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

Abstract

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.

Investigating the cause of a 2021 winter wave of COVID-19 in a border region in Eastern Germany: a mixed-methods study, August to November 2021

“…In line with multiple previous reports (e.g. [23][24][25][26][27][28][29][30][31] ), functional analyses revealed that the Delta sub-lineages (AY.122 and AY.36.1) were more resistant against antibody-mediated neutralization compared to the Alpha variant (B.1.1.7), but much more sensitive in comparison with the Omicron variant (BA.1). The two Delta sub-lineages AY.122 and AY.36.1 had similar neutralization sensitivity, but AY.36.1 showed a clear replication advantage compared to AY.122.…”

“…All the Delta sub-lineages were outcompeted by the Omicron variant in the beginning of 2022 34 . As also reported by several other studies 24,25,27,31,35,36 , the robust neutralization evasion by the Omicron variant indicates that the Omicron variant is more adept than the Delta to spread in populations that are vaccinated, which explains the takeover of AY.36.1 by the Omicron variant despite the early Omicron variant BA.1 has no clear replication advantage compared to AY.36.1.…”

“…The cluster derived from the locally occurring variant AY.36.1 displayed a distinct transmission pattern: geographically much more widely spread in a short time and more elder people got infected from the very beginning. This means the consequence of the spreading of this variant could be: many elder people got infected in a short time, which may impose big pressure on the healthcare system, and this was what actually happened in Saxony in late 2021.In line with multiple previous reports (e.g [23][24][25][26][27][28][29][30][31]. ), functional analyses revealed that the Delta sub-lineages (AY.122 and AY.36.1) were more resistant against antibody-mediated neutralization compared to the Alpha variant (B.1.1.7), but much more sensitive in comparison with the Omicron variant (BA.1).…”

Impact of vaccination on the presence and severity of symptoms of hospitalised patients with an infection by the Omicron variant (B.1.1.529) of the SARS-CoV-2 (subvariant BA.1)

“…Interestingly, if Omicron infection is less associated with severe COVID-19, it was also shown to be more contagious than Delta infection (Syed et al 2022;Cui et al 2022); this explains why many deaths were still observed during the BA-1 and BA-2 waves, the low frequency of severe form being counterbalanced by the massive number of infections. This observation undermines the statements describing Omicron as a step of SARS-CoV-2 toward a more "banal" coronavirus (Balloux et al 2022;Callaway 2021;Gudina, Ali, et Froeschl 2022), such as 229E, NL63, OC43 and HKU1, and is an argument to maintain high During the second quarter of 2022, new Omicron subvariants, BA.4 and BA.5, progressively became predominant in Europe.…”

“…Between December 2021 and April 2022, it was responsible for the most massive waves so far of SARS-CoV-2 infection in Europe, North America, China and Japan since the beginning of the pandemic (ECDC 2022). The range of Omicron VOC waves is considered to be related to increased infectivity and to immune escape from neutralising antibodies resulting from previous SARS-CoV-2 infection, vaccination, or both (Syed et al 2022;Cui et al 2022).…”