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

<p>A rickettsial pathogen, <em>Ehrlichia chaffeensis</em>, causes an emerging tick-borne disease called human monocytic ehrlichiosis (HME)<em>. E. chaffeensis</em> in ticks expresses a porin OMP-1B, the immunodominant major outer membrane protein, which is required for nutrient uptake across the 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 <em>E. chaffeensis</em> infection following a challenge with <em>E. chaffeensis</em>-infected tick cells. Following vaccination, increased OMP-1B-specific serum IgG, IgG1, and IgG2a titres, as well as <em>E. chaffeensis</em> 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 that OMP-1B antigen-specific IFN-γ-producing CD4⁺ and CD8⁺ T cells as well as 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 <em>E. chaffeensis</em> 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 that the mRNA-LNP approach is a viable strategy for developing efficient anti-rickettsial vaccines<em>.</em></p>