A novel class of antibodies has been discovered that binds to a previously untargeted portion of the malaria parasite—a cryptic pGlu-CSP site on the Plasmodium falciparum (Pf) sporozoite surface. The most potent of the new antibodies was found to provide protection against malaria parasites in an animal model. The researchers say antibodies in this class are particularly promising because they bind to regions of the malaria parasite not included in current malaria vaccines, providing a potential new tool for fighting the disease.
This work is published in Science in the paper, “Protective antibodies target cryptic epitope unmasked by cleavage of malaria sporozoite protein.”
Malaria is a life-threatening disease caused by Plasmodium parasites, spread through the bites of infected mosquitoes. In 2023, the World Health Organization estimated that there were 263 million cases and 597,000 deaths.
In recent years, new interventions have been developed against malaria, including vaccines that currently are being rolled out for young children in regions where the disease is prevalent. Anti-malarial monoclonal antibodies are another promising new tool that have been shown to be safe and efficacious against infection with P. falciparum in adults and children in early clinical trials.
The anti-malarial mAbs currently being evaluated in trials in malaria-endemic regions target the P. falciparum sporozoite. By binding to and neutralizing the sporozoite, the mAbs prevent sporozoites from infecting the liver, where they otherwise develop into blood-stage parasites that infect blood cells and cause disease and death.
The most promising anti-malarial mAbs tested in humans to date bind to the circumsporozoite protein (PfCSP) on the sporozoite surface at locations near to (or containing amino acid repeats in) the central repeat region. This portion of PfCSP is also included in the two available malaria vaccines. The researchers in the current study aimed to find mAbs that target new sites on the sporozoite surface.
The research team isolated human mAbs produced in response to whole sporozoites, rather than to specific parts of the parasite, and then tested the mAbs to see if they could neutralize sporozoites in a mouse model of malaria.
More specifically, they “screened plasma from 941 Pf sporozoite–exposed individuals and identified five donors who retained antibody reactivity to Pf sporozoites after preblocking with recombinant PfCSP. Using our antigen-agnostic workflow, we identified 10 mAbs from these donors that bound strongly to Pf sporozoites but not to recombinant PfCSP.”
They noted that, surprisingly, these mAbs bound “exclusively to sporozoite-expressed PfCSP, because they required two sequential parasite-driven modifications to this protein: cleavage of the N terminus of PfCSP and conversion of the resultant N-terminal residue from glutamine to pyroglutamate.”
One mAb, MAD21-101, was found to be the most potent, providing protection against P. falciparum infection in mice. This new mAb binds to an epitope on PfCSP outside of the central repeat region that is conserved between different strains of P. falciparum. Notably, the epitope, pGlu-CSP, is exposed only after a specific step in the development of the sporozoite, but it is widely accessible on the sporozoite surface. This scenario could mean pGlu-CSP would be effective at eliciting a protective immune response if used in a vaccine. As pGlu-CSP is not included in currently used malaria vaccines, mAbs targeting this epitope are unlikely to interfere with the efficacy of these vaccines if the vaccines and mAbs are co-administered. According to the scientists, this could provide an advantage because this new class of antibodies may be suitable to prevent malaria in at-risk infants who have not yet received a malaria vaccine, but may receive one in the future.
