9/11/97
PRINT MEDIA CONTACT:
Tim Stephens, (650) 725-8047 or 723-6911; e-mail [email protected].
BROADCAST MEDIA CONTACT:
M.A. Malone, (650) 723-6912 or 723-6911; e-mail [email protected]
COMMENT:
Dr. Peter Small and Dr. Marcel Behr may be reached directly at (650) 725-7908.
For immediate release
STUDY CASTS DOUBT ON EFFECTIVENESS OF TB VACCINE
STANFORD -- The tuberculosis vaccine known as BCG has been given to more people worldwide than any other vaccine, yet its effectiveness remains controversial. A new analysis by researchers at Stanford School of Medicine suggests that the bacterial strains used in current BCG vaccines have evolved in the laboratory and are now considerably weaker -- and less likely to provide protection from tuberculosis -- than the original vaccine developed about 75 years ago in France.
Tuberculosis causes more adult deaths worldwide than any other infectious disease. In the United States, BCG vaccination is currently recommended only for infants and children in special circumstances, such as ongoing exposure to people with active cases of drug-resistant tuberculosis. Tuberculosis control efforts in the United States have focused primarily on identifying and treating people with the disease, rather than on widespread vaccination.
The emergence of tuberculosis strains resistant to multiple drugs, however, is prompting renewed interest in vaccination, said Dr. Peter Small, an assistant professor of medicine (infectious diseases) at Stanford.
"Our findings provide a very interesting starting point for scientists who are trying to improve the vaccine," he said.
Small and Dr. Marcel Behr, a postdoctoral fellow supported by the McLaughlin Foundation of Canada, describe the results of their new analysis in the Sept. 11 issue of the scientific journal Nature.
BCG (an abbreviation for "Bacille Calmette-Guerin") is a live bacterial vaccine derived from the bovine form of tuberculosis by French scientists Calmette and Guerin. It was first used in humans in 1921 and was subsequently distributed to major medical laboratories around the world.
Over the years, researchers in various countries have conducted about 20 controlled trials of BCG, with highly inconsistent results. "There has always been a controversy, because some studies show that BCG is 80 percent effective and others show that it has no effect whatsoever," said Small.
Small and Behr performed a novel analysis of past clinical trials conducted with BCG. The results led them to propose that subtle selective pressures, including the investigators' desire to minimize adverse reactions to the vaccine, have caused a decline in its protective power.
With modern technology, a live vaccine can be freeze-dried for long-term storage. But for several decades after BCG was first developed, the only way to keep it viable was to grow the bacteria continuously in the laboratory. To keep the vaccine culture going, scientists would transfer a subsample to a flask of fresh culture broth approximately every two weeks. This process of subculturing is called an "in vitro passage" of the vaccine.
There are now 18 different strains of BCG vaccine, and some have been through as many as 1,500 passages, Small said.
"BCG spent around 50 years in the laboratory before it was first freeze-dried, and that's why it may have lost its original vigor," said Behr.
In several cases, the same strain of the vaccine gave good results in one trial and weak results in another. Behr looked at five BCG strains that were used in more than one clinical trial and found that four of them showed an efficacy decline that correlated with the number of in vitro passages they had undergone between successive trials.
"The passage itself does not represent anything in the biology of the bacteria, but it serves as a unit of time for how long the strain has been maintained in the lab," Behr noted.
In the past, other investigators have attributed the inconsistent results of BCG trials to differences in study design or in the patient populations receiving the vaccine. Behr and Small, while cautioning that their observations of declining efficacy are not conclusive, said their hypothesis will have important implications if confirmed.
For example, it would be meaningless to evaluate BCG's effectiveness by averaging the results of various trials if some of the trials used ancestral strains of BCG that are no longer available. Investigating the differences between old and new strains, however, may yield valuable insights into how the vaccine confers protection from tuberculosis.
Behr and Small also found that a reduction in adverse reactions to the vaccine correlated with decreased efficacy. With the advent of antibiotics in the 1940s, making tuberculosis curable, people became less willing to accept a vaccine that had undesirable side effects. As a result, investigators appear to have selected strains with fewer side effects, according to the Stanford researchers.
Behr noted that descriptions of side effects from BCG vaccinations in the 1930s are very different from those in the 1960s. "In the 1930s, 75 percent had ulcers at the site of the injection, sometimes with pus draining for months, whereas in the 1960s the effects were minimal," he said.
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