Seattle scientists ready to human-test malaria vaccine

Seattle scientists are ready to start human tests of a malaria vaccine that takes an approach pioneered more than 30 years ago but abandoned as wildly impractical.

In mice, the vaccine provided 100 percent protection. If it can approach those levels in people, it could slash the toll from one of the world's worst scourges, said Stefan Kappe, of Seattle Biomedical Research Institute (SBRI).

"We're shooting for 90 percent-plus protection," said Kappe, leader of a collaboration that includes researchers from Australia, Japan and Canada. "I am extremely optimistic this will work."

SBRI was flooded with calls and e-mails last year when the independent research lab announced plans for a local facility where volunteers can participate in malaria-vaccine trials. The facility won't open until mid-2010, so the initial trials on Kappe's vaccine are tentatively scheduled to start in January at Walter Reed Army Medical Center in Maryland. U.S. Food and Drug Administration approval is required.

"This is a great step forward," said Mary Galinski, director of the International Center for Malaria Research, Education & Development at Emory University in Georgia. "The clinical testing ... is now awaited with much anticipation," added Galinski, who is not involved in the project.

Many experimental drugs falter in the leap from mouse to man. And even if all goes well, it will be nearly 10 years before the new vaccine would be ready to roll out, Kappe estimated.

The $17 million project is funded by the Bill & Melinda Gates Foundation, which has poured more than $1 billion into the fight against malaria in the developing world.

Origins in the 1970s

Until recently, the quest for a malaria vaccine has been fraught with failure and frustration. Funding dwindled after the mosquito-borne disease was eradicated in the United States and other wealthy nations, though a million people worldwide — mostly African children — still die of malaria each year.

The early 1970s saw one notable success: Researchers zapped infected mosquitoes with radiation, then let them bite volunteers. The radiation weakened the malaria parasites so that they did not cause disease in people, but induced near-perfect immunity.

Vaccines for flu, measles and many common diseases contain live bacteria or viruses that have been rendered harmless through irradiation or other treatment. But the malaria parasite is complex and requires mosquitoes to complete its life cycle. Until recent years, no one thought it would ever be possible to mass-produce a vaccine inside mosquitoes and deliver it by way of a bug bite.

But thanks to advances in genetic engineering, that's essentially what Kappe and his colleagues have done on a small scale in their lab in Seattle's South Lake Union neighborhood.

"We said: Why don't we go back to the roots and do what works, but be a little smarter and a little more sophisticated," Kappe said.

Instead of using radiation, the researchers weaken the parasites by snipping out two crucial genes.

When laboratory mice were inoculated with the weakened parasites, the bugs lodged in their livers but were unable to proliferate and burst into the bloodstream where malaria wreaks its havoc. Instead, the harmless parasites primed the animals' immune systems to fight future infections. For most of the mice, the resulting immunity lasted throughout their lives.

Protection undoubtedly won't last a lifetime in humans, but it could be maintained through booster shots, Kappe said. For any commercial vaccine that comes out of the research, the weakened parasites would be "manufactured" inside mosquitoes but administered to people via syringe.

Human form of disease

Kappe initially experimented with a mouse version of malaria. His group recently began working with the real thing: Plasmodium falciparum, the most deadly human form of the disease. In Monday's Proceedings of the National Academies of Science, the team reported that its approach worked equally well with human malaria.

"For the first time, we have shown that we can create a weakened strain of the parasite that can be used as a live vaccine," said Kappe. "The next step is to show that it's safe in humans and actually protects humans from malaria."

Brian Greenwood, a malaria expert at the London School of Hygiene & Tropical Medicine who is not part of the team, praised the Seattle group's "elegant experiments" and agrees the vaccine is ready for human trials.

One potential concern is that the weakened parasites used in the vaccine might regain their potency by evolving ways to compensate for the deleted genes, Greenwood cautioned. If that happens, the vaccine could lose its effectiveness over time and might actually cause malaria.

Kappe believes the "one-two punch" of deleting a pair of vital genes will prevent the weakened parasites from ever becoming dangerous.

Other approaches

A similar vaccine is under development in Maryland, scaling up the 1970s-era approach of blasting mosquitoes with radiation.

Kappe believes genetic engineering will prove more reliable and reproducible than radiation as a way to weaken parasites for a vaccine. Greenwood said in an e-mail that it's not clear yet which method will be superior.

A third Gates-funded vaccine is being tested in more than 16,000 children in Africa and could be on the market as early as 2012. Instead of containing whole parasites, the vaccine developed by GlaxoSmithKline uses a fragment of the parasite's surface to induce immunity. But the vaccine protects only about half the children who get the shot.

It's a good start, Kappe said. "But in order to get rid of malaria, we need a vaccine that is 90 percent effective, or more."

Sandi Doughton: 206-464-2491 or sdoughton@seattletimes.com

The information in this article, originally published july 20, 2009, was corrected July 29, 2009. A subheadline incorrectly stated the amount the Gates Foundation is paying for the project. The foundation is paying $17 million, as the story reported.