May 5, 2006

New vaccine technology may curtail TB’s march

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Doug Kernodle, M.D., and Cindy Hager, senior research specialist, look over data in the lab.
Photo by Dana Johnson

New vaccine technology may curtail TB’s march

A Vanderbilt-led team of researchers has developed a new vaccine technology that may prevent the spread of tuberculosis, which kills more than 2 million people worldwide each year.

The technology has been licensed for further product development by the Aeras Global TB Vaccine Foundation. It could lead to a more effective TB vaccine capable of stemming the rising tide of the disease, officials said.

“Currently one-third of the world's population is infected with TB, and every second, one more person is newly infected. A new vaccine is the best hope for defeating this terrible disease,” said Foundation President and CEO Jerald Sadoff, M.D., in announcing the exclusive licensing agreement. “We are excited about using Vanderbilt's technology for developing an effective vaccine against TB.”

The current Bacillus Calmette-Guérin (BCG) vaccine, named for the French researchers who developed it in the 1920s, provides inadequate protection against the pulmonary form of TB.

As a result, rates of active — and highly contagious — TB are skyrocketing in developing countries, especially those with a heavy burden of AIDS, said Vanderbilt University Medical Center's Douglas Kernodle, M.D.

While researching TB pathogenesis at Vanderbilt and the Veterans Affairs Medical Center in Nashville several years ago, Kernodle and Markian Bochan, M.D., Ph.D., discovered a way to modify the BCG vaccine so that it triggers a broader, more potent immune response. In particular, their method stimulates the “apoptosis” or death of macrophages (a type of white blood cell) that have been infected with the TB bacterium.

Aeras will develop, produce and market Vanderbilt's “pro-apoptotic” bacterial vaccine technology, which so far has been tested only in animals. The non-profit organization, based in Bethesda, Md., is dedicated to developing new TB vaccines and distributing them in areas of the world hardest hit by the disease.

With the help of a five-year, $82.9 million grant awarded in 2004 by the Bill & Melinda Gates Foundation, Aeras works as a Product Development Partnership (PDP) with leading public and private organizations around the world to bring an improved TB vaccine to market within the next seven to 10 years, officials said.

The foundation recently opened a new vaccine production facility in Rockville, Md., with the capacity to make 150 million vaccine doses annually.

"TB is a deadly disease, with tremendous cost to human life," said Jeffrey R. Balser, M.D., Ph.D., Vanderbilt's associate vice chancellor for Research. "This vaccine technology will help change all that — and is a platform for attacking other devastating disorders across the globe."

According to the World Health Organization, the tide of TB rises by an estimated 8 million newly diagnosed cases every year.

While TB can be treated with drugs, the basic therapeutic regimen requires patients to take as many as four different drugs for at least six months. In addition to AIDS, the emergence of multi-drug resistant strains of Mycobacterium tuberculosis has made TB an increasingly worrisome global health problem.

The BCG vaccine is made using a related bacterium, Mycobacterium bovis, which has been weakened or “attenuated” so it cannot cause disease.

The vaccine, which is given annually to 100 million newborns worldwide, provides only limited protection against TB in the lung, but it does prevent spread to other organs.

M. 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, however, the bacterium can re-emerge in a highly contagious form that can be spread to other people through coughing.

In the mid-1990s, Kernodle, Kathryn Edwards, M.D., professor of Pediatrics, and their colleagues at Vanderbilt and the Nashville VA 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, as a human-adapted pathogen, TB “probably evolved high-level superoxide dismutase secretion as part of its strategy for infecting human hosts,” Kernodle recalled.

Eureka moment

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.

Bochan, at the time a fellow in infectious diseases with a background in tumor immunology, 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 recalled. “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 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 current vaccine 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 in TB, they stripped away successive layers of anti-oxidant factors from BCG 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.”

The ability to trim a microorganism of its anti-apoptotic abilities also may be relevant to the search for new and improved vaccines against other chronic infections that plague the developing world, including typhoid fever and leishmaniasis, he added.

Five years ago, Kernodle shared some of his group's initial findings with Aeras' predecessor, the Sequella Global Tuberculosis Foundation. Because BCG sells for only 25 cents a dose, big pharma was unlikely to invest in improving the vaccine. He also realized he did not have the time or wherewithal to start his own biotech company.

So when the board of Aeras expressed interest in the technology, Kernodle jumped at the chance.

Under the licensing agreement announced this week, Aeras will use the technology to modify BCG and will shepherd the new vaccine through clinical trials towards FDA approval.

The foundation has developed a field site in India, near Bangalore, and another field site near Cape Town, South Africa.

Vanderbilt retains rights to the pro-apoptotic BCG technology as a delivery system to induce immune responses to other antigens. This creates opportunities for additional research and could lead to new vaccines or immunotherapies against other diseases, from HIV and malaria to cancer.

“New technologies for producing immunity to infectious diseases and cancers are active topics of research and development in the biopharmaceutical industry,” said Kenneth J. Holroyd, M.D., M.B.A., assistant vice chancellor for Research at Vanderbilt. “We will be actively seeking partners to develop these additional applications.”

“For me, this is wonderful,” Kernodle said. “I'm just so grateful that Aeras is there.”

Kernodle is also grateful to Bochan, now in private practice in Indianapolis, for providing his “eureka!” moment. “I would not have had that idea had it not been for Mark,” he said.