Local Delivery of Interferon-β1a for Respiratory Viral Infections: A Systematic Review

Respiratory viral infections represent a major global health burden, with impaired antiviral interferon responses contributing to disease progression in several respiratory conditions. This systematic review evaluated the efficacy, safety, and biological effects of locally delivered intranasal or inhaled interferon-β1a (IFN-β1a), a host-directed antiviral therapy, across prophylactic, therapeutic, and experimental models of respiratory viral infections. A systematic review was conducted according to PRISMA 2020 guidelines by searching PubMed, Embase, Scopus, Web of Science, Google Scholar, patent databases, and ClinicalTrials.gov up to July 2025. Peer-reviewed clinical and experimental studies, as well as relevant patent records, were identified. Patent and grey-literature sources were examined to provide a comprehensive overview of the development of locally delivered IFN-β1a and to identify relevant technological approaches that might not be captured in conventional bibliographic databases; however, these records were not considered evidence of clinical efficacy or safety. Eligible clinical and experimental evidence included randomized controlled trials (RCTs), in vitro, and in vivo studies. Owing to substantial clinical and methodological heterogeneity, findings were synthesised using a structured narrative and stratified approach rather than quantitative pooling. Risk of bias was assessed using RoB 2 for RCTs, ToxRTool for in vitro studies, and the SYRCLE tool for in vivo studies. Twenty-four studies met the inclusion criteria, including 12 RCTs, seven in vitro studies, one in vivo study, and four patent reports. Preclinical evidence consistently demonstrated antiviral and immunomodulatory activity, including reduced viral replication and induction of interferon-stimulated genes. Clinical studies demonstrated consistent antiviral activity and immune modulation (e.g., ISG upregulation, viral load reduction). However, clinically meaningful benefit varied across populations and was most consistent in asthma, COPD, and hospitalised COVID-19 patients, whereas other trials did not demonstrate significant improvements in their primary clinical outcomes. Early prophylactic studies in rhinovirus infection showed limited and inconsistent clinical preventive efficacy despite detectable antiviral activity. Pharmacokinetic studies supported effective airway delivery, while safety findings indicated generally favourable tolerability with predominantly mild, transient adverse events. Available evidence indicates that intranasal or inhaled IFN-β may enhance antiviral immunity and provide clinical benefit in selected respiratory viral conditions, particularly among individuals with impaired antiviral responses. However, evidence for prophylactic efficacy against community-acquired upper respiratory tract infections remains limited, and further studies are required to define optimal indications, dosing strategies, and target populations.