Structures of deadly viruses point to new avenues for vaccine design

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Each year, hundreds of thousands of people in West Africa become infected with the Lassa virus, which can cause Lassa fever and lead to serious illness, long-term side effects, or death. There are currently no widely approved treatments or vaccines for the disease. Now, Scripps Research scientists have determined the structure of the critical protein complex that allows Lassa virus to infect human cells. The research, published online in cell reportsit also identified novel antibodies that bind to these proteins and neutralize the virus, paving the way for more effective Lassa virus vaccines and treatments.

“This work is a major step forward in our ability to isolate new antibodies at relevant sites of virus vulnerability, and provides a foundation for rational vaccine design to broadly protect people against many Lassa virus lineages.” says the lead author. Andrew Ward, PhD, Professor of Integrative Computational and Structural Biology at Scripps Research. “These new reagents described in the paper are already being put to good use and yielding new and exciting results.”

Like many viruses, Lassa virus exists in a variety of lineages, each with slight variations in its genes. This diversity has made it difficult to identify antibodies that recognize all versions of the Lassa virus. Scientists have also struggled to isolate Lassa glycoproteins, the spike-shaped proteins that surround the virus and are the target of most antibodies. In the infectious virus, these glycoproteins exist in complexes of three, called trimers. However, for decades, scientists were only able to isolate glycoproteins in the laboratory as individual proteins and not in their trimer complexes.

In 2022, Ward and his colleagues figured out how to use nanoparticles to hold glycoproteins together in trimers. In the new work, they used this technique to isolate and structurally characterize the glycoprotein trimers of four different Lassa virus lineages. Surprisingly, the glycoprotein structures of the different lineages were extremely similar.

“We expected to see more obvious differences that would explain why the antibodies did not recognize all lineages,” says Hailee Perrett, a Scripps Research graduate student and first author of the paper. “Instead, we found a very high level of conservation in the peptide and sugar components of the protein.”

Using the same stable glycoproteins, Ward, Perrett, and their colleagues then used blood samples from patients who had recovered from the Lassa virus to isolate antibodies against the glycoprotein trimers. They found new antibodies and characterized previously discovered antibodies that recognize different lineages of the Lassa virus glycoprotein, which may be useful for developing a treatment or preventative vaccine against the virus.

The team is already planning future experiments to identify more antibodies against Lassa virus glycoproteins, as well as further analyze the protein structures to identify places on the glycoproteins that are ideal for drug targeting.

“Our goals were to not only try to define some of the structural details of these different Lassa viruses, but also to provide critical protocols and resources for the field,” says Perrett. “We hope that our initial approaches and findings will help advance the science in this field.”

This work was supported by a grant from the David C. Fairchild Endowed Fellowship, Achievement Rewards for College Scientists Foundation, the National Institutes of Health (1F31Al172358, R01 AI165692, R01 AI171438), the Netherlands Organization for Scientific Research, amfAR Mathilde Krim Fellowship in Biomedical Research (#110182-69-RKVA), a Vici grant from the Netherlands Organization for Scientific Research, the Fondation Dormeur in Vaduz, the Deutsche Forschungsgemeinschaft (197785619/SFB1021), the International AIDS Vaccine Initiative (INV008352/ OPP1153692) and the Melinda Gates Foundation and Law Project (OPP1170236).