mRNA vaccines targeting Leptospira immunoglobulin-like proteins confer partial protection in a hamster model of leptospirosis

Abstract

Leptospirosis is a neglected tropical disease with significant global health and economic impacts, particularly in resource-limited regions. This study reports the development of the first mRNA-based vaccines for leptospirosis, targeting the C-terminal region of LigA (LigAc) and the N-terminal region of LigB (LigBn) of Leptospira interrogans serovar Pomona. Transfection of lipid nanoparticle (LNP)-encapsulated mRNA constructs into HEK293T cells confirmed antigen expression and secretion, with proteins exhibiting higher-than-expected molecular weights due to glycosylation. In Jcl:ICR mice, LigAc- and LigBn-mRNA-LNPs elicited rapid and robust antibody responses, with significantly higher IgG titers than recombinant proteins formulated with AddaVax adjuvant. Immune sera from Lig-mRNA-LNP-vaccinated mice promoted complement-mediated killing of pathogenic leptospires in vitro. Moreover, the mRNA-LNP vaccines generated antigen-stimulated IFN-γ–ELISpot responses consistent with Th1-associated cellular activation, similar to recombinant proteins. Protective efficacy was then evaluated in golden Syrian hamsters immunized either intramuscularly or intradermally. Lig-mRNA-LNPs conferred partial protection, with a maximum survival rate of 25 % in LigBn-mRNA-LNPs vaccinated hamsters. The protective rates of Lig-mRNA-LNPs were equivalent to those of recombinant Lig protein formulations. The surviving hamsters showed reduced renal leptospiral colonization and histopathological changes, comparable to those observed in the uniformly surviving killed-leptospires group. These findings establish proof-of-concept for an mRNA vaccine platform against leptospirosis and highlight its potential application pending further optimization.