Engineered ACE2 counteracts vaccine-evading SARS-CoV-2 Omicron variant (preprint)

The novel SARS-CoV-2 variant, Omicron (B.1.1.529) contains an unusually high number of mutations (>30) in the spike protein, raising concerns of escape from vaccines, convalescent sera and therapeutic drugs. Here we analyze the alteration of neutralizing titer with Omicron pseudovirus. Sera of 3 months after double BNT162b2 vaccination exhibit approximately 18-fold lower neutralization titers against Omicron. Convalescent sera from Alpha and Delta patients allow similar levels of breakthrough by Omicron. However, some Delta patients have relatively preserved neutralization efficacy, comparable to 3-month double BNT162b2 vaccination. Domain-wise analysis using chimeric spike revealed that this efficient evasion was, at least in part, caused by multiple mutations in the N-terminal domain. Omicron escapes the therapeutic cocktail of imdevimab and casirivimab, whereas sotrovimab, which targets a conserved region to avoid viral mutation, remains effective against Omicron. The ACE2 decoy is another virus-neutralizing drug modality that is free, at least in theory, from mutational escape. Deep mutational analysis demonstrated that, indeed, the engineered ACE2 overcomes every single-residue mutation in the receptor-binding domain, similar to immunized sera. Like previous SARS-CoV-2 variants, Omicron and some other sarbecoviruses showed high sensitivity against engineered ACE2, confirming the therapeutic value against diverse variants, including those that are yet to emerge.

Emerging SARS-CoV-2 variants follow a historical pattern recorded in outgroups infecting non-human hosts (preprint)

The ability to predict emerging variants of SARS-CoV-2 would be of enormous value, as it would enable proactive design of vaccines in advance of such emergence. Based on molecular evolutionary analysis of the S protein, we found a significant correspondence in the location of amino acid substitutions between SARS-CoV-2 variants recently emerging and their relatives that infected bat and pangolin before the pandemic. This observation suggests that a limited number of sites in this protein are repeatedly substituted in different lineages of this group of viruses. It follows, therefore, that the sites of future emerging mutations in SARS-CoV-2 can be predicted by analyzing their relatives (outgroups) that have infected non-human hosts. We discuss a possible evolutionary mechanism behind these substitutions and provide a list of frequently substituted sites that potentially include future emerging variants in SARS-CoV-2.