![]() ![]() We determined the cryo-electron microscopy (cryo-EM) structures of these S-trimers at overall resolutions of 3.1–3.5 Å. All the S-trimers contain Gly-Ser-Ala-Ser (GSAS) and 6P mutations along with the T4 fibritin trimerization domain for increased stability 14, 15. We expressed and purified the prefusion-stabilized trimeric ectodomains of BA.1, BA.2, BA.3, BA.2.12.1, BA.2.13 and BA.4/BA.5 spike (S-trimer). There is an urgent and immediate need to investigate the receptor binding and immune-evasion capabilities of these new Omicron variants. The Omicron variants that have emerged more recently contain similar RBD sequences to BA.2, with the addition of L452 and F486 substitutions-L452Q in BA.2.12.1, L452M in BA.2.13 and L452R/F486V in BA.4 and BA.5-and exhibit a transmission advantage over BA.2. S371L on BA.1 is also substituted with S371F in BA.2. Compared with the RBD of BA.1, BA.2 contains three additional mutations, T376A, D405N and R408S, and lacks the BA.1 mutations G446S and G496S (Extended Data Fig. Omicron sublineage BA.2 has rapidly surged worldwide, out-competing BA.1. Owing to multiple mutations to the spike protein, including in the receptor-binding domain (RBD) and N-terminal domain, Omicron BA.1 infection can result in substantial NAb evasion 3, 10, 11, 12, 13. ![]() The recent emergence and global spread of the SARS-CoV-2 variant Omicron (B.1.1.529) have posed a critical challenge to the efficacy of COVID-19 vaccines and neutralizing antibody (NAb) therapy 6, 7, 8, 9. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants. The therapeutic neutralizing antibodies bebtelovimab 4 and cilgavimab 5 can effectively neutralize BA.2.12.1 and BA.4/BA.5, whereas the S371F, D405N and R408S mutations undermine most broadly sarbecovirus-neutralizing antibodies. Nevertheless, these neutralizing antibodies are largely evaded by BA.2 and BA.4/BA.5 owing to D405N and F486V mutations, and react weakly to pre-Omicron variants, exhibiting narrow neutralization breadths. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1. However, most of these cross-reactive neutralizing antibodies are evaded by spike mutants L452Q, L452R and F486V. The resulting elicited antibodies could neutralize both WT SARS-CoV-2 and BA.1 and are enriched on epitopes on spike that do not bind ACE2. BA.1 infection after vaccination predominantly recalls humoral immune memory directed against ancestral (hereafter referred to as wild-type (WT)) SARS-CoV-2 spike protein. To delineate the underlying antibody-evasion mechanism, we determined the escape mutation profiles 2, epitope distribution 3 and Omicron-neutralization efficiency of 1,640 neutralizing antibodies directed against the receptor-binding domain of the viral spike protein, including 614 antibodies isolated from people who had recovered from BA.1 infection. Of note, BA.2.12.1 and BA.4/BA.5 display increased evasion of neutralizing antibodies compared with BA.2 against plasma from triple-vaccinated individuals or from individuals who developed a BA.1 infection after vaccination. Here, coupled with structural comparisons of the spike proteins, we show that BA.2.12.1, BA.4 and BA.5 (BA.4 and BA.5 are hereafter referred collectively to as BA.4/BA.5) exhibit similar binding affinities to BA.2 for the angiotensin-converting enzyme 2 (ACE2) receptor. The receptor binding and immune-evasion capability of these recently emerged variants require immediate investigation. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility than the BA.2 lineage 1. Nature volume 608, pages 593–602 ( 2022) Cite this article BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection ![]()
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