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

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Item Type:Article
Title:A design strategy to generate a SARS-CoV-2 RBD vaccine that abrogates ACE2 binding and improves neutralizing antibody responses
Creators Name:Ratswohl, C., Vázquez García, C., Ahmad, A.U.W., Gonschior, H., Lebedin, M., Silvis, C.E., Spatt, L., Gerhard, C., Lehmann, M., Sander, L.E., Kurth, F., Olsson, S. and de la Rosa, K.
Abstract: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 (RBD) 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 RBD-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.
Keywords:SARS-CoV-2 Vaccine, Receptor-Binding Abrogation, BIBAX, Body-Inert B-Cell-Activating Vaccines, Vaccine Design, Animals, Rabbits
Source:European Journal of Immunology
ISSN:0014-2980
Publisher:Wiley
Volume:53
Number:10
Page Range:e2350408
Date:October 2023
Official Publication:https://doi.org/10.1002/eji.202350408
PubMed:View item in PubMed

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