Efficacy and immunological correlates of an mRNA-LNP vaccine for protection against an emerging rickettsial pathogen

A rickettsial pathogen <i>Ehrlichia chaffeensis</i> causes emerging tick-borne disease called human monocytic ehrlichiosis (HME)<i>. E. chaffeensis</i> in ticks expresses a porin OMP-1B, the immunodominant major outer membrane protein, which is required for nutrient uptake across outer membrane of bacteria. We developed an OMP-1B-encoding mRNA-lipid nanoparticle (hereafter OMP-1B mRNA-LNP) vaccine. Immunization of naïve mice with OMP-1B mRNA-LNP showed significant protection against <i>E. chaffeensis</i> infection following challenge with <i>E. chaffeensis</i>-infected tick cells. Following vaccination, increased OMP-1B-specific serum IgG, IgG1, and IgG2a titers, and <i>E. chaffeensis</i> infection-neutralizing antibodies were detected. An ELISpot assay revealed significant increase in OMP-1B-specific IFN-γ-secreting cells in the blood and spleen samples from mice vaccinated with OMP-1B mRNA-LNP. Flow cytometry analysis of spleen samples showed OMP-1B antigen-specific IFN-γ-producing CD4⁺ and CD8⁺ T cells and granzyme B-producing cytotoxic CD8⁺ T cells were significantly increased in the vaccinated mice. Our results demonstrate that an mRNA vaccine targeting OMP-1B conferred protection against <i>E. chaffeensis</i> infection, with significant humoral immune responses including infection-neutralizing antibodies, balanced Th1/Th2 response, and antigen-specific T helper and cytotoxic T cell activation. These data suggest mRNA-LNP approach is a viable strategy for developing efficient anti-rickettsial vaccines.