Despite widespread vaccination, COVID-19 continues to pose a global public health threat. Current treatment strategies primarily focus on the use of antiviral agents and immunomodulators. Antiviral drugs such as remdesivir, favipiravir, and lopinavir/ritonavir have been widely tested in clinical trials, aiming to inhibit viral replication. However, their efficacy has varied across studies and may be influenced by the specific viral variants causing the infection. The investigation of immune-modulating therapies as a treatment option emerged from the frequent observation of “cytokine storms” in severe COVID-19 cases. Accordingly, immunomodulators such as tocilizumab and baricitinib are used to suppress excessive immune responses, thereby reducing inflammation and tissue damage to promote recovery. Nevertheless, immunosuppression can potentially lead to uncontrolled viral replication, resulting in variable outcomes across different patient populations [[1], [2]].

Type I Interferons (IFNs), widely considered the first line of host defense against viral infection, present an attractive naturally occurring medicine to explore for treating COVID-19. Their antiviral actions rely on binding to specific surface receptors expressed in a wide range of cells, triggering a cascade of signal transduction pathways that lead to upregulation of interferon-stimulating genes (ISGs). Many ISGs can serve as effector molecules to inhibit viral infection and replication [3]. In the case of SARS-CoV-2 infection, IFN has demonstrated robust antiviral activity, even higher than seen with SARS-CoV [4]. Notably, different subtypes of interferon-α have shown varying abilities to suppress SARS-CoV-2 infection in cultured primary human airway epithelial cells (hAECs) and mouse models, a difference attributed to their distinct immune signatures [5].

. However, this activity does not consistently translate to clinical success, as some studies have shown that IFN treatment has little effect on overall mortality and hospital stay in patients infected with SARS-CoV-2 [[6], [7], [8]]. One possible explanation is that SARS-CoV-2 can evade or antagonize IFN's inhibitory effects through the action of specific viral proteins it encodes [9]. Interestingly, this antagonism may vary among different virus variants, and recent studies have indicated that the Omicron variant has a lower resistance to IFN-mediated inhibition than the wild-type virus [10,11]. Therefore, IFN treatment might hold more promise in treating infections caused by the Omicron variant.

An important factor that could affect the treatment efficacy of interferon is administration routes. The majority of previous clinical trials on IFN treatment of SARS-CoV-2 infection used intramuscular injections. Given the nature of SARS-CoV-2 as a respiratory virus, spray administration might be a more attractive option as it delivers IFN directly to the respiratory epithelial cells, the main target of evading viruses. Indeed, interferon alpha-2b spray has demonstrated efficacy in preventing respiratory infections caused by influenza virus, parainfluenza virus, and adenovirus [12]. Considering such success, we conducted a randomized, single-blind clinical study to evaluate the efficacy and safety of nebulized inhalation of recombinant human interferon alpha-2b in treating SARS-CoV-2 infected Chinese patients during a period when Omicron was the dominant variant. Here we present the results of this study.