tetano
Editor, Senior Moderator
J Virol
. 2021 Mar 10;JVI.00194-21.
doi: 10.1128/JVI.00194-21. Online ahead of print.
Cryo-EM structure of S-Trimer, a subunit vaccine candidate for COVID-19
Jiahao Ma[SUP] 1 2 [/SUP], Danmei Su[SUP] 3 [/SUP], Yinyan Sun[SUP] 2 [/SUP], Xueqin Huang[SUP] 3 [/SUP], Ying Liang[SUP] 3 [/SUP], Linqiang Fang[SUP] 2 [/SUP], Yan Ma[SUP] 2 1 [/SUP], Wenhui Li[SUP] 2 1 [/SUP], Peng Liang[SUP] 4 [/SUP], Sanduo Zheng[SUP] 5 1 [/SUP]
Affiliations
Abstract
Within a year after its emergence, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people worldwide with a death toll over 2 million. Vaccination remains the best hope to ultimately put this pandemic to an end. Here, using Trimer-Tag technology, we produced both wild-type (WT) and furin site mutant (MT) S-Trimers for COVID-19 vaccine studies. Cryo-EM structures of the WT and MT S-Trimers, determined at 3.2 ? and 2.6 ? respectively, revealed that both antigens adopt a tightly closed conformation and their structures are essentially identical to that of the previously solved full-length WT S protein in detergent. The tightly closed conformation is stabilized by fatty acid and polysorbate 80 binding at the receptor binding domains (RBDs) and the N terminal domains (NTDs) respectively. Additionally, we identified an important pH switch in the WT S-Trimer that shows dramatic conformational change and accounts for its increased stability at lower pH. These results validate Trimer-Tag as a platform technology in production of metastable WT S-Trimer as a candidate for COVID-19 subunit vaccine.IMPORTANCEEffective vaccine against SARS-CoV-2 is critical to end the COVID-19 pandemic. Here, using Trimer-Tag technology, we are able to produce stable and large quantities of WT S-Trimer, a subunit vaccine candidate for COVID-19 with high safety and efficacy from animal and Phase 1 clinical trial studies. Cryo-EM structures of the S-Trimer subunit vaccine candidate show that it predominately adopts tightly closed pre-fusion state, and resembles that of the native and full-length spike in detergent, confirming its structural integrity. WT S-Trimer is currently being evaluated in global Phase 2/3 clinical trial. Combining with published structures of the S protein, we also propose a model to dissect the conformation change of the spike protein before receptor binding.
. 2021 Mar 10;JVI.00194-21.
doi: 10.1128/JVI.00194-21. Online ahead of print.
Cryo-EM structure of S-Trimer, a subunit vaccine candidate for COVID-19
Jiahao Ma[SUP] 1 2 [/SUP], Danmei Su[SUP] 3 [/SUP], Yinyan Sun[SUP] 2 [/SUP], Xueqin Huang[SUP] 3 [/SUP], Ying Liang[SUP] 3 [/SUP], Linqiang Fang[SUP] 2 [/SUP], Yan Ma[SUP] 2 1 [/SUP], Wenhui Li[SUP] 2 1 [/SUP], Peng Liang[SUP] 4 [/SUP], Sanduo Zheng[SUP] 5 1 [/SUP]
Affiliations
- PMID: 33692215
- DOI: 10.1128/JVI.00194-21
Abstract
Within a year after its emergence, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people worldwide with a death toll over 2 million. Vaccination remains the best hope to ultimately put this pandemic to an end. Here, using Trimer-Tag technology, we produced both wild-type (WT) and furin site mutant (MT) S-Trimers for COVID-19 vaccine studies. Cryo-EM structures of the WT and MT S-Trimers, determined at 3.2 ? and 2.6 ? respectively, revealed that both antigens adopt a tightly closed conformation and their structures are essentially identical to that of the previously solved full-length WT S protein in detergent. The tightly closed conformation is stabilized by fatty acid and polysorbate 80 binding at the receptor binding domains (RBDs) and the N terminal domains (NTDs) respectively. Additionally, we identified an important pH switch in the WT S-Trimer that shows dramatic conformational change and accounts for its increased stability at lower pH. These results validate Trimer-Tag as a platform technology in production of metastable WT S-Trimer as a candidate for COVID-19 subunit vaccine.IMPORTANCEEffective vaccine against SARS-CoV-2 is critical to end the COVID-19 pandemic. Here, using Trimer-Tag technology, we are able to produce stable and large quantities of WT S-Trimer, a subunit vaccine candidate for COVID-19 with high safety and efficacy from animal and Phase 1 clinical trial studies. Cryo-EM structures of the S-Trimer subunit vaccine candidate show that it predominately adopts tightly closed pre-fusion state, and resembles that of the native and full-length spike in detergent, confirming its structural integrity. WT S-Trimer is currently being evaluated in global Phase 2/3 clinical trial. Combining with published structures of the S protein, we also propose a model to dissect the conformation change of the spike protein before receptor binding.