Effect of inhaled interferon-β1a on SARS-CoV-2 diversity and evolution
Year: 2026
Type: article
Abstract: ABSTRACT Interferon resistance has been implicated in SARS-CoV-2 escape from innate immunity, but exogenous interferon’s impact on viral evolution and diversity is unknown. SNG001, an inhaled interferon-β1a treatment, was evaluated in the ACTIV-2/A5401 randomized controlled trial of therapeutics for COVID-19. We measured viral kinetics and performed whole-genome sequencing on longitudinal nasal swabs collected from ACTIV-2 participants who received either SNG001 or placebo to assess viral sequence diversity. No difference in nasal viral load decay was detected between study arms when stratifying by SARS-CoV-2 variant or by viral culture conversion. Compared to placebo participants, the SNG001-treated participants displayed significantly lower nonsynonymous amino acid average pairwise distance, indicating lower sequence diversity. Similarly, SNG001-treated individuals also developed numerically fewer nonsynonymous mutations during their infection in ORF1a, ORF1b, Spike, and Nucleocapsid. No specific emerging SARS-CoV-2 nonsynonymous amino acid changes indicating signatures of viral escape were enriched in those receiving SNG001. These in vivo data provide an intriguing signal that exogenous interferon-β1a may restrict SARS-CoV-2 viral diversity and add to growing evidence that interferon levels play a critical role in antiviral responses during COVID-19. IMPORTANCE SARS-CoV-2 encodes several genes which can antagonize the interferon signaling cascade, preventing it from activating antiviral responses and thereby facilitating viral establishment and dissemination. It is unknown how the administration of exogenous interferon might affect viral evolution and immune escape. ACTIV-2/A5401 represents a unique opportunity to study the virologic effects of interferon treatment in a rigorous randomized, placebo-controlled clinical trial setting. Our characterization of longitudinal nasal samples shows that interferon-treated individuals had lower viral diversity and no evidence of viral escape mutations. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT04518410 .
Source: Microbiology Spectrum
Authors: Gregory E. Edelstein, Tatum N. Sass, Rinki Deo, Owen T. Glover, Julie Boucau, Prasanna Jaganathan, Kara W. Chew, Mark J. Giganti, Michael D. Hughes, Carlee Moser, Arzhang Cyrus Javan, Courtney V. Fletcher, Caitlyn McCarthy, David A. Wohl, Eric S. Daar, Joseph J. Eron, Judith S. Currier, Upinder Singh, Davey M. Smith, William Fischer, Amy K. Barczak, Manish C. Choudhary, Jonathan Z. Li, for the ACTIV-2/A5401 Study Team
Institutions: Brigham and Women's Hospital, Ragon Institute of MGH, MIT and Harvard, Mass General Brigham, Stanford Medicine, Stanford University, University of California, Los Angeles, Harvard University, National Institutes of Health, University of Nebraska Medical Center, University of North Carolina at Chapel Hill, Harbor–UCLA Medical Center
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: AIDS Clinical Trials Group Network, UCLA AIDS Prevention and Treatment Clinical Trials Unit, UCSD Collaborative Clinical Trials Unit, Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections, AIDS Clinical Trial Group Laboratory Center, Statistical and Data Management Center (SDMC), Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG), Harvard University Center for AIDS Research
OpenAlex ID: W7161559498