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 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.
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All data supporting the conclusions of this study are present in the main text and supplementary materials. Additional information is available from the corresponding authors upon request.
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Acknowledgements
We gratefully acknowledge the histology and staining services provided by the Louise Pelletier HCF at the University of Ottawa. We gratefully acknowledge the technical contribution of Simon Lord-Dufour, Brian Cass, and Louis Bisson at the NRC-HHT for recombinant spike production. We also would like to acknowledge the assistance provided by the Animal Care Facility staff at Health Canada and the National Research Council of Canada. We thank Dr. Lu Huixin and Dr. Roger Tam for commenting on the manuscript and Greg Beaudoin for preparing the photomicrographs. Schematic representations were created in BioRender. This work is supported by the Government of Canada (intramural funding from Health Canada).
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Conceptualization, L.T., A.T., M.J.W.J., X.L.; Methodology, L.T., C.L., W.Z., G.F., M.S., A.T.; Formal Analysis and Visualization, L.T., A.S.; Investigation, L.T., C.L., W.Z., D.D., J.B., G.F., A.P., S.N.R. J.W., C.G., A.S., W.C.; Resources, C.L., S.N.R., C.G., M.S., Y.D., A.T.; Writing—Original Draft, L.T.; Writing—Review & Editing, L.T., C.L., W.Z., D.D., J.B., G.F., A.P., S.N.R. J.W., C.G., A.S., M.S., Y.D., W.C., L.W., S.S., A.T., M.J.W.J., X.L.; Supervision, Y.D., L.W., S.S., A.T., M.J.W.J., X.L.; Project Administration L.T., A.T., M.J.W.J., X.L.; Funding Acquisition, Y.D., L.W., S.S., A.T., M.J.W.J., X.L.
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Tamming, L., Lansdell, C., Zhang, W. et al. Durability of DNA-LNP and mRNA-LNP vaccine-induced immunity against sars-cov-2 xbb.1.5. npj Vaccines (2026). https://doi.org/10.1038/s41541-026-01382-3
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DOI: https://doi.org/10.1038/s41541-026-01382-3
