could be done to stop the spread of the disease except to isolate the patients. Treatment consisted of providing good nutrition and sometimes heroic surgical procedures like collapsing or removing lungs. The clinics or sanitaria were often located in isolated areas such as the tops of mountains. To get a good idea of what conditions were like at that time, the novel The Magic Mountain (1924) by Thomas Mann provides an excellent description of the contemporary treatment. The causative organism was isolated by Robert Koch in 1882 and named M. tuberculosis although, at the time, this observation proved controversial. Koch went on to claim that a sterile filtrate of a growing virulent strain of the tuberculosis organism could act as a vaccine against the disease. Unfortunately this claim proved to be invalid, although the filtrate (“Old Tuberculin”) became a valuable diagnostic agent, producing a marked dermal reaction in a patient who had tuberculosis antibodies even if clinical signs of the disease were not present.

Spread mainly as an airborne droplet infection, the disease remains prevalent in overcrowded communities, such as those found in industrial cities of the time. Today the disease has often become associated with AIDS. In France the disease was endemic among the working classes of the city of Lille. In 1894 the physician Albert Calmette was sent from the Institut Pasteur in Paris to set up a branch laboratory devoted to studying the disease in the community and, if possible develop a vaccine against it. Calmette was mainly interested in the social impact of the disease and spent much of his time organizing clinics and obtaining relief for the factory workers affected by the disease.

He was joined in 1897 by Camille Guérin, a microbiologist. In 1908 they discovered accidentally that the addition of a bile extract to a growing culture of tuberculosis isolates allowed the hydrophobic cells to be dispersed more evenly, thus allowing reproducible samples to be taken more readily from the growing culture. Using an extremely virulent bovine strain of tuberculosis (the original culture has been lost so the designation may not be correct) they started what turned out to be a long process of progressively affecting the virulence of the organism by passage. The organism is very slow growing so this process involved growing a culture for 3 weeks and placing a sample in a fresh sterile broth which was then grown for another 3 weeks and so on. It took a total of 13 years and 231 transplants for the organism to lose its virulence, initially to a series of different animals such as mice, rats, and guinea pigs. Eventually the investigators became convinced that it was safe to test in humans. It is interesting to note that virulence of this organism has never been restored. The immunological protection, although it has never been lost, has been affected sometimes by cultural conditions. Another interesting observation about this work is that the vaccine was initially administered orally and was proven effective by this route. The dermal scarification procedure now used was only introduced into medicine much later. Like all other crowded industrial manufacturing centers, Chicago was badly affected by tuberculosis, especially among the poorest members of the community. There was a small laboratory in Cook County Hospital (the local hospital in Chicago set up in 1835 for the poor community that still serves this function) under the direction of Dr. Frederick Tice who was studying the disease in the 1930s. The main efforts were devoted to controlling the spread of the disease by setting up and maintaining a sanitarium south of Chicago. However, Dr. Tice sent a young doctor, Sol Roy Rosenthal, to study at the Institut Pasteur from 1933 to 1934; in particular, to study the new and controversial BCG vaccine as part of his doctoral studies. Dr. Rosenthal returned and brought back with him samples of the Pasteur BCG vaccine given to him by Guérin for further study. This was part of an enlightened policy adopted by
the Institut Pasteur to allow the attenuated organism to be both freely and readily available to all countries.

Scientifically this may have had some unforeseen effects in the fact that each national laboratory began to grow the vaccine under different cultural conditions from those laid down by the originators. The net result was that a number of different BCG vaccines, each identified by its country of origin, began to appear and, with hindsight, these different cultural procedures resulted in vaccines with different potencies.

Dr. Rosenthal was aware of this and, in fact, by 1950 had developed his own BCG vaccine which he claimed was more potent than most of the other brands then available. To show his gratitude he named the improved vaccine after his mentor and it is still known as the Tice strain BCG. In all fairness, in many tests undertaken since that time the Tice vaccine has usually been demonstrated to be superior to most of the other sources of vaccine, with the possible exception of the original Pasteur strain. In the United States the use of BCG vaccination in the community proved to be different from almost every other country. Rosenthal encountered an entrenched medical opinion, especially with members of the U.S. Public Health Service who assumed a defeatist attitude toward BCG. The medical establishment had decided by the late 1930s, based on some incorrect or otherwise unconvincing evidence, that BCG was unreliable and too dangerous to be used on the American public. Rosenthal spent most of his working life trying to convince them otherwise. He organized clinical trials of the vaccine on a large scale on the south side of Chicago, then a major industrial hub associated with meat processing. These trials are interesting because he managed to organize follow-up examination of the patients, in some cases for as long as 25 years, and, in the process, made some interesting parallel discoveries. He may have been among the first to report in 1936 that BCG was a potent stimulant of the reticuloendothelial system, finding that neoplasms could be suppressed by BCG. For example, an unexpected observation from the tuberculosis trials in Chicago involving over 1500 patients was that diseases such as leukemia and soft tissue tumors were significantly suppressed among the patients treated with BCG, quite apart from a reduction in the development of active tuberculosis.

The significance of this observation has only been appreciated more recently. Rosenthal wrote a book in 1957 called BCG Vaccination Against Tuberculosis. The second edition of 1980, substantially rewritten from the first, was called BCG Vaccine: Tuberculosis–Cancer, and this simple change graphically illustrates the change in emphasis in the use of BCG. By 1960 the menace of tuberculosis was perceived as being overcome by the use of antibacterials such as streptomycin and isoniazide, and the need for a tuberculosis vaccine was generally considered to be less relevant to the needs of the time.

However, since then there has been a major resurgence of drug resistant-tuberculosis, associated with the AIDS pandemic, and this has caused increasing concern over the past decade. BCG vaccination of medical and nursing personnel involved in these areas has now become an accepted precaution since there is no other approved vaccine available and any acellular vaccine, for example, will probably not receive regulatory approval for at least another decade, if at all. The Tice substrain of BCG is still the only licensed source of the vaccine in the United States, although manufacturing is now carried out in North Carolina. The fresh liquid form of the vaccine, with a shelf life of only 10 days, was later improved by freeze drying the product, extending the shelf life to 18 months.

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