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

Journal Article · Tue Jul 19 00:00:00 EDT 2022 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.2200592119· OSTI ID:2470957

Syed, Abdullah M. ^[1]; Ciling, Alison ^[2]; Taha, Taha Y. ^[3]; Chen, Irene P. ^[4]; Khalid, Mir M. ^[3]; Sreekumar, Bharath ^[3]; Chen, Pei-Yi ^[5]; Kumar, G. Renuka ^[3]; Suryawanshi, Rahul ^[3]; Silva, Ines ^[6]; Milbes, Bilal ^[6]; Kojima, Noah ^[7]; Hess, Victoria ^[6]; Shacreaw, Maria ^[6]; Lopez, Lauren ^[6]; Brobeck, Matthew ^[6]; Turner, Fred ^[6]; Spraggon, Lee ^[6]; Tabata, Takako ^[3]; Ott, Melanie ^[8] ; Doudna, Jennifer A. ^[9]

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1. Gladstone Institutes, San Francisco, CA (United States); University of California, Berkeley, CA (United States)
2. Gladstone Institutes, San Francisco, CA (United States); University of California, Berkeley, CA (United States)
3. Gladstone Institutes, San Francisco, CA (United States)
4. Gladstone Institutes, San Francisco, CA (United States); University of California, San Francisco, CA (United States)
5. Gladstone Institutes, San Francisco, CA (United States); Vanderbilt Univ., Nashville, TN (United States)
6. Curative Inc., San Dimas, CA (United States)
7. Univ. of California, Los Angeles, CA (United States)
8. Gladstone Institutes, San Francisco, CA (United States); Univ. of California, San Francisco, CA (United States); Chan Zuckerberg Biohub, San Francisco, CA (United States)
9. Gladstone Institutes, San Francisco, CA (United States); Univ. of California, Berkeley, CA (United States)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant 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 (VLPs), we examined mutations in all four structural proteins and found that Omicron and Delta showed 4.6-fold higher luciferase delivery overall relative to the ancestral B.1 lineage, a property conferred mostly by enhancements in the S and N proteins, while mutations in M and E were mostly detrimental to assembly. Thirty-eight antisera samples from individuals vaccinated with Pfizer/BioNTech, Moderna, or Johnson & Johnson vaccines and convalescent sera from unvaccinated COVID-19 survivors had 15-fold lower efficacy to prevent cell transduction by VLPs containing the Omicron mutations relative to the ancestral B.1 spike protein. A third dose of Pfizer vaccine elicited substantially higher neutralization titers against Omicron, resulting in detectable neutralizing antibodies in eight out of eight subjects compared to one out of eight preboosting. Furthermore, the monoclonal antibody therapeutics casirivimab and imdevimab had robust neutralization activity against B.1 and Delta VLPs but no detectable neutralization of Omicron VLPs, while newly authorized bebtelovimab maintained robust neutralization across variants. Our results suggest that Omicron has similar assembly efficiency and cell entry compared to Delta and that its rapid spread is due mostly to reduced neutralization in sera from previously vaccinated subjects. In addition, most currently available monoclonal antibodies will not be useful in treating Omicron-infected patients with the exception of bebtelovimab.

• Research Organization: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
• Sponsoring Organization: USDOE
• Grant/Contract Number: AC02-05CH11231
• OSTI ID: 2470957
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 31 Vol. 119; ISSN 0027-8424
• Publisher: National Academy of Sciences
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
SARS-COV-2
omicron
virus-like particles