Impact of mutations defining SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 on Spike function and neutralization

Chiara Pastorio; Sabrina Noettger; Rayhane Nchioua; Fabian Zech; Konstantin M J Sparrer; Frank Kirchhoff

doi:10.1016/j.isci.2023.108299

Impact of mutations defining SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 on Spike function and neutralization

iScience. 2023 Oct 27;26(11):108299. doi: 10.1016/j.isci.2023.108299. eCollection 2023 Nov 17.

Authors

Chiara Pastorio¹, Sabrina Noettger¹, Rayhane Nchioua¹, Fabian Zech¹, Konstantin M J Sparrer¹, Frank Kirchhoff¹

Affiliation

¹ Institute of Molecular Virology, Ulm University Medical Centre, 89081 Ulm, Germany.

Abstract

Additional mutations in the viral Spike protein helped the BA.2.12.1 and BA.4/5 SARS-CoV-2 Omicron subvariants to outcompete the parental BA.2 subvariant. Here, we determined the functional impact of mutations that newly emerged in the BA.2.12.1 (L452Q, S704L) and BA.4/5 (Δ69-70, L452R, F486V, R493Q) Spike proteins. Our results show that mutation of L452Q/R or F486V typically increases and R493Q or S704L impair BA.2 Spike-mediated infection. In combination, changes of Δ69-70, L452R, and F486V contribute to the higher infectiousness and fusogenicity of the BA.4/5 Spike. L452R/Q and F486V in Spike are mainly responsible for reduced sensitivity to neutralizing antibodies. However, the combined mutations are required for full infectivity, reduced TMPRSS2 dependency, and immune escape of BA.4/5 Spike. Thus, it is the specific combination of mutations in BA.4/5 Spike that allows increased functionality and immune evasion, which helps to explain the temporary dominance and increased pathogenicity of these Omicron subvariants.

Keywords: Virology.