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

• Published in: Nature medicine Vol. 18; no. 12; pp. 1820 - 1826
• Main Authors: Graham, Rachel L, Becker, Michelle M, Eckerle, Lance D, Bolles, Meagan, Denison, Mark R, Baric, Ralph S
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2012; Nature Publishing Group
• Subjects: 631/250/590/1867; 631/326/596/2557; 692/420; 692/699/255/2514; Age Factors; Animal models; Animals; Antiviral agents; Attenuation; Base Sequence; Biomedicine; Cancer Research; Coronaviruses; COVID-19; Deactivation; Disease; Diseases; DNA Primers - genetics; Drug Design; Editing; Exonuclease; Exoribonucleases - antagonists & inhibitors; Exoribonucleases - genetics; Exoribonucleases - metabolism; Exoribonucleases - physiology; Female; Fidelity; Genetic aspects; Genotype & phenotype; Genotypes; Immunocompromised Host - immunology; Inactivation; Infectious Diseases; Metabolic Diseases; Mice; Mice, Inbred BALB C; Molecular Medicine; Molecular Sequence Data; Neurosciences; Pathogenesis; Phenotypes; Physiological aspects; Plasmids - genetics; Proofreading; Real-Time Polymerase Chain Reaction; Replication; Reversion; RNA; RNA viruses; Rodents; SARS coronavirus; SARS Virus - enzymology; SARS Virus - genetics; SARS Virus - pathogenicity; Sequence Analysis, DNA; Severe acute respiratory syndrome; Severe Acute Respiratory Syndrome - drug therapy; Severe Acute Respiratory Syndrome - immunology; Severe Acute Respiratory Syndrome - virology; Statistics, Nonparametric; Vaccines; Viral diseases; Viral vaccines; Viral Vaccines - pharmacology; Virulence; Virulence (Microbiology); Virus replication; Virus Replication - physiology; Viruses; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2972

Attenuated viruses can be highly effective vaccines. In this issue, Ralph Baric and colleagues report that inactivating mutations in the exonuclease ExoN of a mouse-adapted SARS coronavirus impair replication fidelity and cause a mutator phenotype. The resulting attenuated virus protected mice against a lethal coronavirus challenge. 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.