Evolving antibody evasion and receptor affinity of the Omicron BA.2.75 sublineage of SARS-CoV-2

Abstract

SARS-CoV-2 Omicron BA.2.75 has diversified into multiple subvariants with additional spike mutations, and several are expanding in prevalence, particularly CH.1.1 and BN.1. Here, we investigated the viral receptor affinities and neutralization evasion properties of major BA.2.75 subvariants actively circulating in different regions worldwide. We found two distinct evolutionary pathways and three newly identified mutations that shaped the virological features of these subvariants. One phenotypic group exhibited a discernible decrease in viral receptor affinities, but a noteworthy increase in resistance to antibody neutralization, as exemplified by CH.1.1, which is apparently as resistant as XBB.1.5. In contrast, a second group demonstrated a substantial increase in viral receptor affinity but only a moderate increase in antibody evasion, as exemplified by BN.1. We also observed that all prevalent SARS-CoV-2 variants in the circulation presently, except for BN.1, exhibit profound levels of antibody evasion, suggesting this is the dominant determinant of virus transmissibility today.

Antigenicity and receptor affinity of SARS-CoV-2 BA.2.86 spike

“…On the other hand, mutations V445H and L452W seem to introduce steric clashes with the CDRs of RBD class 3 mAbs LY-CoV1404 ( Figure 3E ) and A19-46.1 ( Figure 3F ), respectively. Importantly, we also found two new mutations (S50L and I332V) that conferred a degree of sensitization to neutralization by certain mAbs, along with two previously known mutations (R403K and R493Q) that were also sensitizing 8,9,31 ( Figure 3A ). The rest of the new mutations that are unique to BA.2.86 showed only minor or no effect on its antigenicity as assessed by this panel of mAbs.…”

“…Since receptor binding also occurs when the RBD is “up”, this conclusion is in line with the finding that the spike of BA.2.86 has a >2-fold higher affinity for the viral receptor compared to the spike of XBB.1.5 or EG.5.1 ( Figures 4A and 4B ). In fact, BA.2.86 spike has one of the highest receptor affinities we have measured, together with the spikes of some of the viruses in the BA.2.75 sublineage 8 but the K D is undoubtedly determined by additional properties including the electrostatic charge of the RBD ( Figures 4C ).…”

“…The F486P mutation appears to reduce the hydrophobic interaction with the ACE2-mimicking antibody S2K146 ( Figure 3C) , hence impairing its neutralization activity. The K356T mutation, also shared by the DS.1 variant, conferred broad resistance to a number of RBD class 1, class 2, and class 3 mAb, possibly due to steric hindrance caused by the introduction of an additional glycosylation site 8 . Several other RBD mutations, including V445H, N450D, L452W, and A484K compromised the neutralizing activity of some RBD class 3 mAbs.…”

“…Compared with the spike of BA.2, BA.2.86 possesses 34 additional mutations, including 13 mutations in the N-terminal domain (NTD), 14 in RBD, 2 in SD1, 3 in the subdomain 2 (SD2), and 2 in the S2 region ( Figures 1B and 1C ). Mutations H69V70 deletion (H69V70△), Y144 deletion (Y144△), G446S, N460K, F486P, and R493Q have been identified previously 5,6,8,9 , but mutations V445H, N450D, N481K, V483 deletion (V483△), and E554K have been seldom observed in circulating viruses ( Figure 1C ). This extensive array of spike mutations in BA.2.86 is alarming because of the heightened potential for the virus to evade serum antibodies elicited by prior infections and/or vaccinations or mAbs intended for clinical use.…”

Deep immunological imprinting due to the ancestral spike in the current bivalent COVID-19 vaccine

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