Omicron, the great escape artist.

The sequence of the SARS-CoV-2 Omicron variant was first announced on 24 Nov 2021. Less than a month later, a number of articles in Nature and Cell report the immune evasion characteristics of the heavily mutated variant.

Compared to the ancestral Wuhan-Hu-1 strain, Omicron contains over 30 mutations in its spike protein, with 15 located in the receptor binding domain (RBD), one of the main targets of neutralizing antibodies (nAbs). Some of these confer tighter binding to human ACE2 (Cameroni et al. show a 2.4-fold increase in binding affinity and Garcia-Beltran et al. show that Omicron-spike containing pseudovirus with was twice as efficient at infecting cells as Delta), while other mutations drive immune escape. Interestingly, they also allow for binding to ACE2 from a broader range of species (Hoffmann et al., Cameroni et al.).

Overall, the studies agree that sera from convalescent as well as fully vaccinated individuals (BNT162b2, mRNA-1273, Ad26.COV2.5 or ChAdOx1-nCoV19, Sputnik V or BBIBP-CorV) contain very low to undetectable levels of nAbs against Omicron. Recent boosting with a third dose of mRNA vaccine (even though these encode ancestral spike) appears to restore neutralizing activity, potentially by increasing the breadth of humoral immunity and cross-reactivity to variants. Some of the studies also show that double vaccination followed by Delta breakthrough infection, or prior infection followed by mRNA vaccine double vaccination, appear to generate increased and potentially protective levels of neutralizing antibodies (Dejnirattisai et al., Cele et al., Carreño et al.).

Several studies also demonstrate that Omicron evades binding and neutralization by most therapeutic SARS-CoV-2 monoclonal antibodies (mAbs), with the exception of some broadly neutralizing mAbs such as sotrovimab (Cao et al., Hoffmann et al., Dejnirattisai et al., Cameroni et al., Planas et al., Liu et al.). Cao et al. show that out of a panel of 247 human RBD-targeted mAbs, 85% fail to bind Omicron.

Boosting with a third dose of mRNA vaccine … appears to restore neutralizing activity

Although viral escape from nAbs can facilitate breakthrough infections in vaccinated and convalescent individuals, it is worth noting that pre-existing cellular and innate immunity, non-neutralizing antibodies, as well as residual neutralizing antibodies are still likely to protect from severe disease.