In a recent study published in bioRxiv* Prepress server, researchers from ETH Zurich, Imperial College London and Karolinska Institutet, identified an increased resistance to antibody-mediated neutralization by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sub-BA.2.75.2.
Stady: Omicron strain BA.2.75.2 displays extensive efflux from neutralizing antibodies. Image Credit: Kateryna Kon / Shutterstock
The emerging SARS SARS-CoV-2 omicron subunit harbors mutations in genes coding for several Spike Protein residues, leading to increased immune evasion. Omicron BA.4.6 is currently a circulating strain and carries the R346T and N658S mutations, while the emerging sub-strain BA.2.10.4 harbors mutations at position 486.
Several recent studies demonstrated increased evasion of antibody neutralization by different Omicron variants, including BA.5 and BA.1 strains. Specifically, mutations leading to an increase in residue 346 have been linked to improved immune evasion.
Given the rapidly emerging variants that carry mutations that aid antibody escape, it is important to test consistently effectiveness Monoclonal antibodies are currently used against these variants to prevent recurrence of severe coronavirus disease 2019 (COVID-19) symptoms.
The current study investigated the equivalence sensitivity of three substrains of Omicron BA.4.6, BA.2.10.4 and BA.2.75.2, against a combination of clinically and preclinically used monoclonal antibodies and recently donated blood serum. The authors used multi-site directed mutagenesis of the BA.4, BA.2 and BA.2.75 expression plasmids to produce pseudovirions of the BA.4.6, BA.2.10.4 and BA.2.75.2 sublines.
Human embryonic kidney 293 cells (HEK293T) expressing human angiotensin converting enzyme 2 (ACE2) were used to test the sensitivity of the equation. In addition, pseudoviral neutralization assays were performed using a combination of monoclonal antibodies, including bebtelovimab, cilgavimab, and tixagevimab. Neutralizing efficacy of serum antibodies was performed using heat inactivated sera. Furthermore, the geometric equivalent titers (GMT) were also calculated to compare the equation sensitivity for the different subspecies.
The results indicate that the BA.4.6 and BA.2.75.2 substrains completely evaded neutralization by cilgavimab and the Evusheld vaccine, which is a combination of two monoclonal antibodies cilgavimab and tixagevimab. The BA.2.10.4 substrain showed low sensitivity against cilgavimab. However, bebtelovimab was able to neutralize all substrains. Sotrovimab showed low neutralizing efficacy against all three sub-strains tested in the study, in addition to the BA.5 sub-strain.
When tested against recently donated serum, BA.2.10.4 and BA.4.6 (311 and 356 GMT, respectively) showed increased resistance to neutralization compared to the globally dominant BA.5 substrain (453 GMT). Sub-strain BA.2.75.2 showed a value of GMT five times lower than that of sub-strain BA.5, indicating a high neutralization resistance.
BA 2.75.2 Escape neutralizing antibodies. (a) Differences from BA.2 in BA.2.75 (orange), and BA.2.75.2 (red, underlined), shown on SARS-CoV-2 BA.2 RBD (pdb: 7UB0). * Indicates bounce. Sensitivity of SARS-CoV-2 omicron substrains relative to B.1 (D614G) to neutralization by monoclonal antibody (B), sera taken randomly from donated blood in Stockholm, Sweden between (C) 8-14 November 2021 (N) = 18), (d) April 11-17, 2022 (n = 18) and (e) August 29 – September 4, 2022 (n = 16). Sera with neutralization <50% with the lowest dilution tested (20) are plotted as 20 (dotted line). ID50, 50% inhibitory dilution; IC50, 50% inhibitory concentration.
In conclusion, the study tested the neutralizing efficacy of different monoclonal antibodies in clinical use and preclinical trials against three substrains arising from the SARS-CoV-2 Omicron variant, namely BA.4.6, BA.2.10.4 and BA.2.75.2. The efficacy of the serum in neutralizing these substrains was also tested.
The two widely used monoclonal antibodies, cilgavimab and tixagevimab, which were used individually and in combination as the Evusheld vaccine, showed almost ineffectiveness against the three substrains. The monoclonal antibody that was able to neutralize all of the substrains tested was bebtelovimab. Serum antibodies also showed low neutralizing efficacy against BA.4.6 and BA.2.10.4. Subspecies BA.2.75.2 showed the highest equivalency avoidance.
Overall, the results indicate that the emerging substrains of Omicron carry mutations that improve their ability to escape humoral immunity, highlighting the need for improved monoclonal antibody and antiviral methods.
bioRxiv publishes primary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behaviour, or be treated as established information
- Omicron substrain BA.2.75.2 shows extensive escaping from neutralizing antibodies: Daniel J Sheward, Changil Kim, Julian Fischbach, Sandra Muschiol, Roy A Ehling, Niklas K Björkström, Gunilla B Karlsson Hedestam, Sai T Reddy, Jan Albert, Thomas Peacock, and Ben Morrell. bioRxiv. 2022. DOI: https://doi.org/10.1101/2022.09.16.508299And the https://www.biorxiv.org/content/10.1101/2022.09.16.508299v2