Interferon alpha-based combinations suppress SARS-CoV-2 infection in vitro and in vivo

Ianevski, Aleksandr; Yao, Rouan; Zusinaite, Eva; Lello, Laura Sandra; Wang, Sainan; Jo, Eunji; Yang, Jaewon; Ravlo, Erlend; Wang, Wei; Lysvand, Hilde; Løseth, Kirsti; Oksenych, Valentyn; Tenson, Tanel; Windisch, Marc P.; Poranen, Minna; Nieminen, Anni I.; Nordbø, Svein Arne; Fenstad, Mona Høysæter; Grødeland, Gunnveig; Aukrust, Pål; Trøseid, Marius; Kantele, Anu; Vitkauskiene, Astra; Legrand, Nicolas; Merits, Andres; Bjørås, Magnar; Kainov, Denis E.

There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. In the present study, we found that recombinant human interferon-alpha (IFNa) triggers intrinsic and extrinsic cellular antiviral responses, as well as reduces replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. Although IFNa alone was insufficient to completely abolish SARS-CoV-2 replication, combinations of IFNa with remdesivir or other antiviral agents (EIDD-2801, camostat, cycloheximide, or convalescent serum) showed strong synergy and effectively inhibited SARS-CoV-2 infection in human lung epithelial Calu-3 cells. Furthermore, we showed that the IFNa-remdesivir combination suppressed virus replication in human lung organoids, and that its single prophylactic dose attenuated SARS-CoV-2 infection in lungs of Syrian hamsters. Transcriptome and metabolomic analyses showed that the combination of IFNa-remdesivir suppressed virus-mediated changes in infected cells, although it affected the homeostasis of uninfected cells. We also demonstrated synergistic antiviral activity of IFNa2a-based combinations against other virus infections in vitro. Altogether, our results indicate that IFNa2a-based combination therapies can achieve higher efficacy while requiring lower dosage compared to monotherapies, making them attractive targets for further pre-clinical and clinical development.