Antigenic characterization of the SARS-CoV-2 Omicron subvariant BA.2.75

Wang, Qian; Iketani, Sho; Li, Zhiteng; Guo, Yicheng; Yeh, Andre Yanchen; Liu, Mengmeng; Yu, Jian; Sheng, Zizhang; Huang, Yaoxing; Liu, Lihong

doi:10.1101/2022.07.31.502235

Cited by 28 publications

(38 citation statements)

References 33 publications

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“…9b). Regarding the five NTD mutations harbored by BA.2.75, we found W152R and K147E strikingly escaped similar NTD-targeting mAbs, while I210V and G257S did not significantly affect any tested mAbs, consistent with previous sera neutralization data 18 . R237T escaped another group of NTD-targeting mAbs, which is distinct from the K147E/W152R-sensitive group 20 .…”

Section: Mainsupporting

confidence: 90%

Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution

Cao

Jian

Wang

et al. 2022

Preprint

115

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Continuous evolution of Omicron has led to numerous subvariants that exhibits growth advantage over BA.5. Such rapid and simultaneous emergence of variants with enormous advantages is unprecedented. Despite their rapidly divergent evolutionary courses, mutations on their receptor-binding domain (RBD) converge on several hotspots, including R346, R356, K444, L452, N460K and F486. The driving force and destination of such convergent evolution and its impact on humoral immunity established by vaccination and infection remain unclear. Here we demonstrate that these convergent mutations can cause striking evasion of convalescent plasma, including those from BA.5 breakthrough infection, and existing antibody drugs, including Evusheld and Bebtelovimab. BA.2.75.2 is the most evasive strain tested, and only BQ.1.1 could compare. To clarify the origin of the convergent evolution, we determined the escape mutation profiles and neutralization activity of monoclonal antibodies (mAbs) isolated from convalescents of BA.2 and BA.5 breakthrough infection. Importantly, due to humoral immune imprinting, BA.2 and especially BA.5 breakthrough infection caused significant reductions of neutralizing antibody epitope diversity and increased proportion of non-neutralizing mAbs, which in turn concentrated humoral immune pressure and promoted the convergent RBD evolution. Additionally, the precise convergent RBD mutations and evolution trends of BA.2.75/BA.5 subvariants could be inferred by integrating the neutralization-weighted DMS profiles of mAbs from various immune histories (3051 mAbs in total). Moreover, we demonstrated that as few as five additional convergent mutations based on BA.5 or BA.2.75 could completely evade most plasma samples, including those from BA.5 breakthrough infections, while remaining sufficient hACE2-binding affinity. These results suggest herd immunity established by natural infection could hardly stop RBD evolution, and vaccine boosters using BA.5 may not provide sufficiently broad protection. Broad-spectrum SARS-CoV-2 vaccines and NAb drugs development should be in high priority and the constructed convergent mutants could serve to examine their effectiveness in advance.

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Section: Mainsupporting

confidence: 90%

Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution

Cao

Jian

Wang

et al. 2022

Preprint

115

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“…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 S-mediated 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.…”

Section: Discussionsupporting

confidence: 67%

“…Notably, the G446S mutation occurs in an epitope bound by class III neutralizing antibodies, rather than class II neutralizing antibodies that target the epitope of the R493Q mutation (Greaney et al, 2021). Structural analysis suggests that the side chain addition by G446S creates a steric clash with the CDR region of class III neutralizing antibodies, thus potentially hampering their recognition (Liu et al, 2022; Wang et al, 2022a). Hence, the exchange of these mutations may alter the susceptibility of BA.2.75 to class II and class III nAbs.…”

Section: Discussionmentioning

confidence: 99%

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

Evans

Zheng

et al. 2022

Preprint

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The newly emerged BA.2.75 SARS-CoV-2 variant exhibits an alarming 9 additional mutations in its spike (S) protein compared to the ancestral BA.2 variant. Here we examine the neutralizing antibody escape of BA.2.75 in mRNA-vaccinated and BA.1-infected individuals, as well as the molecular basis underlying functional changes in the S protein. Notably, BA.2.75 exhibits enhanced neutralization resistance over BA.2, but less than the BA.4/5 variant. The G446S and N460K mutations of BA.2.75 are primarily responsible for its enhanced resistance to neutralizing antibodies. The R493Q mutation, a reversion to the prototype sequence, reduces BA.2.75 neutralization resistance. The mutational impact is consistent with their locations in common neutralizing antibody epitopes. Further, the BA.2.75 variant shows enhanced cell-cell fusion over BA.2, driven largely by the N460K mutation, which enhances S processing. Structural modeling revealed a new receptor contact introduced by N460K, supporting a mechanism of potentiated receptor utilization and syncytia formation.

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“…Besides mutations on RBD, BA.2.75 also harbors multiple NTD mutations that may cause anti-NTD NAb evasion 28 . We tested in total 25 NTD-directing NAbs of their neutralizing capability against SARS-CoV-2 VOCs, including BA.2.75 and BA.2.76 (Table S3 and S6A).…”

Section: Ba275 Evades Ba5 Effective Anti-ntd Nabsmentioning

confidence: 99%

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

Cao

Song

et al. 2022

Preprint

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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.

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Antigenic characterization of the SARS-CoV-2 Omicron subvariant BA.2.75

Cited by 28 publications

References 33 publications

Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution

Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution

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

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

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