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

Rachel L Graham, Michelle M Becker, Lance D Eckerle, Meagan Bolles, Mark R Denison & Ralph S Baric. Nat Med, 18, 1820-1826 (2012)

Speaker: Chin-Yu Chen (陳謦伃)                                Time: 13:10~14:00, Nov. 6, 2013.

Commentator: Dr. Ai-Li Shiau (蕭璦莉老師)             Place: Room 601

Abstract:

Live, attenuated RNA virus vaccines (LAV) remain the most efficacious of all vaccines but carry risk of reversion to virulence. So far, the mechanisms of LAV-mediated protection remain unclear. Coronaviruses (CoVs) are a family of RNA viruses that cause significant diseases in humans such as severe acute respiratory syndrome (SARS) and other respiratory infections (1). Nsp 14 contains a 3’à5’ exonuclease (ExoN) activity which plays an essential role in the CoV replication fidelity by mediating its RNA proofreading (2). In this study, the authors inactivated nsp 14 activity in the SARS-CoVs to generate ExoN mutant virus. The mutator phenotype lacking the proofreading ability resulted in a decreased fidelity and attenuated pathogenesis in the mouse model. They previously showed that the mutator phenotype had decreased fidelity and virulence (3). Here, they further found that the mutator phenotype was stable and did not revert to virulence after serial passage or long-term persistent infection in young, aged and immunocompromised mice. Moreover, the attenuated viruses replicated well and generated a protective immune response even in immunocompromised animals. These results reveal that exonuclease inactivation has potential for the production of a functional vaccine for new epidemic coronaviruses and additionally, broad applications in the stable attenuation of coronavirus and other RNA viruses.

References:

1.     Denison MR, Graham RL, Donaldson EF, Eckerle LD, Baric RS. (2011) Coronaviruses an rna proofreading machine regulates replication fidelity and diversity. RNA Biol. 8, 270-279.

2.     Eckerle LD, Lu X, Sperry SM, Choi L, Denison MR. (2007) High fidelity of murine hepatitis virus replication is decreased in nsp14 exoribonuclease mutants. J Virol. 81, 12135-12144.

3.     Eckerle LD, Becker MM, Halpin RA, Li K, Venter E, Lu X, Scherbakova S, Graham RL, Baric RS, Stockwell TB, Spiro DJ, Denison MR. (2010) Infidelity of SARS-Cov nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing. PLoS Pathog. 6, e1000896.