Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

Science, Journal Year: 2022, Volume and Issue: 378(6620), P. 619 - 627

Published: Oct. 20, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity vaccine boosters elicit plasma-neutralizing against BA.1, BA.2, BA.2.12.1, and BA.4/5, breakthrough infections, but not vaccination alone, induce neutralizing the nasal mucosa. Consistent with immunological imprinting, most derived memory B cells plasma of cases cross-react Wuhan-Hu-1, BA.4/5 receptor-binding domains, whereas primary infections narrow specificity up to 6 months after infection. Although clinical have reduced neutralization Omicron, we identified an ultrapotent pan-variant–neutralizing antibody is a strong candidate for development.

Language: Английский

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Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains

PLoS Pathogens, Journal Year: 2022, Volume and Issue: 18(11), P. e1010951 - e1010951

Published: Nov. 18, 2022

SARS-CoV-2 continues to acquire mutations in the spike receptor-binding domain (RBD) that impact ACE2 receptor binding, folding stability, and antibody recognition. Deep mutational scanning prospectively characterizes impacts of on these biochemical properties, enabling rapid assessment new seen during viral surveillance. However, effects can change as virus evolves, requiring updated deep scans. We determined all single amino acid Omicron BA.1 BA.2 RBDs ACE2-binding affinity, RBD folding, escape from binding by LY-CoV1404 (bebtelovimab) monoclonal antibody. The some differ those measured ancestral Wuhan-Hu-1 background. These epistatic shifts largely resemble previously Alpha variant due convergent epistatically modifying N501Y substitution. variants show additional lineage-specific shifts, including examples phenomenon entrenchment causes Q498R substitutions present be more favorable background than earlier strains. In contrast, substitution Q493R exhibits no sign entrenchment, with derived state, R493, being unfavorable for Wuhan-Hu-1. Likely this reason, R493Q reversion has occurred sub-variants BA.4/BA.5 BA.2.75, where affinity buffer may potentiate concurrent antigenic change. Consistent prior studies, we find have reduced expression, identify candidate stabilizing ameliorate deficit. Last, our maps highlight a broadening sites compared datasets landscape inform ongoing efforts

Language: Английский

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SARS-CoV-2 Omicron BA.5: Evolving tropism and evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern

EBioMedicine, Journal Year: 2022, Volume and Issue: 84, P. 104270 - 104270

Published: Sept. 18, 2022

BackgroundGenetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. The introduction global vaccine programs has contributed to lower COVID-19 hospitalisation and mortality rates, particularly in developed countries. In late 2021, Omicron BA.1 emerged, with substantially altered genetic differences clinical effects from other concern. Shortly after dominating spread early 2022, was supplanted by the genetically lineage BA.2. A sub-lineage BA.2, designated BA.5, presently an outgrowth advantage over BA.2 sub-lineages. Here we study neutralisation BA.1, BA.5 pre-Omicron using a range convalescent sera therapeutic monoclonal antibodies live virus assay. Using primary nasopharyngeal swabs, also tested relative fitness compared lineages their ability use ACE2-TMPRSS2 pathway.MethodsUsing low passage isolates Clade A.2.2, Beta, Delta, determined humoral vitro vaccinated cohorts, concentrated human IgG pooled thousands plasma donors, licensed antibody therapies. We then infectivity particle ratios samples expanded engineered ACE2/TMPRSS2 cell line presence absence TMPRSS2 inhibitor Nafamostat.FindingsPeak responses 3 doses BNT162b2 were associated 9-fold reduction for BA.5. Concentrated donors vaccination breakthrough infections greater breadth neutralisation, although potency still reduced 7-fold across all lineages. Testing grade revealed 14.3-fold Evusheld 16.8-fold Sotrovimab Whilst attenuated entry, observed be equivalent that 2020 circulating clade had sensitivity Nafamostat.InterpretationObservations support significantly escape neutralising and/or responses. Potency is differs key difference sub-variants reversion tropism back well-known pathway, utilised efficiently Monitoring if these changes influence transmission disease severity will ongoing tracking management waves globally.FundingThis work primarily supported Australian Medical Foundation research grants MRF2005760 (ST, GM & WDR), MRF2001684 (ADK ST) Research Future Fund Antiviral Development Call grant (WDR), (MRFF2001684, ADK SGT) New South Wales Health Grants Round (SGT).

Language: Английский

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Neutralization, effector function and immune imprinting of Omicron variants

Nature, Journal Year: 2023, Volume and Issue: 621(7979), P. 592 - 601

Published: Aug. 30, 2023

Abstract Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain 1 (RBD) of spike protein. The effects these on viral infection and transmission efficacy vaccines therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 XBB.1.5 bind host ACE2 with high affinity promote membrane fusion more efficiently than earlier Omicron variants. Structures BQ.1.1, XBB.1 BN.1 RBDs bound to fragment antigen-binding region S309 antibody (the parent for sotrovimab) human explain preservation binding through conformational selection, altered recognition immune evasion. We show sotrovimab binds avidly all variants, promotes Fc-dependent effector functions protects mice challenged hamsters XBB.1.5. Vaccine-elicited plasma antibodies cross-react trigger against current despite a reduced neutralizing activity, suggesting mechanism protection disease, exemplified by S309. Cross-reactive RBD-directed memory B cells remained dominant even after two exposures spikes, underscoring role persistent imprinting.

Language: Английский

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SARS-CoV-2 Omicron boosting induces de novo B cell response in humans

Nature, Journal Year: 2023, Volume and Issue: 617(7961), P. 592 - 598

Published: April 3, 2023

Language: Английский

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Analysis of anti-SARS-CoV-2 Omicron-neutralizing antibody titers in different vaccinated and unvaccinated convalescent plasma sources

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

Published: Oct. 29, 2022

Abstract The latest SARS-CoV-2 variant of concern Omicron, with its immune escape from therapeutic anti-Spike monoclonal antibodies and WA-1 vaccine-elicited sera, demonstrates the continued relevance COVID-19 convalescent plasma (CCP) therapies. Lessons learnt previous usage CCP suggests focusing on early outpatients immunocompromised recipients, high neutralizing antibody titer units. Here, we systematically review Omicron-neutralizing activity data, report that approximately 47% (424/902) samples unvaccinated pre-Omicron donors neutralizes Omicron BA.1 a very low geometric mean titers for 50% neutralization GM(GMT 50 ) ~13, representing > 20-fold reduction neutralization. Non-convalescent subjects who had received two doses mRNA vaccines GM(GMT50) ~27. However, vaccinees recovering either variants infection, or third-dose uninfected was nearly 100% against BA.1, BA.2 BA.4/5 GM(GMT( )) all over 189, 10 times higher than CCP. Fully vaccinated post-BA.1 (Vax-CCP) 450 >1,500 BA.2. These findings have implications both stocks collected in prior pandemic periods future plans to restart collections. Thus, Vax-CCP provides an effective tool combat ongoing antibodies.

Language: Английский

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BA.2 and BA.5 omicron differ immunologically from both BA.1 omicron and pre-omicron variants

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

Published: Dec. 13, 2022

Several studies have shown that SARS-CoV-2 BA.1 omicron is an immune escape variant. Meanwhile, however, BA.2 and BA.5 became dominant in many countries replaced BA.1. As both several mutations compared to BA.1, we analyzed whether show further relative Here, characterized neutralization profiles against the sub-variants plasma samples from individuals with different history of exposures infection/vaccination found unvaccinated after a single exposure had limited cross-neutralizing antibodies pre-omicron variants Consequently, our antigenic map including all Variants Concern sub-variants, showed are distinct variants, but three also antigenically each other. The antibody landscapes illustrate current space, as described maps, generated only or more close two distant variants. describe space inhabited by relevant understanding which will important implications for vaccine strain adaptations.

Language: Английский

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SARS-CoV-2 spike conformation determines plasma neutralizing activity elicited by a wide panel of human vaccines

Science Immunology, Journal Year: 2022, Volume and Issue: 7(78)

Published: Nov. 10, 2022

Numerous safe and effective coronavirus disease 2019 vaccines have been developed worldwide that use various delivery technologies engineering strategies. We show here containing prefusion-stabilizing S mutations elicit antibody responses in humans with enhanced recognition of the

Language: Английский

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Persistent immune imprinting occurs after vaccination with the COVID-19 XBB.1.5 mRNA booster in humans

Immunity, Journal Year: 2024, Volume and Issue: 57(4), P. 904 - 911.e4

Published: March 14, 2024

Immune imprinting describes how the first exposure to a virus shapes immunological outcomes of subsequent exposures antigenically related strains. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron breakthrough infections and bivalent COVID-19 vaccination primarily recall cross-reactive memory B cells induced by prior Wuhan-Hu-1 spike mRNA rather than priming Omicron-specific naive cells. These findings indicate that immune occurs after repeated exposures, but whether it can be overcome remains unclear. To understand persistence imprinting, we investigated plasma antibody responses administration updated XBB.1.5 vaccine booster. We showed booster elicited neutralizing against current variants were dominated pre-existing previously spike. Therefore, persists multiple spikes through infection, including post vaccination, which will need considered guide future vaccination.

Language: Английский

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SARS-CoV-2 Omicron variants: burden of disease, impact on vaccine effectiveness and need for variant-adapted vaccines

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: May 23, 2023

The highly transmissible Omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in late 2021. Initial waves were primarily made up sub-lineages BA.1 and/or BA.2, BA.4, and BA.5 subsequently became dominant mid-2022, several descendants these have since emerged. infections generally caused less disease on average than those by earlier variants concern healthy adult populations, at least, part, due to increased population immunity. Nevertheless, healthcare systems many countries, particularly with low immunity, been overwhelmed unprecedented surges prevalence during waves. Pediatric admissions also higher compared previous concern. All exhibit partial escape from wild-type (Wuhan-Hu 1) spike-based vaccine-elicited neutralizing antibodies, more enhanced immuno-evasive properties emerging over time. Evaluating vaccine effectiveness (VE) against has become challenging a complex background varying coverage, platforms, prior infection rates, hybrid Original messenger RNA booster doses substantially improved VE or BA.2 symptomatic disease. However, protection waned, reductions months after administration. While original CD8 + CD4 T-cell responses cross-recognize sub-lineages, thereby retaining outcomes, variant-adapted vaccines are required expand the breadth B-cell improve durability protection. Variant-adapted rolled out 2022 increase overall antigenically aligned immune mechanisms.

Language: Английский

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