Prefusion-stabilized Hantaan virus glycoprotein nucleic acid vaccine elicits potent neutralizing antibody responses via germinal center activation

Nat Commun. 2026 Mar 14;17(1):3972. doi: 10.1038/s41467-026-70285-7.

Wei Ye ^# ¹, Yamei Dang ^# ², Yuan Wang ^# ², Qiqi Yang ^# ², Hui Zhang ^# ², Chuantao Ye ^# ³, Jing Wei ^# ² ⁴, Jiawei Pei ², Xuemin Pei ² ⁵, Dongshen Jiang ² ⁶, Xiaojing Yang ² ⁶, Xiaolei Jin ⁷, Hongwei Ma ², He Liu ², Liang Zhang ², Linfeng Cheng ², Yangchao Dong ², Yingfeng Lei ⁸, Zhikai Xu ⁹, Fanglin Zhang ¹⁰

Affiliations

1 Department of Microbiology, School of Basic Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].
2 Department of Microbiology, School of Basic Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China.
3 Department of Infectious Diseases, Tangdu Hospital, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China.
4 Center for Disease Control and Prevention of Shaanxi Province, Xi'an, Shaanxi, China.
5 School of Medicine, Northwest University, Xi'an, Shaanxi, China.
6 School of Medicine, Yan'an University, Yan'an, Shaanxi, China.
7 Student Brigade, School of Basic Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China.
8 Department of Microbiology, School of Basic Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].
9 Department of Microbiology, School of Basic Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].
10 Department of Microbiology, School of Basic Medicine, Airforce Medical University: Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].
# Contributed equally.

PMID: 41832144 DOI: 10.1038/s41467-026-70285-7

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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