Lineage-matched Oropouche virus mRNA-LNP vaccines confer complete, cross-protective immunity in mice

Oropouche virus (OROV) is a re-emerging orthobunyavirus that causes recurrent outbreaks across Central and South America. Although OROV infection is often described as a self-limited febrile illness, neurological complications and, more recently, fetal abnormalities and deaths have been reported, reflecting both the true clinical impact of OROV and improved surveillance. Despite this, no licensed vaccines or antivirals are available. Given the virus's segmented genome and extensive genetic diversity, an effective countermeasure must be both cross-protective and rapidly updateable as new lineages emerge. Here, we show that mRNA-lipid nanoparticle (mRNA-LNP) vaccines encoding OROV envelope glycoproteins from distinct viral lineages elicit strong antibody and T cell responses and provide robust protection in mouse models, including sterilizing immunity against lethal challenge with both prototype and currently circulating strains. Our data indicate that incorporating contemporary antigenic sequences can enhance cross-strain protection, supporting the use of mRNA-LNP platforms as a rapid, adaptable solution for future OROV outbreaks and related emerging pathogens.