Nasal Commensal Viruses May Drive Allergic Rhinitis; Ribavirin Spray Shows Early Promise in Phase 2 Trial
核心洞察
A phase 2 randomized controlled trial found that intranasal ribavirin spray significantly improved total nasal symptom scores in 42 allergic rhinitis (搜索) patients compared to placebo over 4 weeks.
Mechanistic studies in mice revealed that nasal commensal viruses activate type I interferon (搜索) signaling, triggering neutrophil extracellular trap formation and downstream allergic inflammation.
Ribavirin-treated patients showed reduced nasal viral abundance, lower type II cytokine levels, and decreased neutrophil extracellular trap activity, with benefits persisting at 1-year follow-up.
A novel therapeutic approach targeting nasal commensal viruses with ribavirin spray has demonstrated early clinical benefit for allergic rhinitis (搜索) (AR), according to findings from a phase 2 randomized controlled trial published in Signal Transduction and Targeted Therapy. The study, which enrolled 42 patients, suggests that viruses residing harmlessly in the nasal cavity may actively drive allergic inflammation—and that clearing them could open a new treatment path for millions affected by the condition.
The research, led by Ye Zhou of the National Key Laboratory of Immunity and Inflammation at Naval Medical University (搜索) in Shanghai, combined mechanistic studies in mouse models with a single-center, double-blind, placebo-controlled clinical trial known as the Ribavirin-Spray Therapy for Allergic Rhinitis (搜索) (R-STAR) study.
Uncovering a Viral Driver of Allergic Inflammation
Allergic rhinitis (搜索) is a common upper airway disorder characterized by frequent sneezing, nasal itching, and obstruction. When left unmanaged, it can impair sleep and reduce work efficiency. While current treatments—including glucocorticoid nasal sprays, antihistamines, and allergen immunotherapy—provide relief for many patients, limitations related to side effects and variable long-term efficacy have prompted researchers to explore alternative biological pathways.
The investigators hypothesized that commensal viruses in the nasal cavity, which typically do not cause overt infection, might contribute to AR development. Using murine models of AR, the team collected nasal lavage fluid (NLF) and identified viral populations present in the nasal cavities. They then administered intranasal ribavirin drops daily for seven days to reduce nasal viral abundance.
The results were striking: ribavirin administration reduced commensal viral abundance and improved AR symptoms such as sneezing and scratching. Nasal mucosal samples showed reduced eosinophil counts—white blood cells that accumulate in allergic inflammation and can contribute to chronic tissue damage. Production of type I interferon (搜索) and interleukins (ILs) 4, 5, and 13 was also reduced in NLF, alleviating mucosal pathology.
Single-cell RNA sequencing revealed that among immune cells, neutrophils decreased most significantly in the murine nasal mucosa following ribavirin therapy. Specifically, neutrophil populations upregulating CD14 receptors and interferon-stimulated genes (ISGs) during inflammation were reduced. Further knockout experiments demonstrated that deleting innate sensors and transcription factors of IFN-related genes alleviated AR symptoms, while administering IFN-α1b drops aggravated them—confirming the mechanistic role of type I interferon (搜索) signaling.
The researchers also found that reintroducing NLF from control mice restored AR symptoms and type II cytokine production after ribavirin treatment, while administering favipiravir independently reduced AR symptoms, providing convergent evidence for the viral mechanism.
Clinical Translation: The R-STAR Trial
Between April and May 2024, the team screened 43 AR patients and randomized 42 to receive either ribavirin nasal spray (22 patients) or placebo (20 patients) twice daily for four weeks. The primary endpoint was the Total Nasal Symptom Score (TNSS), with secondary outcomes including the Rhinitis Control Assessment Test (RCAT) scores and the Visual Analog Scale (VAS).
Ribavirin-treated patients demonstrated significantly fewer viral commensals in the nose and improved TNSS, RCAT, and VAS values after four weeks of therapy compared to placebo. Exploratory analyses showed that ribavirin reduced nasal commensal virus abundance, whereas viral abundance remained largely unchanged in the placebo group.
Ribavirin therapy also significantly reduced IL-4, IL-5, IL-13, and IL-17A cytokine levels and neutrophil extracellular trap (NET) activity, with these cytokines positively correlated with IFN-α and IFN-β in NLF samples. Metatranscriptomic analysis identified reductions in the Betaretrovirus genus and viral sequences classified as the candidate Betaretrovirus species enzootic nasal tumor virus 2 (ENTV-2) and bovine retrovirus CH15 (BoRV CH15).
The therapeutic effects were more pronounced in participants with severe symptoms or high nasal commensal virus abundance. Notably, some benefits persisted at 1-year follow-up after the 4-week treatment course, with exploratory data suggesting lower symptom scores and reduced use of AR medications among ribavirin-treated patients.
House dust mite and dust mite sensitization were identified as the most common allergens, with half of participants testing positive. Three participants required rescue medications, including cetirizine and emedastine. Importantly, no grade 3 or higher adverse events, serious adverse events, or adverse drug reactions were reported during the study.
A Potential New Treatment Paradigm
"Our basic and clinical data suggest that the reduction of nasal commensal viruses using antiviral drugs may be effective in AR therapy," wrote Zhou and colleagues. If validated in larger studies, ribavirin could provide an alternative to existing treatments by addressing limitations related to side effects and variable long-term efficacy.
However, the authors acknowledged several important limitations. The clinical trial was a small, single-center phase 2 study requiring confirmation in larger, multicenter phase 3 trials. Much of the mechanistic evidence was derived from mouse models, and the specific nasal commensal viruses identified in exploratory analyses have not been established as causal drivers of AR in humans. Additionally, nasal viruses may reappear after treatment withdrawal, and ribavirin may affect bacteriophages and the nasal bacterial ecosystem.
The study was published with no competing interests reported by the authors. Xuetao Cao, an associate editor of Signal Transduction and Targeted Therapy, was not involved in the editorial handling of the manuscript.