Thwarting a clever devil
Efforts to improve the TB vaccine
The technology has been licensed for further product development by the non-profit Aeras Global TB Vaccine Foundation.
With support from the Bill & Melinda Gates Foundation, Aeras is working as a “product development partnership” with public and private organizations around the world. The goal is to bring an improved TB vaccine to market within the next seven to 10 years.
Mycobacterium tuberculosis can hold out in the lungs of its victims for decades, effectively “walled off” by the immune system. When immunity is compromised by diseases like AIDS, the bacterium can re-emerge in a highly contagious form that can be spread to other people through coughing.
As a result, rates of active—and highly contagious—TB are skyrocketing in developing countries, especially those with a heavy burden of AIDS, says Douglas Kernodle, M.D., the David E. Rogers Professor of Medicine at Vanderbilt University Medical Center.
The current Bacillus Calmette-Guérin (BCG) vaccine is made using a related bacterium that has been weakened or “attenuated” so it cannot cause disease. The vaccine is given annually to 100 million newborns worldwide but provides inadequate protection against the pulmonary form of TB.
In the mid-1990s, Kernodle, Kathryn Edwards, M.D., professor of Pediatrics, and their colleagues at Vanderbilt and the Veterans Affairs Medical Center in Nashville began to study superoxide dismutase, an enzyme secreted by the TB bacterium in large amounts.
The enzyme “detoxifies” oxidants (reactive oxygen species) released by certain immune cells to kill foreign invaders. The researchers believed that TB “probably evolved high-level superoxide dismutase secretion as part of its strategy for infecting human hosts,” Kernodle recalls.
Through a bit of genetic engineering, they were able to reduce secretion of the protective enzyme. When Kernodle’s colleague at the Syracuse VA Medical Center, Michael Cynamon, M.D., infected mice with the impaired bacteria, the bugs were wiped out by the animals’ immune systems.
Then, in late 2000, came Kernodle’s “Eureka moment.”
One of his colleagues, Markian Bochan, M.D., Ph.D., noted that superoxide dismutase can help rescue a cell from apoptosis, a type of programmed cell “suicide” that clears diseased or defective cells from the body.
“Then I got weak in my knees and chills down my spine because I realized that TB was pumping this (enzyme) out,” Kernodle recalls. “Clever devil,” he thought. “TB wants to live inside of a macrophage, so it is going to prevent that macrophage from committing suicide, and it’s going to keep it alive.”
The macrophage, a type of white blood cell, is the target of TB infection. The researchers realized that preventing apoptosis might also be the way the bacterium inhibits the immune system, thereby enabling it to cause a chronic infection.
If the infected macrophage fails to undergo apoptosis, then bacterial antigens—protein markers that ordinarily would trigger a more vigorous immune attack—would not get processed efficiently. In scientific terms, M. tuberculosis is able to evade “apoptosis-associated cross priming” of the immune system.
The researchers decided to see what would happen if they reduced the ability of the attenuated bacterium in BCG to produce superoxide dismutase and other anti-oxidant factors. Over the course of several years, with help from other investigators skilled in performing genetic manipulations, they stripped away successive layers of anti-oxidant factors from the vaccine as if they were peeling an onion.
The genetically engineered bugs have been progressively weakened in such a way that they can no longer prevent the death of the macrophages they inhabit or the resulting cross priming of the immune system.
“It’s this broader repertoire of immune responses that you need to ‘melt’ (the infection) away and get rid of it for good,” Kernodle says. “And that’s the kind of responses now that we’re getting (in animals)… with progressively more potent vaccines.”
Under the licensing agreement announced this spring, Aeras will use the technology to modify BCG and will shepherd the new vaccine through clinical trials toward FDA approval. The foundation has developed field sites for testing near Bangalore, India, and Cape Town, South Africa.
“Currently one-third of the world’s population is infected with TB, and every second, one more person is newly infected,” says Foundation President and CEO Jerald Sadoff, M.D. “A new vaccine is the best hope for defeating this terrible disease.”