Scientists have discovered human antibodies that target proteins linked to severe malaria, which could lead to innovative vaccines or treatments. Utilizing organ-on-a-chip technology, researchers showed that these antibodies prevent infected red blood cells from binding to blood vessel walls, a significant cause of severe malaria symptoms. These antibodies neutralize a specific area of the malarial protein PfEMP1, tackling its well-known variability and offering insights into acquired immunity. This collaborative research, published in *Nature*, emphasizes the effectiveness of global teamwork in addressing critical health issues like malaria.
Malaria, especially in its severe forms, continues to pose a massive global health crisis and economic strain, claiming over 600,000 lives annually—most of whom are African children under five. A new study published in the journal Nature reveals that researchers from EMBL Barcelona, the University of Texas, the University of Copenhagen, and The Scripps Research Institute have identified human antibodies that can effectively recognize and target proteins linked to severe malaria. This advancement may lead to the development of future vaccines or treatments against malaria.
Severe malaria is caused by the parasite Plasmodium falciparum, which infects and alters red blood cells. These alterations can cause red blood cells to cling to the walls of small blood vessels in the brain. This leads to restricted blood flow and the blockage of these vessels, causing brain swelling and potentially leading to cerebral malaria.
The blockage of blood flow is largely caused by a group of approximately 60 virulent proteins, known as PfEMP1, that are found on the surface of infected red blood cells. Certain PfEMP1 types can bind to a human protein called EPCR on the surface of blood vessel lining cells. This interaction negatively affects blood vessels and is closely associated with the development of severe health complications.
The researchers recognized that as children in Africa grow older, they gradually build immunity, and teenagers and adults seldom experience fatal disease complications. This immunity is thought to be due to antibodies that target PfEMP1.
PfEMP1 is highly variable and has traditionally been seen as a challenging target for vaccines. A long-standing query has been whether the immune system can generate antibodies that effectively target the diverse range of PfEMP1 protein types present.
“We were unsure if we could find a single antibody that could recognize them all,” stated Maria Bernabeu, co-senior author of the paper and Group Leader at EMBL Barcelona. “However, our enhanced immunological screening methods developed at the University of Texas quickly identified two examples of human antibodies that are broadly effective against various PfEMP1 protein versions. Both targeted a part of the protein known as CIDRα1, which interacts with the EPCR receptor.”
The team then sought to test whether these antibodies could successfully block binding to EPCR in living blood vessels. In many diseases, this would typically be tested in animal models; however, for malaria, this isn’t feasible because the virulent proteins of the parasites that infect mice are very different from those affecting humans.
The researchers devised an innovative solution to overcome this obstacle. They developed a method to grow a network of human blood vessels in the lab and introduced human blood infected with live parasites into these vessels, effectively simulating the disease in a controlled environment. Their experiments showed that the antibodies could hinder the accumulation of infected cells, indicating they might help prevent the blockages that lead to severe malaria symptoms.
“Using our organ-on-a-chip technology, we recreated brain microvessels in 3D and then infected them with malaria parasites,” remarked Viola Introini, a Marie-Skłodowska Curie postdoctoral fellow in Maria Bernabeu’s group at EMBL Barcelona and co-first author of the study. “When we introduced the two antibodies into the system, we were amazed at their effectiveness in preventing infected blood cells from adhering to the vessels. The inhibition was clearly visible.”
Structural and immunological analysis conducted by collaborators at the University of Copenhagen and The Scripps Research Institute revealed that these antibodies prevent parasite binding by similar mechanisms, recognizing three highly conserved amino acids on CIDRα1. These broadly reactive antibodies likely illustrate a common mechanism of acquired immunity against severe malaria and present new insights for developing a PfEMP1-based vaccine or treatment.
“This study opens new avenues for protecting individuals from severe malaria, such as vaccines or alternative treatments,” Bernabeu added. “This progress is a testament to the importance of international and interdisciplinary collaboration in understanding diseases like malaria. Our global collaborators approach malaria research from various perspectives. We must continue to unite our efforts to tackle significant challenges like this one.”
She further stated, “At EMBL Barcelona, we believe that tissue engineering and organ-on-a-chip technologies allow us to investigate diseases in much greater complexity and detail, and they also provide valuable platforms for screening vaccine candidates.”
