Targeting vaccine fusion proteins to APCs increases immunogenicity of adenoviral and mRNA-LNP vaccines.

mRNA-lipid nanoparticle (LNP) and adenoviral delivery of vaccines have proven effective during the COVID-19 pandemic. Herein, we explored whether antigen-presenting cell (APC) targeting of antigens could further enhance the immunogenicity of these delivery formats. Experiments were performed in mouse models for malaria (Plasmodium falciparum reticulocyte-binding protein homolog 5 [PfRH5] antigen) and influenza (hemagglutinin [HA] antigen). We used genetic constructs encoding bivalent fusion proteins that target antigens to MHC class II (MHCII) molecules on professional APCs. We demonstrate that MHCII-targeted fusion proteins bound to professional APCs and that such APC-targeting increased antibody and T cell responses as well as protection against the influenza virus. The results suggest that the injected mRNA-LNP and adenoviral vectors resulted in the secretion of fusion proteins that targeted APCs. Employing the APC-targeting principle could enhance the efficiency of adenoviral and mRNA-LNP vaccines against a variety of diseases.