Combination attenuation offers strategy for live attenuated coronavirus vaccines

Vineet Menachery, Lisa E. Gralinski, Hugh D. Mitchell, Kenneth H. Dinnon, Sarah R. Leist, Boyd L. Yount, Eileen T. McAnarney, Rachel L. Graham, Katrina M. Waters, Ralph S. Baric

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

With an ongoing threat posed by circulating zoonotic strains, new strategies are required to prepare for the next emergent coronavirus (CoV). Previously, groups had targeted conserved coronavirus proteins as a strategy to generate live attenuated vaccine strains against current and future CoVs. With this in mind, we explored whether manipulation of CoV NSP16, a conserved 2'O methyltransferase (MTase), could provide a broad attenuation platform against future emergent strains. Using the severe acute respiratory syndrome-CoV mouse model, an NSP16 mutant vaccine was evaluated for protection from heterologous challenge, efficacy in the aging host, and potential for reversion to pathogenesis. Despite some success, concerns for virulence in the aged and potential for reversion makes targeting NSP16 alone an untenable approach. However, combining a 2'O MTase mutation with a previously described CoV fidelity mutant produced a vaccine strain capable of protection from heterologous virus challenge, efficacy in aged mice, and no evidence for reversion. Together, the results indicate that targeting the CoV 2'O MTase in parallel with other conserved attenuating mutations may provide a platform strategy for rapidly generating live attenuated coronavirus vaccines.

Original languageEnglish (US)
Article numbere00710-18
JournalJournal of Virology
Volume92
Issue number17
DOIs
StatePublished - Sep 1 2018

Fingerprint

Attenuated Vaccines
Coronavirus
Coronavirinae
vaccines
methyltransferases
live vaccines
Vaccines
mutation
mutants
Severe Acute Respiratory Syndrome
Mutation
Zoonoses
virulence
pathogenesis
animal models
Virulence
viruses
Viruses
mice
proteins

Keywords

  • Aged
  • Coronavirus
  • Live attenuated
  • MERS-CoV
  • SARS-CoV
  • Vaccine

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Menachery, V., Gralinski, L. E., Mitchell, H. D., Dinnon, K. H., Leist, S. R., Yount, B. L., ... Baric, R. S. (2018). Combination attenuation offers strategy for live attenuated coronavirus vaccines. Journal of Virology, 92(17), [e00710-18]. https://doi.org/10.1128/JVI.00710-18

Combination attenuation offers strategy for live attenuated coronavirus vaccines. / Menachery, Vineet; Gralinski, Lisa E.; Mitchell, Hugh D.; Dinnon, Kenneth H.; Leist, Sarah R.; Yount, Boyd L.; McAnarney, Eileen T.; Graham, Rachel L.; Waters, Katrina M.; Baric, Ralph S.

In: Journal of Virology, Vol. 92, No. 17, e00710-18, 01.09.2018.

Research output: Contribution to journalArticle

Menachery, V, Gralinski, LE, Mitchell, HD, Dinnon, KH, Leist, SR, Yount, BL, McAnarney, ET, Graham, RL, Waters, KM & Baric, RS 2018, 'Combination attenuation offers strategy for live attenuated coronavirus vaccines', Journal of Virology, vol. 92, no. 17, e00710-18. https://doi.org/10.1128/JVI.00710-18
Menachery V, Gralinski LE, Mitchell HD, Dinnon KH, Leist SR, Yount BL et al. Combination attenuation offers strategy for live attenuated coronavirus vaccines. Journal of Virology. 2018 Sep 1;92(17). e00710-18. https://doi.org/10.1128/JVI.00710-18
Menachery, Vineet ; Gralinski, Lisa E. ; Mitchell, Hugh D. ; Dinnon, Kenneth H. ; Leist, Sarah R. ; Yount, Boyd L. ; McAnarney, Eileen T. ; Graham, Rachel L. ; Waters, Katrina M. ; Baric, Ralph S. / Combination attenuation offers strategy for live attenuated coronavirus vaccines. In: Journal of Virology. 2018 ; Vol. 92, No. 17.
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