PDF(Pubmed)
Abstract：
Evolution of SARS-CoV-2 alters the antigenicity of the immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining the efficacy of vaccines and antibody therapies. To overcome this challenge, we set out to develop a vaccine focusing antibody responses on the highly conserved but metastable S2 subunit, which folds as a spring-loaded fusion machinery. We describe a strategy for prefusion-stabilization and high yield recombinant production of SARS-CoV-2 S2 trimers with native structure and antigenicity. We demonstrate that our design strategy is broadly generalizable to sarbecoviruses, as exemplified with the SARS-CoV-1 (clade 1a) and PRD-0038 (clade 3) S2 subunits. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S2 trimer elicits broadly reactive sarbecovirus antibodies and neutralizing antibody titers of comparable magnitude against Wuhan-Hu-1 and the immune evasive XBB.1.5 variant. Vaccinated mice were protected from weight loss and disease upon challenge with XBB.1.5, providing proof-of-principle for fusion machinery sarbecovirus vaccines.
摘要：
SARS-CoV-2的进化改变了免疫显性刺突（S）受体结合域和N末端域的抗原性，破坏疫苗和抗体疗法的功效。为了克服这一挑战，我们着手开发一种疫苗，将抗体反应集中在高度保守但亚稳态的S2亚基上，它折叠成弹簧加载的融合机械。我们描述了一种具有天然结构和抗原性的SARS-CoV-2S2三聚体的预融合稳定和高产率重组生产策略。我们证明了我们的设计策略可以广泛推广到肉瘤病毒，以SARS-CoV-1（进化枝1a）和PRD-0038（进化枝3）S2亚基为例。用融合前稳定的SARS-CoV-2S2三聚体对小鼠进行免疫接种，可引起广泛反应性的sb病毒抗体和中和抗体滴度，其与武汉-Hu-1和免疫规避性XBB.1.5变体相当。接种疫苗的小鼠在用XBB.1.5攻击后免受体重减轻和疾病的影响，为融合机器的肉瘤病毒疫苗提供了原理证明。
