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GeneMedi pseudotype virus (pseudovirus) of SARS-COV-2 (2019nCOV) B.1.1.7 lineage

SARS-COV-2 (2019nCOV) B.1.1.7 lineage of Spike protein & ACE2 competition binding assay for efficacy evaluation of COVID-19 vaccines and therapeutic antibodies

GeneMedi codon-optimized spike mammalian expression vector for SARS-COV-2 (2019nCOV) B.1.1.7 lineage

Spike mutant variant of SARS-COV-2 (2019nCOV) B.1.1.7 lineage spreaded in UK

The world is in midst of the COVID-19 pandemic. Recently a novel SARS-COV-2 (2019nCOV) lineage, the B.1.1.7 lineage, with serials of site mutation, shows stronger infection ability in the UK. The SARS-COV-2 B.1.1.7 lineage carries a larger than a usual number of coronavirus genetic changes.

The Spike protein (S-protein) of SARS-CoV-2 (2019nCoV) mediates receptor (ACE2) binding and cell entry and is the dominant target of the immune system.

In SARS-COV-2 B.1.1.7 lineage, most mutations and deletions occur in the coronavirus spike protein. These include spike position 501, one of the key contact residues in the receptor-binding domain (RBD), and experimental data suggest mutation N501Y can increase ACE2 receptor affinity (Starr et al. 2020) and P681H, one of 4 residues comprising the insertion that creates a furin cleavage site between S1 and S2 in spike. The S1/S2 furin cleavage site of SARS-CoV-2 is not found in closely related coronaviruses and has been shown to promote entry into respiratory epithelial cells and transmission in animal models (Hoffmann, Kleine-Weber, and Pöhlmann 2020; Peacock et al. 2020; Zhu et al. 2020). N501Y has been associated with increased infectivity and virulence in a mouse model (Gu et al. 2020). Both N501Y and P681H have been observed independently but not to our knowledge in combination before now.

Also present is the deletion of two amino acids at sites 69-70 in spike - this mutation is one of a number of recurrent deletions observed in the N terminal domain of Spike (McCarthy et al. 2020; Kemp et al. 2020) and has been seen in multiple lineages linked to several RBD mutations. For example, it arose in the mink-associated outbreak in Denmark on the background of the Y453F RBD mutation, and in humans in association with the N439K RBD mutation, accounting for its relatively high frequency in the global genome data (~3000 sequences).

Reference:
1 Avanzato, Victoria A., M. Jeremiah Matson, Stephanie N. Seifert, Rhys Pryce, Brandi N. Williamson, Sarah L. Anzick, Kent Barbian, et al. 2020. “Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with Cancer.” Cell, November. https://doi.org/10.1016/j.cell.2020.10.049 417.

2 Choi, Bina, Manish C. Choudhary, James Regan, Jeffrey A. Sparks, Robert F. Padera, Xueting Qiu, Isaac H. Solomon, et al. 2020. “Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host.” The New England Journal of Medicine 383 (23): 2291–93.

3 Duchene, Sebastian, Leo Featherstone, Melina Haritopoulou-Sinanidou, Andrew Rambaut, Philippe Lemey, and Guy Baele. 2020. “Temporal Signal and the Phylodynamic Threshold of SARS-CoV-2.” Virus Evolution 6 (2): veaa061.

4 Young, Barnaby E. et al. 2020. “Effects of a Major Deletion in the SARS-CoV-2 Genome on the Severity of Infection and the Inflammatory Response: An Observational Cohort Study.” 2020. The Lancet 396 (10251): 603–11.

5 Gamage, Akshamal M., Kai Sen Tan, Wharton O. Y. Chan, Jing Liu, Chee Wah Tan, Yew Kwang Ong, Mark Thong, et al. 2020. “Infection of Human Nasal Epithelial Cells with SARS-CoV-2 and a 382-Nt Deletion Isolate Lacking ORF8 Reveals Similar Viral Kinetics and Host Transcriptional Profiles.” PLoS Pathogens 16 (12): e1009130.

6 Gu, Hongjing, Qi Chen, Guan Yang, Lei He, Hang Fan, Yong-Qiang Deng, Yanxiao Wang, et al. 2020. “Adaptation of SARS-CoV-2 in BALB/c Mice for Testing Vaccine Efficacy.” Science 369 (6511): 1603–7.

7 Hoffmann, Markus, Hannah Kleine-Weber, and Stefan Pöhlmann. 2020. “A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells.” Molecular Cell 78 (4): 779–84.e5.

8 Kemp, S. A., D. A. Collier, R. Datir, S. Gayed, A. Jahun, M. Hosmillo, Iatm Ferreira, et al. 2020. “Neutralising Antibodies Drive Spike Mediated SARS-CoV-2 Evasion.” Infectious Diseases (except HIV/AIDS). medRxiv. https://doi.org/10.1101/2020.12.05.20241927 204

9 McCarthy, Kevin R., Linda J. Rennick, Sham Nambulli, Lindsey R. Robinson-McCarthy, William G. Bain, Ghady Haidar, and W. Paul Duprex. 2020. “Natural Deletions in the SARS-CoV-2 Spike Glycoprotein Drive Antibody Escape.” Microbiology. bioRxiv.

10 Peacock, Thomas P., Daniel H. Goldhill, Jie Zhou, Laury Baillon, Rebecca Frise, Olivia C. Swann, Ruthiran Kugathasan, et al. 2020. “The Furin Cleavage Site of SARS-CoV-2 Spike Protein Is a Key Determinant for Transmission due to Enhanced Replication in Airway Cells.” Cold Spring Harbor Laboratory. https://doi.org/10.1101/2020.09.30.318311 107.

11 Starr, Tyler N., Allison J. Greaney, Sarah K. Hilton, Daniel Ellis, Katharine H. D. Crawford, Adam S. Dingens, Mary Jane Navarro, et al. 2020. “Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding.” Cell 182 (5): 1295–1310.e20.

12 Zhu, Yunkai, Fei Feng, Gaowei Hu, Yuyan Wang, Yin Yu, Yuanfei Zhu, Wei Xu, et al. 2020. “The S1/S2 Boundary of SARS-CoV-2 Spike Protein Modulates Cell Entry Pathways and Transmission.” Cold Spring Harbor Laboratory. https://doi.org/10.1101/2020.08.25.266775 135.




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