Antihistamine nasal spray a promising prophylactic treatment against SARS-CoV-2

The use of the antihistamine nasal spray azelastine may help prevent SARS-CoV-2 respiratory infections, as shown in a phase II study.

In the intention-to-treat (ITT) population, PCR-confirmed SARS-CoV-2 infection occurred less frequently among participants who used azelastine than those on placebo (2.2 percent vs 6.7 percent; odds ratio, 0.31, 95 percent confidence interval [CI], 0.11–0.87; p=0.02). [JAMA Intern Med 2025;doi:10.1001/jamainternmed.2025.4283]

Results for several secondary endpoints also favoured the azelastine arm. The incidence of symptomatic SARS-CoV-2 infections was much lower (1.8 percent vs 6.3 percent), the mean time to infection was roughly 12 days longer (31.2 vs 19.47 days), and the mean duration of SARS-CoV-2 positivity (based on a rapid antigen test) was about 2 days shorter (3.40 vs 5.14 days) relative to the placebo arm.

“In addition to SARS-CoV-2, azelastine nasal spray showed efficacy against symptomatic rhinovirus infection, the most frequently identified non–SARS-CoV-2 pathogen in this trial,” said first author Dr Thorsten Lehr of Saarland University, Saarbruecken, Germany, and colleagues.

The incidence of PCR-confirmed human rhinovirus infection was 1.8 percent in the azelastine arm vs 6.3 percent in the placebo arm. The overall number of PCR-confirmed infections was lower in the azelastine arm (9.3 percent vs 22.0 percent).

To ensure the findings were not influenced by pre-existing immunity, Lehr and colleagues looked at the baseline serostatus of a subset of participants in the azelastine and placebo arms. Nucleocapsid and spike antibody levels did not significantly differ between the two arms.

As for safety, the frequency of adverse events (AE) was similar between the two arms (303 events with azelastine vs 367 with placebo). AEs deemed related to treatment occurred more frequently in the azelastine arm (0.4 vs 0.2 events per participant), with 26.9 percent of participants experiencing at least one treatment-related AE as opposed to 11.2 percent of those in the placebo arm. Lehr and colleagues pointed out that this difference could be largely attributed to the known side effects of azelastine, including bitter taste (9.3 percent vs 1.3 percent), nosebleeds (6.6 percent vs 4 percent), and tiredness (3.1 percent vs 0).

AEs led to treatment discontinuation in two participants on azelastine and one on placebo (0.9 percent vs 0.5 percent). Two participants in the azelastine arm experienced serious AEs, including recurrent headache (which required hospitalization for diagnostic workup) and a new diagnosis of Hashimoto thyroiditis. None of these events were related to treatment, and there were no deaths recorded.

“Together, these results suggest that azelastine may provide meaningful protection against SARS-CoV-2 infection in a prophylactic setting.” according to the authors. “The established safety profile, over-the-counter availability, and ease of use of azelastine nasal spray support its potential as a practical, scalable on demand approach to pre-exposure prophylaxis, particularly in high-risk settings such as large gatherings or travel.”

A total of 450 healthy volunteers (mean age 33.5 years, 66.4 percent female, 92.7 percent White) participated in the study. Nearly all of them were vaccinated at least once against COVID-19 (99.1 percent), with a median of three vaccinations. The median time since the last vaccination was 672 days.

The participants were randomly assigned to receive azelastine 0.1% nasal spray (n=227) or placebo nasal spray (n=223). The nasal spray was administered to each nostril three times per day—in the morning, midday, and evening—for 56 days. SARS-CoV-2 rapid antigen testing was conducted twice weekly, with positive results confirmed by PCR. Symptomatic participants with negative rapid antigen test results underwent multiplex PCR testing for respiratory viruses.

“The use of a three times daily baseline regimen with optional escalation to five times daily in high-risk situations was based on pharmacometric modelling showing increased viral suppression with higher application frequency,” Lehr and colleagues noted. [Pharmaceutics 2022;14:2059]

“Although the said pharmacometric modelling was conducted in infected individuals, it supports the mechanistic rationale that sustained and intensified mucosal exposure enhances local antiviral effects, which is relevant to prophylactic use as well,” they added.

The authors acknowledged the need for larger trials to confirm the efficacy of azelastine against SARS-CoV-2 and to explore its potential benefits against other respiratory pathogens across more diverse populations and settings.