Abstract
Old World orthohantaviruses, including Hantaan virus (HTNV), cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia. Available inactivated vaccines often induce low neutralizing antibodies and short-term protection. We evaluated nucleic acid vaccines expressing a prefusion-stabilized HTNV glycoprotein in female BALB/c mice. Both DNA and mRNA-LNP versions elicited robust neutralizing antibodies by strongly activating germinal centers, which protected mice against high-dose HTNV challenge. We further tested heterologous prime-boost regimens, where mice primed with inactivated vaccine received different boosters. All boosters increased neutralizing titers, but only the prefusion-stabilized glycoprotein mRNA-LNP vaccine raised titers to the level achieved by its own full primary vaccination course. This demonstrates the immunogen’s superiority in developing next-generation vaccines and its unique ability to potently recall memory B cells induced by suboptimal inactivated vaccines. Thus, prefusion-stabilized glycoprotein-based nucleic acid vaccines are promising candidates for advanced orthohantavirus vaccine development.
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All data generated in this study are provided in the Source Data file associated with this paper. No sequencing or other omics data requiring deposition in public repositories were generated. Source data are provided with this paper. All reagents will be made available upon request after the completion of a material transfer agreement. Requests can be directed to the corresponding author. Source data are provided with this paper.
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Acknowledgments
We thank the Center for Medical Innovation of Air Force Medical University for the technical support of the flow cytometry examination. F.L.Z. discloses support for the research of this work from the National Key Research and Development Program of China (No. 2022YFC2604200) and Key Research and Development Project of Shaanxi Province (No. 2019ZDLSF02-04). Z.K.X. discloses support for the research of this work from the National Natural Science Foundation of China (No. 82072268). W.Y. discloses support for the research of this work from the Air Force Medical University (No. 2021JSTS10). L.Z. discloses support for the research of this work from the Air Force Medical University (No. 2025KXKT115). Y.W. discloses support for the research of this work from the Air Force Medical University (No. 2022ZZXM044).
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Conceptualization: W.Y., Y.M.D., and F.L.Z. Methodology: W.Y., Y.M.D., Y.W., Q.Q.Y., H.Z., C.T.Y., J.W., L.Z., L.F.C., H.W.M., and H.L. Resources: C.T.Y., J.W.P., X.M.P., D.S.J., X.J.Y., X.L.J., and Y.C.D. Investigation: W.Y., Y.M.D., Q.Q.Y., H.Z., Y.W., J.W., and C.T.Y. Visualization: W.Y., Q.Q.Y., Z.K.X., Y.F.L., and F.L.Z. Funding acquisition: WY, YW, ZKX, and FLZ. Project administration: Z.K.X. and F.L.Z. Supervision: W.Y., Z.K.X., Y.F.L., and F.L.Z. Writing – original draft: W.Y., Y.M.D., and Q.Q.Y. Writing – review & editing: W.Y., Z.K.X., Y.F.L., and F.L.Z.
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Authors W.Y., F.L.Z., Y.D., L.F.C., H.Z., L.Z., H.L., and Z.K.X. are inventors on a provisional patent application filed in China (Application No. CN202310156260.7) related to the prefusion-stabilized HTNV glycoprotein vaccine design described in this study. All other authors declare no competing interests.
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Ye, W., Dang, Y., Wang, Y. et al. Prefusion-stabilized Hantaan virus glycoprotein nucleic acid vaccine elicits potent neutralizing antibody responses via germinal center activation. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70285-7
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DOI: https://doi.org/10.1038/s41467-026-70285-7
