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Characterization of SARS-CoV-2 Escape Mutants to a Pair of Neutralizing Antibodies Targeting the RBD and the NTD.
Peter, Antonia Sophia; Grüner, Eva; Socher, Eileen; Fraedrich, Kirsten; Richel, Elie; Mueller-Schmucker, Sandra; Cordsmeier, Arne; Ensser, Armin; Sticht, Heinrich; Überla, Klaus.
  • Peter AS; Institute of Clinical and Molecular Virology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • Grüner E; Institute of Clinical and Molecular Virology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • Socher E; Institute of Clinical and Molecular Virology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • Fraedrich K; Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • Richel E; Institute of Anatomy, Functional and Clinical Anatomy, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • Mueller-Schmucker S; Institute of Clinical and Molecular Virology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • Cordsmeier A; Institute of Clinical and Molecular Virology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • Ensser A; Institute of Clinical and Molecular Virology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • Sticht H; Institute of Clinical and Molecular Virology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
  • Überla K; Institute of Clinical and Molecular Virology, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Int J Mol Sci ; 23(15)2022 Jul 25.
Article in English | MEDLINE | ID: covidwho-1957347
ABSTRACT
Mutations in the spike protein of SARS-CoV-2 can lead to evasion from neutralizing antibodies and affect the efficacy of passive and active immunization strategies. Immunization of mice harboring an entire set of human immunoglobulin variable region gene segments allowed to identify nine neutralizing monoclonal antibodies, which either belong to a cluster of clonally related RBD or NTD binding antibodies. To better understand the genetic barrier to emergence of SARS-CoV-2 variants resistant to these antibodies, escape mutants were selected in cell culture to one antibody from each cluster and a combination of the two antibodies. Three independently derived escape mutants to the RBD antibody harbored mutations in the RBD at the position T478 or S477. These mutations impaired the binding of the RBD antibodies to the spike protein and conferred resistance in a pseudotype neutralization assay. Although the binding of the NTD cluster antibodies were not affected by the RBD mutations, the RBD mutations also reduced the neutralization efficacy of the NTD cluster antibodies. The mutations found in the escape variants to the NTD antibody conferred resistance to the NTD, but not to the RBD cluster antibodies. A variant resistant to both antibodies was more difficult to select and only emerged after longer passages and higher inoculation volumes. VOC carrying the same mutations as the ones identified in the escape variants were also resistant to neutralization. This study further underlines the rapid emergence of escape mutants to neutralizing monoclonal antibodies in cell culture and indicates the need for thorough investigation of escape mutations to select the most potent combination of monoclonal antibodies for clinical use.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antibodies, Neutralizing / COVID-19 Type of study: Prognostic study Topics: Variants Limits: Animals / Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms23158177

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antibodies, Neutralizing / COVID-19 Type of study: Prognostic study Topics: Variants Limits: Animals / Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms23158177