A design strategy to generate a SARS-CoV-2 RBD vaccine that abrogates ACE2 binding and improves neutralizing antibody responses

Ratswohl, Christoph (author): Freie Universität Berlin,Max Delbrueck Centrum Fuer Molekulare Medizin,The Max Delbrück Center for Molecular Medicine

Vázquez García, Clara (author): Charité Universitätsmedizin Berlin,Charité University Medicine Berlin,Max Delbrueck Centrum Fuer Molekulare Medizin,The Max Delbrück Center for Molecular Medicine

Ahmad, Ata ul Wakeel (author): Max Delbrueck Centrum Fuer Molekulare Medizin,The Max Delbrück Center for Molecular Medicine,Charité Universitätsmedizin Berlin,Charité University Medicine Berlin

Gonschior, Hannes (author)

Lebedin, Mikhail (author): Charité Universitätsmedizin Berlin,Charité University Medicine Berlin,Max Delbrueck Centrum Fuer Molekulare Medizin,The Max Delbrück Center for Molecular Medicine

Silvis, Casper Ewijn (author): Max Delbrueck Centrum Fuer Molekulare Medizin,The Max Delbrück Center for Molecular Medicine,Charité Universitätsmedizin Berlin,Charité University Medicine Berlin

Spatt, Lisa (author): Max Delbrueck Centrum Fuer Molekulare Medizin,The Max Delbrück Center for Molecular Medicine

Gerhard, Cathrin (author): Max Delbrueck Centrum Fuer Molekulare Medizin,The Max Delbrück Center for Molecular Medicine

Lehmann, Martin (author)

Sander, Leif Erik (author): Charité Universitätsmedizin Berlin,Charité University Medicine Berlin

Kurth, Florian (author): Charité Universitätsmedizin Berlin,Charité University Medicine Berlin

Olsson, Simon, 1985 (author): Chalmers tekniska högskola,Chalmers University of Technology

de la Rosa, Kathrin (author): Max Delbrueck Centrum Fuer Molekulare Medizin,The Max Delbrück Center for Molecular Medicine

(creator_code:org_t)

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Abstract Subject headings

The structure-based design of antigens holds promise for developing vaccines with higher efficacy and improved safety profiles. We postulate that abrogation of host receptor interaction bears potential for the improvement of vaccines by preventing antigen-induced modification of receptor function as well as the displacement or masking of the immunogen. Antigen modifications may yet destroy epitopes crucial for antibody neutralization. Here, we present a methodology that integrates deep mutational scans to identify and score SARS-CoV-2 receptor binding domain variants that maintain immunogenicity, but lack interaction with the widely expressed host receptor. Single point mutations were scored in silico, validated in vitro, and applied in vivo. Our top-scoring variant receptor binding domain-G502E prevented spike-induced cell-to-cell fusion, receptor internalization, and improved neutralizing antibody responses by 3.3-fold in rabbit immunizations. We name our strategy BIBAX for body-inert, B-cell-activating vaccines, which in the future may be applied beyond SARS-CoV-2 for the improvement of vaccines by design.

By the author/editor: Ratswohl, Christ ...; Vázquez García, ...; Ahmad, Ata ul Wa ...; Gonschior, Hanne ...; Lebedin, Mikhail; Silvis, Casper E ...; show more...; Spatt, Lisa; Gerhard, Cathrin; Lehmann, Martin; Sander, Leif Eri ...; Kurth, Florian; Olsson, Simon, 1 ...; de la Rosa, Kath ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Infectious Medic ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Immunology in th ...

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