Visible blue light inactivates SARS-CoV-2 variants and inhibits Delta replication in differentiated human airway epithelia.

The emergence of SARS-CoV-2 variants that evade host immune responses has prolonged the COVID-19 pandemic. Thus, the development of an efficacious, variant-agnostic therapeutic for the treatment of early SARS-CoV-2 infection would help reduce global health and economic burdens. Visible light therapy has the potential to fill these gaps. In this study, visible blue light centered around 425 nm efficiently inactivated SARS-CoV-2 variants in cell-free suspensions and in a translationally relevant well-differentiated tissue model of the human large airway. Specifically, 425 nm light inactivated cell-free SARS-CoV-2 variants Alpha, Beta, Delta, Gamma, Lambda, and Omicron by up to 99.99% in a dose-dependent manner, while the monoclonal antibody bamlanivimab did not neutralize the Beta, Delta, and Gamma variants. Further, we observed that 425 nm light reduced virus binding to host ACE-2 receptor and limited viral entry to host cells in vitro . Further, the twice daily administration of 32 J/cm 2 of 425 nm light for three days reduced infectious SARS-CoV-2 Beta and Delta variants by >99.99% in human airway models when dosing began during the early stages of infection. In more established infections, logarithmic reductions of infectious Beta and Delta titers were observed using the same dosing regimen. Finally, we demonstrated that the 425 nm dosing regimen was well-tolerated by the large airway tissue model. Our results indicate that blue light therapy has the potential to lead to a well-tolerated and variant-agnostic countermeasure against COVID-19.

A randomized, controlled, feasibility study of RD-X19 in subjects with mild-to-moderate COVID-19 in the outpatient setting.

The RD-X19 is an investigational, handheld medical device precisely engineered to emit blue light through the oral cavity to target the oropharynx and surrounding tissues. At doses shown to be noncytotoxic in an in vitro three-dimensional human epithelial tissue model, the monochromatic visible light delivered by RD-X19 results in light-initiated expression of immune stimulating cytokines IL-1α and IL-1ß, with corresponding inhibition of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) replication. A single exposure of 425 nm blue light at 60 J/cm2 led to greater than 99% reductions against all SARS-CoV-2 strains tested in vitro, including the more transmissible (Alpha) and immune evasive (Beta) variants. These preclinical findings along with other studies led to a randomized, double-blind, sham-controlled early feasibility study using the investigational device as a treatment for outpatients with mild to moderate coronavirus disease 2019 (COVID-19). The study enrolled 31 subjects with a positive SARS-CoV-2 antigen test and at least two moderate COVID-19 signs and symptoms at baseline. Subjects were randomized 2:1 (RD-X19: sham) and treated twice daily for 4 days. Efficacy outcome measures included assessments of SARS-CoV-2 saliva viral load and clinical assessments of COVID-19. There were no local application site reactions and no device-related adverse events. At the end of the study (day 8), the mean change in log10 viral load was -3.29 for RD-X19 and -1.81 for sham, demonstrating a treatment benefit of -1.48 logs (95% confidence internal, -2.88 to -0.071, nominal p = 0.040). Among the clinical outcome measures, differences between RD-X19 and sham were also observed, with a 57-h reduction of median time to sustained resolution of COVID-19 signs and symptoms (log rank test, nominal p = 0.044).

Visible blue light inhibits infection and replication of SARS-CoV-2 at doses that are well-tolerated by human respiratory tissue.

The delivery of safe, visible wavelengths of light can be an effective, pathogen-agnostic, countermeasure that would expand the current portfolio of SARS-CoV-2 intervention strategies beyond the conventional approaches of vaccine, antibody, and antiviral therapeutics. Employing custom biological light units, that incorporate optically engineered light-emitting diode (LED) arrays, we harnessed monochromatic wavelengths of light for uniform delivery across biological surfaces. We demonstrated that primary 3D human tracheal/bronchial-derived epithelial tissues tolerated high doses of a narrow spectral band of visible light centered at a peak wavelength of 425 nm. We extended these studies to Vero E6 cells to understand how light may influence the viability of a mammalian cell line conventionally used for assaying SARS-CoV-2. The exposure of single-cell monolayers of Vero E6 cells to similar doses of 425 nm blue light resulted in viabilities that were dependent on dose and cell density. Doses of 425 nm blue light that are well-tolerated by Vero E6 cells also inhibited infection and replication of cell-associated SARS-CoV-2 by > 99% 24 h post-infection after a single five-minute light exposure. Moreover, the 425 nm blue light inactivated cell-free betacoronaviruses including SARS-CoV-1, MERS-CoV, and SARS-CoV-2 up to 99.99% in a dose-dependent manner. Importantly, clinically applicable doses of 425 nm blue light dramatically inhibited SARS-CoV-2 infection and replication in primary human 3D tracheal/bronchial tissue. Safe doses of visible light should be considered part of the strategic portfolio for the development of SARS-CoV-2 therapeutic countermeasures to mitigate coronavirus disease 2019 (COVID-19).