Abstract
Efficient therapeutic options are needed to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has caused more than 922,000 fatalities as of 13 September 2020. We report the isolation and characterization of two ultrapotent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that protect hamsters against SARS-CoV-2 challenge. Cryo-electron microscopy structures show that S2E12 and S2M11 competitively block angiotensin-converting enzyme 2 (ACE2) attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Antibody cocktails that include S2M11, S2E12, or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions. Our results pave the way to implement antibody cocktails for prophylaxis or therapy, circumventing or limiting the emergence of viral escape mutants.
Highlights
Efficient therapeutic options are needed to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has caused more than 922,000 fatalities as of 13 September 2020
To identify highly potent monoclonal Ab (mAb) elicited upon SARS-CoV-2 infection, we sorted memory B cells from two individuals recovering from severe COVID-19 disease, using biotinylated prefusion SARS-CoV-2 S ectodomain trimer as bait
S2M11 and S2E12 were identified among almost 800 screened Abs isolated from 12 individuals who recovered from COVID-19
Summary
Efficient therapeutic options are needed to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has caused more than 922,000 fatalities as of 13 September 2020. The finding that S2M11 preferentially interacts with the S trimer relative to the RBD suggests that this mAb might bind to a quaternary epitope only displayed in the context of a native closed prefusion S.
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