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

Autor:	Ávila-Nieto C; IrsiCaixa AIDS Research Institute, Badalona, Spain., Vergara-Alert J; Unitat Mixta d'Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.; IRTA Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Barcelona, Spain., Amengual-Rigo P; Life Sciences Department, Barcelona Supercomputing Center (BSC), Barcelona, Spain., Ainsua-Enrich E; IrsiCaixa AIDS Research Institute, Badalona, Spain., Brustolin M; Unitat Mixta d'Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.; IRTA Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Barcelona, Spain., Rodríguez de la Concepción ML; IrsiCaixa AIDS Research Institute, Badalona, Spain., Pedreño-Lopez N; IrsiCaixa AIDS Research Institute, Badalona, Spain., Rodon J; Unitat Mixta d'Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.; IRTA Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Barcelona, Spain., Urrea V; IrsiCaixa AIDS Research Institute, Badalona, Spain., Pradenas E; IrsiCaixa AIDS Research Institute, Badalona, Spain., Marfil S; IrsiCaixa AIDS Research Institute, Badalona, Spain., Ballana E; IrsiCaixa AIDS Research Institute, Badalona, Spain.; Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.; Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Instituto de Salud Carlos III (ISCIII), Madrid, Spain., Riveira-Muñoz E; IrsiCaixa AIDS Research Institute, Badalona, Spain., Pérez M; Unitat Mixta d'Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.; IRTA Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Barcelona, Spain., Roca N; Unitat Mixta d'Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.; IRTA Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Barcelona, Spain., Tarrés-Freixas F; IrsiCaixa AIDS Research Institute, Badalona, Spain., Carabelli J; IrsiCaixa AIDS Research Institute, Badalona, Spain., Cantero G; Unitat Mixta d'Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.; IRTA Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Barcelona, Spain., Pons-Grífols A; IrsiCaixa AIDS Research Institute, Badalona, Spain., Rovirosa C; IrsiCaixa AIDS Research Institute, Badalona, Spain., Aguilar-Gurrieri C; IrsiCaixa AIDS Research Institute, Badalona, Spain., Ortiz R; IrsiCaixa AIDS Research Institute, Badalona, Spain., Barajas A; IrsiCaixa AIDS Research Institute, Badalona, Spain., Trinité B; IrsiCaixa AIDS Research Institute, Badalona, Spain., Lepore R; Life Sciences Department, Barcelona Supercomputing Center (BSC), Barcelona, Spain., Muñoz-Basagoiti J; IrsiCaixa AIDS Research Institute, Badalona, Spain., Perez-Zsolt D; IrsiCaixa AIDS Research Institute, Badalona, Spain., Izquierdo-Useros N; IrsiCaixa AIDS Research Institute, Badalona, Spain.; Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.; Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Instituto de Salud Carlos III (ISCIII), Madrid, Spain., Valencia A; Life Sciences Department, Barcelona Supercomputing Center (BSC), Barcelona, Spain.; Catalan Institution for Research and Advanced Studies, Barcelona, Spain., Blanco J; IrsiCaixa AIDS Research Institute, Badalona, Spain.; Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.; Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.; Centre for Health and Social Care Research (CESS), Faculty of Medicine, University of Vic - Central University of Catalonia (UVic - UCC), Vic, Spain., Clotet B; IrsiCaixa AIDS Research Institute, Badalona, Spain.; Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.; Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.; Centre for Health and Social Care Research (CESS), Faculty of Medicine, University of Vic - Central University of Catalonia (UVic - UCC), Vic, Spain.; Fundació Lluita contra les Infeccions, Hospital Germans Trias i Pujol, Badalona, Spain., Guallar V; Life Sciences Department, Barcelona Supercomputing Center (BSC), Barcelona, Spain.; Catalan Institution for Research and Advanced Studies, Barcelona, Spain., Segalés J; Unitat Mixta d'Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.; Departament de Sanitat i Anatomia Animals, Facultat de Veterinària, UAB, Cerdanyola del Vallès, Spain., Carrillo J; IrsiCaixa AIDS Research Institute, Badalona, Spain.; Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.; Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Dec 04; Vol. 14, pp. 1291972. Date of Electronic Publication: 2023 Dec 04 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1291972
Abstrakt:	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. Competing Interests: Author PA-R is currently employed by the company Sanofi, which has no association with any content related to this work. Unrelated to the submitted work, JB and JC are founders and shareholders of AlbaJuna Therapeutics, S.L. BC is founder and shareholder of AlbaJuna Therapeutics, S.L. and AELIX Therapeutics, S.L, and VG is founder and shareholder of Nostrum Biodiscovery. Unrelated to the submitted work, NI-U is supported by institutional funding from Pharma Mar, HIPRA, Amassence and Palobiofarma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2023 Ávila-Nieto, Vergara-Alert, Amengual-Rigo, Ainsua-Enrich, Brustolin, Rodríguez de la Concepción, Pedreño-Lopez, Rodon, Urrea, Pradenas, Marfil, Ballana, Riveira-Muñoz, Pérez, Roca, Tarrés-Freixas, Carabelli, Cantero, Pons-Grífols, Rovirosa, Aguilar-Gurrieri, Ortiz, Barajas, Trinité, Lepore, Muñoz-Basagoiti, Perez-Zsolt, Izquierdo-Useros, Valencia, Blanco, Clotet, Guallar, Segalés and Carrillo.)
Databáze:	MEDLINE
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