A new, souped-up version of the BCG vaccine may offer new hope in the global fight against tuberculosis

TB is one of the planet’s biggest killers. One third of the world’s population is infected with the microbe, Mycobacterium tuberculosis, and about 10% of these people go on to develop the devastating illness. In some parts of sub-Saharan Africa, a lethal combination of TB and HIV infection is accelerating deaths from both diseases. The BCG – or Bacillus Calmette-Guérin – vaccine has given reasonable protection against TB since it was created in the 1920s. The vaccine consists of live, weakened Mycobacterium bovis microbes and invokes an immune response without causing illness when given to newborn babies and young children. But its effectiveness is limited in adults and against newly emerging drug-resistant strains. BCG’s usefulness also varies with region – in areas with a lot of natural exposure to Mycobacterium strains in soil, it is less effective.

Now, Stefan Kaufmann, director of the Max Planck Institute for Infection Biology in Berlin, Germany, and colleagues have devised a way of boosting BCG’s power. Their souped-up vaccine was 10 times more effective than conventional BCG in protecting mice from infection. And it slashed the presence of “drug-resistant” TB bacteria to about 1% of its initial level in mice infected with this strain – the standard BCG had no effect. “We think it’s a very promising vaccine,” says Kaufmann. He envisions the new vaccine working in tandem with another. “We shouldn’t have competing vaccines, but should combine them,” he told New Scientist.

The improved BCG could “prime” the immune system if given early in life. And this immune response could be boosted in adults by a “subunit” vaccine. The latter type of vaccine uses just a component of the organism, such as its DNA, to trigger the previously established immune response. The traditional BCG vaccine protects against TB infection by enlisting immune cells called CD4 helper T-cells. These cells activate other immune cells called macrophages, which eat up invading organisms, alongside other defence mechanisms.

But BCG does not invoke killer T cells, or CD8 T-cells, which provide another strong immune response. Inducing this response would be especially beneficial as the TB bacterium hijacks macrophages for its own use. Macrophages gobble up most invaders in a pouch called a phagosome. This is a “dead-end street” for most bacteria, explains Kaufmann, but the TB bacterium actually makes use of the phagosome. Kaufmann’s team engineered a new BCG strain which secretes a protein that punches holes in the membranes of the phagosome, spilling the invader’s proteins out into the macrophage cell’s cytoplasm. This also lets out degrading enzymes into the cell – leading to the cell’s death.

It is the broken down vesicles of the dying macrophage that are ultimately what attracts CD4 and CD8 cells. It is this powerful “cross-priming” immune response which makes the new version of the BCG vaccine very effective. However, Douglas Lowrie at the National Institute for Medical Research in London, UK, whose group researches TB vaccines, cautions that developing another live vaccine based on BCG may not address some of the problems associated with the conventional vaccine. “There is a tendency to move away from live vaccines,” he notes, since immuno-deficiencies caused by the growing HIV problem mean that the BCG itself could cause disease. “A change in the nature of the immune response is needed, not merely an intensification,” he told New Scientist. Other candidate vaccines have been shown to alter the response, he adds.

Kaufmann says he is aware of the issue, and that at this stage there is no question of the vaccine being used in immuno-compromised patients. But he also notes that their souped-up BCG was safe in immuno-compromised mice. Lowrie also suggests that the new BCG vaccine does not tackle the problem of BCG’s effectiveness being diluted by environmental exposure to Mycobacterium. But Kaufmann points out environmental exposure is only a problem when BCG is given in adulthood. “We want to focus on a replacement for BCG early in life.” He hopes to move the new vaccine to clinical safety trials in humans in 2006.

Journal reference: Journal of Clinical Investigation

New Scientist
September 13, 2005

Original web page at New Scientist