Abstract
Coronavirus disease 2019, caused by SARS-CoV-2, remains an on-going pandemic, partly due to the emergence of variant viruses that can "break-through" the protection of the current vaccines and neutralizing antibodies (nAbs), highlighting the needs for broadly nAbs and next-generation vaccines. We report an antibody that exhibits breadth and potency in binding the receptor-binding domain (RBD) of the virus spike glycoprotein across SARS coronaviruses. Initially, a lead antibody was computationally discovered and crystallographically validated that binds to a highly conserved surface of the RBD of wild-type SARS-CoV-2. Subsequently, through experimental affinity enhancement and computational affinity maturation, it was further developed to bind the RBD of all concerning SARS-CoV-2 variants, SARS-CoV-1 and pangolin coronavirus with pico-molar binding affinities, consistently exhibited strong neutralization activity against wild-type SARS-CoV-2 and the Alpha and Delta variants. These results identify a vulnerable target site on coronaviruses for development of pan-sarbecovirus nAbs and vaccines.
Keywords:
Computational antibody discovery; Sars-CoV-2; broad-spectrum vaccine; broadly neutralizing antibody; emerging variants.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin-Converting Enzyme 2 / chemistry
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Angiotensin-Converting Enzyme 2 / metabolism
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Antibodies, Viral / genetics
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Antibodies, Viral / immunology*
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Antibodies, Viral / metabolism
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Antibody Affinity
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Antibody Specificity
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Antigen-Antibody Reactions
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Antigens, Viral / chemistry
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Antigens, Viral / genetics
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Antigens, Viral / immunology*
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Broadly Neutralizing Antibodies / genetics
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Broadly Neutralizing Antibodies / immunology*
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Broadly Neutralizing Antibodies / metabolism
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COVID-19 / immunology*
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Crystallography, X-Ray
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Epitopes / chemistry
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Epitopes / immunology
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Humans
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Immunoglobulin Fragments / immunology
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Molecular Docking Simulation
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Monte Carlo Method
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Neutralization Tests
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Peptide Fragments / chemistry
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Peptide Fragments / metabolism
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Protein Domains
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / metabolism
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SARS-CoV-2 / genetics
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SARS-CoV-2 / immunology*
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Spike Glycoprotein, Coronavirus / chemistry
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Spike Glycoprotein, Coronavirus / genetics
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Spike Glycoprotein, Coronavirus / immunology*
Substances
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Antibodies, Viral
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Antigens, Viral
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Broadly Neutralizing Antibodies
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Epitopes
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Immunoglobulin Fragments
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Peptide Fragments
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Recombinant Fusion Proteins
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Spike Glycoprotein, Coronavirus
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immunoglobulin Fv
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spike protein, SARS-CoV-2
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ACE2 protein, human
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Angiotensin-Converting Enzyme 2
Grants and funding
This work was supported by the National Research Council of Science and Technology [CRC-16-01-KRICT]; National Research Foundation of Korea [NRF-2019M3E5D6063903];Korea Advanced Institute of Science and Technology [MCM-2021-N11210036].