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Introduction of Two Prolines and Removal of the Polybasic Cleavage Site Lead to Higher Efficacy of a Recombinant Spike-Based SARS-CoV-2 Vaccine in the Mouse Model

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as the prime target for vaccine development. The spike protein mediates both binding to host cells and membrane fusion and is also so far the only known viral target of neutralizing antibodies. Coro...

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Autores principales: Amanat, Fatima, Strohmeier, Shirin, Rathnasinghe, Raveen, Schotsaert, Michael, Coughlan, Lynda, García-Sastre, Adolfo, Krammer, Florian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092267/
https://www.ncbi.nlm.nih.gov/pubmed/33653892
http://dx.doi.org/10.1128/mBio.02648-20
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author Amanat, Fatima
Strohmeier, Shirin
Rathnasinghe, Raveen
Schotsaert, Michael
Coughlan, Lynda
García-Sastre, Adolfo
Krammer, Florian
author_facet Amanat, Fatima
Strohmeier, Shirin
Rathnasinghe, Raveen
Schotsaert, Michael
Coughlan, Lynda
García-Sastre, Adolfo
Krammer, Florian
author_sort Amanat, Fatima
collection PubMed
description The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as the prime target for vaccine development. The spike protein mediates both binding to host cells and membrane fusion and is also so far the only known viral target of neutralizing antibodies. Coronavirus spike proteins are large trimers that are relatively unstable, a feature that might be enhanced by the presence of a polybasic cleavage site in SARS-CoV-2 spike. Exchange of K986 and V987 for prolines has been shown to stabilize the trimers of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus spike proteins. Here, we test multiple versions of a soluble spike protein for their immunogenicity and protective effect against SARS-CoV-2 challenge in a mouse model that transiently expresses human angiotensin-converting enzyme 2 via adenovirus transduction. Variants tested include spike proteins with a deleted polybasic cleavage site, proline mutations, or a combination thereof, besides the wild-type protein. While all versions of the protein were able to induce neutralizing antibodies, only the antigen with both a deleted cleavage site and the K986P and V987P (PP) mutations completely protected from challenge in this mouse model.
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spelling pubmed-80922672021-05-04 Introduction of Two Prolines and Removal of the Polybasic Cleavage Site Lead to Higher Efficacy of a Recombinant Spike-Based SARS-CoV-2 Vaccine in the Mouse Model Amanat, Fatima Strohmeier, Shirin Rathnasinghe, Raveen Schotsaert, Michael Coughlan, Lynda García-Sastre, Adolfo Krammer, Florian mBio Research Article The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as the prime target for vaccine development. The spike protein mediates both binding to host cells and membrane fusion and is also so far the only known viral target of neutralizing antibodies. Coronavirus spike proteins are large trimers that are relatively unstable, a feature that might be enhanced by the presence of a polybasic cleavage site in SARS-CoV-2 spike. Exchange of K986 and V987 for prolines has been shown to stabilize the trimers of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus spike proteins. Here, we test multiple versions of a soluble spike protein for their immunogenicity and protective effect against SARS-CoV-2 challenge in a mouse model that transiently expresses human angiotensin-converting enzyme 2 via adenovirus transduction. Variants tested include spike proteins with a deleted polybasic cleavage site, proline mutations, or a combination thereof, besides the wild-type protein. While all versions of the protein were able to induce neutralizing antibodies, only the antigen with both a deleted cleavage site and the K986P and V987P (PP) mutations completely protected from challenge in this mouse model. American Society for Microbiology 2021-03-02 /pmc/articles/PMC8092267/ /pubmed/33653892 http://dx.doi.org/10.1128/mBio.02648-20 Text en Copyright © 2021 Amanat et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Amanat, Fatima
Strohmeier, Shirin
Rathnasinghe, Raveen
Schotsaert, Michael
Coughlan, Lynda
García-Sastre, Adolfo
Krammer, Florian
Introduction of Two Prolines and Removal of the Polybasic Cleavage Site Lead to Higher Efficacy of a Recombinant Spike-Based SARS-CoV-2 Vaccine in the Mouse Model
title Introduction of Two Prolines and Removal of the Polybasic Cleavage Site Lead to Higher Efficacy of a Recombinant Spike-Based SARS-CoV-2 Vaccine in the Mouse Model
title_full Introduction of Two Prolines and Removal of the Polybasic Cleavage Site Lead to Higher Efficacy of a Recombinant Spike-Based SARS-CoV-2 Vaccine in the Mouse Model
title_fullStr Introduction of Two Prolines and Removal of the Polybasic Cleavage Site Lead to Higher Efficacy of a Recombinant Spike-Based SARS-CoV-2 Vaccine in the Mouse Model
title_full_unstemmed Introduction of Two Prolines and Removal of the Polybasic Cleavage Site Lead to Higher Efficacy of a Recombinant Spike-Based SARS-CoV-2 Vaccine in the Mouse Model
title_short Introduction of Two Prolines and Removal of the Polybasic Cleavage Site Lead to Higher Efficacy of a Recombinant Spike-Based SARS-CoV-2 Vaccine in the Mouse Model
title_sort introduction of two prolines and removal of the polybasic cleavage site lead to higher efficacy of a recombinant spike-based sars-cov-2 vaccine in the mouse model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092267/
https://www.ncbi.nlm.nih.gov/pubmed/33653892
http://dx.doi.org/10.1128/mBio.02648-20
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