There may be more than one viable way to wage biological warfare against malaria, a scourge that kills nearly 1 million people—most of them African children—each year.
Two new studies, led or co-authored by Howard Hughes Medical Institute investigator Christopher V. Plowe, highlight different but promising vaccine strategies to prevent malaria parasites from causing illness and death. The parasites are transmitted to humans via the bite of the Anopheles mosquito, leading to about 250 million cases of malaria worldwide each year.
“We have to carry on with both and see which hits the mark of 90 percent efficacy first. It’s the first time we’ve had multiple approaches vying for that possibility at once.”
Christopher V. Plowe
In a phase 2 clinical trial, Plowe led a vaccine field test in the western African nation of Mali. The team tested a vaccine based on a modified protein from the malaria parasite in an attempt to quash its effects in the bloodstream. That work is described in the September 15, 2011, issue of The New England Journal of Medicine. The other study, performed on volunteers in a Baltimore lab and published online September 8, 2011, in Science, used whole parasites—a unique approach.
Both strategies require further development and testing, but Plowe says the current results are encouraging. “We have to carry on with both and see which hits the mark of 90 percent efficacy first. It’s the first time we’ve had multiple approaches vying for that possibility at once.”
Earlier, Phase 1 testing in Mali of the modified-protein vaccine had shown that it provoked the immune systems of adults and children to make “whopping antibody levels that persisted beyond a year,” Plowe says. Phase 1 trials are conducted in small groups of people and evaluate the safety of an experimental treatment or vaccine, determine a safe dosage range, and identify side effects. To see if it is effective and to further evaluate its safety, the experimental treatment or vaccine is given to a larger group of people in a Phase 2 trial.
The Phase 2 trial of the modified-protein vaccine, a randomized study in 400 rural Mali children, concluded that three monthly doses of the vaccine might prevent only about one in five malaria infections from progressing to symptomatic, or clinical, disease. That’s not good enough to further develop the vaccine on its own, says Plowe, a professor of medicine at the University of Maryland School of Medicine.
The test vaccine did, however, prevent development of clinical malaria in 64 percent of cases where a gene called AMA1 in the infecting parasite was identical in eight key mutation sites to that of the parasite strain used to make the vaccine. U.S. Army scientists based the vaccine on a modified AMA1 protein from a strain of the most deadly species of malaria parasite, Plasmodium falciparum. The protein is combined with a substance produced by drug maker GlaxoSmithKline that is designed to boost the body’s immune response.
While other, similar vaccines have undergone Phase 2 testing, none before this one has been shown to prevent clinical malaria, Plowe says. For the Mali test, the researchers defined clinical malaria as a measurement of 2,500 parasites per cubic milliliter of blood, along with fever.
Antibodies against the protein in the Mali vaccine have been shown to block the malaria parasite, in what’s known as the merozoite stage of its life cycle, from invading the body’s red blood cells. The idea behind the vaccine is to stimulate production of such antibodies, causing the parasite to sputter out in the blood stage, rather than multiply.
“There have been a lot of failures, especially with the blood-stage vaccines. I think the field was ready to give up on blood-stage vaccines until our findings came out,” Plowe says. “There’s still a lot of work to be done… but this has moved things substantially forward.”
The immunity provided by the blood-stage vaccine that Plowe’s team tested could supplement protection offered by another vaccine, based on a different protein, that is currently in Phase 3 testing in several African countries. That vaccine, which interferes with malaria at the point of human infection, so far appears to work about half the time, Plowe says. It has virtually the same immune-boosting ingredient as the vaccine in the Mali test, making it easy to formulate the two vaccines together.
“The hope would be that by adding a blood-stage component we would go from 50 to 80 or 90 percent efficacy,” Plowe says. “That’s really the target. That’s what we achieve with most other licensed vaccines.”
Another possibility is a blood-stage vaccine using three or four variants of the AMA1 protein to provide protection against most of the different malaria strains in the community—an approach that Plowe notes is currently used with vaccines against pneumonia and polio. If such a blood-stage vaccine far outperformed the one Plowe’s team tested, that vaccine could instead be combined with another targeting the parasites at the infection stage, he says.
In the study reported in Science, researchers adopted what Plowe called a blunderbuss approach, using the whole Plasmodium falciparum parasite—in a live but weakened, or attenuated, form—to confer immunity, rather than a precise piece of the pathogen. The whole-parasite vaccine is created by infecting mosquitoes and allowing the parasites to proceed through the early stages of their life cycle, until they reach the insects’ salivary glands in a form called sporozoites. The mosquitoes are then irradiated, their salivary glands are dissected, and the compromised sporozoites are removed and frozen. When thawed, the sporozoites are still alive and capable of invading human liver cells—and of generating an immune response—but they can no longer multiply.
“People thought you would never be able to manufacture a vaccine in mosquitoes,” Plowe says. “The company we’re working with, Sanaria, figured out how to grow parasites in mosquitoes in aseptic conditions. It’s quite amazing that this scenario has gotten as far as it has.” Such live, attenuated vaccines for humans have been created with viruses but never with parasites, he adds. The vaccine described in Science represents the first whole-parasite approach to be approved for clinical trials by the U.S. Food and Drug Administration.
Testing of the vaccine in Baltimore was led by Kirsten Lyke, a colleague of Plowe’s in the Malaria Section of the University of Maryland’s Center for Vaccine Development. Volunteers were recruited and injected under the skin with whole thawed sporozoites from irradiated mosquitoes, then exposed to, and bitten by, malaria-infected mosquitoes.
The vaccine proved safe but not as effective as hoped, the scientists found. Only two of 44 people receiving it derived full protection. But Plowe notes that study scientists recorded much stronger immune responses in monkeys when the injections were instead given intravenously.
A crucial challenge for the whole-parasite vaccine is effective preservation—freezing it, shipping it where it’s needed in underdeveloped countries, then thawing it safely. But that same challenge currently is being met in Africa for a vaccine that protects cattle from a disease called East Coast fever, Plowe says.
“I’m optimistic that this could work, and even do better than the recombinant single-protein approaches,” he says of the whole-parasite vaccine.