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

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.

Wei Pang, Ying Lu, Yan-Bo Zhao, Fan Shen, Chang-Fa Fan, Qian Wang, Wen-Qiang He, Xiao-Yan He, Ze-Kai Li, Tao-Tao Chen, Cui-Xian Yang, You-Zhi Li, Si-Xuan Xiao, Zu-Jiang Zhao, Xu-Sheng Huang, Rong-Hua Luo, Liu-Meng Yang, Mi Zhang, Xing-Qi Dong, Ming-Hua Li, Xiao-Li Feng, Qing-Cui Zhou, Wang Qu, Shibo Jiang, Songying Ouyang, Yong-Tang Zheng