ABSTRACT
The fear and devastation caused by the COVID-19 pandemic has been mitigated by the successful development and deployment of prophylactic vaccines that substantially lowered the incidences of symptomatic infection, hospitalization, and death. However, as the causative agent SARS-CoV-2 continues to spread and evolve worldwide, vaccine-breakthrough infections have become frequent, especially after the emergence of viral variants that are antigenically distant from the ancestral strain used in the current vaccines. Additional approaches are therefore needed in our prevention tool kit. Here, we report on a glycolipid termed 7DW8-5 that exploits the host innate immune system to enable rapid control of viral infections in vivo. This glycolipid binds to CD1d on antigen-presenting cells and thereby stimulates NKT cells to release a cascade of cytokines and chemokines. The intranasal administration of 7DW8-5 prior to virus exposure significantly blocked infection by three different authentic variants of SARS-CoV-2, as well as by respiratory syncytial virus and influenza virus, in mice or hamsters. We also found that this protective antiviral effect is both host-directed and mechanism-specific, requiring both the CD1d molecule and interferon- gamma. A chemical compound like 7DW8-5 that is easy to administer and cheap to manufacture may be useful not only in slowing the spread of COVID-19 but also in responding to future pandemics that include currently ongoing influenza, SARS-CoV-2 and respiratory syncytia virus- associated tripledemic long before vaccines or drugs are developed.