The Omicron variant is highly resistant against antibody-mediated neutralization – implications for control of the COVID-19 pandemic

Abstract

SUMMARYThe rapid spread of the SARS-CoV-2 Omicron variant suggests that the virus might become globally dominant. Further, the high number of mutations in the viral spike-protein raised concerns that the virus might evade antibodies induced by infection or vaccination. Here, we report that the Omicron spike was resistant against most therapeutic antibodies but remained susceptible to inhibition by Sotrovimab. Similarly, the Omicron spike evaded neutralization by antibodies from convalescent or BNT162b2-vaccinated individuals with 10- to 44-fold higher efficiency than the spike of the Delta variant. Neutralization of the Omicron spike by antibodies induced upon heterologous ChAdOx1/BNT162b2-vaccination or vaccination with three doses of BNT162b2 was more efficient, but the Omicron spike still evaded neutralization more efficiently than the Delta spike. These findings indicate that most therapeutic antibodies will be ineffective against the Omicron variant and that double immunization with BNT162b2 might not adequately protect against severe disease induced by this variant.

Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift

“…The enhanced binding of the Omicron RBD to mouse ACE2 is likely explained by the Q493R substitution which is similar to the Q493K mutation isolated upon mouse-adaptation of SARS-CoV-2 19 . Our binding data correlate with our observation of Omicron S-mediated but not Wuhan-Hu-1/G614 S-mediated entry of VSV pseudoviruses into mouse ACE2-expressing cells (Fig 1d), as recently reported 25 . Collectively, these findings highlight the plasticity of the SARS-CoV-2 RBM, which in the case of the Omicron VOC acquired enhanced binding to human and mouse ACE2 orthologues, relative to other SARS-CoV-2 isolates.…”

Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement

“…Although the N501Y mutation has previously been described to enable some SARS-CoV-2 VOC to infect and replicate in mice, the Alpha and Beta variant RBDs only weakly bound mouse ACE2 ( 39, 40 ). The SARS-CoV-2 Omicron RBD, however, interacts more strongly with mouse ACE2 than the aforementioned variant RBDs when evaluated side-by-side (fig S3 A) and can utilize mouse ACE2 as an entry receptor for S-mediated entry ( 6, 11 ). We propose that the Q493R mutation plays a key role in enabling efficient mouse ACE2 binding, through formation of electrostatic interactions with the N31 side chain amide (K31 in human ACE2), as supported by in silico modeling based on our human ACE2-bound crystal structure (fig S3 B) .…”

“…The Omicron receptor-binding domain (RBD) and the N-terminal domain (NTD) contain 15 and 11 mutations, respectively, which lead to severe dampening of plasma neutralizing activity in infected or vaccinated individuals (6)(7)(8)(9)(10). Although the Omicron RBD harbors 15 residue mutations, it retains high affinity binding to human ACE2, the primary entry receptor, while gaining the capacity to recognize mouse ACE2 efficiently (6,11). As a result of this antigenic shift, all authorized or approved therapeutic monoclonal antibodies (mAbs) lost their neutralizing activity against Omicron with the exception of S309 (sotrovimab parent) and the COV2-2196/COV2-2130 cocktail (cilgavimab/tixagevimab parent), which respectively experienced 2-3-fold and 12-200-fold reduced potency using pseudovirus or authentic virus assays (6)(7)(8)(9)(10).…”

Spike selection in SARS-CoV-2 variants across different geographical regions reveals unique signature patterns and differential stability with drug interaction

“…This maybe the reason for high spread of Omicron variant as this enables the virus to infect other cells along their entry in the upper airway which expresses ACE2 alone as opposed to the conventional method of infecting the cells with both TMPRSS2 and ACE2 (TMPRSS2-rich lung cells) expression (15). In addition to the aforementioned mutations, several new mutations have been reported in the RBD and N terminal domain of the Omicron variant's spike protein which make it difficult for the antibodies to bind and neutralize them (16). Though some mutations, for example, substitution of asparagine for lysine at position 417 (K417N) led to reduction in ACE2 binding affinity, it appears that mutated residues arginine-493, serine-496, and arginine-498 in the RBD forms new salt bridges and hydrogen bonds with ACE2.…”