German Study Warns That Current Antibody Based Therapeutics Not Effective Against Omicron. B.1.1.529 Has A Significant Zoonotic Potential!

Omicron Research: 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 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.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.12.12.472286v1
 
Although vaccination is thought to be crucial in bringing the COVID-19 outbreak to an end, inequities in vaccine distribution, as well as the emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, pose a threat to this strategy.
 
In late 2020, a number of SARS-CoV-2 variants of concern (VOC) emerged, with the Delta variant (B.1.617.2) and its various ever emerging subvariants presently dominating the pandemic. Increased transmissibility and/or immune evasion are characteristics of these VOC, which have been connected to mutations in the viral spike protein (S).
 
The B.1.1.529 or Omicron variant, a unique VOC, was recently discovered in South Africa, and its development was linked to a sharp increase in cases and hospitalizations. Infected air travelers brought the Omicron form into various European, African, and Asian countries, as well as the United States. Local transmission events were observed in the United Kingdom, with case counts doubling every two to three days as of December 2021.
 
Alarmingly, the Omicron variant's S protein has a disproportionately high number of mutations, which could promote immune evasion and/or transmissibility.
 
Indeed, according to a recent study, the Omicron variant is more effective at infecting convalescent people than previously circulating versions. As a result, the Omicr on variant is a fast-developing public health danger that could jeopardize worldwide attempts to contain the COVID-19 pandemic. https://www.samrc.ac.za/news/tshwane-district-omicron-variant-patient-profile-early-features
 
https://www.medrxiv.org/content/10.1101/2021.11.11.21266068v2
 
To date, the Omicron variant's sensitivity to antibody-mediated neutralization has yet to be determined.
 
The German study team found that the Omicron S protein evades antibodies with a 44-fold higher efficiency than the Delta variant's spike, rendering therapeutic antibodies ineffective and likely negatively impacting antibody protection induced by infection or vaccination with two doses of BNT162b2 (BNT).
 
The study team used vesicular stomatitis virus (VSV) particles pseudotyped with SARS-CoV-2 S proteins to study host cell entrance. These pseudotyped particles accurately imitate critical aspects of SARS-CoV-2 entrance into target cells, such as receptor and protease selection, as well as antibody neutralization.
 
The study team first questioned if the Omicron spike differed from other VOC spikes in terms of target cell selection and entry efficiency.
 
As the virus circulated early in the pandemic and does not include changes identified in the S proteins of VOCs, the spike from SARS-CoV-2 B.1 (which is identical to the S protein of the Wuhan-Hu-1 isolate except for the inclusion of mutation D614G) was studied in parallel.
 
The cell lines Vero (African green monkey, kidney), 293T (human, kidney), A549 (human, lung) modified to express angiotensin-converting enzyme 2 (ACE2), Huh-7 (human, liver), Caco-2 (human, colon), and Calu-3 (human, lung) cells were used to study cell tropism. VSV-G and SARS-CoV-2 B.1 spikes were particularly sensitive to penetration in all cell lines. In addition, all VOC S proteins facilitated robust entrance into the cell lines studied, but there were minor discrepancies.
 
From the study findings it was the Delta spike enabled enhanced access into Calu-3 and Caco-2 cells, whereas the Omicron spike facilitated increased entry into Vero, Huh-7, and particularly 293T cells.
 
Furthermore, B.1 and Omicron spike facilitated similar entry into A549-ACE2 cells, whereas the other S protein-mediated less efficient entry.
 
Also, it was found that the Omicron spike linked to human ACE2 efficiently and used ACE2 to enter the host cell, demonstrating that the receptor-binding domain (RBD) mutations do not impact ACE2 interactions.
 
The subsequent question was whether the Omicron spike can enter target cells using human ACE2 and ACE2 orthologues from diverse animal species, such as horseshoe bats, masked palm civets, raccoon dogs, and pangolin.
 
The B.1 and Delta spikes, as well as VSV-G, were used as controls for entry. The expression of the ACE2 orthologues had no effect on VSV-G-driven entry, but it did allow robust and somewhat equivalent entrance from the B.1, Delta, and Omicron spikes in most cases.
 
Interestingly there were two exceptions ie the Delta spike exploited murine ACE2 more efficiently than the B.1 spike, and it facilitated entrance triggered by the Omicron spike with the maximum efficiency.
 
Also, the B.1 spike was unable to exploit ACE2 from Pearson's horseshoe bat for entry, whereas Delta and, in particular, the Omicron spike, were successful.
 
Significantly the study findings show that the Omicron spike uses ACE2 orthologues extensively for host cell penetration, implying a significant zoonotic potential.
 
The usage of pseudotyped virus and the lack of investigation of T cell responses are two of the study's limitations.
 
Considering the critical role that antibodies play in immune protection against SARS-CoV-2, the study findings imply that preventive and therapeutic strategies for the Omicron variant should be revised. While these adaptations are underway, heterologous or booster vaccines, as well as traditional control measures such as face masks and social distancing, will serve to reduce the Omicron variant's impact on public health.
 
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