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A variant-proof SARS-CoV-2 vaccine targeting HR1 domain in S2 subunit of spike protein

Wei Pang1,2,† , Ying Lu1,2,† , Yan-Bo Zhao3,† , Fan Shen1,2,† , Chang-Fa Fan4 , Qian Wang5 , Wen-Qiang He1,2 , Xiao-Yan He1,2 , Ze-Kai Li3 , Tao-Tao Chen3 , Cui-Xian Yang6 , You-Zhi Li3 , Si-Xuan Xiao3 , Zu-Jiang Zhao1,2 , Xu-Sheng Huang1,2 , Rong-Hua Luo1 , Liu-Meng Yang1 , Mi Zhang6 , Xing-Qi Dong6 , Ming-Hua Li7 , Xiao-Li Feng7 , Qing-Cui Zhou7 , Wang Qu7 , Shibo Jiang5,* , Songying Ouyang3,* , Yong-Tang Zheng1,2,7,*

1Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
2University of the Chinese Academy of Sciences, Beijing, China
3The Key Laboratory of Innate Immune Biology of Fujian Province, Provincial University Key Laboratory of Cellular Stress Response and Metabolic Regulation, Biomedical Research Center of South China, Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian, China
4Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing, China
5Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai, China
6Yunnan Provincial Infectious Disease Hospital, Kunming, Yunnan, China
7Kunming National High-level Biosafety Research Center for Non-human Primates, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
These authors contributed equally: Wei Pang, Ying Lu, Yan-Bo Zhao, Fan Shen
* Correspondence: Shibo Jiang( Ouyang( Zheng(

The emerging SARS-CoV-2 variants, commonly with many mutations in S1 subunit of spike (S) protein are weakening the efficacy of the current vaccines and antibody therapeutics. This calls for the variant-proof SARS-CoV-2 vaccines targeting the more conserved regions in S protein. Here, we designed a recombinant subunit vaccine, HR121, targeting the conserved HR1 domain in S2 subunit of S protein. HR121 consisting of HR1–linker1–HR2–linker2–HR1, is conformationally and functionally analogous to the HR1 domain present in the fusion intermediate conformation of S2 subunit. Immunization with HR121 in rabbits and rhesus macaques elicited highly potent cross-neutralizing antibodies against SARS-CoV-2 and its variants, particularly Omicron sublineages. Vaccination with HR121 achieved near-full protections against prototype SARS-CoV-2 infection in hACE2 transgenic mice, Syrian golden hamsters and rhesus macaques, and effective protection against Omicron BA.2 infection in Syrian golden hamsters. This study demonstrates that HR121 is a promising candidate of variant-proof SARS-CoV-2 vaccine with a novel conserved target in the S2 subunit for application against current and future SARS-CoV-2 variants.


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