Zhao Fangxin, Zhang Yue, Zhang Zhiling, Chen Zhengshan, Wang Xiaolin, Wang Shaoyan, Li Ruihua, Li Yaohui, Zhang Zhang, Zheng Wanru, Wang Yudong, Zhang Zhe, Wu Shipo, Yang Yilong, Zhang Jun, Zai Xiaodong, Xu Junjie, Chen Wei
School of Medicine, Zhejiang University, Hangzhou, 310058, China.
Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, 100071, China.
J Nanobiotechnology. 2025 Feb 18;23(1):119. doi: 10.1186/s12951-025-03200-9.
The continuous emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants highlights the need to update coronavirus 2019 disease (COVID-19) vaccine components. Epitope-based vaccine designs targeting conserved and immunorecessive regions of SARS-CoV-2 are critically needed. Here, we report an engineered epitope-focused immunogen design based on a novel horseshoe-shaped natural protein scaffold, named ribonuclease inhibitor 1 (RNH1), that can multiply display of conserved neutralizing epitopes from SARS-CoV-2 S2 stem helix. The designed immunogen RNH1-S1139 demonstrates high binding affinity to S2-specific neutralizing antibodies and elicits robust epitope-targeted antibody responses either through homologous or heterologous vaccination regimens. RNH1-S1139 immune serum has been proven to have similar binding ability against SARS-CoV, SARS-CoV-2 and its variants, providing broad-spectrum protection as a membrane fusion inhibitor. Further studies showed that RNH1 has the potential to serve as a versatile scaffold that displays other helical epitopes from various antigens, including respiratory syncytial virus (RSV) F glycoprotein. Our proposed immunogen engineering strategy via tailored horseshoe-shape nano-scaffold supports the continued development of epitope-focused vaccines as part of a next-generation vaccine design.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变种的不断出现凸显了更新2019冠状病毒病（COVID-19）疫苗成分的必要性。迫切需要针对SARS-CoV-2保守和免疫隐性区域的基于表位的疫苗设计。在此，我们报告了一种基于新型马蹄形天然蛋白质支架的工程化表位聚焦免疫原设计，该支架名为核糖核酸酶抑制剂1（RNH1），它可以多次展示来自SARS-CoV-2 S2茎螺旋的保守中和表位。设计的免疫原RNH1-S1139对S2特异性中和抗体表现出高结合亲和力，并通过同源或异源疫苗接种方案引发强烈的表位靶向抗体反应。RNH1-S1139免疫血清已被证明对SARS-CoV、SARS-CoV-2及其变种具有相似的结合能力，作为膜融合抑制剂提供广谱保护。进一步研究表明，RNH1有潜力作为一种通用支架，展示来自各种抗原（包括呼吸道合胞病毒（RSV）F糖蛋白）的其他螺旋表位。我们通过定制的马蹄形纳米支架提出的免疫原工程策略支持了作为下一代疫苗设计一部分的表位聚焦疫苗的持续开发。
