A Seattle lab’s unconventional approach to a malaria vaccine, once dismissed as crazy, worked well in early tests but faces a long road to reality.
Getting bit by malaria-infected mosquitoes may seem like an odd way to protect yourself against the disease, but Seattle researchers have demonstrated that the unconventional strategy can work.
In an experimental trial, 10 local volunteers bared their forearms to the bloodsucking insects — and no one got sick, scientists reported Wednesday in the journal Science Translational Medicine. After the bites, the volunteers’ bodies produced antibodies that could be potent enough to confer immunity to future infections.
“We are very excited,” said team leader Stefan Kappe, of the Center for Infectious Disease Research (CIDR) in the South Lake Union neighborhood. “It’s really a milestone in the development of a vaccine.”
It took Kappe and his group more than a decade to reach that milestone. It may be another 10 years before they have a commercial vaccine based on an approach long considered intriguing — but highly impractical.
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“This is an important first step, but there are several pretty large challenges still on the horizon before this could be considered a product that’s going to help those who need it most,” said Ashley Birkett, director of the PATH Malaria Vaccine Initiative, which was not involved in the project.
Malaria, which kills more than 400,000 people every year, is caused by a parasite transmitted to humans via mosquito bites. Kappe set out to create a weakened form of the parasite, which would stimulate immunity but pose no risk of infection, and use it as the basis for a vaccine.
The idea isn’t new. Vaccines against measles, mumps and chickenpox contain weakened strains of viruses. But malaria parasites are much more complicated, and can only be grown effectively in living mosquitoes. So Kappe and his colleagues have to use mosquitoes, instead of syringes, to inject the weakened parasites into their volunteers.
Defanging the parasites was also fraught with difficulty. In its first attempt, the team used genetic engineering to knock out two genes crucial for the parasite’s development in humans. But the fix wasn’t perfect, and one of its early volunteers got malaria.
(The trials, which are conducted with the Fred Hutchinson Cancer Research Center, use an easily cured type of malaria. Volunteers are hospitalized and treated at the first sign of infection.)
The experiments reported this week were designed to test the scientists’ new technique, which knocks out three genes. That none of the volunteers got sick shows the team devised a winning combination, Kappe said.
“It’s truly astonishing that you can completely prevent infection by eliminating three genes,” he said.
A robust immune response in all of the volunteers suggests — but doesn’t prove — that the defanged parasites may work as a vaccine to prevent infection. The researchers did see long-lasting immunity in mice inoculated with antibodies from the human volunteers.
The next round of human trials, which will start later this year, will be a pivotal test of Kappe’s vaccine concept. Volunteers will first be inoculated a varying number of times with weakened parasites, via mosquito bites. Then they will roll up their sleeves, allow themselves to be bitten by mosquitoes carrying infectious malaria parasites — and cross their fingers that they won’t get sick.
The research was originally funded by The Bill & Melinda Gates Foundation, which ended its support after the early volunteer got infected. The Department of Defense paid for the most recent trail, and the National Institutes of Health will fund the next one.
With a vision of eradicating malaria by 2040, the Gates Foundation is bankrolling research on new drugs, new diagnostics, new mosquito killers — and vaccines, said deputy director for malaria Bruno Moonen.
The foundation helped develop the world’s first malaria vaccine, called RTS, S, or Mosquirix. But the vaccine in its current regime, which requires four shots, provides no more than 50 percent protection, not enough to be truly effective in wiping out the parasite in areas with high transmission. “We are hoping to find a better vaccine,” Moonen said.
Mosquirix relies on a single protein from the malaria parasite to induce immunity. Kappe’s approach, which uses the entire parasite to prime the immune system, has the potential to be more effective — but no one knows yet how long the protection will last, said Birkett, whose PATH Malaria Vaccine Initiative is largely funded by Gates.
Birkett and Moonen both remain wary of the practical challenges to using whole parasites in a vaccine.
Kappe is optimistic the challenges can be overcome. To get around the problem of injections-by-mosquito, he’s working with a Maryland company called Sanaria to mass-produce weakened parasites in mosquitoes then extract them for use in syringes. The researchers are also trying to eliminate live mosquitoes altogether by growing parasites in the lab.
Meanwhile, experts continue to debate the role a vaccine might play in the push to eliminate malaria. Simple tools like insecticidal bed nets, indoor spraying and better drugs have halved the disease’s death toll in the past 15 years.
But those tools require constant investment, Kappe pointed out. A highly effective vaccine would provide a less expensive alternative that could also block the cycle of transmission.
“Vaccines are very cost-effective,” Kappe said. “You give them once or twice, and then you have the protection and you don’t have to worry about it anymore.”