A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines.
A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines.
复制标题
一种广泛适用的 sarbecovirus 融合机器疫苗的稳定策略。
DOI：
10.1101/2023.12.12.571160
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Veesler,David
中科院分区：
文献类型：
--
作者：
Lee,Jimin;Stewart,Cameron;Schaefer,Alexandra;Leaf,ElizabethM;Park,Young-Jun;Asarnow,Daniel;Powers,JohnM;Treichel,Catherine;Corti,Davide;Baric,Ralph;King,NeilP;Veesler,David
SARS-CoV-2的进化改变了免疫显性刺突（S）受体结合结构域和N-末端结构域的抗原性，破坏了疫苗和抗体治疗的有效性。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，该亚基作为弹簧加载的融合机器折叠。我们描述了一种融合前稳定和高产量重组生产具有天然结构和抗原性的SARS-CoV-2 S2三聚体的策略。我们证明，我们的设计策略是广泛推广的sarbecoviruses，作为例证与SARS-CoV-1（进化枝1a）和PRD-0038（进化枝3）S2亚基。用融合前稳定的SARS-CoV-2 S2三聚体免疫小鼠，产生了广泛反应的Sarbecovirus抗体，中和抗体滴度与武汉-Hu-1和免疫逃避性XBB.1.5变体相当。接种疫苗的小鼠在用XBB.1.5攻击后免于体重减轻和疾病，为融合机器肉瘤病毒疫苗提供了原理证明。
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 S2subunit, which folds as a spring-loaded fusion machinery. We describe a strategy for prefusion-stabilization and high yield recombinant production of SARS-CoV-2 S2trimers 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) S2subunits. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S2trimer 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.