Antibodies are immune proteins that our bodies produce to help fight off infection. Where they recognize and bind a pathogen — and how — can give important clues to the microbe’s vulnerabilities. Fred Hutch Cancer Center structural biologists Marie Pancera, PhD, and Nicholas Hurlburt, PhD, understand how subtleties of antibody-target interaction can guide development of better treatments and vaccines.
“When you look at the structures of antibodies and their targets, you learn how they interact and where the antibody binds,” Pancera said. “The visualization of ‘sites of vulnerability’ gives you information you can use to inform vaccine design.”
These insights can reveal where investigators should focus vaccine efforts and how to modify microbial structures to improve protective responses to vaccines. Pancera hopes to provide these insights for antibodies that scientists can use to help prevent or treat diseases, like malaria and HIV, that remain health burdens around the world.
Most recently, she and Hurlburt, a staff scientist on Pancera’s team, contributed structural insights that helped an international team of investigators show that two newly isolated broadly inhibitory antibodies can target a key part of the protein that malarial parasites use to stick infected red blood cells to blood vessel walls.
In work published today in Nature, the investigators found that this critical stretch of amino acids is vulnerable to antibody interference. Contributors hailed from Fred Hutch, the Scripps Research Institute, the University of Copenhagen and The University of Texas Health Science Center at San Antonio, as well as the Tanga Research Centre, the Infectious Disease Research Collaboration in Uganda, and the University of California, San Francisco.
“The idea would be that we can use this structural information about how the antibody binds a specific epitope [target] to then try to computationally design [a vaccine] that would elicit this sort of antibody response,” Hurlburt said.
His work could also provide insights that could guide the development of monoclonal antibodies that could help reduce disease severity, he said.
Photos by Robert Hood / Fred Hutch News Service
Antibodies are Y-shaped proteins that reach out to their targets with the tips of each arm. If the antibody interacts with a key part of a microbial structure, it can block infection. Antibodies (like their targets) come in a dizzying array — which means that some antibodies block their targets better than others.
“When you do antibody structures, you see two things,” Pancera said.
First, she said, these studies show where an antibody binds its target, and whether it can bind different variants of a microbe. Secondly, researchers begin to see where (and how) the microbial structure might be modified or the antibody could be modified to improve vaccine response or therapeutic effectiveness.
And using the template created by nature, scientists can also modify the antibody so that it binds better or lasts longer in the body, she said. Pancera and her team have contributed structural insights to work on HIV and another antibody aimed at malaria.
Despite several available malaria vaccines, the mosquito-borne infection remains a heavy burden in many areas of the world. According the World Health Organization, 249 million people contracted the parasite in 2022, and more than 600,000 people died from it. Most new malaria infections occur in young children, who can suffer lifelong consequences even if they survive the infection.
Malaria vaccines greatly reduce incidence and severity of the disease, but there’s plenty of room for improvement: Vaccination reduces the incidence of uncomplicated malaria by 40%, severe malaria by 30% and all-cause mortality by 13%. (In contrast, the very effective varicella vaccine prevents severe chickenpox nearly 100% of the time.)
The Plasmodium parasites’ complex life cycle makes vaccine improvement a bumpy road. Transmitted via the bite of an infected mosquito, the parasites first infect and damage liver cells. In a new form, they spread to red blood cells. Infected red blood cells studded with malarial proteins snag on blood vessels’ inner walls and clog up the tiny blood vessels that carry oxygen and nutrients to vital organs. In severe cases, too many clogs cause organ failure and even death.
In the current work, the collaborators focused on antibodies that protect against severe disease by blocking a protein (P. falciparum erythrocyte membrane protein-1, or PfEMP1) that sticks infected cells to blood vessels.
“This protein is polymorphic in malaria, so it has a bunch of different variants it can express,” Hurlburt said.
If our bodies mount a protective antibody against one variant, the parasite can sidestep them by expressing a different version. But some antibodies can block many versions of their target. Called broadly neutralizing antibodies, they’re what scientists hope to induce with a vaccine. Severe disease mostly occurs in children under five, suggesting that a broadly protective response can develop over time, Hurlburt said.
The teams of co-senior authors Evelien Bunnik, PhD, at UT Health San Antonio, and Thomas Lavstsen, PhD, at the University of Copenhagen had identified two broadly neutralizing antibodies against PfEMP1. Though each was isolated from a different individual, they exhibited similar properties when the collaborators tested their ability to interfere with PfEMP1’s ability to interact with the molecule it uses as a toehold on blood vessel walls. And in lab dish-based models of malaria infection, both antibodies prevented infected red blood cells from sticking to blood vessel walls.
But how do the antibodies interfere?
Hurlburt used X-ray crystallography to visualize how an arm of one of the broadly neutralizing antibodies interacts with a key segment of PfEMP1. He showed that it docks at the region of PfEMP1 that grabs the toehold molecule on blood vessels walls.
“This informed what direction to go in,” Hurlburt said.
Hurlburt and collaborators’ further work, including the use of cutting-edge cryo-electron microscopy, showed that both of the broadly neutralizing antibodies zero in on the same critical section of PfEMP1, a section that is known to be made up of a consistent (or “conserved”) set of amino acids in different versions of PfEMP1.
Hurlburt also used an optical biosensing technology called bio-layer interferometry to test how well the two antibodies bind different versions of PfEMP1.
“I showed that the antibody doesn’t just bind one PfEMP1 well, it binds the whole class [of proteins] very well,” he said.
The structural work helps shed light on both the pathogen and the immune system, Hurlburt said.
“We found that both broadly neutralizing antibodies target a very conserved site that's necessary for severe malaria,” Hurlburt said. “But they do so in different manners.”
This suggests that vaccine developers may have more than one route open to them as they map out improvements more likely to generate a protective response.
This work was funded by the National Institutes of Health, the United States Department of Energy, The Lundbeck Foundation, the Independent Research Fund Denmark, the Marie-Skłodowska-Curie Actions and the European Molecular Biology Laboratory.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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