Determinants of Spike Infectivity, Processing and Neutralization in SARS-CoV-2 Omicron Subvariants BA.1 and BA.2

Abstract

The SARS-CoV-2 Omicron variant rapidly outcompeted other variants and currently dominates the COVID-19 pandemic. Its enhanced transmission, immune evasion and pathogenicity is thought to be driven by numerous mutations in the Omicron Spike protein. Here, we examined the impact of amino acid changes that are characteristic for the BA.1 and/or BA.2 Omicron lineages on Spike function, processing and susceptibility to neutralization. Individual mutations of S371F/L, S375F and T376A in the ACE2 receptor-binding domain as well as Q954H and N969K in the hinge region 1 impaired infectivity, while changes of G339D, D614G, N764K and L981F moderately enhanced it. Most mutations in the N-terminal region and the receptor binding domain reduced sensitivity of the Spike protein to neutralization by sera from individuals vaccinated with the BNT162b2 vaccine or therapeutic antibodies. Our results represent a systematic functional analysis of Omicron Spike adaptations that allowed this SARS-CoV-2 variant to overtake the current pandemic.

Funding Information: This study was supported by DFG grants to F.K. (CRC 1279, SPP 1923), K.M.J.S. (CRC 1279, SPP 1923, SP 1600/6-1) and T.J. (CRC 1279). F.K., and K.M.J.S. were supported by the BMBF (Restrict SARS-CoV-2 and IMMUNOMOD).

Conflict of Interests: All authors declare no competing interests

Ethical Approval: Ethics approval was provided by the Ethic Committee of Ulm University (vote 99/21– FSt/Sta).

Keywords: SARS-CoV-2, Omicron, Spike protein, COVID-19, neutralization, BA.1, BA.2, variant evolution