UNLABELLED: Emergence of SARS-CoV-2 variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the four genera , including the nine human coronaviruses, through recognition of a conserved motif that includes the S2' site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization and, like fp.006 and hr2.016, protects mice when present as bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive with Orthocoronavirinae , including SARS-CoV-2 variants. ONE SENTENCE SUMMARY: Broadly cross-reactive antibodies that protect from SARS-CoV-2 variants are revealed by virus coldspot-driven discovery.

Chan Zuckerberg Biohub; San Francisco USA

Clinical Research Unit Clinica Luganese Moncucco; Lugano Switzerland

Czech Centre of Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences; Vestec Czech Republic

Department of Biology Stanford University; Stanford USA

Department of Biosciences and Nutrition Karolinska Institutet; Huddinge Sweden

Department of Chemistry and Biochemistry Mendel University in Brno; Brno Czech Republic

Department of Clinical Surgical Diagnostic and Pediatric Sciences University of Pavia; Pavia Italy

Department of Experimental Biology Faculty of Science Masaryk University; Brno Czech Republic

Department of Pharmacology and Pharmacy Faculty of Veterinary Medicine University of Veterinary Sciences; Brno Czech Republic

European Commission Joint Research Centre ; Ispra Italy

Faculty of Science University of South Bohemia; Ceske Budejovice Czech Republic

Institute for Research in Biomedicine Università della Svizzera italiana; Bellinzona Switzerland

Institute of Parasitology Biology Centre of the Czech Academy of Sciences; Ceske Budejovice Czech Republic

Internal Medicine and Infectious Diseases Clinica Luganese Moncucco; Lugano Switzerland

Laboratory of Molecular Microbiology and Biotechnology Department of Medical Biotechnologies; University of Siena Siena Italy

Microbiology and Virology Department Fondazione IRCCS Policlinico San Matteo; Pavia Italy

Research Center for Immunodeficiencies Pediatrics Center of Excellence Children's Medical Center Tehran University of Medical Sciences; Tehran Iran

Sarafan ChEM H Macromolecular Structure Knowledge Center Stanford University; Stanford USA

Swiss Institute of Bioinformatics; Lausanne Switzerland

Veterinary Research Institute; Brno Czech Republic

Aktualizováno

Sci Immunol. 2023 Mar 17;8(81):eade0958. doi: 10.1126/sciimmunol.ade0958. PubMed

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