A dual mRNA-LNP vaccine encoding Leishmania PEPCK and IL-12 to promote durable dermal-resident memory T cell responses.

Cutaneous leishmaniasis affects millions of people globally, causing disfiguring lesions and significant morbidity. Optimal protection depends on generating a population of dermal resident memory T cells (dTrm), rather than an antibody response. There are currently no vaccines for human leishmaniasis, and the traditional platforms used for other vaccines have been developed to induce strong antibody responses. Such platforms do not effectively induce robust dermal resident memory T cells (dTrm) and, therefore, fail to provide long-term immunity.

The inventors have developed a lipid‑nanoparticle (LNP) formulation that co‑delivers mRNA for the Leishmania antigen phosphoenolpyruvate carboxykinase (PEPCK) and mRNA for the immune‑stimulatory cytokine IL‑12. IL‑12 acts in situ to up‑regulate skin‑homing receptors and stimulate dTRM formation, while PEPCK supplies the cognate antigen, together generating potent, long‑lived local immunity against leishmaniasis.

The vaccine includes two critical mRNA components: 1) mRNA encoding a protective Leishmania antigen (PEPCK), optimized for high expression to ensure effective presentation to the immune system and activation of antigen-specific T cells and 2) IL-12 mRNA formulated in the same lipid nanoparticle serves as an adjuvant by enhancing T-cell activation, proliferation, and migration through the upregulation of skin-homing receptors such as CXCR6 and P and E selectin ligands (PESLs). This co-delivery approach results in a marked increase in dTrm cell formation in both inflamed and non-inflamed skin, thereby enabling broad tissue seeding. These findings highlight the potential of IL-12–augmented mRNA vaccines to induce tissue-resident immunity not only against leishmaniasis but also for other cutaneous and vector borne infectious diseases.

• Co-delivery of IL-12 mRNA-LNP enhances the expression of skin-homing molecules (e.g., CXCR6, PESLs), facilitating global seeding of dTrm cells
• Overcomes the limitations of traditional vaccines by driving robust T-cell immunity, rather than relying solely on antibody responses, through the use of IL-12 mRNA
• The technology could be applied to other skin-targeted infections