Cryo-EM structures of broadly neutralizing antibodies (pink/tan) targeting the key site (red/orange) of PfEMP1 protein (blue). Credit: Scripps Research
Cryo-EM structures of broadly neutralizing antibodies (pink/tan) targeting the key site (red/orange) of PfEMP1 protein (blue). Credit: Scripps Research

A long-standing question in the field of severe malaria has remained for decades: Do people living in regions with continuous malaria transmission develop specialized antibodies against the parasite and its many strains? The answer is yes, as recently discovered through a collaborative effort among researchers from Scripps Research; the University of Copenhagen; the University of Texas Health Science Center at San Antonio; the Fred Hutchinson Cancer Research Center in Seattle, EMBL Barcelona; the University of California, San Francisco; the Tanga Research Centre in Tanzania; and the Infectious Disease Research Centre in Uganda.

This discovery, published in Nature on November 20, 2024, sheds light on how antibodies protect the body against Plasmodium falciparum, the parasite responsible for the most severe forms of malaria—a disease that can cause seizures, kidney failure and, ultimately, death if left untreated. The mechanistic understanding offers a promising pathway for developing improved malaria vaccines.

Study co-first author and postdoctoral associate Sai Sundar Rajan Raghavan, PhD
Study co-first author and postdoctoral associate Sai Sundar Rajan Raghavan, PhD

“Importantly, this study reveals how immunity can arise despite the parasite’s use of a highly mutated antigen to infect its host—a puzzle that has baffled scientists for many years,” says study co-first author Sai Sundar Rajan Raghavan, PhD, a postdoctoral associate at Scripps Research.

The researchers found that broadly neutralizing antibodies (bnAbs)—specialized immune molecules—recognize and block a specific site of the PfEMP1 protein, which plays a critical role in the malaria parasite’s red blood cell stage. That specific key site of PfEMP1 represents a critical vulnerability of the parasite, as it cannot be altered without compromising the parasite’s ability to bind onto host cells. PfEMP1 works by attaching to EPCR, a receptor that allows it to adhere to the host cell surface and avoid being detected and cleared by the spleen—a necessary step in the parasite’s survival and development of severe malaria. Therefore, antibodies targeting this site effectively neutralize PfEMP1’s binding to EPCR and reduces the parasite’s virulence.

To explore the mechanism of these bnAbs targeting PfEMP1, researchers from the lab of Integrative Structural and Computational Biology Professor Andrew Ward, PhD,employed single-particle cryo-EM. This technology allowed them to successfully obtain high-resolution structures of the parasite’s receptor binding site in complex with the antibodies—all in spite of the complex’s relatively small size, which typically poses a challenge in the field of cryo-EM.

“Advancements in vaccine and protein design, including novel AI technologies, present exciting opportunities to accelerate vaccine development for critical targets, such as those discovered in this study that are central to acquiring immunity to severe malaria,” Raghavan adds.

At Scripps Research, scientists plan to next investigate the existence of these antibodies in children less than five years of age, as they are the most vulnerable to this disease. Then, the researchers will embark on understanding how these antibodies evolve during and post-infection, as well as how they translate into long-lasting immunity against severe malaria.