viernes, 9 de agosto de 2013

New Hope for 'Crazy' Malaria Vaccine

ORIGINAL: Science Magazine


Creating a buzz. A mosquito's salivary glands are removed to produce Sanaria's vaccine.

When a biotech company called Sanaria presented the results of a clinical study of its unconventional malaria vaccine last year, many researchers were disappointed. The vaccine, the only one that uses mosquitoes' bodies as bioreactors, had fully protected only two out of 44 volunteers from malaria.

But a new animal study shows that the vaccine performs much better when given intravenously instead of into the skin, as it was in the clinical trial. The results offer hope that the vaccine may have a future after all—but they could also complicate an eventual rollout in developing countries.

There are no approved malaria vaccines. The results of a large phase III study in seven African countries, which used a vaccine based on a protein snippet from Plasmodium falciparum, the malaria parasite, will be released before the end of the year. That vaccine, called RTS,S and produced by GlaxoSmithKline, has provided between 50% and 60% protection in previous studies; although it could make a major dent in malaria deaths, researchers are hoping for something far better in the long run.

Sanaria's vaccine aims for 90% protection or even higher, says CEO Stephen Hoffman, a former U.S. Navy researcher who started the company in his kitchen 8 years ago. Past results suggest that this target is possible, he says. Decades ago, Hoffman and other researchers discovered that people are almost completely protected after being bitten by hundreds of mosquitoes that carry malaria parasites inactivated by radiation.

Apparently, a vaccine made from the parasitic cells—called sporozoites when they're at this stage—triggers an immune reaction that a vaccine based on a single protein or protein fragment can't, scientists concluded. Studies suggested that sporozoites achieve this level of protection by activating so-called CD8+ T cells that secrete a molecule called interferon γ in the liver.

But vaccinating people by setting mosquitoes loose on them isn't practical. That's why Sanaria is producing the vaccine by breeding mosquitoes, infecting them, and then meticulously cutting out their salivary glands. The sporozoite cells are then purified and preserved in liquid nitrogen to make the vaccine.

Sanaria had hoped that injecting the vaccine intradermally would suffice to trigger protection, Hoffman says. But the results of the clinical trial, first presented at a meeting a year ago, showed that the vaccine failed to raise an adequate CD8+ response, and it protected only two people. "It wasn't what we were hoping for," Hoffman says.

But he wasn't ready to give up. He teamed up with Robert Seder of the Vaccine Research Center (VCR) at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and scientists at other labs to test immune responses to the vaccine in animals. When the team injected the vaccine into the skin of macaque monkeys, the reaction was similar to that in humans, but when injected into the bloodstream, the vaccine provided a strong and long-lasting CD8+ response in all three animals studied.

Macaques can't be infected with Plasmodium falciparum, but when the researchers repeated the experiment in mice, using a mouse model of malaria, they found they could reach levels of protection between 71% and 100% using intravenous administration. The difference with injection into the skin is "staggering," Hoffman says. "It was an 'aha' moment," Seder adds.

A new clinical trial in which the vaccine will be given intravenously to 51 volunteers is scheduled to start next month at VCR; another trial in Tanzania is on the drawing board. Given the animal data, "there's a good chance that it will work," says Brian Greenwood, a malaria researcher at the London School of Hygiene and Tropical Medicine.
But the intravenous route will pose new problems, he cautions. Although an intravenous vaccine will be fine for Western travelers or soldiers, giving the injections safely will be a challenge in poor countries where skilled health workers are scarce—especially in small children whose veins are hard to find. "That's pretty tricky," Greenwood says. Seder says there may be alternatives; for instance, intradermal administration may work better when coupled with immune-boosting compounds called adjuvants.

The vaccine's labor-intensive production—Sanaria staff members can pick apart about 100 mosquitoes an hour—could pose another obstacle. "If you talk to people in a large pharmaceutical company about it, they would say you are nuts," Seder says. But Hoffman says those problems can be overcome. He is studying ways of automating the process, and Sanaria may move its production facilities to developing countries, where the vaccine could be produced less expensively because labor costs are lower. "Our goal has always been to show that this vaccine is highly protective," he says. "Once we have done that, we'll figure out how to make it practical."

[9/8/11, 6:47 p.m. EDT] This item has been corrected. It originally said that 2 out of 80 volunteers were protected from malaria. However, of the 80 study participants who received the experimental vaccine, only 44 were later exposed to the malaria parasite.

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