SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Abstract

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant.

Evolution of enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants

“…1h, i). Consistent with a previous report using a primary upper airway model 13,14 we found that Omicron isolates replicated faster than Delta by 24 hpi (Fig. 1h, i).…”

SARS-CoV-2 Omicron BA.1 and BA.2 are attenuated in rhesus macaques as compared to Delta

“…In our entry studies, we show a reduced entry of Omicron compared to Delta for both human and rhesus macaque ACE2 in a BHK cell line. A similar difference in entry has been observed in Calu-3 and A549 cell lines, but not HEK cell lines, which may be driven by the TMPRSS2-independent, cathepsin-dependent endosomal entry pathway that Omicron favors compared to Delta (16).…”

Longitudinal analysis of serum neutralization of SARS-CoV-2 Omicron BA.2, BA.4 and BA.5 in patients receiving monoclonal antibodies

“…As of July 2022, Omicron was composed of 5 main sublineages, BA.1, BA.2, BA.3, BA.4 and BA.5 1,2 , harboring numerous mutations compared to the ancestral wuhan strain 1,2 . The BA.1 strain has 34 mutations in its spike, associated with antibody escape [3][4][5][6][7][8][9][10][11][12][13][14] , CD8 T cell evasion 15 and modified tropism [16][17][18] . BA.2 harbors 30 mutations, 21 of which are not present in BA.1 2 .…”