Novel Spike-stabilized trimers with improved production protect K18-hACE2 mice and golden Syrian hamsters from the highly pathogenic SARS-CoV-2 Beta variant
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Author
Ávila-Nieto, Carlos
Amengual-Rigo, Pep
Ainsua-Enrich, Erola
Rodríguez de la Concepción, María Luisa
Pedreño-Lopez, Núria
Urrea, Victor
Pradenas, Edwards
Marfil, Silvia
Ballana, Ester
Riveira-Muñoz, Eva
Pérez, Mònica
Roca, Núria
Tarrés-Freixas, Ferran
Carabelli, Julieta
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
Carrillo, Jorge
Publication date
2023-12-04ISSN
1664-3224
Abstract
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.
Document Type
Article
Document version
Published version
Language
English
Subject (CDU)
619 - Veterinary science
Pages
14
Publisher
Frontiers Media
Is part of
Frontiers in Immunology
Citation
Ávila‐Nieto, Carlos, Júlia Vergara‐Alert, Pep Amengual-Rigo, Erola Ainsua-Enrich, Marco Brustolin, Maria Luisa Rodrı́guez De La Concepción, and Núria Pedreño-López, et al. 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”. Frontiers in Immunology 14: 1291972. doi: 10.3389/fimmu.2023.1291972.
Grant agreement number
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/H2020/101046118/EC/RBD Dimer recombinant protein vaccine against SARSCoV2/RBDCOV
Program
Sanitat Animal
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