Researchers at the Icahn School of Medicine at Mount Sinai have published a comprehensive study that maps how antibodies interact with the SARS-CoV-2 virus and how mutations allow the virus to evade immune responses. The findings, released in Cell Systems on November 21, provide new insight into why COVID-19 variants such as Omicron can escape immunity and offer guidance for developing more effective therapies and vaccines.
The research team analyzed over one thousand three-dimensional structures of antibodies bound to the spike protein of SARS-CoV-2. By compiling these data into a structural atlas, they revealed detailed information about how the immune system targets the virus and how viral evolution undermines antibody effectiveness.
“Scientists around the world have solved thousands of individual antibody-virus structures, but until now, no one had looked at them together,” said Yi Shi, PhD, Associate Professor of Pharmacological Sciences and Director of the Center for Protein Engineering and Therapeutics at Icahn School of Medicine. “By uniting all these data, we were able to see the bigger picture—how fully antibodies cover the virus’s surface and how mutations in newer variants like Omicron can undermine that protection. It gives us a clearer view of both the strengths and limits of our immune system.”
The analysis found that while antibodies target nearly every exposed part of the spike protein’s receptor-binding domain—a critical area for infection—mutations in newer variants have weakened this binding across almost all antibodies. Despite differences in sequence, many antibodies attach to similar regions in comparable ways. This convergence helps explain why SARS-CoV-2 can mutate to escape immunity so efficiently.
The study also points to nanobodies—small antibody fragments—as promising tools because they can reach areas on the spike protein that are less likely to change as the virus evolves. These properties could make nanobodies valuable for future antiviral drug development.
“Our findings highlight the limits of the antibodies we currently rely on,” Dr. Shi stated. “While these antibodies have been remarkably effective, the virus keeps finding ways to escape them.”
Frank (Zirui) Feng, first author and master’s student in Biomedical Data Science and AI at Mount Sinai, added: “To stay ahead, we’ll need to design next-generation antibodies that can recognize and latch onto multiple regions of the virus at once, making it much harder for the virus to evade our defenses as it continues to evolve.”
Although focused on one region—the receptor-binding domain—the researchers note similar patterns may exist elsewhere on SARS-CoV-2. They emphasize their results do not mean current vaccines or natural immunity are ineffective; vaccination still provides broad protection through various immune mechanisms even if some antibodies lose strength.
Looking forward, researchers plan to use this large-scale structural approach with other viruses to identify common principles in antibody recognition. They hope their work will support development of durable treatments that remain effective against evolving pathogens.
“The immune system is remarkably adaptable, but the virus is clever,” said co-author Adolfo Garcia-Sastre, PhD, Irene and Dr. Arthur M. Fishberg Professor of Medicine and Director of Global Health and Emerging Pathogens Institute at Icahn School of Medicine. “By analyzing how antibodies attach to the virus and where they fall short, we gain a detailed map of the virus’s vulnerabilities. This insight not only helps us understand why some antibodies stop working as the virus evolves but also guides the design of next-generation therapies that can stay one step ahead, potentially improving how we prevent and treat COVID-19 and other viral infections.”
As part of this effort, an open-access dataset and interactive web tool has been made available for scientists worldwide to explore antibody structures related to COVID-19 research.
The paper is titled “One Thousand SARS-CoV-2 Antibody Structures Reveal Convergent Binding and Near-Universal Immune Escape.” Authors include Zirui Feng, Zhe Sang, Yufei Xiang, Alba Escalera, Adi Weshler, Dina Schneidman-Duhovny, Adolfo García-Sastre, and Yi Shi.
Funding was provided by several National Institutes of Health grants including R01 AI163011; contract #75N93021C00014 from NIAID’s Center for Research on Influenza Pathogenesis; grant U19AI135972; as well as NIAID Award G20AI174733.
The Icahn School of Medicine at Mount Sinai is recognized internationally for its research programs across education and clinical care fields. It partners academically with seven hospitals within New York City through the Mount Sinai Health System, which serves a diverse patient population throughout New York City.
