Malaria remains one of the world’s most devastating diseases, resulting in almost 600,000 deaths annually, as estimated by the World Health Organization (WHO). While vaccines and monoclonal antibodies (mAbs) have made significant strides in reducing the burden of this disease, current WHO prequalified vaccines (RTS, S and R21) primarily target a single region of Plasmodium falciparum (the deadliest malaria-causing parasite), leading to limitations in the vaccines’ ability to provide broad and lasting protection.

Now, researchers led by Joshua Tan, PhD, from the National Institute of Allergy and Infectious Diseases, a part of the National Institutes of Health, with key contributions from scientists at Scripps Research, have uncovered a novel class of mAbs that bind to a previously untapped vulnerability in P. falciparum. This discovery—outlined in a preclinical study published in Science on January 3, 2025—could lead to more comprehensive strategies for preventing malaria.

Among the newly identified mAbs from the Tan lab, one known as MAD21-101 demonstrated notable potential. It binds to a unique site on P. falciparum called pGlu-CSP, which isn’t targeted by existing malaria vaccines. This site becomes accessible after the parasite sheds part of its main surface protein during its stage as a sporozoite—the form of P. falciparum that travels through the skin and bloodstream and then infects the liver.

At this point, the circumsporozoite protein (CSP), which coats the sporozoite, undergoes a change: its now-exposed N-terminal glutamine (a type of amino acid) is chemically modified into a version called pyroglutamate (pGlu). This modification creates the pGlu-CSP site. The exposure of this site at a critical stage in the parasite’s life cycle offers a new target for prevention strategies that aim to stop the onset of malaria infection in the liver.

“These results mark an important advance in malaria research,” explains co-author Ian A. Wilson, DSc, the Hansen Professor of Structural Biology at Scripps Research.

“The distinct post-translational modification producing the pGlu-CSP site isn’t targeted by existing therapeutics, making this site an attractive target for combination therapies that could act to improve protection of vulnerable populations,” adds co-first author Re’em Moskovitz, PhD, a postdoctoral fellow in the Wilson lab.

As well as being a promising candidate for combination therapies or standalone interventions, MAD21-101 targets a highly conserved region of P. falciparum that remains consistent across strains.

Furthermore, the researchers suggest that the novel mAbs could provide a preventive option for infants in malaria-endemic regions, offering protection to those who haven’t yet received a vaccine. The findings could also inform development of next-generation vaccines that incorporate the novel target on P. falciparum.

Although MAD21-101 showed significant potential in preclinical models, further research is needed to assess its effectiveness in humans. Nevertheless, the results highlight the potential for innovative approaches to malaria prevention. The method used—isolating mAbs that bind to less obvious but crucial regions of pathogens—could also be applied to other infectious diseases.

At its core, this study underscores the importance of exploring novel strategies to address persistent global health challenges.

“The fight against malaria is far from over, but these findings offer new opportunities for novel therapies for the millions of people affected by the disease each year,” says Wilson.

Research reported in this article was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.