Unraveling the mechanism of type-1 immunity induction by defective viral genomederived oligonucleotides

Abstract

Abstract Many newly developed vaccines use killed pathogens or pathogen subunits as antigens. Unfortunately, these inert antigens do not contain danger signals required to induce robust adaptive immunity. Adjuvants are added to vaccines to provide danger signals that help boost and shape the immune response. Currently, no approved adjuvants can effectively skew the immune response towards type-1 immunity including CD8+ T cells necessary for the clearance of viruses and other intracellular pathogens. Most viruses induce type-1 immunity and this process can be leveraged to generate type-1 immunity inducing adjuvants. The primary immunostimulatory molecules during paramyxovirus infections are defective viral genomes (DVGs). We identified the immunostimulatory motif of a Sendai virus DVG and created a DVG-derived oligonucleotide (DDO) to test as an adjuvant. Intramuscular injection of DDO with inactivated influenza virus induced robust protective type-1 immunity characterized by CD8+ T-cell responses and antibodies of the IgG2c isotype. This immune response was dependent on type I interferon signaling. Mice lacking MyD88, the adaptor for TLR and IL-1 signaling, did not produce type-1 humoral or cellular responses in response to a DDO-adjuvanted vaccine. Current studies focus on further understanding the molecular and cellular mechanisms mediating the type I interferon-dependent response to DDOs. This knowledge may allow for directed vaccine design for intracellular pathogens.