Virological characteristics of the SARS-CoV-2 Omicron BA.2 subvariants, including BA.4 and BA.5

Cell, Journal Year: 2022, Volume and Issue: 185(21), P. 3992 - 4007.e16

Published: Sept. 14, 2022

After the global spread of SARS-CoV-2 Omicron BA.2, some BA.2 subvariants, including BA.2.9.1, BA.2.11, BA.2.12.1, BA.4, and BA.5, emerged in multiple countries. Our statistical analysis showed that effective reproduction numbers these subvariants are greater than original BA.2. Neutralization experiments revealed immunity induced by BA.1/2 infections is less against BA.4/5. Cell culture BA.2.12.1 BA.4/5 replicate more efficiently human alveolar epithelial cells particularly, fusogenic We further provided structure spike receptor-binding domain binds to ACE2 considered how substitutions play roles binding immune evasion. Moreover, using hamsters suggested pathogenic multiscale investigations suggest risk particularly BA.4/5, health

Language: Английский

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Virological characteristics of the SARS-CoV-2 Omicron BA.2.75 variant

Cell Host & Microbe, Journal Year: 2022, Volume and Issue: 30(11), P. 1540 - 1555.e15

Published: Oct. 18, 2022

The SARS-CoV-2 Omicron BA.2.75 variant emerged in May 2022. is a BA.2 descendant but phylogenetically distinct from BA.5, the currently predominant descendant. Here, we show that has greater effective reproduction number and different immunogenicity profile than BA.5. We determined sensitivity of to vaccinee convalescent sera as well panel clinically available antiviral drugs antibodies. Antiviral largely retained potency, antibody varied depending on several key BA.2.75-specific substitutions. spike exhibited profoundly higher affinity for its human receptor, ACE2. Additionally, fusogenicity, growth efficiency alveolar epithelial cells, intrinsic pathogenicity hamsters were those BA.2. Our multilevel investigations suggest acquired virological properties independent potential risk global health

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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Susceptibility of SARS-CoV-2 Omicron Variants to Therapeutic Monoclonal Antibodies: Systematic Review and Meta-analysis

Microbiology Spectrum, Journal Year: 2022, Volume and Issue: 10(4)

Published: June 14, 2022

SARS-CoV-2 Omicron variants contain many mutations in its spike receptor-binding domain, the target of all authorized monoclonal antibodies (MAbs). Determining extent to which reduced MAb susceptibility is critical preventing and treating COVID-19. We systematically reviewed PubMed three preprint servers, last updated 11 April 2022, for vitro activity MAbs against variants. Fifty-one studies were eligible, including 50 containing BA.1 data 17 BA.2 data. The first two combinations, bamlanivimab/etesevimab casirivimab/imdevimab, largely inactive In 34 studies, sotrovimab displayed a median 4.0-fold (interquartile range [IQR]: 2.6 6.9) reduction BA.1, 12 it 17-fold (IQR: 13 30) BA.2. 15 combination cilgavimab/tixagevimab 86-fold 27 151) six 5.4-fold 3.7 eight BA.2, bebtelovimab no activity. Disparate results between assays common. For MAbs, 51/268 (19.0%) wild-type control 78/348 (22.4%) more than 4-fold below or above result that MAb. Highly disparate published indicate need improved test standardization interassay calibration. IMPORTANCE Monoclonal (MAbs) targeting protein are among most effective measures However, their domains, MAbs. Therefore, determining identified 51 reported main therapeutic advanced clinical development, individual combinations. estimated degree different marked loss underscores importance developing conserved regions spike. standardization.

Language: Английский

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Evolution of enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants

Nature Microbiology, Journal Year: 2024, Volume and Issue: 9(2), P. 451 - 463

Published: Jan. 16, 2024

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human adaptation resulted in distinct lineages with enhanced transmissibility called variants of concern (VOCs). Omicron is the first VOC to evolve globally dominant subvariants. Here we compared their replication cell lines and primary airway cultures measured host responses infection. We discovered that subvariants BA.4 BA.5 have improved suppression innate immunity when earlier BA.1 BA.2. Similarly, more recent (BA.2.75 XBB lineages) also triggered reduced immune activation. This correlated increased expression viral antagonists Orf6 nucleocapsid, reminiscent VOCs Alpha Delta. Increased levels suppressed infection by decreasing IRF3 STAT1 signalling transcription factor phosphorylation nuclear translocation. Our data suggest convergent evolution antagonist a common pathway link subvariant dominance evasion.

Language: Английский

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Vaccine-induced protection against SARS-CoV-2 requires IFN-γ-driven cellular immune response

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 10, 2023

The overall success of worldwide mass vaccination in limiting the negative effect COVID-19 pandemics is inevitable, however, recent SARS-CoV-2 variants concern, especially Omicron and its sub-lineages, efficiently evade humoral immunity mounted upon or previous infection. Thus, it an important question whether these variants, vaccines against them, induce anti-viral cellular immunity. Here we show that mRNA vaccine BNT162b2 induces robust protective K18-hACE2 transgenic B-cell deficient (μMT) mice. We further demonstrate protection attributed to depending on IFN-γ production. Viral challenge with BA.1 BA.5.2 sub-variants boosted responses vaccinated μMT mice, which highlights significance ever-emerging evading antibody-mediated Our work, by providing evidence can significant mice are unable produce antibodies, thus importance SARS-CoV-2.

Language: Английский

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High-resolution map of the Fc functions mediated by COVID-19-neutralizing antibodies

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(3)

Published: Jan. 10, 2024

A growing body of evidence shows that fragment crystallizable (Fc)-dependent antibody effector functions play an important role in protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To unravel the mechanisms drive these responses, we analyzed phagocytosis and complement deposition mediated by a panel 482 human monoclonal antibodies (nAbs) neutralizing original Wuhan virus, expressed as recombinant IgG1. Our study confirmed nAbs no longer SARS-CoV-2 Omicron variants can retain their Fc functions. Surprisingly, found with most potent function recognize N-terminal domain, followed those targeting class 3 epitopes receptor binding domain. Interestingly, direct against 1/2 motif, which are were weakest The divergent properties function-mediating use different B cell germlines observation polyclonal sera differ profile observed nAbs, suggesting non-neutralizing also contribute to These data provide high-resolution picture Fc-antibody response suggest contribution should be considered for design improved vaccines, selection therapeutic antibodies, evaluation correlates protection.

Language: Английский

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SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(4), P. 632 - 657

Published: April 1, 2024

Over four years have passed since the beginning of COVID-19 pandemic. The scientific response has been rapid and effective, with many therapeutic monoclonal antibodies small molecules developed for clinical use. However, given ability viruses to become resistant antivirals, it is perhaps no surprise that field identified resistance nearly all these compounds. Here, we provide a comprehensive review profile each therapeutics. We hope this resource provides an atlas mutations be aware agent, particularly as springboard considerations next generation antivirals. Finally, discuss outlook thoughts moving forward in how continue manage this, next,

Language: Английский

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Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

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

Published: May 10, 2022

SARS-CoV-2 Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity vaccine boosters result potent plasma neutralizing activity against BA.1 BA.2 breakthrough infections, but not vaccination-only, induce the nasal mucosa. Consistent with immunological imprinting, most derived memory B cells of cases cross-react Wuhan-Hu-1, receptor-binding domains whereas primary infections elicit narrow specificity. While clinical have reduced neutralization Omicron, we identified ultrapotent pan-variant antibody, is unaffected any lineage a strong candidate for development.

Language: Английский

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Effectiveness and durability of BNT162b2 vaccine against hospital and emergency department admissions due to SARS-CoV-2 omicron sub-lineages BA.1 and BA.2 in a large health system in the USA: a test-negative, case-control study

The Lancet Respiratory Medicine, Journal Year: 2022, Volume and Issue: 11(2), P. 176 - 187

Published: Oct. 7, 2022

Language: Английский

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