Let us Talk Malaria
August 15, 2013 06:17 PM
Study boosts hope for a better malaria vaccine
Spider-Man got his superhuman abilities after being bitten by an irradiated spider. Irradiated mosquitoes aren't quite as powerful, but they might help humanity in another way: the fight against malaria.
A recently published study reveals that all six volunteers who received five vaccinations of a new experimental vaccine containing irradiated noninfectious malaria parasites were protected from controlled malaria infection three weeks after the last vaccination (Science 2013, doi: 10.1126/science.1241800). The vaccine, which was found to be safe in these volunteers, also protected six of nine volunteers who received four doses, while five of six unvaccinated volunteers got infected.
The phase I trial testing this novel vaccine was conducted by NIAID’s Vaccine Research Center (VRC) in collaboration with Sanaria, a biotech company based in Rockville, Maryland, which developed the vaccine. Robert Seder of the VRC, who led the trial, says the results are reason for—cautious—optimism, as the study is small. “You just have to do it in much larger numbers of people and repeat it and extend it,” he says.
Should the results hold up, the new candidate vaccine would be far more efficacious than the most advanced Malaria vaccine candidate to date, RTS,S, which protects up to50% of vaccinees two to three weeks after vaccination. RTS,S contains a protein found on the surface of sporozoites, the stage of the malaria parasite Plasmodium falziparum (Pf) that mosquitoes inject into human blood. In contrast, the new vaccine, called PfSPZ, contains intact sporozoites (SPZ).
The observation that sporozoite vaccination can induce highly protective and long-lasting immune responses is based on 40 years of studies, Seder says, adding that previously, researchers irradiated sporozoite-carrying mosquitoes to make the parasite noninfectious, and found that more than a thousand bites from such mosquitoes were able to protect from infection.
While it’s not feasible to use mosquitoes to vaccinate large numbers of people, the new study is a proof of principle that sporozoites could be used to try this vaccination approach on a larger scale. “You have established a proof of principle that something made and put in a vial can mediate protection,” Seder says.
To produce the vaccine, the Sanaria researchers gave mosquitoes infected blood under aseptic conditions, irradiated the mosquitoes to make the sporozoites noninfectious without killing them, isolated the sporozoites from the salivary glands and, finally, purified and cryopreserved them.
This way, they were able to prepare an injectable sporozoite vaccine that passes the high good manufacturing practice standards for human medicines. “I think the major advance was that Sanaria [was] able to actually isolate and purify the sporozoites from the mosquito salivary gland, count them, and put them in a vial as a vaccine,” says Seder. “You have now gone from the mosquito as the vaccine delivery device to something that’s in a vial that’s been made under good manufacturing practices.”
The route of administration was also important for the study’s success: A previous study showed that injecting the vaccine into or under the skin of human volunteers was not very protective and did not induce strong immune responses, whereas intravenous injection into monkeys elicited far better immune responses. The new study shows that injecting the vaccine intravenously is indeed much more protective in humans.
Still, there are unanswered questions. Perhaps most importantly, what kind of immune responses were responsible for the observed protection? Previous animal studies suggest that CD8+ T cells are more important for protection after vaccination with attenuated sporozoites than are antibodies, Seder says.
But the new phase I study was too small to determine the exact correlate of protection. Only three out of fifteen people who received four or five doses of PfSPZ weren’t protected—too few to do a meaningful comparison of immune responses of protected and unprotected vaccine recipients. It also remains to be seen how well PfSPZ can protect from infection with a malaria parasite that’s different from the one used as a vaccine, and whether the protective effect lasts longer than three weeks after the last vaccination.
To answer these questions, the researchers plan to test the PfSPZ candidate in additional volunteers in the US, Tanzania, Mali and Germany, Seder says.
Another potential issue is that intravenous immunizations are more involved than skin or muscle injections. It is conceivable that other routes can be used at different doses or devices developed to deliver the vaccine, Seder says. Because the study shows that higher doses induce more potent immune responses and lead to more protection, it’s possible that even skin delivery might protect if higher doses are used, he adds.
Another challenge is to scale up production of the vaccine to the volumes required to address the global Malaria epidemic. According to the WHO, in 2010 alone, the malaria parasite infected about 219 million people, killing about 660,000 of them.
A recently published study reveals that all six volunteers who received five vaccinations of a new experimental vaccine containing irradiated noninfectious malaria parasites were protected from controlled malaria infection three weeks after the last vaccination (Science 2013, doi: 10.1126/science.1241800). The vaccine, which was found to be safe in these volunteers, also protected six of nine volunteers who received four doses, while five of six unvaccinated volunteers got infected.
The phase I trial testing this novel vaccine was conducted by NIAID’s Vaccine Research Center (VRC) in collaboration with Sanaria, a biotech company based in Rockville, Maryland, which developed the vaccine. Robert Seder of the VRC, who led the trial, says the results are reason for—cautious—optimism, as the study is small. “You just have to do it in much larger numbers of people and repeat it and extend it,” he says.
Should the results hold up, the new candidate vaccine would be far more efficacious than the most advanced Malaria vaccine candidate to date, RTS,S, which protects up to50% of vaccinees two to three weeks after vaccination. RTS,S contains a protein found on the surface of sporozoites, the stage of the malaria parasite Plasmodium falziparum (Pf) that mosquitoes inject into human blood. In contrast, the new vaccine, called PfSPZ, contains intact sporozoites (SPZ).
The observation that sporozoite vaccination can induce highly protective and long-lasting immune responses is based on 40 years of studies, Seder says, adding that previously, researchers irradiated sporozoite-carrying mosquitoes to make the parasite noninfectious, and found that more than a thousand bites from such mosquitoes were able to protect from infection.
While it’s not feasible to use mosquitoes to vaccinate large numbers of people, the new study is a proof of principle that sporozoites could be used to try this vaccination approach on a larger scale. “You have established a proof of principle that something made and put in a vial can mediate protection,” Seder says.
To produce the vaccine, the Sanaria researchers gave mosquitoes infected blood under aseptic conditions, irradiated the mosquitoes to make the sporozoites noninfectious without killing them, isolated the sporozoites from the salivary glands and, finally, purified and cryopreserved them.
This way, they were able to prepare an injectable sporozoite vaccine that passes the high good manufacturing practice standards for human medicines. “I think the major advance was that Sanaria [was] able to actually isolate and purify the sporozoites from the mosquito salivary gland, count them, and put them in a vial as a vaccine,” says Seder. “You have now gone from the mosquito as the vaccine delivery device to something that’s in a vial that’s been made under good manufacturing practices.”
The route of administration was also important for the study’s success: A previous study showed that injecting the vaccine into or under the skin of human volunteers was not very protective and did not induce strong immune responses, whereas intravenous injection into monkeys elicited far better immune responses. The new study shows that injecting the vaccine intravenously is indeed much more protective in humans.
Still, there are unanswered questions. Perhaps most importantly, what kind of immune responses were responsible for the observed protection? Previous animal studies suggest that CD8+ T cells are more important for protection after vaccination with attenuated sporozoites than are antibodies, Seder says.
But the new phase I study was too small to determine the exact correlate of protection. Only three out of fifteen people who received four or five doses of PfSPZ weren’t protected—too few to do a meaningful comparison of immune responses of protected and unprotected vaccine recipients. It also remains to be seen how well PfSPZ can protect from infection with a malaria parasite that’s different from the one used as a vaccine, and whether the protective effect lasts longer than three weeks after the last vaccination.
To answer these questions, the researchers plan to test the PfSPZ candidate in additional volunteers in the US, Tanzania, Mali and Germany, Seder says.
Another potential issue is that intravenous immunizations are more involved than skin or muscle injections. It is conceivable that other routes can be used at different doses or devices developed to deliver the vaccine, Seder says. Because the study shows that higher doses induce more potent immune responses and lead to more protection, it’s possible that even skin delivery might protect if higher doses are used, he adds.
Another challenge is to scale up production of the vaccine to the volumes required to address the global Malaria epidemic. According to the WHO, in 2010 alone, the malaria parasite infected about 219 million people, killing about 660,000 of them.
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