Abstract
mRNA vaccines were instrumental in limiting the extent of the COVID-19 pandemic. Despite being presented as an alternative to mRNA vaccines, DNA vaccines have not achieved similar levels of clinical success. We evaluated the immunogenicity and protective efficacy of a CD40L-adjuvanted Spike DNA vaccine based on the B.1.617.2 (Delta) variant when encapsulated in lipid nanoparticle formulations, created using DLin-KC2-DMA and SM-102 ionizable lipids. Syrian hamsters were vaccinated twice intramuscularly with unformulated or LNP-encapsulated DNA vaccines before being challenged with homologous or heterologous BA.5 (Omicron) strains of SARS-CoV-2. LNP encapsulation enhanced immune responses following one and two doses, increasing binding and neutralizing antibody titers. LNP encapsulation also enabled the neutralization of multiple omicron sub variants. LNP encapsulation also provided greater protection from challenge with both Delta and Omicron strains of SARS-CoV-2, reducing weight loss and suppressing viral replication in the upper and lower respiratory tract. This reduced viral burden coincided with the prevention of lung pathology. These results highlight the increased effectiveness of DNA vaccines afforded using similar delivery vehicles as those found in commercial mRNA vaccine formulations. Further studies are required to fully understand the safety and tolerability of this approach, as well as to directly compare the DNA formulations with mRNA vaccines.
