Exosome co-delivery of a STING agonist augments immunogenicity elicited by CVB3 VP1 vaccine via promoting antigen cross-presentation of CD8 + DCs

The induction of a robust CD8 + T cell response is critical for the success of an antiviral vaccine. In this study, we incorporated a STING agonist (SA) 2′3’-cGAMP into a previously developed exosome-based CVB3 viral myocarditis vaccine (Exo-VP1) to enhance its ability to induce CD8 + T cell responses and immunoprotection. Our results showed that compared to free SA adjuvant, exosome-mediated co-delivery (Exo SA -VP1) significantly enhanced SA uptake by dendritic cells (DCs) and more potently stimulated DC maturation. Immunization of mice showed that the Exo SA -VP1 vaccine-induced higher levels of CVB3-specific T cell proliferation and cytotoxicity, significantly increased the percentage of IFN-γ + CD8 + rather than CD4 + T cells, effectively reduced cardiac viral loads, attenuated myocarditis and improved survival in mice compared to the previous Exo-VP1 vaccine. Further investigation showed that Exo SA -VP1 significantly increased both the percentage and antigen cross-presentation capacity of splenic CD8 + DCs. Depletion of these CD8 + DCs by cytochrome C administration nearly abolished the advantage of Exo SA -VP1 in dominantly inducing IFN-γ + CD8 + cytotoxic T lymphocyte (CTL) production in immunized mice. Taken together, our results demonstrated the potential of Exo SA -VP1 as a promising candidate for anti-CVB3 vaccines and provide insights into immune-enhancing strategies aiming at augmenting antigen cross-presentation by DCs and enhancing potent CTL responses.