Rationale for the Use of Interferons in New Pandemic

Before COVID-19

1. Interferons are among the earliest cytokines produced during a viral infection² and generate a cascade that culminates in controlling viral replication and inducing an adaptive immune response.³ 
2. Type 1 interferons (IFN-1) have frequently been studied against coronaviruses, having the most antiviral properties.
   • They can be subdivided in α, β, ε, ω and κ subtypes;
   • They are secreted by various cell types, especially plasmacytoid dendritic cells, upon recognition of viral constituents by pattern recognition receptors (PRRs)²;
   • Once produced, interferons are recognized cells and activate the JAK-STAT pathway. This then leads to the phosphorylation of transcriptional factors STAT1 and STAT2, and together with a third transcription factor, IRF9, they form the Interferon Stimulated Gene Factor 3 (ISGF3) complex. The complex is then relocalized to the nucleus so that it can activate the transcription of interferon stimulated genes (ISG);^1,2,3
   • ISGs produce proteins can interfere with viral replication by mechanisms such as slowing of cell metabolism and secretion of cytokines promoting adaptive immunity.²
3. SARS-CoV-2 is closely similar to MERS-CoV and SARS-CoV coronaviruses, against which IFN-1 treatments have been studied in vitro and in vivo, combined or not with other medications.
   
   • Though some potential benefit has been demonstrated, a lack of significant improvement was possibly explained by the mechanisms of suppression of the IFN signaling pathway used by SARS-CoV and MERS-CoV.^{2, 3}
     • The Orf6 and Orf3 protein of SARS-CoV plays major role in inhibiting IFN type 1 response, thus decreasing STAT1 phosphorylation².
     • This delayed IFN type 1 can potentially lead to a pro-inflammatory cytokines response³.

During COVID-19 outbreak 

1. The Orf3 and Orf6 proteins of SARS-CoV-2 are truncated and have therefore potentially lost their anti-IFN function.²
2. In vitro study showed that SARS-CoV-2 is unable to completely inhibit IFN-1 response compared to SARS-CoV¹.
   • Significant reduction in viral replication at 24 and 48 hours was seen
   • Infected cells were capable of inducing STAT1 phosphorylation by 48 hours post-infection;
   • Augmented levels of ISGs were produced.
3. As opposed to SARS-CoV, SARS-CoV-2 could be more sensitive to recombinant IFN-1α pretreatment in vitro, lacking the capacity to restrain a type 1 interferon response.^1-2

This data comes from a study conducted at the University of Texas Medical Branch in Galveston, Texas, with firstly, VeroE6 cells that were incubated with 1000 units/mL of recombinant type 1 IFN alpha 18 hours prior to infection with SARS-CoV-2 and that were compared with cells free of IFN-1. Secondly, IFN competent Calu3 2B4 cells were infected with SARS-CoV-2. Multiple outcomes were examined for both cell types, such as titers of viral and host proteins, viral replication and ISG expression.

Clinical trials for Interferons are currently underway

Sources:

1. Lokugamage, K.G., Hage, A., Schindewolf, C., et al (April 9, 2020). SARS-CoV-2 is sensitive to type I interferon pretreatment. bioRxiv. https://doi.org/10.1101/2020.03.07.982264
2. Sallard, E., Lescure, F., Yazdanpanah, Y., et al (April 7, 2020). Type 1 interferons as a potential treatment against COVID-19. Antiviral Research. https://doi.org/10.1016/j.antiviral.2020.104791
3. Prompetchara E., Ketloy C., Palaga T. (March 2020). Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pacific Journal of Allergy and Immunology. https://doi.org/10.12932/AP-200220-0772