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A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease

Live, attenuated RNA virus vaccines are efficacious but subject to reversion to virulence. Among RNA viruses, replication fidelity is recognized as a key determinant of virulence and escape from antiviral therapy; increased fidelity is attenuating for some viruses. Coronavirus (CoV) replication fide...

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Autores principales: Graham, Rachel L, Becker, Michelle M, Eckerle, Lance D, Bolles, Meagan, Denison, Mark R, Baric, Ralph S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518599/
https://www.ncbi.nlm.nih.gov/pubmed/23142821
http://dx.doi.org/10.1038/nm.2972
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author Graham, Rachel L
Becker, Michelle M
Eckerle, Lance D
Bolles, Meagan
Denison, Mark R
Baric, Ralph S
author_facet Graham, Rachel L
Becker, Michelle M
Eckerle, Lance D
Bolles, Meagan
Denison, Mark R
Baric, Ralph S
author_sort Graham, Rachel L
collection PubMed
description Live, attenuated RNA virus vaccines are efficacious but subject to reversion to virulence. Among RNA viruses, replication fidelity is recognized as a key determinant of virulence and escape from antiviral therapy; increased fidelity is attenuating for some viruses. Coronavirus (CoV) replication fidelity is approximately 20-fold greater than that of other RNA viruses and is mediated by a 3′→5′ exonuclease (ExoN) activity that probably functions in RNA proofreading. In this study we demonstrate that engineered inactivation of severe acute respiratory syndrome (SARS)-CoV ExoN activity results in a stable mutator phenotype with profoundly decreased fidelity in vivo and attenuation of pathogenesis in young, aged and immunocompromised mice. The ExoN inactivation genotype and mutator phenotype are stable and do not revert to virulence, even after serial passage or long-term persistent infection in vivo. ExoN inactivation has potential for broad applications in the stable attenuation of CoVs and, perhaps, other RNA viruses. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nm.2972) contains supplementary material, which is available to authorized users.
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spelling pubmed-35185992013-06-01 A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease Graham, Rachel L Becker, Michelle M Eckerle, Lance D Bolles, Meagan Denison, Mark R Baric, Ralph S Nat Med Article Live, attenuated RNA virus vaccines are efficacious but subject to reversion to virulence. Among RNA viruses, replication fidelity is recognized as a key determinant of virulence and escape from antiviral therapy; increased fidelity is attenuating for some viruses. Coronavirus (CoV) replication fidelity is approximately 20-fold greater than that of other RNA viruses and is mediated by a 3′→5′ exonuclease (ExoN) activity that probably functions in RNA proofreading. In this study we demonstrate that engineered inactivation of severe acute respiratory syndrome (SARS)-CoV ExoN activity results in a stable mutator phenotype with profoundly decreased fidelity in vivo and attenuation of pathogenesis in young, aged and immunocompromised mice. The ExoN inactivation genotype and mutator phenotype are stable and do not revert to virulence, even after serial passage or long-term persistent infection in vivo. ExoN inactivation has potential for broad applications in the stable attenuation of CoVs and, perhaps, other RNA viruses. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nm.2972) contains supplementary material, which is available to authorized users. Nature Publishing Group US 2012-11-11 2012 /pmc/articles/PMC3518599/ /pubmed/23142821 http://dx.doi.org/10.1038/nm.2972 Text en © Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2012 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Article
Graham, Rachel L
Becker, Michelle M
Eckerle, Lance D
Bolles, Meagan
Denison, Mark R
Baric, Ralph S
A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease
title A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease
title_full A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease
title_fullStr A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease
title_full_unstemmed A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease
title_short A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease
title_sort live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518599/
https://www.ncbi.nlm.nih.gov/pubmed/23142821
http://dx.doi.org/10.1038/nm.2972
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