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Vaccinia Virus Attenuation by Codon Deoptimization of the A24R Gene for Vaccine Development

Poxviruses have large DNA genomes, and they are able to infect multiple vertebrate and invertebrate animals, including humans. Despite the eradication of smallpox, poxvirus infections still remain a significant public health concern. Vaccinia virus (VV) is the prototypic member in the poxviridae fam...

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Autores principales: Lorenzo, María M., Nogales, Aitor, Chiem, Kevin, Blasco, Rafael, Martínez-Sobrido, Luis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241885/
https://www.ncbi.nlm.nih.gov/pubmed/35583360
http://dx.doi.org/10.1128/spectrum.00272-22
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author Lorenzo, María M.
Nogales, Aitor
Chiem, Kevin
Blasco, Rafael
Martínez-Sobrido, Luis
author_facet Lorenzo, María M.
Nogales, Aitor
Chiem, Kevin
Blasco, Rafael
Martínez-Sobrido, Luis
author_sort Lorenzo, María M.
collection PubMed
description Poxviruses have large DNA genomes, and they are able to infect multiple vertebrate and invertebrate animals, including humans. Despite the eradication of smallpox, poxvirus infections still remain a significant public health concern. Vaccinia virus (VV) is the prototypic member in the poxviridae family and it has been used extensively for different prophylactic applications, including the generation of vaccines against multiple infectious diseases and/or for oncolytic treatment. Many attempts have been pursued to develop novel attenuated forms of VV with improved safety profiles for their implementation as vaccines and/or vaccines vectors. We and others have previously demonstrated how RNA viruses encoding codon-deoptimized viral genes are attenuated, immunogenic and able to protect, upon a single administration, against challenge with parental viruses. In this study, we employed the same experimental approach based on the use of misrepresented codons for the generation of a recombinant (r)VV encoding a codon-deoptimized A24R gene, which is a key component of the viral RNA polymerase. Similar to our previous studies with RNA viruses, the A24R codon-deoptimized rVV (v-A24cd) was highly attenuated in vivo but able to protect, after a single intranasal dose administration, against an otherwise lethal challenge with parental VV. These results indicate that poxviruses can be effectively attenuated by synonymous codon deoptimization and open the possibility of using this methodology alone or in combination with other experimental approaches for the development of attenuated vaccines for the treatment of poxvirus infection, or to generate improved VV-based vectors. Moreover, this approach could be applied to other DNA viruses. IMPORTANCE The family poxviridae includes multiple viruses of medical and veterinary relevance, being vaccinia virus (VV) the prototypic member in the family. VV was used during the smallpox vaccination campaign to eradicate variola virus (VARV), which is considered a credible bioterrorism threat. Because of novel innovations in genetic engineering and vaccine technology, VV has gained popularity as a viral vector for the development of vaccines against several infectious diseases. Several approaches have been used to generate attenuated VV for its implementation as vaccine and/or vaccine vector. Here, we generated a rVV containing a codon-deoptimized A24R gene (v-A24cd), which encodes a key component of the viral RNA polymerase. v-A24cd was stable in culture cells and highly attenuated in vivo but able to protect against a subsequent lethal challenge with parental VV. Our findings support the use of this approach for the development of safe, stable, and protective live-attenuated VV and/or vaccine vectors.
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spelling pubmed-92418852022-06-30 Vaccinia Virus Attenuation by Codon Deoptimization of the A24R Gene for Vaccine Development Lorenzo, María M. Nogales, Aitor Chiem, Kevin Blasco, Rafael Martínez-Sobrido, Luis Microbiol Spectr Research Article Poxviruses have large DNA genomes, and they are able to infect multiple vertebrate and invertebrate animals, including humans. Despite the eradication of smallpox, poxvirus infections still remain a significant public health concern. Vaccinia virus (VV) is the prototypic member in the poxviridae family and it has been used extensively for different prophylactic applications, including the generation of vaccines against multiple infectious diseases and/or for oncolytic treatment. Many attempts have been pursued to develop novel attenuated forms of VV with improved safety profiles for their implementation as vaccines and/or vaccines vectors. We and others have previously demonstrated how RNA viruses encoding codon-deoptimized viral genes are attenuated, immunogenic and able to protect, upon a single administration, against challenge with parental viruses. In this study, we employed the same experimental approach based on the use of misrepresented codons for the generation of a recombinant (r)VV encoding a codon-deoptimized A24R gene, which is a key component of the viral RNA polymerase. Similar to our previous studies with RNA viruses, the A24R codon-deoptimized rVV (v-A24cd) was highly attenuated in vivo but able to protect, after a single intranasal dose administration, against an otherwise lethal challenge with parental VV. These results indicate that poxviruses can be effectively attenuated by synonymous codon deoptimization and open the possibility of using this methodology alone or in combination with other experimental approaches for the development of attenuated vaccines for the treatment of poxvirus infection, or to generate improved VV-based vectors. Moreover, this approach could be applied to other DNA viruses. IMPORTANCE The family poxviridae includes multiple viruses of medical and veterinary relevance, being vaccinia virus (VV) the prototypic member in the family. VV was used during the smallpox vaccination campaign to eradicate variola virus (VARV), which is considered a credible bioterrorism threat. Because of novel innovations in genetic engineering and vaccine technology, VV has gained popularity as a viral vector for the development of vaccines against several infectious diseases. Several approaches have been used to generate attenuated VV for its implementation as vaccine and/or vaccine vector. Here, we generated a rVV containing a codon-deoptimized A24R gene (v-A24cd), which encodes a key component of the viral RNA polymerase. v-A24cd was stable in culture cells and highly attenuated in vivo but able to protect against a subsequent lethal challenge with parental VV. Our findings support the use of this approach for the development of safe, stable, and protective live-attenuated VV and/or vaccine vectors. American Society for Microbiology 2022-05-18 /pmc/articles/PMC9241885/ /pubmed/35583360 http://dx.doi.org/10.1128/spectrum.00272-22 Text en Copyright © 2022 Lorenzo et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Lorenzo, María M.
Nogales, Aitor
Chiem, Kevin
Blasco, Rafael
Martínez-Sobrido, Luis
Vaccinia Virus Attenuation by Codon Deoptimization of the A24R Gene for Vaccine Development
title Vaccinia Virus Attenuation by Codon Deoptimization of the A24R Gene for Vaccine Development
title_full Vaccinia Virus Attenuation by Codon Deoptimization of the A24R Gene for Vaccine Development
title_fullStr Vaccinia Virus Attenuation by Codon Deoptimization of the A24R Gene for Vaccine Development
title_full_unstemmed Vaccinia Virus Attenuation by Codon Deoptimization of the A24R Gene for Vaccine Development
title_short Vaccinia Virus Attenuation by Codon Deoptimization of the A24R Gene for Vaccine Development
title_sort vaccinia virus attenuation by codon deoptimization of the a24r gene for vaccine development
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241885/
https://www.ncbi.nlm.nih.gov/pubmed/35583360
http://dx.doi.org/10.1128/spectrum.00272-22
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