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Identification of the Mechanisms Causing Reversion to Virulence in an Attenuated SARS-CoV for the Design of a Genetically Stable Vaccine

AuthorsEnjuanes Sánchez, Luis CSIC ORCID ; Jiménez-Guardeño, José Manuel CSIC ORCID ; Regla-Nava, José Ángel ; Nieto-Torres, José L. ; DeDiego, Marta L. CSIC ORCID ; Castaño-Rodríguez, Carlos ; Gutierrez-Alvarez, Francisco J. ; Fernandez-Delgado, Raúl ; Perlman, Stanley; Solá Gurpegui, Isabel
Issue Date18-Jun-2016
Citation35th Annual Meeting American Society for Virology (2016)
AbstractA SARS-CoV lacking the full-length E gene (SARS-CoV-ΔE) was attenuated and an effective vaccine. This mutant virus regained ftness after serial passages in cell culture or in vivo, resulting in the partial duplication of the membrane gene or in the insertion of a new sequence in gene 8a, respectively. During SARS-CoV-ΔE passage in mice, the virus incorporated a mutated variant of 8a protein, resulting in reversion to a virulent phenotype. When the full-length E protein was deleted or its PDZ-binding motif (PBM) was mutated, the revertant viruses either incorporated a novel chimeric protein with a PBM or restored the sequence of the PBM on the E protein, respectively. Similarly, after passage in mice, SARS-CoV-ΔE protein 8a mutated, to now encode a PBM, and also regained virulence. These data indicated that the virus requires a PBM on a transmembrane protein to compensate for removal of this motif from the E protein. To increase the genetic stability of the vaccine candidate, we introduced small attenuating deletions in E gene that did not affect the endogenous PBM, preventing the incorporation of novel chimeric proteins in the virus genome. To increase vaccine biosafety, we introduced additional attenuating mutations into the nsp1 protein leading to higher host interferon responses. Recombinant viruses including attenuating mutations in E and nsp1 genes were stable in vitro and in vivo. These viruses fully protected mice against challenge with the lethal parental virus, and are therefore safe vaccine candidates for protection against SARS-CoV.
DescriptionTrabajo presentado en el 35th Annual Meeting American Society for Virology celerado en Blacksburg, Virginia (Estados Unidos) del 18 al 22 de junio de 2016
Appears in Collections:(CNB) Comunicaciones congresos
(VICYT) Colección Especial COVID-19

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