Nucleoside-modified messenger RNA lipid nanoparticle (mRNA-LNP) vaccines have had a tremendous impact on vaccine development against infectious pathogens, particularly since the onset of the COVID-19 pandemic. The platform is an effective stimulator of humoral and cellular immune responses due to unique features of the mRNA and LNP components. We sought to optimize the performance of the mRNA-LNP platform against a specific viral target, developing a vaccine against Hepatitis C virus (HCV) that would improve HCV-like particle secretion and enhance the humoral immune response. We designed an mRNA-LNP vaccine targeting HCV and improved its efficacy by including the nonstructural HCV viroporin p7, and measured cellular and humoral immune responses in immunized mice. Both constructs induced antigen-specific functional CD4+ and CD8+ T cell responses, as well as T follicular helper cell responses associated with humoral immunity, consistent with other applications of the mRNA-LNP platform. Mice immunized with the optimized construct showed superior binding and neutralizing antibody responses compared to the non-optimized one. Notably, the optimized construct elicited stronger humoral responses against heterologous viral strains. Our findings underscore the potential of mRNA-LNP vaccines for HCV, yet translating these findings into humans requires further investigation. These results demonstrate the value of optimizing the mRNA-LNP platform through inclusion of elements with utility beyond presenting epitopes of the pathogen being targeted. This study pushes HCV vaccine development forward and extends the utility of the mRNA-LNP platform against infectious diseases.
