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Engineering potent live attenuated coronavirus vaccines by targeted inactivation of the immune evasive viral deubiquitinase

Author

Listed:
  • Sebenzile K. Myeni

    (Leiden University Medical Center)

  • Peter J. Bredenbeek

    (Leiden University Medical Center)

  • Robert C. M. Knaap

    (Leiden University Medical Center)

  • Tim J. Dalebout

    (Leiden University Medical Center)

  • Shessy Torres Morales

    (Leiden University Medical Center)

  • Igor A. Sidorov

    (Leiden University Medical Center)

  • Marissa E. Linger

    (Leiden University Medical Center)

  • Nadia Oreshkova

    (Leiden University Medical Center)

  • Sophie Zanen-Gerhardt

    (Leiden University Medical Center)

  • Serge A. L. Zander

    (Leiden University Medical Center)

  • Luis Enjuanes

    (Campus Universidad Autonoma de Madrid)

  • Isabel Sola

    (Campus Universidad Autonoma de Madrid)

  • Eric J. Snijder

    (Leiden University Medical Center)

  • Marjolein Kikkert

    (Leiden University Medical Center)

Abstract

Coronaviruses express a papain-like protease (PLpro) that is required for replicase polyprotein maturation and also serves as a deubiquitinating enzyme (DUB). In this study, using a Middle East respiratory syndrome virus (MERS-CoV) PLpro modified virus in which the DUB is selectively inactivated, we show that the PLpro DUB is an important MERS-CoV interferon antagonist and virulence factor. Although the DUB-negative rMERS-CoVMA replicates robustly in the lungs of human dipeptidyl peptidase 4 knock-in (hDPP4 KI) mice, it does not cause clinical symptoms. Interestingly, a single intranasal vaccination with DUB-negative rMERS-CoVMA induces strong and sustained neutralizing antibody responses and sterilizing immunity after a lethal wt virus challenge. The survival of naïve animals also significantly increases when sera from animals vaccinated with the DUB-negative rMERS-CoVMA are passively transferred, prior to receiving a lethal virus dose. These data demonstrate that DUB-negative coronaviruses could be the basis of effective modified live attenuated vaccines.

Suggested Citation

  • Sebenzile K. Myeni & Peter J. Bredenbeek & Robert C. M. Knaap & Tim J. Dalebout & Shessy Torres Morales & Igor A. Sidorov & Marissa E. Linger & Nadia Oreshkova & Sophie Zanen-Gerhardt & Serge A. L. Za, 2023. "Engineering potent live attenuated coronavirus vaccines by targeted inactivation of the immune evasive viral deubiquitinase," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36754-z
    DOI: 10.1038/s41467-023-36754-z
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    References listed on IDEAS

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    1. Lu Lu & Qi Liu & Yun Zhu & Kwok-Hung Chan & Lili Qin & Yuan Li & Qian Wang & Jasper Fuk-Woo Chan & Lanying Du & Fei Yu & Cuiqing Ma & Sheng Ye & Kwok-Yung Yuen & Rongguang Zhang & Shibo Jiang, 2014. "Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor," Nature Communications, Nature, vol. 5(1), pages 1-12, May.
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