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

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. Zander, Luis Enjuanes, Isabel Sola, Eric J. Snijder and Marjolein Kikkert ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36754-z

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