Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant

Most COVID-19 vaccines are based on the SARS-CoV-2 Spike glycoprotein (S) or their subunits. However, S shows some structural instability that limits its immunogenicity and production, hampering the development of recombinant S-based vaccines. The introduction of the K986P and V987P (S-2P) mutations...

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Autores: Ávila-Nieto, Carlos, Serra Gironella, Joan, Amengual-Rigo, Pep, Ainsua-Enrich, Erola, Brustolin, Marco, Rodríguez de la Concepción, María Luisa, Pedreño-Lopez, Núria, Rodon, Jordi, Urrea, Victor, Pradenas, Edwards, Marfil, Silvia, Ballana, Ester, Riveira-Muñoz, Eva, Pérez, Mònica, Roca, Núria, Tarrés-Freixas, Ferran, Carabelli, Julieta, Cantero, Guillermo, Pons-Grífols, Anna, Rovirosa, Carla, Aguilar-Gurrieri, Carmen, Ortiz, Raquel, Barajas, Ana, Trinité, Benjamin, Lepore, Rosalba, Muñoz-Basagoiti, Jordana, Perez-Zsolt, Daniel, Izquierdo-Useros, Nuria, Valencia, Alfonso, Blanco, Julià, Clotet, Bonaventura, Guallar, Victor, Segalés, Joaquim, Carrillo, Jorge
Formato: artículo
Fecha de publicación:2023
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:20.500.12327/2723
Acesso em linha:http://hdl.handle.net/20.500.12327/2723
https://doi.org/10.3389/fimmu.2023.1291972
Access Level:acceso abierto
Palavra-chave:619
id ES_d68a8ad58393ef32ee72cc5dfda8d736
oai_identifier_str oai:recercat.cat:20.500.12327/2723
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant
title Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant
spellingShingle Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant
Ávila-Nieto, Carlos
619
title_short Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant
title_full Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant
title_fullStr Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant
title_full_unstemmed Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant
title_sort Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant
dc.creator.none.fl_str_mv Ávila-Nieto, Carlos
Serra Gironella, Joan
Amengual-Rigo, Pep
Ainsua-Enrich, Erola
Brustolin, Marco
Rodríguez de la Concepción, María Luisa
Pedreño-Lopez, Núria
Rodon, Jordi
Urrea, Victor
Pradenas, Edwards
Marfil, Silvia
Ballana, Ester
Riveira-Muñoz, Eva
Pérez, Mònica
Roca, Núria
Tarrés-Freixas, Ferran
Carabelli, Julieta
Cantero, Guillermo
Pons-Grífols, Anna
Rovirosa, Carla
Aguilar-Gurrieri, Carmen
Ortiz, Raquel
Barajas, Ana
Trinité, Benjamin
Lepore, Rosalba
Muñoz-Basagoiti, Jordana
Perez-Zsolt, Daniel
Izquierdo-Useros, Nuria
Valencia, Alfonso
Blanco, Julià
Clotet, Bonaventura
Guallar, Victor
Segalés, Joaquim
Carrillo, Jorge
author Ávila-Nieto, Carlos
author_facet Ávila-Nieto, Carlos
Serra Gironella, Joan
Amengual-Rigo, Pep
Ainsua-Enrich, Erola
Brustolin, Marco
Rodríguez de la Concepción, María Luisa
Pedreño-Lopez, Núria
Rodon, Jordi
Urrea, Victor
Pradenas, Edwards
Marfil, Silvia
Ballana, Ester
Riveira-Muñoz, Eva
Pérez, Mònica
Roca, Núria
Tarrés-Freixas, Ferran
Carabelli, Julieta
Cantero, Guillermo
Pons-Grífols, Anna
Rovirosa, Carla
Aguilar-Gurrieri, Carmen
Ortiz, Raquel
Barajas, Ana
Trinité, Benjamin
Lepore, Rosalba
Muñoz-Basagoiti, Jordana
Perez-Zsolt, Daniel
Izquierdo-Useros, Nuria
Valencia, Alfonso
Blanco, Julià
Clotet, Bonaventura
Guallar, Victor
Segalés, Joaquim
Carrillo, Jorge
author_role author
author2 Serra Gironella, Joan
Amengual-Rigo, Pep
Ainsua-Enrich, Erola
Brustolin, Marco
Rodríguez de la Concepción, María Luisa
Pedreño-Lopez, Núria
Rodon, Jordi
Urrea, Victor
Pradenas, Edwards
Marfil, Silvia
Ballana, Ester
Riveira-Muñoz, Eva
Pérez, Mònica
Roca, Núria
Tarrés-Freixas, Ferran
Carabelli, Julieta
Cantero, Guillermo
Pons-Grífols, Anna
Rovirosa, Carla
Aguilar-Gurrieri, Carmen
Ortiz, Raquel
Barajas, Ana
Trinité, Benjamin
Lepore, Rosalba
Muñoz-Basagoiti, Jordana
Perez-Zsolt, Daniel
Izquierdo-Useros, Nuria
Valencia, Alfonso
Blanco, Julià
Clotet, Bonaventura
Guallar, Victor
Segalés, Joaquim
Carrillo, Jorge
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Producció Animal
Sanitat Animal
dc.subject.none.fl_str_mv 619
topic 619
description Most COVID-19 vaccines are based on the SARS-CoV-2 Spike glycoprotein (S) or their subunits. However, S shows some structural instability that limits its immunogenicity and production, hampering the development of recombinant S-based vaccines. The introduction of the K986P and V987P (S-2P) mutations increases the production and immunogenicity of the recombinant S trimer, suggesting that these two parameters are related. Nevertheless, S-2P still shows some molecular instability and it is produced with low yield. Here we described a novel set of mutations identified by molecular modeling and located in the S2 region of the S-2P that increase its production up to five-fold. Besides their immunogenicity, the efficacy of two representative S-2P-based mutants, S-29 and S-21, protecting from a heterologous SARS-CoV-2 Beta variant challenge was assayed in K18-hACE2 mice (an animal model of severe SARS-CoV-2 disease) and golden Syrian hamsters (GSH) (a moderate disease model). S-21 induced higher level of WH1 and Delta variants neutralizing antibodies than S-2P in K18-hACE2 mice three days after challenge. Viral load in nasal turbinate and oropharyngeal samples were reduced in S-21 and S-29 vaccinated mice. Despite that, only the S-29 protein protected 100% of K18-hACE2 mice from severe disease. When GSH were analyzed, all immunized animals were protected from disease development irrespectively of the immunogen they received. Therefore, the higher yield of S-29, as well as its improved immunogenicity and efficacy protecting from the highly pathogenic SARS-CoV-2 Beta variant, pinpoint the S- 29 mutant as an alternative to the S-2P protein for future SARS-CoV-2 vaccine development.
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12327/2723
https://doi.org/10.3389/fimmu.2023.1291972
url http://hdl.handle.net/20.500.12327/2723
https://doi.org/10.3389/fimmu.2023.1291972
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Frontiers in Immunology
ISCII/Programa Estatal de fomento de la investigación científica y técnica de excelencia/PI17-01518/ES/Desarrollo de una plataforma de vacunas contra el VIH basada en partículas similares a virus (VLP) envueltas y de alta densidad antigénica/
ISCII/Programa Estatal de fomento de la investigación científica y técnica de excelencia/PI18-01332/ES/Identificación, aislamiento y caracterización de anticuerpos que interfieren con la acción de los anticuerpos neutralizantes en personas infectadas por el virus de la inmunodeficiencia humana/
MICINN/Programa Estatal de I+D+I orientada a los retos de la sociedad/PID2020-117145RB-I00/ES/NUEVAS TERAPIAS ANTIVIRALES E INMUNOMODULADORAS FRENTE AL SARS-COV-2/
EU/HE/101046118/EC/RBD Dimer recombinant protein vaccine against SARSCoV2/RBDCOV
dc.rights.none.fl_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 14
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variantÁvila-Nieto, CarlosSerra Gironella, JoanAmengual-Rigo, PepAinsua-Enrich, ErolaBrustolin, MarcoRodríguez de la Concepción, María LuisaPedreño-Lopez, NúriaRodon, JordiUrrea, VictorPradenas, EdwardsMarfil, SilviaBallana, EsterRiveira-Muñoz, EvaPérez, MònicaRoca, NúriaTarrés-Freixas, FerranCarabelli, JulietaCantero, GuillermoPons-Grífols, AnnaRovirosa, CarlaAguilar-Gurrieri, CarmenOrtiz, RaquelBarajas, AnaTrinité, BenjaminLepore, RosalbaMuñoz-Basagoiti, JordanaPerez-Zsolt, DanielIzquierdo-Useros, NuriaValencia, AlfonsoBlanco, JuliàClotet, BonaventuraGuallar, VictorSegalés, JoaquimCarrillo, Jorge619Most COVID-19 vaccines are based on the SARS-CoV-2 Spike glycoprotein (S) or their subunits. However, S shows some structural instability that limits its immunogenicity and production, hampering the development of recombinant S-based vaccines. The introduction of the K986P and V987P (S-2P) mutations increases the production and immunogenicity of the recombinant S trimer, suggesting that these two parameters are related. Nevertheless, S-2P still shows some molecular instability and it is produced with low yield. Here we described a novel set of mutations identified by molecular modeling and located in the S2 region of the S-2P that increase its production up to five-fold. Besides their immunogenicity, the efficacy of two representative S-2P-based mutants, S-29 and S-21, protecting from a heterologous SARS-CoV-2 Beta variant challenge was assayed in K18-hACE2 mice (an animal model of severe SARS-CoV-2 disease) and golden Syrian hamsters (GSH) (a moderate disease model). S-21 induced higher level of WH1 and Delta variants neutralizing antibodies than S-2P in K18-hACE2 mice three days after challenge. Viral load in nasal turbinate and oropharyngeal samples were reduced in S-21 and S-29 vaccinated mice. Despite that, only the S-29 protein protected 100% of K18-hACE2 mice from severe disease. When GSH were analyzed, all immunized animals were protected from disease development irrespectively of the immunogen they received. Therefore, the higher yield of S-29, as well as its improved immunogenicity and efficacy protecting from the highly pathogenic SARS-CoV-2 Beta variant, pinpoint the S- 29 mutant as an alternative to the S-2P protein for future SARS-CoV-2 vaccine development.The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Grifols pharmaceutical, the CERCA Program (2021 SGR 00452; Generalitat de Catalunya), Direcció General de Recerca i Innovació en Salut (Generalitat de Catalunya) (projects SLD0015 and SLD0016), the Carlos III Health Institute (PI17/01518 and PI18/01332), and the crowdfunding projects “YomeCorono”, BonPreu/ Esclat, and Correos. JB is supported by the Health Department of the Catalan Government (Generalitat de Catalunya). CÁ-N, AP-G, and PA-R were supported by predoctoral grants from Generalitat de Catalunya and Fons Social Europeu (2020 FI_B_0742; 2022 FI_B_00698 and 2020FI_B2_00138, respectively). EP was supported by a doctoral grant from National Agency for Research and Development of Chile (ANID: 72180406). NI-U is supported by the Spanish Ministry of Science and Innovation (grant PID2020-117145RB-I00), EU HORIZON-HLTH-2021-CORONA-01 (grant 101046118). This study was also supported by CIBER - Consorcio Centro de Investigación Biomédica en Red (CB 2021), Carlos III Health Institute, Ministerio de Ciencia e Innovación and Unión Europea – NextGenerationEU. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.info:eu-repo/semantics/publishedVersionFrontiers MediaProducció AnimalSanitat Animal2023info:eu-repo/semantics/article14http://hdl.handle.net/20.500.12327/2723https://doi.org/10.3389/fimmu.2023.1291972reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésFrontiers in ImmunologyISCII/Programa Estatal de fomento de la investigación científica y técnica de excelencia/PI17-01518/ES/Desarrollo de una plataforma de vacunas contra el VIH basada en partículas similares a virus (VLP) envueltas y de alta densidad antigénica/ISCII/Programa Estatal de fomento de la investigación científica y técnica de excelencia/PI18-01332/ES/Identificación, aislamiento y caracterización de anticuerpos que interfieren con la acción de los anticuerpos neutralizantes en personas infectadas por el virus de la inmunodeficiencia humana/MICINN/Programa Estatal de I+D+I orientada a los retos de la sociedad/PID2020-117145RB-I00/ES/NUEVAS TERAPIAS ANTIVIRALES E INMUNOMODULADORAS FRENTE AL SARS-COV-2/EU/HE/101046118/EC/RBD Dimer recombinant protein vaccine against SARSCoV2/RBDCOVAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:20.500.12327/27232026-05-29T05:05:01Z
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