A small-molecule RIG-I agonist functions to enhance vaccine protection against influenza A virus infection.

Viral sensing by RIG-I and downstream activation of antiviral defenses along with the induction of innate immune cytokines is essential from protection against influenza A virus (IAV) infection. We have identified a novel, small-molecule RIG-I agonist, KIN1148, which binds and activates RIG-I to signal the activation of IRF3 and the innate immune response. We are developing this molecule as an adjuvant to enhance vaccination against pandemic H1N1 (pH1N1) IAV. Ex vivo treatment of dendritic cells with KIN1148 leads to their activation and maturation. We determined the ability of KIN1148 to enhance suboptimal IAV vaccine responses in vivo . Administration of KIN1148 leads enhanced protection during high dose pH1N1 infection following a single, intramuscular administration of KIN1148 with IAV vaccine. This increase in protection is accompanied by a significant reduction in virus titers, as well as lung pathology. Analysis of the immune response induced following vaccination with KIN1148 as well as challenge demonstrates an increase in chemoattractant cytokines, germinal center B cells, IAV-specific antibodies, and IAV-specific CD4 and CD8 T cells compared to vaccination alone, indicating the induction of a broad anti-IAV immune response. Together these results demonstrate that prophylactic drug targeting of the RIG-I pathway with a small molecule enhances vaccine protection and highlight the potential of KIN1148 to enhancing vaccines against RNA virus infection.