Therapeutic antibodies deemed ineffective against Omicron variant of SARS-CoV-2

By Colin Lightfoot, M.Sc. Infection and ImmunityDec 16 2021Reviewed by Aimee Molineux

Vaccination is thought to be crucial in bringing coronavirus disease 2019 (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 the last year, a number of SARS-CoV-2 variants of concern (VOC) have developed, with the Delta variant (B.1.617.2) 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 Omicron (B.1.1.529) 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.

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 Omicron variant is a fast-developing public health danger that could jeopardize worldwide attempts to contain the COVID-19 pandemic. The Omicron variant's sensitivity to antibody-mediated neutralization, on the other hand, has yet to be determined.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

In this study, a group of researchers from various German institutions 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).

A preprint version of this study, which is yet to undergo peer review, is available on the bioRxiv* server.

The study

The authors 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 authors first questioned if the Omicron spike differed from other VOC spikes in terms of target cell selection and entry efficiency.

Since this 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.

According to published research, 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. Finally, 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 next 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.

There were two exceptions. 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. Finally, 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. These findings show that the Omicron spike uses ACE2 orthologues extensively for host cell penetration, implying a significant zoonotic potential.

Implications

The use of pseudotyped virus and the lack of investigation of T cell responses are two of the study's limitations. Given the critical role that antibodies play in immune protection against SARS-CoV-2, these 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.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources