A new way to prevent malaria that showed promise in nine U.S. volunteers deliberately exposed to parasite-laden mosquitoes last year has now shown its mettle in a real-world situation in Africa. A study published today in The New England Journal of Medicine (NEJM) showed a single dose of lab-produced monoclonal antibodies can protect recipients from infection for up to 6 months during Mali’s intense malaria season.
Monoclonal antibodies are expensive to produce and can be cumbersome to administer if they are infused straight into the bloodstream. That makes some researchers skeptical that the new ones to thwart malaria will be of much use except to protect travelers from high-income, nonendemic countries, who now often take tablets to prevent parasitic infection transmitted by mosquitoes. But the team behind the study is working on an easier way to administer the protective proteins and hopes costs will come down.
“Everybody always ends their papers saying: ‘This has tremendous applications, tremendous potential.’ It’s true in this case,” says protein chemist Tim Wells, chief scientific officer at the Medicines for Malaria Venture, which invests in new malaria remedies. “It’s the first time [scientists] have brought a malaria monoclonal to the field. And it was highly successful,” adds Kirsten Lyke, a vaccinologist at the University of Maryland School of Medicine who conducted laboratory tests of the antibody.
The need for new malaria defenses is great: In 2020, malaria infected an estimated 241 million people and killed 627,000, 12% more than in 2019. About two-thirds of the deaths were children younger than 5 in Africa. Malaria parasites have developed resistance against many drugs, and the mosquitoes that spread them have adapted to withstand some insecticides. A vaccine made by GSK was approved last year by the World Health Organization and is now being rolled out. But it provides mediocre protection; another one developed at the University of Oxford has yet to show it can provide lasting protection.
The study’s monoclonal antibodies—labmade versions of a natural immune protein that can target the most deadly malaria parasite, Plasmodium falciparum—offer a potential new weapon in the armamentarium that might be used to protect children and pregnant women, another vulnerable group.
A team led by Robert Seder of the U.S. National Institute of Allergy and Infectious Diseases isolated the original antibody, named CIS43LS, from the blood of a person who had received an experimental malaria vaccine in a clinical trial. It binds to the protein that studs the surface of the sporelike form of the parasite, preventing it from invading liver cells. Researchers tweaked the antibody to prevent it from being too quickly degraded in the human body and mass-produced it in Chinese hamster ovary cells. A “human challenge” study published last year found the antibody, given intravenously, prevented infection in all nine volunteers intentionally exposed to the parasite.
In the Mali clinical trial, carried out with scientists at the University of Sciences, Techniques and Technology of Bamako, 330 volunteers intravenously received a low or high dose of the antibody, or a placebo. Next, researchers collected their blood and checked it for P. falciparum infection at least every 2 weeks. In the high-dose group, 18% became infected over a period of 6 months, compared with 36% in the low-dose group and 78% in a placebo group. By analyzing the time to an infection after a person received the monoclonals, the scientists found the high dose was 88% efficacious in preventing infection and the low dose 75% efficacious, compared with the placebo. When they analyzed the total proportion of participants who were infected in each group by the end of 6 months, the efficacy fell but still looked promising. The higher dose antibody was 77% efficacious and the lower dose 54%, compared with the placebo.
“This will help us to save more lives of children and pregnant women in African countries,” says epidemiologist Kassoum Kayentao, who presented the findings today at the annual meeting of the American Society of Tropical Medicine and Hygiene in Seattle and is first author on the NEJM paper.
Faith Osier, a malaria immunologist and vaccinologist at Imperial College London, calls the paper “hugely exciting.” Still, “I have quite a few ‘yes buts,’” she says. Among them is that infection rates in the study may have been higher than reported because the team used the so-called thick blood smear method to detect parasites, a method that is less sensitive than polymerase chain reaction (PCR) testing. (The authors say they are now running PCR analysis on archived specimens.)
Osier and others also point out that the trial’s researchers in the current study measured infection rates, not clinical illness, which would have been more meaningful. “For those of us who live with people with parasites all the time, my question is: ‘Does it prevent them progressing to clinical malaria?’” says Osier, who is from Kenya.
Even if intravenously delivered monoclonal antibodies prevent disease really well, they have drawbacks, particularly costs, others note. “How much money does it cost to make a monoclonal antibody? Is production cost going to get cheaper and cheaper as the number of antibodies we’re making gets to be bigger and bigger?” asks Myron Cohen, an infectious disease specialist at the University of North Carolina, Chapel Hill, who has helped develop monoclonal antibodies against HIV and SARS-CoV-2.
Intravenous infusion is also a lengthy procedure ill-suited to the target population: small children. “There is no 5-year-old that’s just going to relax and let you infuse something over half an hour,” Osier says.
Seder hopes a trial happening right now will address those concerns. His lab has already developed another antibody, L9LS, that targets the same protein region but is three times more powerful than CIS43LS. In a human challenge study in U.S. adults published in August, L9LS prevented infection in four of five volunteers when given subcutaneously—as an injection under the skin—which is far quicker and less cumbersome. And according to calculations from Wells, who wrote a commentary on the study, a dose of the same antibody sufficient to protect an infant might only cost $5.
A new study already underway in Mali is using subcutaneous injections to test L9LS in children ages 6 to 10. It will measure symptoms, not just infection. A similar trial of L9LS in children ages 5 months to 5 years is also underway in Kenya. “It all rides on the subcutaneous” version working, Seder concedes. As to the cost, he is hoping increasing yields and potency will eventually make these proteins affordable for use throughout Africa—about on par with the cost of malaria vaccines. And Seder is already developing a third candidate that he says is even more powerful.
Importantly, the protein region targeted by the antibodies varies very little across different strains of the malaria parasite, which suggests mutations in that region incur a high cost for the parasite. That could mean resistance to the antibodies is unlikely to arise, Lyke says.
Brian Greenwood, a malaria researcher at the London School of Hygiene & Tropical Medicine, sees a place for monoclonal antibodies in the fight against malaria, at least in the short-to-medium term. “A vaccine that gave a high level of protection for several years would be more promising,” Underwood says—but they don’t exist yet. Until they emerge, he says, monoclonals are “a potentially very valuable new tool.”