Stabilizing the closed SARS-CoV-2 spike trimer

Jarek Juraszek, Lucy Rutten, Sven Blokland, Pascale Bouchier, Richard Voorzaat, Tina Ritschel, Mark J. G. Bakkers, Ludovic L. R. Renault and Johannes P. M. Langedijk ()
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Jarek Juraszek: Janssen Vaccines & Prevention B.V.
Lucy Rutten: Janssen Vaccines & Prevention B.V.
Sven Blokland: Janssen Vaccines & Prevention B.V.
Pascale Bouchier: Janssen Vaccines & Prevention B.V.
Richard Voorzaat: Janssen Vaccines & Prevention B.V.
Tina Ritschel: Janssen Vaccines & Prevention B.V.
Mark J. G. Bakkers: Janssen Vaccines & Prevention B.V.
Ludovic L. R. Renault: NeCEN, Leiden University
Johannes P. M. Langedijk: Janssen Vaccines & Prevention B.V.

Nature Communications, 2021, vol. 12, issue 1, 1-8

Abstract: Abstract The trimeric spike (S) protein of SARS-CoV-2 is the primary focus of most vaccine design and development efforts. Due to intrinsic instability typical of class I fusion proteins, S tends to prematurely refold to the post-fusion conformation, compromising immunogenic properties and prefusion trimer yields. To support ongoing vaccine development efforts, we report the structure-based design of soluble S trimers with increased yields and stabilities, based on introduction of single point mutations and disulfide-bridges. We identify regions critical for stability: the heptad repeat region 1, the SD1 domain and position 614 in SD2. We combine a minimal selection of mostly interprotomeric mutations to create a stable S-closed variant with a 6.4-fold higher expression than the parental construct while no longer containing a heterologous trimerization domain. The cryo-EM structure reveals a correctly folded, predominantly closed pre-fusion conformation. Highly stable and well producing S protein and the increased understanding of S protein structure will support vaccine development and serological diagnostics.

Date: 2021
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DOI: 10.1038/s41467-020-20321-x

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