Characterizations of enhanced infectivity and antibody evasion of Omicron BA.2.75

Abstract

The Omicron subvariants BA.2.75 is rapidly raising in India. BA.2.75 also shows a local growth advantage compared to BA.2.38 and BA.4/BA.51. Its immune evasion capability and receptor binding affinity is unclear and requires investigation. Here, we show that BA.2.75 is more neutralization evasive than BA.2.12.1 against the plasma from post-vaccination BA.2 infection, but less compared to BA.4/BA.5. However, as shown in a small sample of plasma from post-vaccination Delta infection, BA.2.75 seems to be more immune evasive than BA.4/BA.5 in Delta-stimulated immune background, which may explain BA. 2.75’s growth advantage over BA.4/BA.5 in India. The additional N460K, G446S, D339H and R493Q mutations carried by BA.2.75 allows it to escape BA.2-effective neutralizing antibodies of different RBD epitopes, and BA.2.75 has a distinct antibody escaping profile from BA.4/BA.5. Compared to BA.2, REGN10933 and COV2-2196 partially recovered neutralization against BA.2.75 due to R493Q reversion. However, the efficacy of their corresponding cocktail was not significantly changed, since REGN10987 and COV2-2130 showed reduced neutralizing activity due to G446S. BA.2.75 exhibits higher ACE2-binding affinity than BA.4/BA.5, which should be contributed by R493Q and N460K, according to deep mutational scanning (DMS) results2. This affinity-strengthening feature is being further examined and verified, which will be updated soon.

Evasion of Neutralizing Antibody Response by the SARS-CoV-2 BA.2.75 Variant

“…Limitations of this study include a relatively small sample size for the boosted health care workers and the utilization of pseudotyped lentivirus for the neutralization assay rather than an authentic virus assay. However, our results for neutralization resistance are in accordance with several recent preprints (Cao et al, 2022; Gruell et al, 2022; Saito et al, 2022; Sheward et al, 2022; Wang et al, 2022b; Xie et al, 2022; Yamasoba et al, 2022a). Additionally, the lentiviral psedotype neutralization assay has been previously validated by assays with authentic SARS-CoV-2 (Zeng et al, 2020), and confirmed by numerous laboratories in the field.…”

“…We further demonstrate that BA.2.75 exhibits enhanced S-mediated cell-cell fusion compared to BA.2, albeit to a lesser extent than BA.4/5. This enhanced triggering of BA.2.75 Smediated fusion may reflect improved receptor utilization that is not present in earlier Omicron subvariants, consistent with several recent preprints (Cao et al, 2022;Saito et al, 2022;Wang et al, 2022a). Critically, we find that the N460K mutation present in BA.2.75 is essential for the enhanced fusion phenotype.…”

Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses

“…Compared with S309, LY-CoV1404 was able to neutralize all SARS-CoV-2 VOC without much change in neutralization potency, especially against the Omicron variants 48 . Among the antibodies approved for clinical trials, LY-CoV1404 was the only antibody that retained its neutralization potency against Omicron sublineages 35 , 36 , 48 , 57 , 61 , 62 . Taken together, these findings suggest LY-CoV1404 is a specific and effective mAb for the treatment of COVID-19.…”

Neutralisation sensitivity of the SARS-CoV-2 omicron BA.2.75 sublineage

“…Although our analysis of vaccinee sera was limited to a single post-booster timepoint, our results and those of others suggest that antibody escape is an overall less pronounced characteristic of BA.2.75 compared with BA.4/5. 7 , 8 , 9 Thus, additional features favouring viral expansion beyond vaccine escape might be required for BA.2.75 to gain a growth advantage over BA.4/5.…”