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Malaria is a life-threatening disease caused by Plasmodium parasites, which are spread through the bites of infected mosquitoes. The disease sickens almost 250 million people a year worldwide and kills more than 600,000, mostly children.

Two vaccines to help prevent malaria infection in young children are now available. Monoclonal antibodies (mAbs), which bind to malaria parasites and disrupt their lifecycle, have also been developed. But these tools don’t provide complete protection against the disease.

The malaria vaccines and mAbs developed to date all target sites near to or at the central region of the main protein, called PfCSP, on the surface of the malaria sporozoite. Sporozoites are the life stage of the parasite that are transmitted from mosquitoes to people. Research to date has not identified other potential targets to prevent infection.

In a new study led by Dr. Joshua Tan from NIH, researchers collected blood samples from about 950 people previously infected with malaria. They performed a range of experiments to isolate and identify antibodies that bound to targets other than the central region of PfCSP. Their results were published on January 3, 2025, in Science.

Most antibodies that bound to sporozoites in these blood samples also bound to laboratory-made PfCSP, called recombinant PfCSP (rPfCSP). When these antibodies were removed, five of the donors had antibodies that still bound to sporozoites.

The researchers next screened B cells, the immune cells that produce antibodies, from these five people for further study. They found that less than 1% of the B cells studied made antibodies that reacted to whole sporozoites but not rPfCSP. The team sequenced the genes of these B cells and used them to produce 10 new mAbs.

The new mAbs bound to a protein in whole sporozoites that seemed to be PfCSP, but the mAbs didn’t bind to lab-made rPfCSP. This suggested that the antibodies might be targeting a part of PfCSP that is altered in live sporozoites. Further studies revealed that the new mAbs bind to a region of PfCSP that the team called pGlu-CSP. This region isn’t accessible in lab-made rPfCSP. It is exposed only after a specific step in the development of live sporozoites. 

The team tested the most potent of these antibodies, called MAD21-101, in mice. Four out of five mice that received a high dose of MAD21-101 before exposure to sporozoites remained free from infection up to nine days. In contrast, mice not given the antibody had high levels of malaria parasites in their blood.

The researchers next looked at gene sequences from more than 16,000 different malaria parasites from around the globe. They found that most contained the same pGlu-CSP region or had a single mutation in the region that didn’t affect the binding of most of the new antibodies, including MAD21-101.

None of the new antibodies, including MAD21-101, bound to the PfCSP sequence used in current malaria vaccines. This suggests that new preventive treatments based on these antibodies wouldn’t interfere with current strategies.

“More work needs to be done before testing these new antibodies in people, but they show promise as a potential addition to our anti-malaria arsenal,” Tan says.