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[Preprint]. 2022 Jan 2:2021.12.20.21268048.

doi: 10.1101/2021.12.20.21268048.

Omicron mutations enhance infectivity and reduce antibody neutralization of SARS-CoV-2 virus-like particles

Abdullah M Syed^{1

2}, Alison Ciling^{1

2}, Mir M Khalid¹, Bharath Sreekumar¹, Pei-Yi Chen¹, G Renuka Kumar¹, Ines Silva³, Bilal Milbes³, Noah Kojima³, Victoria Hess³, Maria Shacreaw³, Lauren Lopez³, Matthew Brobeck³, Fred Turner³, Lee Spraggon³, Taha Y Taha¹, Takako Tabata¹, Irene P Chen¹, Melanie Ott^{1

4}, Jennifer A Doudna^{1

2

5

6

7

8

9}

Affiliations

¹ Gladstone Institutes, San Francisco, CA, USA.
² Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
³ Curative Inc., 430 S Cataract Ave San Dimas, CA, 91773-2902, USA.
⁴ Department of Medicine, University of California, San Francisco, CA, USA.
⁵ Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
⁶ Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA.
⁷ Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
⁸ Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
⁹ California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA.

PMID: 34981067
PMCID: PMC8722610
DOI: 10.1101/2021.12.20.21268048

Omicron mutations enhance infectivity and reduce antibody neutralization of SARS-CoV-2 virus-like particles

Abdullah M Syed et al. medRxiv. 2022.

[Preprint]. 2022 Jan 2:2021.12.20.21268048.

doi: 10.1101/2021.12.20.21268048.

Authors

Affiliations

¹ Gladstone Institutes, San Francisco, CA, USA.
² Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.
³ Curative Inc., 430 S Cataract Ave San Dimas, CA, 91773-2902, USA.
⁴ Department of Medicine, University of California, San Francisco, CA, USA.
⁵ Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
⁶ Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA.
⁷ Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
⁸ Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
⁹ California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, CA, USA.

PMID: 34981067
PMCID: PMC8722610
DOI: 10.1101/2021.12.20.21268048

Update in

Omicron mutations enhance infectivity and reduce antibody neutralization of SARS-CoV-2 virus-like particles.
Syed AM, Ciling A, Taha TY, Chen IP, Khalid MM, Sreekumar B, Chen PY, Kumar GR, Suryawanshi R, Silva I, Milbes B, Kojima N, Hess V, Shacreaw M, Lopez L, Brobeck M, Turner F, Spraggon L, Tabata T, Ott M, Doudna JA. Syed AM, et al. Proc Natl Acad Sci U S A. 2022 Aug 2;119(31):e2200592119. doi: 10.1073/pnas.2200592119. Epub 2022 Jul 19. Proc Natl Acad Sci U S A. 2022. PMID: 35858386 Free PMC article.

Abstract

The Omicron SARS-CoV-2 virus contains extensive sequence changes relative to the earlier arising B.1, B.1.1 and Delta SARS-CoV-2 variants that have unknown effects on viral infectivity and response to existing vaccines. Using SARS-CoV-2 virus-like particles (SC2-VLPs), we examined mutations in all four structural proteins and found that Omicron showed increased infectivity relative to B.1, B.1.1 and similar to Delta, a property conferred by S and N protein mutations. Thirty-eight antisera samples from individuals vaccinated with tozinameran (Pfizer/BioNTech), elasomeran (Moderna), Johnson & Johnson vaccines and convalescent sera from unvaccinated COVID-19 survivors had moderately to dramatically reduced efficacy to prevent cell transduction by VLPs containing the Omicron mutations. The Pfizer/BioNTech and Moderna vaccine antisera showed strong neutralizing activity against VLPs possessing the ancestral spike protein (B.1, B.1.1), with 3-fold reduced efficacy against Delta and 15-fold lower neutralization against Omicron VLPs. Johnson & Johnson antisera showed minimal neutralization of any of the VLPs tested. Furthermore, the monoclonal antibody therapeutics Casirivimab and Imdevimab had robust neutralization activity against B.1, B.1.1 or Delta VLPs but no detectable neutralization of Omicron VLPs. Our results suggest that Omicron is at least as efficient at assembly and cell entry as Delta, and the antibody response triggered by existing vaccines or previous infection, at least prior to boost, will have limited ability to neutralize Omicron. In addition, some currently available monoclonal antibodies will not be useful in treating Omicron-infected patients.

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Conflict of interest statement

Competing interests: AMS and JAD are inventors on a patent application filed by the Gladstone Institutes and the University of California that covers the method and composition of SARS-CoV-2 VLP preparations for RNA transduction and expression in cells.

Figures

**Fig. 1.. Omicron structural gene variants alter infectivity of SC2-VLPs.**
(A) Sequence differences in genes encoding the structural proteins S, E, M and N between B.1, B.1.1, Delta and Omicron viral variants (vertical lines); Omicron-Class1 and Omicron-Class 3 mutations were created for this study. (B) Workflow for generating SC2-VLPs and testing their ability to transduce ACE2- and TMPRSS2-expressing HEK293T cells; SC2-VLPs assembled in packaging cells transformed with plasmids encoding S, E, M and N genes as well as a luciferase mRNA fused to the SARS-CoV-2 packaging signal are tested for receptor-mediated cell transduction using a luciferase detection assay. (**C-F**) Luminescence measured as a function of VLPs generated with the component protein shown, in a background of B.1 genes (see text for details).

**Fig. 2.. Antiserum neutralization of VLPs generated with different S genes.**
(A-D) 50% neutralization titers of sera isolated from individuals vaccinated using Pfizer/BioNTech, Moderna, Johnson and Johnson vaccines or from convalescent COVID-19 patients. Neutralization curves were determined using VLPs with either S-B.1, S-Delta, S-Omicron, S-OmC1 or S-OmC3. (E-H) Neutralization titers of sera collected before and after third dose vaccination from individuals receiving the Pfizer/BioNTech vaccine. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 evaluated using Friedman’s exact test for repeated measures.

**Fig. 3.. Antibody neutralization of VLPs generated with different S genes.**
Neutralization curves and IC50 values of Casirivimab and Imdevimab against the S-variants: S-B.1, S-Delta, S-Omicron, S-OmC1 or S-OmC3. Inset shows IC50 values for each monoclonal antibody.

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References

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This is a preprint.

Omicron mutations enhance infectivity and reduce antibody neutralization of SARS-CoV-2 virus-like particles

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Omicron mutations enhance infectivity and reduce antibody neutralization of SARS-CoV-2 virus-like particles

Authors

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Update in

Abstract

Conflict of interest statement

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