Frontiers in Immunology (Dec 2023)

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

  • Carlos Ávila-Nieto,
  • Júlia Vergara-Alert,
  • Júlia Vergara-Alert,
  • Pep Amengual-Rigo,
  • Erola Ainsua-Enrich,
  • Marco Brustolin,
  • Marco Brustolin,
  • María Luisa Rodríguez de la Concepción,
  • Núria Pedreño-Lopez,
  • Jordi Rodon,
  • Jordi Rodon,
  • Victor Urrea,
  • Edwards Pradenas,
  • Silvia Marfil,
  • Ester Ballana,
  • Ester Ballana,
  • Ester Ballana,
  • Eva Riveira-Muñoz,
  • Mònica Pérez,
  • Mònica Pérez,
  • Núria Roca,
  • Núria Roca,
  • Ferran Tarrés-Freixas,
  • Julieta Carabelli,
  • Guillermo Cantero,
  • Guillermo Cantero,
  • Anna Pons-Grífols,
  • Carla Rovirosa,
  • Carmen Aguilar-Gurrieri,
  • Raquel Ortiz,
  • Ana Barajas,
  • Benjamin Trinité,
  • Rosalba Lepore,
  • Jordana Muñoz-Basagoiti,
  • Daniel Perez-Zsolt,
  • Nuria Izquierdo-Useros,
  • Nuria Izquierdo-Useros,
  • Nuria Izquierdo-Useros,
  • Alfonso Valencia,
  • Alfonso Valencia,
  • Julià Blanco,
  • Julià Blanco,
  • Julià Blanco,
  • Julià Blanco,
  • Bonaventura Clotet,
  • Bonaventura Clotet,
  • Bonaventura Clotet,
  • Bonaventura Clotet,
  • Bonaventura Clotet,
  • Victor Guallar,
  • Victor Guallar,
  • Joaquim Segalés,
  • Joaquim Segalés,
  • Jorge Carrillo,
  • Jorge Carrillo,
  • Jorge Carrillo

DOI
https://doi.org/10.3389/fimmu.2023.1291972
Journal volume & issue
Vol. 14

Abstract

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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.

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