Researchers Identify New Antibodies Against Current and Future Coronaviruses
The single-domain antibodies naturally produced by llamas can also bind to and neutralize a range of coronaviruses.
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Scientists have identified a new class of small antibodies that provide strong protection against a broad range of SARS-related coronaviruses. These include SARS-CoV-1 and various SARS-CoV-2 variants from both early and recent stages of the COVID-19 pandemic.
The antibodies target a highly conserved site at the base of the virus’s spike protein, preventing the structural changes needed for infection.
The findings, published in Nature Communications, point to potential new antiviral therapies that may retain effectiveness as the virus evolves.
Targeting a stable region of the spike protein
The ongoing evolution of SARS-CoV-2 continues to generate variants that resist approved antibody treatments. This resistance typically arises because most antibodies target regions of the spike protein that frequently mutate, such as the receptor binding domain.
To overcome this limitation, a team led by Prof. Xavier Saelens and Dr. Bert Schepens at the VIB-UGent Center for Medical Biotechnology focused on a different region. They examined the S2 subunit of the spike protein, which is essential for the virus to fuse with host cells. This subunit is also more conserved across different coronaviruses.
“This region is so crucial to the virus that it can’t easily mutate without weakening the virus itself,” said Schepens, senior author of the study. “That gives us a rare advantage: a target that’s both essential and stable across variants.”
Small antibodies with a unique mode of action
The researchers used single-domain antibodies, also known as nanobodies, which are naturally produced by llamas. These antibodies are much smaller than typical mammalian antibodies. The team identified several nanobodies from a llama named Winter that neutralized a wide range of SARS coronaviruses.
Single-domain antibodies
Also called nanobodies, these are antibodies that consist of a single variable domain. They are naturally produced by members of the camelid family, such as llamas. Nanobodies are much smaller than conventional antibodies, making them useful for binding to hidden or structurally complex targets.
These antibodies work by binding to a coiled coil of three alpha helices at the base of the spike protein. By attaching to this poorly exposed and highly conserved site, the antibodies act as a molecular clamp. They lock the spike protein in its prefusion shape, preventing it from adopting the structure required for cell entry.
Strong protection and a high barrier to resistance
In laboratory experiments, the antibodies provided strong protection against infection in animal models, even at low doses. When the researchers attempted to induce viral escape by forcing the virus to evolve resistance, only rare variants with much lower infectivity emerged. This suggests that the targeted site is both essential to the virus and difficult to mutate without compromising the virus’s ability to infect cells.
The study represents a step forward in the development of broad-spectrum antiviral therapies. By targeting a structurally and functionally critical region of the spike protein, the antibodies identified by the team may offer a foundation for treatments that can remain effective as the virus evolves.
"The combination of high potency, broad activity against numerous viral variants, and a high barrier to resistance is incredibly promising," said Saelens. "This work provides a strong foundation for developing next-generation antibodies that could be vital in combating not only current but also future coronavirus threats."
Reference: De Cae S, Van Molle I, Van Schie L, et al. Ultrapotent SARS coronavirus-neutralizing single-domain antibodies that clamp the spike at its base. Nat Commun. 2025;16(1):5040. doi: 10.1038/s41467-025-60250-1
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