New York, NY [November 21, 2025]—Researchers at the Icahn School of Medicine at Mount Sinai and collaborators have created the most comprehensive map to date showing how antibodies attach to the SARS-CoV-2 virus, which causes COVID-19, and how viral mutations weaken that attachment. The findings, published in the November 21 online issue of Cell Systems, a Cell Press journal, explain why variants like Omicron can evade immune defenses and suggest new strategies for building longer-lasting antibody therapies and vaccines.
The team analyzed more than a thousand three-dimensional structures of antibodies bound to the virus’s spike protein, the main target for immune recognition, and compiled them into a structural atlas of COVID-19 antibodies. By studying these structures together for the first time, the researchers revealed a detailed picture of how the immune system targets the virus and how the virus evolves to evade it.
“Scientists around the world have solved thousands of individual antibody-virus structures, but until now, no one had looked at them together,” says senior author Yi Shi, PhD, Associate Professor of Pharmacological Sciences, and Director of the Center for Protein Engineering and Therapeutics, at the 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 researchers found that antibodies, including many used in clinical treatments, recognize nearly every exposed region of the spike protein’s receptor-binding domain, a critical region of the virus. Despite this broad coverage, mutations in newer variants have weakened the binding of almost all antibodies to some degree. Many antibodies, though different in sequence, bind to the virus in strikingly similar ways, suggesting that there are only a few effective structural ways to neutralize it. That convergence, say the investigators, helps explain why the virus can mutate around immunity so efficiently.
The study also highlights the potential of nanobodies—tiny, highly stable antibody fragments that can reach parts of the virus that standard antibodies often miss. Because they can recognize deeply buried regions of the spike protein that tend to remain unchanged as the virus evolves, nanobodies could serve as powerful starting points for developing next-generation antiviral drugs.
“Our findings highlight the limits of the antibodies we currently rely on,” Dr. Shi says. “While these antibodies have been remarkably effective, the virus keeps finding ways to escape them.”
“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,” adds Frank (Zirui) Feng, the study’s first author and a master’s student in the Biomedical Data Science and AI program at Mount Sinai.
Although the study focused on one key part of the spike—the receptor-binding domain—the researchers note that similar patterns of immune escape are likely occurring elsewhere in the virus. They emphasize that the results do not mean the immune system or vaccines no longer work. Vaccination and natural immunity still provide vital protection through a wide range of immune responses, even when certain antibodies lose potency.
Next, the team plans to apply this large-scale structural approach to other viruses to uncover shared principles of antibody recognition. Ultimately, they hope these insights will guide the development of durable antibody treatments capable of withstanding viral evolution and improving preparedness for future pandemics.
“The immune system is remarkably adaptable, but the virus is clever,” says co-author Adolfo Garcia-Sastre, PhD, Irene and Dr. Arthur M. Fishberg Professor of Medicine, and Director of the Global Health and Emerging Pathogens Institute at the 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 a part of this research, the team has created an open-access data set and interactive web tool that allows scientists to explore antibody structures in detail, providing a powerful resource to collectively accelerate research on COVID-19 and other viruses.
The paper is titled “One Thousand SARS-CoV-2 Antibody Structures Reveal Convergent Binding and Near-Universal Immune Escape.”
The study’s authors, as listed in the journal, are Zirui Feng, Zhe Sang, Yufei Xiang, Alba Escalera, Adi Weshler, Dina Schneidman- Duhovny, Adolfo García-Sastre, and Yi Shi.
This work is supported by National Institutes of Health grant R01 AI163011. This work is also partly supported by the Center for Research on Influenza Pathogenesis and Transmission, an National Institute of Allergy and Infectious Diseases (NIAID) Center of Excellence for Influenza Research and Response (contract # 75N93021C00014), and by NIAID grant U19AI135972. Research reported in this publication was supported by NIAID Award G20AI174733. See the Cell Systems paper for details on conflicts of interest.
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About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the seven member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City’s large and diverse patient population.
The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master’s degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,600 clinical residents and fellows training throughout the Health System. Its Graduate School of Biomedical Sciences offers 13 degree-granting programs, conducts innovative basic and translational research, and trains more than 560 postdoctoral research fellows.
Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges. More than 4,500 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai
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