An antibody class with a common CDRH3 motif broadly neutralizes sarbecoviruses

Guo

et al. 2022

Nature

Self Cite

659

481

SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 have surged notably to become dominant in the United States and South Africa, respectively1,2. These new subvariants carrying further mutations in their spike proteins raise concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. However, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called class 2 and 3 regions of the receptor-binding domain3. The F486V mutation found in BA.4/5 facilitates escape from certain class 1 and 2 antibodies but compromises the spike affinity for the viral receptor. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.

Section: Neutralization By Monoclonal Antibodiesmentioning

confidence: 99%

Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5

Guo

et al. 2022

Nature

Self Cite

659

481

“…To understand antigenic differences of BA.2.12.1 and BA.4/5 from previous Omicron subvariants (BA.1, BA.1.1, and BA.2) and the wild-type SARS-CoV-2 (D614G), we produced each pseudovirus and then assessed the sensitivity of each pseudovirus to neutralization by a panel of 21 monoclonal antibodies (mAbs) directed to known neutralizing epitopes on the viral spike. Among these, 19 target the four epitope classes in RBD 4 , including REGN10987 (imdevimab) 5 , REGN10933 (casirivimab) 5 , COV2-2196 (tixagevimab) 6 , COV2-2130 (cilgavimab) 6 , LY-CoV555 (bamlanivimab) 7 , CB6 (etesevimab) 8 , Brii-196 (amubarvimab) 9 , Brii-198 (romlusevimab) 9 , S309 (sotrovimab) 10 , LY-CoV1404 (bebtelovimab) 11 , ADG-2 12 , DH1047 13 , S2X259 14 , CAB-A17 15 and ZCB11 16 , as well as 1-20, 2-15, 2-7 17 and 10-40 18 from our group. Two other mAbs, 4-18 and 5-7 17 , target the N-terminal domain (NTD).…”

Section: Neutralization By Monoclonal Antibodiesmentioning

confidence: 99%

Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4, and BA.5

Guo

et al. 2022

Preprint

Self Cite

123

172

The Omicron subvariant BA.2 accounts for a large majority of the SARS-CoV-2 infection worldwide today1. However, its recent descendants BA.2.12.1 and BA.4/5 have surged dramatically to become dominant in the United States and South Africa, respectively2,3. That these novel Omicron subvariants carry additional mutations in their spike proteins raises concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of our COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. On the other hand, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called Class 2 and Class 3 regions of the receptor-binding domain (RBD)4. The F486V mutation found in BA.4/5 facilitates escape from certain Class 1 and Class 2 antibodies to the RBD but compromises the spike affinity for the cellular receptor ACE2. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab (LY-COV1404) retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.

“…We next assessed the neutralization resistance of BA.2.75 to a panel of 23 mAbs directed to known neutralizing epitopes on the viral spike. Among these, 21 target the four epitope classes in the RBD 5 , including REGN10987 (imdevimab) 6 , REGN10933 (casirivimab) 6 , COV2-2196 (tixagevimab) 7 , COV2-2130 (cilgavimab) 7 , LY-CoV555 (bamlanivimab) 8 , CB6 (etesevimab) 9 , Brii-196 (amubarvimab) 10 , Brii-198 (romlusevimab) 10 , S309 (sotrovimab) 11 , LY-CoV1404 (bebtelovimab) 12 , CAB-A17 13 , ZCB11 14 , Omi-3 15 , Omi-18 15 , XGv282 16 , XGv347 16 , S2E12 17 , A19-46.1 18 , 35B5 19 , and JMB2002 20 , as well as 10-40 21 from our group. The other two mAbs, C1717 22 and S3H3 23 , target NTD-SD2 and SD1, respectively.…”

Section: Main Textmentioning

confidence: 99%

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

et al. 2022

Preprint

Self Cite

The SARS-CoV-2 Omicron subvariant BA.2.75 emerged recently and appears to be spreading rapidly. It has nine mutations in its spike compared to BA.2, raising concerns it may further evade vaccine-elicited and therapeutic antibodies. Here, we found BA.2.75 to be moderately more neutralization resistant to sera from vaccinated/boosted individuals than BA.2 (1.8-fold), similar to BA.2.12.1 (1.1-fold), but more neutralization sensitive than BA.4/5 (0.6-fold). Relative to BA.2, BA.2.75 showed heightened resistance to class 1 and class 3 monoclonal antibodies to the receptor-binding domain, while gaining sensitivity to class 2 antibodies. The resistance was largely conferred by the G446S and R460K mutations. Of note, BA.2.75 was slightly resistant (3.7-fold) to bebtelovimab, the only therapeutic antibody with potent activity against all Omicron subvariants. BA.2.75 also exhibited higher receptor binding affinity than other Omicron subvariants. BA.2.75 provides yet another example of the ongoing evolution of SARS-CoV-2 as it gains transmissibility while incrementally evading antibody neutralization.