Rapid Identification of Neutralizing Antibodies against SARS-CoV-2 Variants by mRNA Display

Journal home page for Cell ReportsShow moreAdd to Mendeleyhttps://doi.org/10.1016/j.celrep.2022.110348Get rights and content

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Highlights (3 to 4 main points)o

Broadly-reactive neutralizing antibodies (nAbs) may overcome SARS-CoV-2 variant escape

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mRNA display is used to rapidly identify SARS-CoV-2 spike (S) protein-directed nAbs

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Structural studies reveal distinct binding modes for several identified antibodies

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An engineered nAb sustains binding to variant Gamma E484K and Delta L452R spike

Summary

The increasing prevalence of SARS-CoV-2 variants with the ability to escape existing humoral protection conferred by previous infection and/or immunization necessitates the discovery of broadly-reactive neutralizing antibodies (nAbs). Utilizing mRNA display, we identify a set of antibodies against SARS-CoV-2 spike (S) proteins and characterize the structures of nAbs that recognize epitopes in the S1 subunit of the S glycoprotein. These structural studies reveal distinct binding modes for several antibodies, including targeting of rare cryptic epitopes in the receptor-binding domain (RBD) of S that interacts with angiotensin-converting enzyme 2 (ACE2) to initiate infection, as well as the S1 subdomain 1. Further, we engineer a potent ACE2-blocking nAb to sustain binding to S RBD with the E484K and L452R substitutions found in multiple SARS-CoV-2 variants. We demonstrate that mRNA display is a promising approach for the rapid identification of nAbs that can be used in combination to combat emerging SARS-CoV-2 variants.

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