Small molecule agonists of IRF3 activation function as influenza vaccine adjuvants by modulating the humoral and cellular anti-viral immune response

We have identified a panel of small molecule immunomodulators that activate IRF3 and induce innate immune signaling to drive an antigen-specific protective immune response against viral infections. Our lead adjuvant candidate, KIN1148, binds to retinoic acid inducible gene-I (RIG-I) and induces RIG-I signaling to drive IRF3 activation. Studies using the H1N1 influenza virus challenge model demonstrate that immunization with monovalent influenza split vaccine (SV) and KIN1148 is dose sparing and protects mice against a lethal H1N1 A/California/04/2009 challenge. The SV-H1N1/KIN1148 adjuvant system induces functional antibodies neutralizing viral infectivity and inhibiting influenza hemagglutinin-mediated blood agglutination. SV-H1N1/KIN1148 prime/boost immunizations mediate a strong influenza-specific Th2 response and enhance the production of the immunoregulatory cytokine IL-10 by lung and draining lymph-node-derived T cells from challenged mice. In addition, prime immunization with SV-H1N1/KIN1148 alone provides protection against a 10xLD50 H1N1 challenge by reducing the viral load in the lungs of infected mice. Passive transfer experiments suggest that the protection after prime immunization is at least partially mediated by a cellular immune component. In summary, the KIN1148 split vaccine adjuvant system controls influenza virus infection by boosting the production of functional antibodies, reducing viral load, and inducing a Th2-type immune response. The induction of Th2 and immunoregulatory cytokines by KIN1148-adjuvanted SV might be beneficial to ameliorate the immunopathogenesis of an immune response to highly pathogenic avian influenza virus in infected individuals.