Omicron SARS-CoV-2 mutations stabilize spike up-RBD conformation and lead to a non-RBM-binding monoclonal antibody escape

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Aug. 24, 2022

Omicron SARS-CoV-2 is rapidly spreading worldwide. To delineate the impact of emerging mutations on spike's properties, we performed systematic structural analyses apo spike and its complexes with human ACE2 or S309 neutralizing antibody (NAb) by cryo-EM. The preferentially adopts one-RBD-up conformation both before after binding, which in sharp contrast to orchestrated conformational changes create more up-RBDs upon binding as observed prototype other four variants concern (VOCs). Furthermore, found that S371L, S373P S375F substitutions enhance stability prevent exposing triggered binding. increased restricts accessibility S304 NAb, targets a cryptic epitope closed conformation, thus facilitating immune evasion Omicron. These results expand our understanding receptor mechanism.

Language: Английский

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BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: May 2, 2022

Abstract SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility over BA.2 1 . The new variants’ receptor binding immune evasion capability require immediate investigation. Here, coupled with Spike structural comparisons, we show that BA.2.12.1 BA.4/BA.5 comparable ACE2-binding affinities to BA.2. Importantly, display stronger neutralization than against the plasma from 3-dose vaccination and, most strikingly, post-vaccination BA.1 infections. To delineate underlying antibody mechanism, determined escaping mutation profiles 2 , epitope distribution 3 efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated convalescents. Interestingly, infection mainly recalls wildtype-induced humoral memory. resulting elicited could neutralize both wildtype are enriched on non-ACE2-competing epitopes. However, these cross-reactive NAbs heavily escaped by L452Q, L452R F486V. can also induce clones BA.1-specific potently BA.1; nevertheless, largely BA.2/BA.4/BA.5 due D405N F486V, react weakly pre-Omicron variants, exhibiting poor breadths. As for therapeutic NAbs, Bebtelovimab 4 Cilgavimab 5 effectively BA.4/BA.5, while S371F, R408S mutations would undermine broad sarbecovirus NAbs. Together, our results indicate may evolve evade immunity infection, suggesting BA.1-derived vaccine boosters not achieve broad-spectrum protection variants.

Language: Английский

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Convergent evolution of SARS-CoV-2 XBB lineages on receptor-binding domain 455–456 synergistically enhances antibody evasion and ACE2 binding

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(12), P. e1011868 - e1011868

Published: Dec. 20, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) XBB lineages have achieved dominance worldwide and keep on evolving. Convergent evolution of the receptor-binding domain (RBD) L455F F456L is observed, resulting in variants with substantial growth advantages, such as EG.5, FL.1.5.1, XBB.1.5.70, HK.3. Here, we show that neutralizing antibody (NAb) evasion drives convergent F456L, while epistatic shift caused by enables subsequent convergence through ACE2 binding enhancement further immune evasion. evade RBD-targeting Class 1 public NAbs, reducing neutralization efficacy breakthrough infection (BTI) reinfection convalescent plasma. Importantly, single substitution significantly dampens receptor binding; however, combination forms an adjacent residue flipping, which leads to enhanced NAbs resistance affinity. The perturbed mode exceptional NAb evasion, revealed structural analyses. Our results indicate flexibility contributed epistasis cannot be underestimated, potential SARS-CoV-2 RBD remains high.

Language: Английский

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Repeated Omicron exposures override ancestral SARS-CoV-2 immune imprinting

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 2, 2023

Abstract The continuous emergence of highly immune evasive SARS-CoV-2 variants, like XBB.1.5 1,2 and XBB.1.16 3,4 , highlights the need to update COVID-19 vaccine compositions. However, imprinting induced by wildtype (WT)-based vaccination would compromise antibody response Omicron-based boosters 5-9 . Vaccination strategies that can counter are critically needed. In this study, we investigated degree dynamics in mouse models human cohorts, especially focusing on role repeated Omicron stimulation. Our results show mice, efficacy single Omicron-boosting is heavily limited imprinting, when using variants antigenically distinct from WT, XBB, while concerning situation could be largely mitigated a second booster. Similarly, humans, found infections also alleviate WT-vaccination-induced generate high neutralizing titers against both plasma nasal mucosa. By isolating 781 RBD-targeting mAbs infection revealed double exposure alleviates generating large proportion matured potent Omicron-specific antibodies. Importantly, epitope characterization deep mutational scanning (DMS) showed these antibodies target RBD epitopes compared WT-induced antibodies, bias towards non-neutralizing observed exposures due was restored after stimulation, together leading substantial shift. Based DMS profiles, identified evolution hotspots demonstrated combinations mutations further boost XBB.1.5’s immune-evasion capability maintaining ACE2 binding affinity. findings suggest WT component should abandoned updating antigen compositions XBB lineages, those who haven’t been exposed yet receive two updated boosters.

Language: Английский

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Evolving antibody response to SARS-CoV-2 antigenic shift from XBB to JN.1

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 22, 2024

Abstract The continuous evolution of SARS-CoV-2, particularly the emergence BA.2.86/JN.1 lineage replacing XBB lineages, necessitates re-evaluation current vaccine compositions. Here, we provide a comprehensive analysis humoral immune response to and JN.1 human exposures, emphasizing need for JN.1-lineage-based boosters. We demonstrate antigenic distinctiveness lineages in SARS-CoV-2-naive individuals but not those with prior vaccinations or infections, infection elicits superior plasma neutralization titers against its subvariants. highlight strong evasion receptor binding capability KP.3, supporting foreseeable prevalence. Extensive BCR repertoire, isolating ∼2000 RBD-specific monoclonal antibodies (mAbs) their targeting epitopes characterized by deep mutational scanning (DMS), underscores systematic superiority JN.1-elicited memory B cells (MBCs). Notably, Class 1 IGHV3-53/3-66-derived neutralizing (NAbs) contribute majorly within wildtype (WT)-reactive NAbs JN.1. However, KP.2 KP.3 evade substantial subset them, even induced JN.1, advocating booster updates optimized enrichment. JN.1-induced Omicron-specific also high potency across all Omicron lineages. Escape hotspots these have mainly been mutated RBD, resulting higher barrier escape, considering probable recovery previously escaped NAbs. Additionally, prevalence broadly reactive IGHV3-53/3-66- encoding MBCs, competing suggests inhibitory role on de novo activation naive cells, potentially explaining heavy imprinting mRNA-vaccinated individuals. These findings delineate evolving antibody shift from importance developing lineage, especially KP.3-based boosters, enhance immunity future SARS-CoV-2 variants.

Language: Английский

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Therapeutic targets and interventional strategies in COVID-19: mechanisms and clinical studies

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Aug. 26, 2021

Abstract Owing to the limitations of present efforts on drug discovery against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and lack understanding biological regulation mechanisms underlying COVID-19, alternative or novel therapeutic targets for COVID-19 treatment are still urgently required. SARS-CoV-2 infection immunity dysfunction two main courses driving pathogenesis COVID-19. Both virus host factors potential antiviral therapy. Hence, in this study, current strategies have been classified into “target virus” host” categories. Repurposing drugs, emerging approaches, promising implementations above strategies. First, a comprehensive review highly acclaimed old drugs was performed according evidence-based medicine provide recommendations clinicians. Additionally, their unavailability fight analyzed. Next, profound analysis approaches conducted, particularly all licensed vaccines monoclonal antibodies (mAbs) enrolled clinical trials primary mutant strains. Furthermore, pros cons were compared from different perspectives. Finally, most reviewed, update progress treatments has summarized based these reviews.

Language: Английский

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Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies

Nature, Journal Year: 2021, Volume and Issue: unknown

Published: Dec. 23, 2021

The SARS-CoV-2 B.1.1.529 (Omicron) variant contains 15 mutations of the receptor-binding domain (RBD). How Omicron evades RBD-targeted neutralizing antibodies requires immediate investigation. Here we use high-throughput yeast display screening1,2 to determine profiles RBD escaping for 247 human anti-RBD and show that can be classified by unsupervised clustering into six epitope groups (A–F)—a grouping is highly concordant with knowledge-based structural classifications3–5. Various single impair different groups. Specifically, in A–D, epitopes which overlap ACE2-binding motif, are largely escaped K417N, G446S, E484A Q493R. Antibodies group E (for example, S309)6 F CR3022)7, often exhibit broad sarbecovirus activity, less affected Omicron, but a subset still G339D, N440K S371L. Furthermore, pseudovirus neutralization showed sustained could also escaped, owing multiple synergetic on their epitopes. In total, over 85% tested were Omicron. With regard neutralizing-antibody-based drugs, potency LY-CoV016, LY-CoV555, REGN10933, REGN10987, AZD1061, AZD8895 BRII-196 was greatly undermined whereas VIR-7831 DXP-604 functioned at reduced efficacy. Together, our data suggest infection would result considerable humoral immune evasion, targeting conserved region will remain most effective. Our results inform development antibody-based drugs vaccines against future variants. A platform used analyse (RBD) enable escape from antibodies, suggests variant.

Language: Английский

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Humoral immunogenicity and reactogenicity of CoronaVac or ZF2001 booster after two doses of inactivated vaccine

Cell Research, Journal Year: 2021, Volume and Issue: 32(1), P. 107 - 109

Published: Dec. 3, 2021

Humoral immunogenicity and reactogenicity of CoronaVac or ZF2001 booster after two doses inactivated vaccine

Language: Английский

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Acceptance of a Third Dose of COVID-19 Vaccine and Associated Factors in China Based on Health Belief Model: A National Cross-Sectional Study

Vaccines, Journal Year: 2022, Volume and Issue: 10(1), P. 89 - 89

Published: Jan. 7, 2022

COVID-19 infections are returning to many countries because of the emergence variants or declining antibody levels provided by vaccines. An additional dose vaccination is recommended be a considerable supplementary intervention. We aim explore public acceptance third vaccine and related influencing factors in China. This nationwide cross-sectional study was conducted general population among 31 provinces November, 2021. collected information on basic characteristics, knowledge attitudes, vaccine-related health beliefs participants. Univariable multivariable logistic regression models were used assess associated with vaccine. A total 93.7% (95% CI: 92.9-94.6%) 3119 Chinese residents willing receive Individuals low level perceived susceptibility, benefit, cues action cues, high barriers, old age, educational level, monthly household income, score less likely have (all p < 0.05). In model, mainly previous history [Sinopharm BBIP (aOR = 6.55, 95% CI 3.30-12.98), Sinovac 5.22, CI:2.72-10.02), Convidecia 5.80, 2.04-16.48)], susceptibility 2.48, 1.48-4.31) 23.66, 9.97-56.23). Overall, China showed willingness accept vaccines, which can help manufacturers manage production distribution for huge domestic international demand. Relevant institutions could increase people's booster shots increasing initial rates, public's perception through various strategies channels. Meanwhile, it also has certain reference significance other formulate promotion strategies.

Language: Английский

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Advances in the design and development of SARS-CoV-2 vaccines

Military Medical Research, Journal Year: 2021, Volume and Issue: 8(1)

Published: Dec. 16, 2021

Abstract Since the end of 2019, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2) has spread worldwide. The RNA genome SARS-CoV-2, which is highly infectious and prone to rapid mutation, encodes both structural nonstructural proteins. Vaccination currently only effective method prevent COVID-19, proteins are critical targets for vaccine development. Currently, many vaccines in clinical trials or already on market. This review highlights ongoing advances design prophylactic therapeutic against including viral vector vaccines, DNA live-attenuated inactivated virus recombinant protein bionic nanoparticle vaccines. In addition traditional some novel based vectors, nanoscience synthetic biology also play important roles combating COVID-19. However, challenges persist trials.

Language: Английский

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