Evidence of antigenic drift in the fusion machinery core of SARS-CoV-2 spike

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(15)

Published: April 1, 2024

Antigenic drift of SARS-CoV-2 is typically defined by mutations in the N-terminal domain and receptor binding spike protein. In contrast, whether antigenic occurs S2 remains largely elusive. Here, we perform a deep mutational scanning experiment to identify that affect three apex public antibodies. Our results indicate spatially diverse mutations, including D950N Q954H, which are observed Delta Omicron variants, respectively, weaken these Although antibodies known be nonneutralizing, show they confer protection vivo through Fc-mediated effector functions. Overall, this study indicates can undergo drift, represents potential challenge for development more universal coronavirus vaccines.

Language: Английский

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A shark-derived broadly neutralizing nanobody targeting a highly conserved epitope on the S2 domain of sarbecoviruses

Journal of Nanobiotechnology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 15, 2025

The continuously evolving Omicron subvariants has diminished the effectiveness of almost all RBD-targeted antibodies in neutralizing these subvariants. development broad-spectrum is desired for addressing both current and future variants. Here, we identified a shark-derived nanobody, 79C11, that can neutralize tested so far, including BA.1 to JN.1 KP.2, exhibits comparable potency against SARS-CoV-1 pangolin coronavirus. Intranasal instillation 79C11 effectively prevent infection subvariant XBB vivo. designs multivalent forms further enhance binding activity. Epitope mapping structure simulation reveal this nanobody binds highly conserved HR1 region S2 domain spikes from sarbecoviruses, suggesting universal vaccine may be designed target eliciting broadly antibody response. This also developed as an intranasally administered prophylactic agent preventing likely SARS-CoV-2 variants, well other animal derived sarbecoviruses infect humans.

Language: Английский

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ACE2 utilization of HKU25 clade MERS-related coronaviruses with broad geographic distribution

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Abstract Dipeptidyl peptidase-4 (DPP4) is a well-established receptor for several MERS-related coronaviruses (MERSr-CoVs) isolated from humans, camels, pangolins, and bats (1–6). However, the usage of many genetically diverse bat MERSr-CoVs with broad geographical distributions remains poorly understood. Recent studies have identified angiotensin-converting enzyme 2 (ACE2) as an entry multiple merbecovirus clades. Here, using viral antigen pseudovirus-based functional assays, we demonstrate that merbecoviruses HKU25 clade previously thought to utilize DPP4 (7), employ ACE2 their receptor. Cryo-electron microscopy analysis revealed HsItaly2011 VsCoV-a7 recognize binding mode sharing similarity HKU5 but involving remodeled interfaces distinct ortholog selectivity, suggesting common evolutionary origin utilization these two clades viruses. EjCoV-3, strain closely related DPP4-using MERSr-CoV BtCoV-422, exhibited relatively tropism could human albeit suboptimally. Despite differences in mechanisms spike proteolytic activation compared MERS-CoV, viruses remain sensitive broadly neutralizing antibodies inhibitors. These findings redefine our understanding evolution among highlight versatility coronaviruses. Significance unexpectedly convergently evolved modes across three continents, challenging dogma primary distributed Eurasia host through shared HKU5, prior findings. reveal prevalence show EjCoV-3 preadapted use ACE2, potential spillover. Our data provide blueprint barrier determinants which will facilitate global surveillance development countermeasures against characterized merbecoviruses.

Language: Английский

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Broadly neutralizing antibodies against COVID-19

Current Opinion in Virology, Journal Year: 2023, Volume and Issue: 61, P. 101332 - 101332

Published: June 7, 2023

The COVID-19 pandemic caused by SARS-CoV-2 has led to hundreds of millions infections and deaths, however, human monoclonal antibodies (mAbs) can be an effective treatment. Since emerged, a variety strains have acquired increasing numbers mutations gain increased transmissibility escape from the immune response. Most reported neutralizing mAbs, including all approved therapeutic ones, been knocked down or out these mutations. Broadly mAbs are therefore great value, treat current possible future variants. Here, we review four types against spike protein with broad potency previously currently circulating These target receptor-binding domain, subdomain 1, stem helix, fusion peptide. Understanding how retain in face mutational change could guide development vaccines.

Language: Английский

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Broad receptor tropism and immunogenicity of a clade 3 sarbecovirus

Cell Host & Microbe, Journal Year: 2023, Volume and Issue: 31(12), P. 1961 - 1973.e11

Published: Nov. 20, 2023

Although Rhinolophus bats harbor diverse clade 3 sarbecoviruses, the structural determinants of receptor tropism along with antigenicity their spike (S) glycoproteins remain uncharacterized. Here, we show that African bat sarbecovirus PRD-0038 S has a broad angiotensin-converting enzyme 2 (ACE2) usage and receptor-binding domain (RBD) mutations further expand promiscuity enable human ACE2 utilization. We determine cryo-EM structure RBD bound to alcyone ACE2, explaining highlighting differences SARS-CoV-1 SARS-CoV-2. Characterization using monoclonal antibody reactivity reveals its distinct relative SARS-CoV-2 identifies cross-neutralizing antibodies for pandemic preparedness. vaccination elicits greater titers cross-reacting vaccine-mismatched 1a sarbecoviruses compared due broader antigenic targeting, motivating inclusion antigens in next-generation vaccines enhanced resilience viral evolution.

Language: Английский

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