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

ABSTRACT 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 antibod...

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Autores principales:	Fatima Amanat, Shirin Strohmeier, Raveen Rathnasinghe, Michael Schotsaert, Lynda Coughlan, Adolfo García-Sastre, Florian Krammer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	COVID-19 SARS-CoV-2 spike vaccine Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3115dd1525384801b253562bd43d4a68
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spelling	oai:doaj.org-article:3115dd1525384801b253562bd43d4a682021-11-10T18:37:48ZIntroduction 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 Model10.1128/mBio.02648-202150-7511https://doaj.org/article/3115dd1525384801b253562bd43d4a682021-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02648-20https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE A vaccine for SARS-CoV-2 is urgently needed. A better understanding of antigen design and attributes that vaccine candidates need to have to induce protective immunity is of high importance. The data presented here validate the choice of antigens that contain the PP mutations and suggest that deletion of the polybasic cleavage site may lead to a further-optimized design.Fatima AmanatShirin StrohmeierRaveen RathnasingheMichael SchotsaertLynda CoughlanAdolfo García-SastreFlorian KrammerAmerican Society for MicrobiologyarticleCOVID-19SARS-CoV-2spikevaccineMicrobiologyQR1-502ENmBio, Vol 12, Iss 2 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	COVID-19 SARS-CoV-2 spike vaccine Microbiology QR1-502
spellingShingle	COVID-19 SARS-CoV-2 spike vaccine Microbiology QR1-502 Fatima Amanat Shirin Strohmeier Raveen Rathnasinghe Michael Schotsaert Lynda Coughlan Adolfo García-Sastre Florian Krammer 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
description	ABSTRACT 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. IMPORTANCE A vaccine for SARS-CoV-2 is urgently needed. A better understanding of antigen design and attributes that vaccine candidates need to have to induce protective immunity is of high importance. The data presented here validate the choice of antigens that contain the PP mutations and suggest that deletion of the polybasic cleavage site may lead to a further-optimized design.
format	article
author	Fatima Amanat Shirin Strohmeier Raveen Rathnasinghe Michael Schotsaert Lynda Coughlan Adolfo García-Sastre Florian Krammer
author_facet	Fatima Amanat Shirin Strohmeier Raveen Rathnasinghe Michael Schotsaert Lynda Coughlan Adolfo García-Sastre Florian Krammer
author_sort	Fatima Amanat
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_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_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_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
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/3115dd1525384801b253562bd43d4a68
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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

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