High-throughput identification of prefusion-stabilizing mutations in SARS-CoV-2 spike

Timothy J. C. Tan, Zongjun Mou, Ruipeng Lei, Wenhao O. Ouyang, Meng Yuan, Ge Song, Raiees Andrabi, Ian A. Wilson, Collin Kieffer, Xinghong Dai, Kenneth A. Matreyek and Nicholas C. Wu ()
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Timothy J. C. Tan: University of Illinois Urbana-Champaign
Zongjun Mou: Case Western Reserve University School of Medicine
Ruipeng Lei: University of Illinois Urbana-Champaign
Wenhao O. Ouyang: University of Illinois Urbana-Champaign
Meng Yuan: The Scripps Research Institute
Ge Song: The Scripps Research Institute
Raiees Andrabi: The Scripps Research Institute
Ian A. Wilson: The Scripps Research Institute
Collin Kieffer: University of Illinois Urbana-Champaign
Xinghong Dai: Case Western Reserve University School of Medicine
Kenneth A. Matreyek: Case Western Reserve University School of Medicine
Nicholas C. Wu: University of Illinois Urbana-Champaign

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Designing prefusion-stabilized SARS-CoV-2 spike is critical for the effectiveness of COVID-19 vaccines. All COVID-19 vaccines in the US encode spike with K986P/V987P mutations to stabilize its prefusion conformation. However, contemporary methods on engineering prefusion-stabilized spike immunogens involve tedious experimental work and heavily rely on structural information. Here, we establish a systematic and unbiased method of identifying mutations that concomitantly improve expression and stabilize the prefusion conformation of the SARS-CoV-2 spike. Our method integrates a fluorescence-based fusion assay, mammalian cell display technology, and deep mutational scanning. As a proof-of-concept, we apply this method to a region in the S2 domain that includes the first heptad repeat and central helix. Our results reveal that besides K986P and V987P, several mutations simultaneously improve expression and significantly lower the fusogenicity of the spike. As prefusion stabilization is a common challenge for viral immunogen design, this work will help accelerate vaccine development against different viruses.

Date: 2023
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DOI: 10.1038/s41467-023-37786-1

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