COVID-19: The Omicron variant is highly resistant against antibody-mediated neutralization


Researchers from the German Primate Center, Göttingen-Germany, Georg-August-University Göttingen-Germany, Friedrich-Alexander University of Erlangen-Nürnberg-Germany, Hannover Medical School-Germany and the German Center for Infection Research-Brunswick, Germany have in study found that current antibody based monoclonal or polyclonal therapeutics are not effective against Omicron Variant.

The study also found that the Omicron spike uses ACE2 orthologues extensively for host cell penetration, implying a significant zoonotic potential.
The extremely rapid spread of the SARS-CoV-2 Omicron variant suggests that the virus might become globally dominant.
The high number of mutations in the viral spike-protein raised concerns that the virus might evade antibodies induced by infection or vaccination.
The German study team reports that the Omicron spike was resistant against most therapeutic antibodies but remained susceptible to inhibition by Sotrovimab.
The Omicron spike also 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.

The study findings were published on a preprint server and are currently being peer reviewed.

Vaccination is considered key to ending the devastating COVID-19 pandemic. However, inequities in vaccine distribution and the emergence of new SARS-CoV-2 variants threaten this approach. Several SARS-CoV-2 variants of concern (VOC) have emerged in the recent year and the Delta variant (B.1.617.2) is currently dominating the pandemic (Harvey et al., 2021b; Tao et al., 2021).

These VOC exhibit increased transmissibility and/or immune evasion, traits that have been linked to mutations in the viral spike protein (S) (Harvey et al., 2021b; Tao et al., 2021).

The coronavirus S protein facilitates viral entry into host cells and constitutes the central target for antibodies that neutralize the virus. Mutations in the N-terminal domain (NTD), which contains an antigenic supersite (McCallum et al., 2021), and the receptor binding domain (RBD), which binds to the ACE2 receptor (Hoffmann et al., 2020b; Zhou et al., 2020), can confer neutralization resistance by altering epitopes of neutralizing antibodies.

In contrast, it is less well understood which mutations in spike increase transmissibility and which mechanisms are responsible, although it is well established that mutation D614G increases viral transmission and promotes ACE2 engagement (Hou et al., 2020; Korber et al., 2020; Mansbach et al., 2021; Plante et al., 2021; Zhou et al., 2021).

A novel VOC, the Omicron variant (Pango lineage B.1.1.529 and sublineages BA.1 and BA.2), was recently identified in South Africa and its emergence was associated with a steep increase in cases and hospitalizations (Abdullah, 2021). The Omicron variant was imported into several European, African and Asian countries as well as the USA via infected air travelers (Abbasi, 2021; Graham, 2021; Gu et al., 2021; Petersen et al., 2021).

In the United Kingdom, local transmission events were reported (Company, 2021) with case numbers doubling every two to three days (Torjesen, 2021). The S protein of the Omicron variant harbors an unusually high number of mutations, which might increase immune evasion and/or transmissibility.

Indeed, a recent study suggested that the Omicron variant is more adept at infecting convalescent individuals as compared to previously circulating variants (Abdullah, 2021; Pulliam et al., 2021). Thus, the Omicron variant constitutes a rapidly emerging threat to public health and might undermine global efforts to control the COVID-19 pandemic.

However, the susceptibility of the Omicron variant to antibody-mediated neutralization remains to be analyzed.

Here, we report that the Omicron S protein evades antibodies with up to 44-fold higher efficiency than the spike of the Delta variant, rendering therapeutic antibodies ineffective and likely compromising protection by antibodies induced upon infection or vaccination with two doses of BNT162b2 (BNT).


The emergence, rapid spread and international dissemination of the highly mutated Omicron variant raised concerns that this variant might soon become globally dominant and that several therapeutic or preventive interventions might be ineffective against this variant. The present study indicates that several of these concerns are justified.

The S protein of the Omicron variant evaded antibody-mediated neutralization with higher efficiency than any previously analyzed S proteins of variants of interest and VOC. It was not appreciably inhibited by two antibody cocktails used for COVID-19 therapy and inhibition by antibodies induced by two immunizations with BNT was strongly reduced as compared to the spike of the Delta variant.

Heterologous vaccinations and a BNT booster shot induced appreciable levels of neutralizing antibodies against the Omicron spike and might offer some protection against this variant. Nevertheless, our tools available to contain SARS-CoV-2 might require expansion and adaptation in order to efficiently combat the Omicron variant.

The findings that the Omicron spike facilitated efficient entry into several human cell lines and robustly bound human ACE2 suggest that the Omicron variant readily infects human cells. Nevertheless, some peculiarities of host cell entry driven by the Omicron spike relative to the B.1 spike were noted.

The Omicron spike mediated slightly but significantly augmented entry into cell lines which only allow for cathepsin L- (293T, Huh-7, A549-ACE2) but not TMPRSS2-dependent entry, due to low or absent TMPRSS2 expression (Hoffmann et al., 2020b). We previously observed a similar phenotype for the S protein of another African SARS-CoV-2 lineage, A.30 (Arora et al., 2021a), and the mutations in spike responsible for this phenotype remain to be determined.

Further, the Omicron spike used ACE2 proteins from different animal species with high efficiency for entry. The efficient usage of murine ACE2 is in keeping with the presence of mutations K417N and N501Y, which can also emerge upon SARS-CoV-2 adaptation to experimentally infected mice (Huang et al., 2021; Sun et al., 2021; Zhang et al., 2021b).

In addition, the Omicron spike harbors mutations Q493R and Q498R that are related to exchanges Q493K and Q498H, which were also detected in mouse-adapted SARS-CoV-2 (Huang et al., 2021; Sun et al., 2021; Zhang et al., 2021b).

However, some of these mutations are present in other VOC and cannot be taken as evidence that the Omicron variant may have evolved in infected mice in the wild. In addition, the Omicron spike was able to use ACE2 from the Pearson’s horseshoe bat (Rhinolophus pearsonii) with high efficiency.

Again, this finding does not indicate the Omicron variant infects these animals (which are found in Asia) in the wild but rather reflects the ability of the Omicron spike to use diverse ACE2 orthologues for entry. Collectively, our results suggest that the mutations in the Omicron spike are compatible with robust usage of diverse ACE2 orthologues for entry and might thus have broadened the ability of the Omicron variant to infect animal species.

Cocktails of the antibodies Casirivimab and Imdevimab (REGN-COV2) as well as Etesevimab and Bamlanivimab (Eli Lilly) are used for COVID-19 therapy. Entry driven by the Omicron spike was fully or largely resistant against each of these antibodies and against the antibody cocktails, most likely due to mutations K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y and Y505H, which are located within or close to the epitopes bound by these antibodies (Figure 2B).

Thus, two frequently used COVID-19 treatment options will not be available to combat the Omicron variant. In contrast, Sotrovimab, a pan-sarbecovirus neutralizing antibody (Gupta et al., 2021), remained active against the Omicron spike, in keeping with Sotrovimab recognizing an epitope not substantially altered by mutations found in the Omicron spike (Figure 2B). Finally, soluble ACE2 robustly blocked entry driven by the Omicron spike and might be an option for treatment of patients infected with the Omicron variant.

Studies conducted before the emergence of the Omicron variant indicated that convalescent COVID-19 patients are efficiently protected against reinfection and antibody responses likely play an important role in protection (Addetia et al., 2020; Hall et al., 2021; Hansen et al., 2021; Harvey et al., 2021a; Krammer, 2021; Lumley et al., 2021).

Our findings with serum/plasma samples collected in Germany during the first wave of the pandemic indicate that this high level of protection might not apply to reinfection with the Omicron variant. Thus, neutralization of the Omicron spike was 80-fold less efficient as compared to controls and several sera did not exert neutralizing activity.

Although neutralization by sera from patients infected with the Delta variant remains to be examined, it is likely that convalescent patients might not be adequately protected against symptomatic reinfection with the Omicron variant, in keeping with recent data (Pulliam et al., 2021).

Neutralizing antibody responses are also believed to be critical for protection against COVID-19 by BNT vaccination (Corbett et al., 2021; Feng et al., 2021; Gilbert et al., 2021). We found that antibodies induced upon BNT/BNT immunization neutralized the Omicron spike with 34-fold reduced efficiency as compared to B.1.

Therefore, two doses of BNT might not provide robust protection against severe disease induced by the Omicron variant and adaptation of the vaccine to the new variant seems required. In the meantime, heterologous AZ/BNT vaccination or a BNT booster (BNT/BNT/BNT) might afford some protection against the Omicron variant, since sera from individuals who had received the respective vaccinations neutralized the Omicron spike with appreciable efficiency. However, it remains to be determined whether this protection is transient or long lasting.

Our study has several limitations, including the use of pseudotyped virus and lack of analysis of T cell responses. However, given the important role that antibodies play in immune protection against SARS-CoV-2, our results suggest that preventive and therapeutic approaches have to be adapted for efficient protection against the Omicron variant. While such adaptations are in progress, heterologous or booster immunizations and conventional control measures like face masks and social distancing will help to limit the impact of the Omicron variant on public health.



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