Durability of DNA-LNP and mRNA-LNP Vaccine-Induced Immunity Against SARS-CoV-2 XBB.1.5

Tamming, L.; Lansdell, C.; Zhang, W.; Duque, D.; Bavananthasivam, J.; Frahm, G.; Pfeifle, A.; Thulasi Raman, S. N.; Wu, J.; Gravel, C.; Stalker, A.; Stuible, M.; Durocher, Y.; Chen, W.; Wang, L.; Sauve, S.; Tran, A.; Johnston, M. J. W.; Li, X.

doi:10.1101/2025.10.15.682549

bioRxiv · 10.1101/2025.10.15.682549

Durability of DNA-LNP and mRNA-LNP Vaccine-Induced Immunity Against SARS-CoV-2 XBB.1.5

Tamming, L.·Lansdell, C.·Zhang, W.·Duque, D.·Bavananthasivam, J.·Frahm, G.·Pfeifle, A.·Thulasi Raman, S. N.·Wu, J.·Gravel, C.·Stalker, A.·Stuible, M.·Durocher, Y.·Chen, W.·Wang, L.·Sauve, S.·Tran, A.·Johnston, M. J. W.·Li, X.

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Abstract

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 present the first comparison of SARS-CoV-2 DNA- and mRNA-LNP vaccines in a long-term in vivo challenge model. Both nucleic acid platforms 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 DNA-LNPs completely protected from weight loss, viral replication, and lung pathology at this late timepoint, 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.

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Tamming, L., Lansdell, C., Zhang, W., Duque, D., Bavananthasivam, J., Frahm, G., Pfeifle, A., Thulasi Raman, S. N., Wu, J., Gravel, C., Stalker, A., Stuible, M., Durocher, Y., Chen, W., Wang, L., Sauve, S., Tran, A., Johnston, M. J. W., Li, X.. 2025-10-15. Durability of DNA-LNP and mRNA-LNP Vaccine-Induced Immunity Against SARS-CoV-2 XBB.1.5. https://doi.org/10.1101/2025.10.15.682549

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