A design strategy to generate a SARS-CoV-2 RBD vaccine that abrogates ACE2 binding and improves neutralizing antibody responses
Journal article, 2023
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.
Receptor-binding abrogation
SARS-CoV-2 vaccine
Vaccine design
Body-inert B-cell-activating vaccines
BIBAX
Author
Christoph Ratswohl
Freie Universität Berlin
The Max Delbrück Center for Molecular Medicine
Clara Vázquez García
Charité University Medicine Berlin
The Max Delbrück Center for Molecular Medicine
Ata ul Wakeel Ahmad
The Max Delbrück Center for Molecular Medicine
Charité University Medicine Berlin
Hannes Gonschior
Leibniz-Institut für Molekulare Pharmakologie
Mikhail Lebedin
Charité University Medicine Berlin
The Max Delbrück Center for Molecular Medicine
Casper Ewijn Silvis
The Max Delbrück Center for Molecular Medicine
Charité University Medicine Berlin
Lisa Spatt
The Max Delbrück Center for Molecular Medicine
Cathrin Gerhard
The Max Delbrück Center for Molecular Medicine
Martin Lehmann
Leibniz-Institut für Molekulare Pharmakologie
Leif Erik Sander
Charité University Medicine Berlin
Berliner Institut für Gesundheitsforschung
Florian Kurth
Charité University Medicine Berlin
Simon Olsson
Chalmers, Computer Science and Engineering (Chalmers), Data Science and AI
Kathrin de la Rosa
Berliner Institut für Gesundheitsforschung
The Max Delbrück Center for Molecular Medicine
European Journal of Immunology
0014-2980 (ISSN) 1521-4141 (eISSN)
Vol. 53 10 2350408Subject Categories
Infectious Medicine
Immunology in the medical area
DOI
10.1002/eji.202350408
PubMed
37435628