DNA co-delivery of seasonal H1 influenza hemagglutinin nanoparticle vaccines with chemokine adjuvant CTACK induces potent immunogenicity for heterologous protection in vivo

Current influenza vaccines induce mostly strain-specific immunity necessitating annual reformulation and dosing. Here, we developed an improved seasonal influenza vaccine based on A/H1N1/Wisconsin/588/2019. We designed a DNA-launched self-assembling nanoparticle that displayed seven Wisconsin/588/2019 hemagglutinin (HA) head domains (WI19-7mer). WI19-7mer nanovaccine improved heterologous HAI titers and CD8+ cellular responses in mice than DNA encoded HA trimer (WI19 HA). In human antibody repertoire mice, WI19-7mer induced superior breadth to a diverse panel of H1 HAs compared to WI19 HA immunized animals. Cross-reactive HAI titers were maintained better in mice immunized with WI19-7mer than WI19 HA. The WI19-7mer induced improved antibody binding breadth and provided superior protection in a heterologous challenge compared to challenge-matched HA trimer. Addition of the cytokine adjuvant (CTACK) to WI19-7mer significantly improved breadth, HAI, peripheral responses, and protection in heterologous challenge. These data demonstrate that combining nucleic acid delivery, immune focusing, low valency nanoparticle, and mucosal adjuvant for enhanced vaccine effectiveness has broader applications for other viruses.