Published: Thursday, 12 August 2021 00:25
Add malaria to the growing list of infectious diseases that one day may be prevented with labmade antibodies. In an unusual study, nine people who received these monoclonal antibodies were deliberately exposed to mosquitoes carrying the parasite that causes malaria. None became infected—and the protection appears to last for more than half a year.
The trial is too small to reach firm conclusions about the efficacy of the monoclonals, and it isn’t a real-world test, but people in the field are impressed by the proof of principle because it opens a new avenue for preventing the deadly disease. “It’s great,” says Dennis Burton, an immunologist at Scripps Research who has developed monoclonal antibodies to prevent HIV infection, COVID-19, and Zika. “This is a landmark study.”
Although monoclonal antibodies come with high production costs that could put them out of reach of many developing countries, the work could also inform efforts to develop a malaria vaccine better than one now in wide use. It demonstrates the importance of targeting immune responses to a critical region of a protein produced by the sporelike stage of Plasmodium falciparum, the protozoan responsible for most of the world’s malaria deaths. The preventive antibody binds to a small portion of the circumsporozoite protein (CSP) that studs the surface of these sporozoites. “It’s the first study that actually assesses the potency of an antibody against the CSP target in humans,” says Hedda Wardemann, an immunologist who studies antimalarial antibodies at the German Cancer Research Center.
There are already drugs that can temporarily protect people from P. falciparum—many travelers to malaria-plagued regions take them. The drugs are also used in some populations who live in regions with malaria seasons, which are typically linked to rain and an explosion of mosquito populations. And bed nets and insecticides can make it more difficult for the mosquitoes to feast on our blood and infect us. But P. falciparum still sickens at least 200 million people a year and kills an estimated 400,000.
A research team first isolated the CSP antibody against P. falciparum from a person who received an experimental malaria vaccine. Hopping between mosquitoes and people, the parasite has a complex, multistage life cycle and the antibody blocks sporozoites from infecting liver cells, where they would mature into another form that can destroy red blood cells and cause disease.
P. falciparum is notorious for developing resistance to antimalarial drugs, undermining their ability to prevent or treat the disease. Previous studies that have analyzed the genetic makeup of 6500 isolates of P. falciparum find that 99.9% are identical in the region of the CSP this antibody targets. The “highly conserved” nature of the CSP region means the parasite needs it to survive and thus, the researchers reasoned, it cannot easily mutate in a way that avoids the antibody.
The team, led by immunologist Robert Seder of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases, then engineered Chinese hamster ovary cells to churn out mass quantities of a version of the antibody modified to more than double the time it can persist in the body before being degraded. In the proof-of-principle study, the team gave infusions of the antibody to people and then allowed mosquitoes carrying P. falciparum to feed on their arms. None receiving the antibody in this “challenge” trial had detectable blood levels of the parasite, whereas five of six people in an untreated control group did, the research team reports today in The New England Journal of Medicine. (They promptly received treatment, and none became sick.)
The COVID-19 pandemic interrupted the study’s original plan to give the participants the antibody and expose all of them to infected mosquitoes a few weeks later. In two people, the challenge with the parasite did not take place for 36 weeks. Their successful protection, the researchers say, suggests a single monoclonal antibody infusion could shield people for more than 6 months.
Seder envisions that travelers, people in the military, or health care workers visiting malarial regions for prolonged periods would receive monoclonal antibodies—which companies can produce in bulk. Ideally, he says, a clinic would administer a relatively low dose of the antibodies with a subcutaneous injection, a much easier and cheaper option than the relatively high doses that this study gave via infusions into the bloodstream.
A more ambitious use of antimalarial monoclonals would administer them in geographic regions that have a high burden of the disease. The antibodies might prove especially helpful to children, as they have not had time to develop much natural immunity, and to pregnant women, who are at increased risk of severe disease from a P. falciparum infection. Seder recognizes that people who are repeatedly exposed to P. falciparum develop complicated immune responses to the parasite, which have compromised experimental malaria vaccines that worked well in clinical trials of unexposed people. “People said to me when I got this result, ‘Have you broken out the champagne?’” Seder recounts. “I said, ‘No, I got a beer.’ I’ll only break out the champagne when I have data from Africa.”
In 2019, three African countries began a large-scale test of an experimental malaria vaccine called RTS,S which uses different parts of CSP. As of April, this pilot program had given 650,000 young children four doses of RTS,S. In earlier clinical trials, RTS,S had cut infection rates in fully immunized children by 50% after 1 year, but that dropped to 28% by year four. Wardemann says she hopes larger studies with monoclonals like Seder’s can help vaccine researchers identify which parts of the CSP may stimulate an even more effective or long-lasting immune response.
W. Ripley Ballou, who works at the International AIDS Vaccine Initiative and pioneered development of RTS,S, notes that manufacturing monoclonals at the doses used in Seder’s study would cost more than $100 for a 50-kilogram person—too expensive for most countries that have malaria. “This is a great proof of concept, but it’s not yet ready as an intervention,” he says.
Seder agrees. He’s developing a new monoclonal antibody that’s two to three times as potent, which his team plans to test next year in a clinical trial in Mali. He also hopes future generations of monoclonals will be even more potent. “Suppose my antibody is 90-plus percent effective for 6 months with one subcutaneous shot,” Seder says. “Is that a tool a country could use for elimination of malaria?”
Wardemann says monoclonals ultimately might contribute to a multipronged elimination strategy. “I doubt that an antibody alone will do it,” she says. “No single measure has done it so far.” Bed nets, drugs, and vaccines have contributed to suppressing malaria in some locations. “An antibody on top may help,” she says.
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