Marburg virus glycoprotein mRNA vaccine is more protective than a virus-like particle-forming mRNA vaccine

Although virus-like particle (VLP) vaccines were shown to be effective against several viruses, their advantage over vaccines that include envelope protein only is not completely clear, particularly for mRNA-encoded VLPs. We conducted a side-by-side comparison of the immunogenicity and protective efficacy of mRNA vaccines encoding the Marburg virus (MARV) full-length glycoprotein (GP) delivered alone or as a VLP. Electron microscopy confirmed VLP formation when MARV GP and matrix protein VP40 were coexpressed. We vaccinated guinea pigs with a 2-component mRNA vaccine encoding GP and VP40 (VLP) or GP alone. At the highest dose, both vaccines protected fully, although the VLP vaccine elicited a slightly lower humoral response than did the GP-only mRNA vaccine. However, at low doses, GP-only mRNA conferred 100% protection, whereas the VLP vaccine conferred only partial protection. In mice, VLP mRNA induced a moderate preference for GP-specific CD8+ T cell responses, whereas the GP-only mRNA somewhat favored CD4+ T cell responses. Guinea pig whole-blood RNA-Seq revealed that the VLP vaccine downregulated genes associated with various biological and metabolic processes, including the NF-κB signaling pathway, whereas the GP-only vaccine upregulated IFN signaling. Overall, the VLP mRNA vaccine was less immunogenic and protective, whereas the GP-only mRNA vaccine conferred robust protection with a dose of as little as 1 μg in guinea pigs.