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

Myeni, S.K.; Bredenbeek, P.J.; Knaap, R.C.M.; Dalebout, T.J.; Morales, S.T.; Sidorov, I.A.; ... ; Kikkert, M. (2023)

Article / Letter to editor

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 naive 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.In this work, authors provide a proof-of-concept study showing that deubiquitinating enzyme inactivation in MERS-CoV leads to attenuation in mice, and protection against a lethal challenge.

• All authors: Myeni, S.K.; Bredenbeek, P.J.; Knaap, R.C.M.; Dalebout, T.J.; Morales, S.T.; Sidorov, I.A.; Linger, M.E.; Oreshkova, N.; Zanen-Gerhardt, S. van; Zander, S.A.L.; Enjuanes, L.; Sola, I.; Snijder, E.J.; Kikkert, M.
• Date: 2023-02-28
• Journal: Nature Communications
• Volume: 14
• Issue: 1
• DOI: doi:10.1038/s41467-023-36754-z
• Sponsorship: Horizon 2020 (H2020)
• Grant number: 952373