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

• Published in: bioRxiv 2021-04
• Main Authors: Ianevski, Aleksandr, Rouan Yao, Zusinaite, Eva, Lello, Laura Sandra, Wang, Sainan, Eunji Jo, Yang, Jaewon, Ravlo, Erlend, Wang, Wei, Lysvand, Hilde, Loseth, Kirsti, Oksenych, Valentyn, Tanel Tenson, Windisch, Marc P, Poranen, Minna, Nieminen, Anni I, Nordbo, Svein A, Fenstad, Mona H, Grodeland, Gunnveig, Aukrust, Pal, Troseid, Marius, Kantele, Anu, Vitkauskiene, Astra, Legrand, Nicolas, Merits, Andres, Bjoras, Magnar, Kainov, Denis E
• Format: Article
• Language: English
• Subjects: Antiviral activity; Antiviral agents; Coronaviruses; Cycloheximide; Dosage; HIV; Human immunodeficiency virus; Infections; Lamivudine; Metabolomics; Microbiology; Replication; Severe acute respiratory syndrome coronavirus 2; Transcriptomes; Viral infections; α-Interferon
• ISSN: 2692-8205
• DOI: 10.1101/2021.01.05.425331

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. Competing Interest Statement The authors have declared no competing interest. Footnotes * We have revised our manuscript (Fig. 7, 8 and discussion section)