New Antibodies Target Malaria Parasite in a Unique Way

Researchers from the National Institutes of Health (NIH) have identified a novel class of antibodies that bind to a previously untargeted region of the malaria parasite. The most potent antibody in this group, named MAD21-101, demonstrated protective effects against malaria in a mouse model. Published in Science, the study highlights how these antibodies may complement existing malaria prevention methods, such as vaccines and monoclonal antibodies, by targeting distinct parts of the parasite.

Malaria and the challenge of prevention

Malaria, caused by Plasmodium parasites, continues to exact a significant toll globally, with 263 million cases and nearly 600,000 deaths reported by the World Health Organization in 2023. The majority of cases occur in Africa, where Plasmodium falciparum is the most prevalent and children account for most deaths. Efforts to combat malaria include vaccines and monoclonal antibodies (mAbs), which focus on the sporozoite stage of the parasite’s lifecycle. Sporozoites, transmitted through mosquito bites, infect the liver and develop into blood-stage parasites that cause the disease.

Existing malaria vaccines and mAbs largely target the circumsporozoite protein (PfCSP), particularly its central repeat region. This approach prevents sporozoites from infecting the liver. However, the central repeat region is already included in currently available malaria vaccines, leaving other potential targets on the parasite unexplored.

Discovering new targets on the sporozoite surface

The NIH team took a different approach, isolating human mAbs generated in response to whole sporozoites rather than specific parasite components. They then screened these antibodies for their ability to neutralize sporozoites in mice. Among the antibodies tested, MAD21-101 emerged as the most potent, providing protection against P. falciparum infection.

MAD21-101 binds to a newly identified epitope on PfCSP called pGlu-CSP, located outside the central repeat region. This epitope is conserved across different strains of P. falciparum and becomes accessible on the sporozoite surface after a specific developmental step. The researchers suggest that pGlu-CSP's broad exposure and conserved nature make it an attractive target for vaccines and mAbs.

Complementing existing malaria interventions

Antibodies targeting pGlu-CSP are unlikely to interfere with current malaria vaccines, allowing for potential co-administration. This feature could be particularly beneficial for infants in malaria-endemic regions who have not yet received a vaccine but are at high risk for infection. Additionally, the conserved nature of the pGlu-CSP epitope suggests it may provide cross-strain protection, enhancing the effectiveness of prevention strategies.

Future implications and broader applications

While the findings offer promising new directions, the researchers emphasize the need for further studies to assess the activity and efficacy of antibodies targeting pGlu-CSP in humans. They also note that the approach used to identify this novel antibody class could inform the development of countermeasures for other infectious diseases. As malaria continues to impose a heavy burden, these advances may contribute to more comprehensive prevention strategies and improved global health outcomes.

Reference: Dacon C, Moskovitz R, Swearingen K, et al. Protective antibodies target cryptic epitope unmasked by cleavage of malaria sporozoite protein. Science. 2025;387(6729):eadr0510. doi: 10.1126/science.adr0510

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