Gaining insight into how our immune system recognizes the SARS-CoV-2 virus is a key component to inform future drug design and vaccine development. A research group from the Scripps Research Institute has recently determined the crystal structure of CR3022—a neutralizing antibody previously isolated from a convalescent SARS patient—in complex with the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein to 3.1 Å.

The study, “A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV,” published in Science, is the first to map a human antibody’s interaction with SARS-CoV-2 at near-atomic-scale resolution.

This is the antibody CR3022 bound to the receptor-binding domain of SARS2-CoV-2. [Meng Yuan and Nicholas Wu]

The antibody was recovered from a survivor of the SARS epidemic in the early 2000s, caused by the SARS-CoV virus, but cross-reacts with the SARS-CoV-2. This finding has revealed a potential vulnerability of SARS-CoV-2, according to the team at Scripps Research. The structural mapping revealed a nearly identical site on both coronaviruses to which the antibody binds, suggesting a functionally important and vulnerable site for this family of coronaviruses.

“The knowledge of conserved sites like this can aid in structure-based design of vaccines and therapeutics against SARS-CoV-2, and these would also protect against other coronaviruses—including those that may emerge in the future,” said the study’s senior author Ian Wilson, DPhil, professor of structural biology and chair of the department of integrative structural and computational biology at Scripps Research.

The Wilson lab is known for its pioneering structural studies of antibodies bound to viruses including HIV and influenza. These studies have been used to inform designs of vaccines and antibody drugs, as well as other therapeutics. “Our ultimate goal here is to obtain structural information on antibodies and their binding sites, and use that to guide SARS-CoV-2 vaccine design, just as our lab has done with influenza and HIV,” said the study’s co-first author Nicholas Wu, PhD, a postdoctoral research associate in the Wilson lab.

The new study centers on an anti-SARS-CoV antibody called CR3022 that was originally isolated in 2006 by the pharmaceutical company Crucell Holland in the Netherlands. A report from Chinese scientists earlier this year indicated that CR3022 cross-reacts against SARS-CoV-2. Wilson’s team used their structural mapping expertise to determine how the antibody binds to SARS-CoV-2.

A key finding is that the antibody’s binding site is highly similar between the two coronaviruses—differing by just four amino acids. That high degree of similarity implies that the site has an important function that would be lost if it mutated significantly.

Yet, the site’s function remains mysterious. The Scripps Research analysis found that the antibody binding site is relatively remote from the part of the virus that grabs hold of cell-surface protein receptors in preparation for penetrating cells in our lungs. That suggests that, at least for SARS-CoV, CR3002 neutralizes the virus’s ability to infect cells in some indirect way.

“CR3022 targets a highly conserved epitope, distal from the receptor-binding site, that enables cross-reactive binding between SARS-CoV-2 and SARS-CoV,” the authors wrote.

Adding to the mystery is the finding that the antibody binding site on these viruses is not normally accessible to antibodies.

The authors noted that “structural modeling further demonstrates that the binding epitope can only be accessed by CR3022 when at least two RBD on the trimeric S protein are in the ‘up’ conformation and slightly rotated.”

“We found that this region is usually hidden inside the virus, and only exposed when that part of the virus changes its structure, as it would in natural infection,” said co-first author Meng Yuan, PhD, also a research associate in the Wilson lab.

Despite the slight difference between the two coronaviruses, the antibody binds much less tightly to SARS-CoV-2 than it does to the SARS virus, and cannot neutralize SARS-CoV-2 in lab dish tests as it does SARS-CoV.

Still, the findings suggest that the binding site for this antibody on SARS-CoV-2 is a site of vulnerability, and that antibodies binding it more tightly would plausibly succeed in neutralizing the virus. Such neutralizing antibodies, if developed into therapies, could be used to treat COVID-19 patients and to provide temporary protection from the virus to uninfected individuals, for example, healthcare workers.

The fact that this binding site is highly conserved between SARS-CoV and SARS-CoV-2 also hints that there may be antibodies, still to be discovered, that can effectively neutralize both viruses—and perhaps in the same way, can neutralize future emergent coronaviruses before they can cause pandemics.

Labs at Scripps Research and throughout the world are currently seeking antibodies, via blood donations, from people who have recovered from COVID-19 for further studies along these lines.

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