Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses

Nature reviews. Immunology, Journal Year: 2022, Volume and Issue: 23(3), P. 189 - 199

Published: Sept. 27, 2022

Language: Английский

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The impact of pre-existing cross-reactive immunity on SARS-CoV-2 infection and vaccine responses

Nature reviews. Immunology, Journal Year: 2022, Volume and Issue: 23(5), P. 304 - 316

Published: Dec. 20, 2022

Language: Английский

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Close relatives of MERS-CoV in bats use ACE2 as their functional receptors

Nature, Journal Year: 2022, Volume and Issue: 612(7941), P. 748 - 757

Published: Dec. 7, 2022

Middle East respiratory syndrome coronavirus (MERS-CoV) and several bat coronaviruses use dipeptidyl peptidase-4 (DPP4) as an entry receptor1-4. However, the receptor for NeoCoV-the closest known MERS-CoV relative found in bats-remains unclear5. Here, using a pseudotype virus assay, we that NeoCoV its close relative, PDF-2180, can efficiently bind to specific angiotensin-converting enzyme 2 (ACE2) orthologues and, less favourably, human ACE2 receptors through their receptor-binding domains (RBDs) on spike (S) proteins. Cryo-electron microscopy analysis revealed RBD-ACE2 binding interface involving protein-glycan interactions, distinct from those of other ACE2-using coronaviruses. We identified residues 337-342 molecular determinant restricting entry, whereas S pseudotyped containing T510F RBD mutation entered cells expressing ACE2. Although polyclonal SARS-CoV-2 antibodies or RBD-specific nanobodies did not cross-neutralize ACE2-specific antibody two broadly neutralizing betacoronavirus inhibited these viruses. describe MERS-CoV-related viruses receptor, underscoring promiscuity potential zoonotic threat.

Language: Английский

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Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents

Cell Reports, Journal Year: 2022, Volume and Issue: 41(12), P. 111845 - 111845

Published: Dec. 1, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages have escaped most receptor-binding domain (RBD)-targeting therapeutic neutralizing antibodies (NAbs), which proves that previous NAb drug screening strategies are deficient against the fast-evolving SARS-CoV-2. Better broad candidate selection methods needed. Here, we describe a rational approach for identifying RBD-targeting SARS-CoV-2 cocktails. Based on high-throughput epitope determination, propose drugs should target non-immunodominant RBD epitopes to avoid herd-immunity-directed escape mutations. Also, their interacting antigen residues focus sarbecovirus conserved sites and associate with critical viral functions, making antibody-escaping mutations less likely appear. Following these criteria, featured non-competing antibody cocktail, SA55+SA58, is identified from large collection of NAbs isolated SARS-CoV-2-vaccinated SARS convalescents. SA55+SA58 potently neutralizes ACE2-utilizing sarbecoviruses, including circulating variants, could serve as prophylactics offer long-term protection, especially individuals who immunocompromised or high-risk comorbidities.

Language: Английский

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Angiotensin-converting enzyme 2—at the heart of the COVID-19 pandemic

Cell, Journal Year: 2023, Volume and Issue: 186(5), P. 906 - 922

Published: Feb. 2, 2023

ACE2 is the indispensable entry receptor for SARS-CoV and SARS-CoV-2. Because of COVID-19 pandemic, it has become one most therapeutically targeted human molecules in biomedicine. serves two fundamental physiological roles: as an enzyme, alters peptide cascade balance; a chaperone, controls intestinal amino acid uptake. ACE2's tissue distribution, affected by co-morbidities sex, explains broad tropism coronaviruses clinical manifestations SARS COVID-19. ACE2-based therapeutics provide universal strategy to prevent treat SARS-CoV-2 infections, applicable all variants other emerging zoonotic exploiting their cellular receptor.

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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Human neutralizing antibodies to cold linear epitopes and subdomain 1 of the SARS-CoV-2 spike glycoprotein

Science Immunology, Journal Year: 2023, Volume and Issue: 8(81)

Published: Jan. 26, 2023

Emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants diminishes the efficacy vaccines and antiviral monoclonal antibodies. Continued development immunotherapies vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions virus spike glycoprotein are both functionally relevant averse change, we identified human neutralizing antibodies highly conserved epitopes. Antibody fp.006 binds fusion peptide cross-reacts against coronaviruses four genera, including nine coronaviruses, through recognition motif includes S2' site proteolytic cleavage. hr2.016 targets stem helix neutralizes SARS-CoV-2 variants. sd1.040 subdomain 1, synergizes with rbd.042 for neutralization, and, similar hr2.016, protects mice expressing angiotensin-converting enzyme infection when present as bispecific antibody. Thus, discovery reveals donor-derived cross-reactive Orthocoronavirinae,

Language: Английский

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Identification of a conserved S2 epitope present on spike proteins from all highly pathogenic coronaviruses

eLife, Journal Year: 2023, Volume and Issue: 12

Published: March 21, 2023

To address the ongoing SARS-CoV-2 pandemic and prepare for future coronavirus outbreaks, understanding protective potential of epitopes conserved across variants lineages is essential. We describe a highly conserved, conformational S2 domain epitope present only in prefusion core β-coronaviruses: apex residues 980–1006 flexible hinge. Antibody RAY53 binds native hinge MERS-CoV spikes on surface mammalian cells mediates antibody-dependent cellular phagocytosis cytotoxicity against spike vitro. Hinge mutations that ablate antibody binding compromise pseudovirus infectivity, but changes elsewhere affect opening dynamics, including those found Omicron BA.1, occlude may evade pre-existing serum antibodies targeting core. This work defines third class while providing insights into potency limitations targeting.

Language: Английский

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Germline-encoded amino acid–binding motifs drive immunodominant public antibody responses

Science, Journal Year: 2023, Volume and Issue: 380(6640)

Published: April 6, 2023

Despite the vast diversity of antibody repertoire, infected individuals often mount responses to precisely same epitopes within antigens. The immunological mechanisms underpinning this phenomenon remain unknown. By mapping 376 immunodominant “public epitopes” at high resolution and characterizing several their cognate antibodies, we concluded that germline-encoded sequences in antibodies drive recurrent recognition. Systematic analysis antibody-antigen structures uncovered 18 human 21 partially overlapping mouse amino acid–binding (GRAB) motifs heavy light V gene segments case studies proved critical for public epitope GRAB represent a fundamental component immune system’s architecture promotes recognition pathogens leads species-specific can exert selective pressure on pathogens.

Language: Английский

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Cryo-EM structure of SARS-CoV-2 postfusion spike in membrane

Nature, Journal Year: 2023, Volume and Issue: 619(7969), P. 403 - 409

Published: June 7, 2023

Language: Английский

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