Durability of DNA-LNP and mRNA-LNP vaccine-induced immunity against SARS-CoV-2 XBB.1.5.

mRNA-lipid nanoparticle (LNP) vaccines induce robust adaptive immune responses and have proven highly effective against SARS-CoV-2. However, their long-term effectiveness is limited by waning humoral responses, which decline substantially within the first six months post-boost vaccination. DNA-LNPs are being investigated as an alternative vaccine platform, offering prolonged antigen expression and robust immunity. Here, we compare DNA- and mRNA-LNP vaccines encoding CD40L-adjuvanted SARS-CoV-2 XBB.1.5 Spike (SXBB.1.5-CD40L) in a long-term in vivo challenge model. Both nucleic acid vaccines induced strong neutralizing antibody responses and conferred equivalent protection in Syrian hamsters challenged three weeks post-boost. Notably, DNA-LNP vaccination maintained high binding and neutralizing antibody titers six months post-boost, whereas mRNA-LNPs exhibited a marked decline. Correspondingly, while SXBB.1.5-CD40L DNA-LNP vaccination completely protected from weight loss, viral replication, and lung pathology at this late timepoint, SXBB.1.5-CD40L mRNA-LNP vaccination conferred minimal protection. These findings demonstrate that DNA-LNPs can sustain durable immunity, highlighting their potential as a next-generation vaccine platform that could reduce the need for frequent boosters.