Cryo-EM structure of S-Trimer, a subunit vaccine candidate for COVID-19

Abstract

Less than a year after its emergence, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 22 million people worldwide with a death toll approaching 1 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 Å and 2.6 Å 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. These results validate Trimer-Tag as a platform technology in production of metastable WT S-Trimer as a candidate for COVID-19 subunit vaccine.

S-Trimer, a COVID-19 subunit vaccine candidate, induces protective immunity in nonhuman primates

“…Negative-stain EM visualization confirmed that S-Trimer particles exist predominantly in a metastable, trimeric pre-fusion form resembling the full-length wild-type spike protein (fig. S3), which was further confirmed by cryo-EM structural studies in the accompanying paper ( 22 ).…”

Viral targets for vaccines against COVID-19

“…The third vaccine candidate, from Russia, combines recombinant human Ad26 and Ad5 in a prime-boost vaccination regimen 80 . The preclinical data showed that the recombinant ChAdOx1 vaccine induced nAb production and balanced T H 1 and and increases the antigen yield 82 . The recombinant trimeric protein structurally mimics the native S protein presented on virus particles and could serve as a target for nAbs, a strategy that is also being pursued in the development of an HIV vaccine 83 .…”

“…Recently, a native-like trimeric S protein was reported for a COVID-19 subunit vaccine candidate being developed in China, in which the S protein is fused to a trimer-tag, the C-terminal region of human type Iα collagen, to form a disulfide-bonded homotrimer 82 . This strategy stabilizes the S protein antigen in its trimeric form protein, which binds viral RNA inside the virion.…”

Getting to the bottom of lncRNA mechanism: structure–function relationships

“…More recently, cryo-EM has taken center stage in protein structural biology. For example, cryo-EM structures of the COVID-19 spike protein in various states were used to optimize stable spike constructs for mRNA-based vaccines (Ma et al 2021 ). In the case of nucleic acids, the DNA double helix structure immediately led to an understanding of the role of DNA in the cell as the carry of reproducible information (Watson and Crick 1953 ).…”