A bivalent Lassa virus mRNA vaccine protects guinea pigs from lethal infection with Lassa virus

Lassa virus (LASV), the causative agent of the life-threatening febrile disease, Lassa fever, remains a major public health concern in West Africa, where hundreds of thousands of infections occur annually. However, no licensed vaccine is currently available, highlighting the urgent need for effective preventive measures. We previously demonstrated that an mRNA-lipid nanoparticle (LNP) vaccine expressing LASV glycoprotein precursor (GPC; LASgpc-mRNA-LNP) conferred protection against lethal infection with a recombinant lymphocytic choriomeningitis virus expressing LASV GPC in mice. In this study, we extended our previous work with the aim of evaluating the efficacy of an mRNA-LNP vaccine expressing LASV nucleoprotein (NP; LASnp-mRNA-LNP) and a bivalent vaccine combining LASgpc-mRNA-LNP and LASnp-mRNA-LNP. Using a lethal CBA/N mouse model of infection with ML29, an LASV live-attenuated vaccine candidate encoding LASV GPC and NP, we found that LASgpc-mRNA-LNP and LASnp-mRNA-LNP each conferred protection in the absence of detectable neutralizing antibody responses. We identified LASV GPC- and NP-derived CD4⁺ and CD8⁺ T-cell epitope peptides in CBA/N mice and demonstrated that vaccination induced robust antigen-specific T-cell responses. Importantly, the bivalent vaccine provided complete protection against lethal challenge with doses at which monovalent vaccines failed to protect all mice, suggesting a potential dose-sparing benefit of the bivalent formulation. Furthermore, the bivalent vaccine fully protected guinea pigs against lethal challenge with authentic LASV. Together, these findings establish LASV NP, in addition to GPC, as a protective antigen in the mRNA vaccine platform and provide a rationale for developing bivalent mRNA-LNP vaccines to improve protection against Lassa fever.