If everything breaks right for Stefan Kappe‘s research, he’ll be able to tell the grandkids he played a leading role in wiping out malaria. It will probably take 10 years, if not longer. But this guy is clearly undaunted. On a Friday afternoon at his office at the Seattle Biomedical Research Institute (SBRI), the German scientist stared me down with an intensity that says he doesn’t have a minute to waste.
“We don’t have a vaccine,” Kappe said. “For nearly 100 years, people have tried. It’s one of the highest priorities in medicine, but we haven’t been accomplish it.”
Malaria kills more than 1 million people each year, making it one of the world’s leading killers, according to the Centers for Disease Control and Prevention. Most of those deaths are among young children in sub-Saharan Africa, yet this disease is on the top of the minds of some of Seattle’s leading biomedical researchers. Kappe is one of those people, and since he isn’t available to discuss his work at our inaugural Xconomy Forum on Thursday, I made sure to track him down in advance. He has a timely story. The vaccine candidate he’s been working on for years is being primed to enter its first clinical trial in the middle of 2009 at Walter Reed Army Institute of Research.
The state of the art in malaria vaccines right now isn’t much to write home about, Kappe says. A candidate from GlaxoSmithKline called RTS,S/AS01 is in the final stage of clinical studies in children in Africa, and has shown an ability to protect them about 50 percent of the time from developing clinical symptoms of malaria.
“That’s not enough,” he says. “That’s not enough to eradicate malaria. We need a vaccine that probably is 90 percent effective or more. It’s a high bar.”
So exactly how does Kappe plan to take on this challenge, and how is this any different from the long list of failures that precedes him?
First, we need to know a few basics about vaccines. There are the whole-killed variety of vaccines, in which an entire bug (like rabies) is killed, and all the hallmarks of the virus are injected to provoke the immune system. Then there are live-attenuated (weakened) vaccines, like the polio or flu vaccine, that usually stimulate the immune defenses a little more vigorously because it’s, well, alive. Then again, it offers a small chance of actually infecting you with the bug. Last, there are snippets of protein, or sub-units, that can be clipped out to give the immune system something specific to attack that can’t actually infect you.
The Glaxo vaccine candidate uses this single-sub-unit protein approach. Kappe isn’t optimistic about this being the answer for malaria, because the parasite is more complex than most bugs, with about 5,000 genes. Waving one hallmark protein like a flag in front of a bull isn’t probably going to do enough to spark a strong, multi-pronged immune response to the malaria invader, he says.
So, Kappe prefers the live-weakened flavor of vaccine. Studies that date back to the 1960s in volunteers, including prisoners, found that if you gave them a vaccine created by blasting the malaria bug with radiation, you could spark an immune response that protected them from infection for as much as nine months or longer.
The big problem with radiation is that it’s hard to control. Too much, and you kill the malaria parasite, which reduces its ability to spark immunity. Too little radiation means that the nasty little bug could actually give you malaria.
In 2001, Kappe embarked on a new idea for how to make a live-weakened parasite that could be used for a vaccine. The genomics era made it possible to have the full genetic blueprint, all 5,000 genes, of the malaria parasite. He hit upon a few critical genes that keep the parasite alive and thriving until it gets into the liver. That’s an essential docking station for the parasite in the first seven days in the body. The bug needs to get to the liver before it mounts its assault on oxygen-carrying red blood cells, making the blood cells sticky and clumpy. These effects can cause a whole lot of awful symptoms, like severe anemia, stroke, and lung failure.
Kappe found that he could delete the genes in the parasite that are essential for it to develop in the liver. Then he could deliver this modified parasite as a vaccine to mice. After that, he exposed the mice to infected mosquitos, and found he could maintain 100 percent protection for the life of the typical lab mouse, about two years. Then, in a critical step, he showed the method could keep the parasite stuck in the liver so it couldn’t migrate back into the blood and cause all that trouble.
“Bingo, we had precise attenuation,” Kappe says.
Yet, as many researchers sadly discover later in their careers, mice and people are not the same things. The clinical trial protocol, frankly, is one that I imagine would make a lot of people really squeamish. It depends on about 25 volunteers at Walter Reed Army Institute of Research. These volunteers will get vaccinated with a unique delivery mechanism—actual mosquitos! The volunteers will hold a box of 200 special mosquitos, who have been sucking up a substance filled with the genetically weakened parasite. The box of mosquitos gets held on the volunteers’ arm, they get bitten, and if all goes well, the parasites will travel to the person’s liver and spark a strong, diversified immune response.
Then the volunteer gets “challenged” with other mosquitos that have been sucking up real malaria parasites, and the people start getting bitten. Researchers are careful to make sure that the strains of malaria are weak ones that can be treated with anti-malarial drugs. Of course, these patients are watched like hawks for any signs or symptoms of the disease so the drugs can be given early when they are effective, Kappe says.
The whole process requires a lot of oversight by the FDA, so SBRI hasn’t yet turned in its investigational new drug application so it can start the trial. The scientists working on the trial also still need clearance from the institutional review board charged with ensuring patient safety, but that process should be completed and the trial should be ready to start by mid-2009, Kappe says. Results on the vaccine’s effectiveness could arrive by early 2010, he says.
If SBRI can reach its goal of 90 percent protection in this study, it still has a lot of work left to do. Pharmaceutical companies aren’t wild about a malaria vaccine to begin with because it’s not a first-world moneymaker, and they’re really not thrilled about using something as difficult to control as live mosquitos as a delivery vehicle for their product. “This isn’t something the Big Pharma companies want to touch,” he says.
So SBRI is in partnership talks with Sanaria, a biotech startup in Rockville, MD, that is working on a way to purify the live-weakened vaccine so it can be made into an injectable form. If this can be done, the new vaccine would need to be tested in another early-stage trial. Some basic math suggests it might be feasible for a startup like Sanaria to manufacture enough of these modified parasites to protect most of Africa, Kappe says. A single dose can be derived from one single mosquito, so it’s possible to build a facility to grow 10 million mosquitos for 10 million doses in Africa, he says. Some money can be made, too, if the small company can sell it to people with first-world purchasing power, like the U.S. military, or American tourists, he says.
If Sanaria is able to show it can do this trick of putting the vaccine in a vial, and do it at a large scale, then there will need to be a gauntlet of clinical trials to show it protects adults in Africa, then children in Africa, and can be repeated in tens of thousands of subjects. The vaccine had also better be safe. The history of live polio vaccines suggests that one in 200,000 or 300,000 subjects can get infected with the bug, and with malaria “we want to be at least as good as that,” Kappe says.
Even if SBRI makes it through the trials, though, it will probably face logistical challenges. The vaccine will require two or three shots instead of just one, and it will have to be kept frozen, meaning it won’t be easy to transport as a dry powder formulation mixed with saline water.
Kappe has heard all this before, and doesn’t dismiss any of it. But at the end of our 45-minute interview, he delivered that same deadpan stare that says he’s unfazed by it all. “We’ve gone 100 years with no vaccine. We may be 10 years away from a truly protective vaccine. That would not be too bad.”
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