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Vaccines and Antiviral Agents

Combination Attenuation Offers Strategy for Live Attenuated Coronavirus Vaccines

Vineet D. Menachery, Lisa E. Gralinski, Hugh D. Mitchell, Kenneth H. Dinnon III, Sarah R. Leist, Boyd L. Yount Jr., Eileen T. McAnarney, Rachel L. Graham, Katrina M. Waters, Ralph S. Baric
Tom Gallagher, Editor
Vineet D. Menachery
aDepartment of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
bDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Lisa E. Gralinski
bDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Hugh D. Mitchell
dBiological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA
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Kenneth H. Dinnon III
bDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Sarah R. Leist
bDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Boyd L. Yount Jr.
bDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Eileen T. McAnarney
aDepartment of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
bDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Rachel L. Graham
bDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Katrina M. Waters
dBiological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA
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Ralph S. Baric
bDepartment of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
cDepartment of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Tom Gallagher
Loyola University Medical Center
Roles: Editor
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DOI: 10.1128/JVI.00710-18
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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.

IMPORTANCE Emergent coronaviruses remain a significant threat to global public health and rapid response vaccine platforms are needed to stem future outbreaks. However, failure of many previous CoV vaccine formulations has clearly highlighted the need to test efficacy under different conditions and especially in vulnerable populations such as the aged and immunocompromised. This study illustrates that despite success in young models, the 2′O methyltransferase mutant carries too much risk for pathogenesis and reversion in vulnerable models to be used as a stand-alone vaccine strategy. Importantly, the 2′O methyltransferase mutation can be paired with other attenuating approaches to provide robust protection from heterologous challenge and in vulnerable populations. Coupled with increased safety and reduced pathogenesis, the study highlights the potential for 2′O methyltransferase attenuation as a major component of future live attenuated coronavirus vaccines.

FOOTNOTES

    • Received 26 April 2018.
    • Accepted 20 June 2018.
    • Accepted manuscript posted online 5 July 2018.
  • Address correspondence to Ralph S. Baric, Rbaric{at}email.unc.edu.
  • Citation Menachery VD, Gralinski LE, Mitchell HD, Deinnon KH, III, Leist SR, Yount BL, Jr, McAnarney ET, Graham RL, Waters KM, Baric RS. 2018. Combination attenuation offers strategy for live attenuated coronavirus vaccines. J Virol 92:e00710-18. https://doi.org/10.1128/JVI.00710-18.

  • Copyright © 2018 American Society for Microbiology.

All Rights Reserved.

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Combination Attenuation Offers Strategy for Live Attenuated Coronavirus Vaccines
Vineet D. Menachery, Lisa E. Gralinski, Hugh D. Mitchell, Kenneth H. Dinnon III, Sarah R. Leist, Boyd L. Yount Jr., Eileen T. McAnarney, Rachel L. Graham, Katrina M. Waters, Ralph S. Baric
Journal of Virology Aug 2018, 92 (17) e00710-18; DOI: 10.1128/JVI.00710-18

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Combination Attenuation Offers Strategy for Live Attenuated Coronavirus Vaccines
Vineet D. Menachery, Lisa E. Gralinski, Hugh D. Mitchell, Kenneth H. Dinnon III, Sarah R. Leist, Boyd L. Yount Jr., Eileen T. McAnarney, Rachel L. Graham, Katrina M. Waters, Ralph S. Baric
Journal of Virology Aug 2018, 92 (17) e00710-18; DOI: 10.1128/JVI.00710-18
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KEYWORDS

coronavirus
SARS-CoV
MERS-CoV
vaccine
live attenuated
aged

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