Spike mRNA Vaccine Encapsulated in a Lipid Nanoparticle Composed of Phospholipid 1,2-Dioleoyl-sn-Glycero-3-Phosphoethanolamine Induced Potent B- and T-cell Responses Associated with Protection against COVID-19 in Hamsters

Lipid nanoparticles (LNPs) have recently emerged as one of the most advanced vehicle platforms for efficient in vivo delivery of nucleoside-modified mRNA vaccine, particularly for COVID-19. LNPs comprise four different lipids: ionizable lipids, helper or neutral lipids, cholesterol, and lipids attached to polyethylene glycol (PEG). Studies on using the mRNA-LNP platform for vaccines have largely focused on the nucleic acid cargo with less attention to the LNP vehicle. While the LNPs protect mRNA from degradation and efficiently deliver the mRNA to antigen-presenting cells the effect of lipid composition and biophysical properties on the immunogenic and protective mRNA vaccine remain to be fully elucidated. In the present study, we used SARS-CoV-2 Spike-mRNA as a prototype vaccine, to study the effect of 4 different of LNPs with various lipid compositions. We demonstrate that when the same Spike-mRNA was delivered in the LNP4 formulation based on phospholipid 1,2-dioleoyl-sn-glycero-3- Phosphoethanolamine it outperformed the immunogenicity and protective efficacy of three LNPs (LNP1, LNP2, and LNP3) that are based on different lipids. Compared to other three LNPs, the LNP4: ( i ) enhanced phenotypic and functional maturation of dendritic cells; ( ii ) induced strong T-cell responses, ( iii ) increased secretion of proinflammatory, pro-follicular T helper (Tfh) cell cytokines; ( iv ) induced higher neutralization IgG titers; and ( v ) and provided better protection against SARS-CoV-2 infection and COVID-19 in the hamster model. We discussed the potential mechanisms by which LNP which include the phospholipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine may activate protective B- and T-cell responses.