Antigenicity and infectivity characterisation of SARS-CoV-2 BA.2.86

The Lancet Infectious Diseases, Год журнала: 2023, Номер 23(11), С. e457 - e459

Опубликована: Сен. 19, 2023

Язык: Английский

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Targetable elements in SARS-CoV-2 S2 subunit for the design of pan-coronavirus fusion inhibitors and vaccines

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Май 10, 2023

Abstract The ongoing global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome 2 (SARS‐CoV‐2), has devastating impacts on the public health and economy. Rapid viral antigenic evolution led to continual generation new variants. Of special note is recently expanding Omicron subvariants that are capable immune evasion from most existing neutralizing antibodies (nAbs). This posed challenges for prevention treatment COVID-19. Therefore, exploring broad-spectrum antiviral agents combat emerging variants imperative. In sharp contrast massive accumulation mutations within SARS-CoV-2 receptor-binding domain (RBD), S2 fusion subunit remained highly conserved among Hence, S2-based therapeutics may provide effective cross-protection against Here, we summarize developed inhibitors (e.g., nAbs, peptides, proteins, small-molecule compounds) candidate vaccines targeting elements in subunit. main focus includes all targetable elements, namely, peptide, stem helix, heptad repeats 1 (HR1-HR2) bundle. Moreover, a detailed summary characteristics action-mechanisms each class cross-reactive inhibitors, which should guide promote future design coronaviruses.

Язык: Английский

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Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents infection of Omicron lineages

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(3)

Опубликована: Янв. 9, 2024

The emergence of Omicron lineages and descendent subvariants continues to present a severe threat the effectiveness vaccines therapeutic antibodies. We have previously suggested that an insufficient mucosal immunoglobulin A (IgA) response induced by mRNA is associated with surge in breakthrough infections. Here, we further show intramuscular and/or inactivated cannot sufficiently boost secretory IgA uninfected individuals, particularly against variant. thus engineered characterized recombinant monomeric, dimeric, IgA1 antibodies derived from four neutralizing IgG monoclonal (mAbs 01A05, rmAb23, DXP-604, XG014) targeting receptor-binding domain spike protein. Compared their parental antibodies, dimeric showed higher activity different variants concern (VOCs), part due increased avidity. Importantly, or form DXP-604 antibody significantly outperformed its antibody, neutralized BA.1, BA.2, BA.4/5 25- 75-fold increase potency. In human angiotensin converting enzyme 2 (ACE2) transgenic mice, single intranasal dose conferred prophylactic protection BA.5. Thus, delivered nasal administration may potentially be exploited for treatment prevention infection, thereby providing alternative tool combating immune evasion current circulating and, potentially, future VOCs.

Язык: Английский

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The SARS-CoV-2 neutralizing antibody response to SD1 and its evasion by BA.2.86

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Март 28, 2024

Abstract Under pressure from neutralising antibodies induced by vaccination or infection the SARS-CoV-2 spike gene has become a hotspot for evolutionary change, leading to failure of all mAbs developed clinical use. Most potent bind receptor binding domain which heavily mutated. Here we study responses conserved epitope in sub-domain-1 (SD1) have more prominent because mutational escape directed domain. Some SD1 reactive show and broad neutralization variants. We structurally map dominant provide mechanism action blocking interaction with ACE2. Mutations not been sustained date, but one, E554K, leads mAbs. This mutation now emerged several sublineages including BA.2.86, reflecting selection on virus exerted increasing prominence anti-SD1 response.

Язык: Английский

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Prefusion-stabilized SARS-CoV-2 S2-only antigen provides protection against SARS-CoV-2 challenge

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 20, 2024

Abstract Ever-evolving SARS-CoV-2 variants of concern (VOCs) have diminished the effectiveness therapeutic antibodies and vaccines. Developing a coronavirus vaccine that offers greater breadth protection against current future VOCs would eliminate need to reformulate COVID-19 Here, we rationally engineer sequence-conserved S2 subunit spike protein characterize resulting S2-only antigens. Structural studies demonstrate introduction interprotomer disulfide bonds can lock in prefusion trimers, although apex samples continuum conformations between open closed states. Immunization with prefusion-stabilized constructs elicits broadly neutralizing responses several sarbecoviruses protects female BALB/c mice from mouse-adapted lethal challenge partially SARS-CoV challenge. These engineering immunogenicity results should inform development next-generation pan-coronavirus therapeutics

Язык: Английский

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

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(15)

Опубликована: Апрель 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.

Язык: Английский

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A generalized framework to identify SARS-CoV-2 broadly neutralizing antibodies

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 18, 2024

Abstract Monoclonal antibodies (mAbs) targeting the SARS-CoV-2 receptor-binding domain (RBD) showed high efficacy in prevention and treatment of COVID-19. However, rapid evolution has rendered all clinically authorized mAbs ineffective continues to stymie development next-generation mAbs. Consequently, ability identify broadly neutralizing (bnAbs) that neutralize both current future variants is critical for successful antibody therapeutic development, especially newly emerged viruses when no knowledge about immune evasive available. Here, we have developed a strategy specifically select potent bnAbs with activity against existing prospective based on accurate viral prediction informed by deep mutational scanning (DMS). By adopting this methodology, increased probability identifying XBB.1.5-effective from ∼1% 40% if were at early stage pandemic, as revealed retrospective analysis >1,000 wildtype (WT)-elicited From collection, identified bnAb, designated BD55-1205, exhibited exceptional historical, contemporary, predicted variants. Structural analyses extensive polar interactions between BD55-1205 XBB.1.5 motif (RBM), backbone atoms, explaining its unusually broad reactivity. Importantly, mRNA-based delivery IgG human FcRn-expressing transgenic mice resulted serum titers selected XBB BA.2.86 subvariants. Together, via prediction, coupled speed flexibility mRNA technology, provides generalized framework antibody-based countermeasures potentially other highly variable pathogens pandemic potential.

Язык: Английский

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Broadly neutralizing antibodies against COVID-19

Current Opinion in Virology, Год журнала: 2023, Номер 61, С. 101332 - 101332

Опубликована: Июнь 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.

Язык: Английский

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Protective effect and molecular mechanisms of human non-neutralizing cross-reactive spike antibodies elicited by SARS-CoV-2 mRNA vaccination

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 29, 2024

Neutralizing antibodies correlate with protection against SARS-CoV-2. Recent studies, however, show that binding antibody titers, in the absence of robust neutralizing activity, also from disease progression. Non-neutralizing cannot directly protect infection but may recruit effector cells thus contribute to clearance infected cells. Also, they often bind conserved epitopes across multiple variants. We characterized 42 human mAbs COVID-19 vaccinated individuals. Most these exhibited no activity

Язык: Английский

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Functional and antigenic characterization of SARS-CoV-2 spike fusion peptide by deep mutational scanning

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Май 14, 2024

Abstract The fusion peptide of SARS-CoV-2 spike protein is functionally important for membrane during virus entry and part a broadly neutralizing epitope. However, sequence determinants at the its adjacent regions pathogenicity antigenicity remain elusive. In this study, we perform series deep mutational scanning (DMS) experiments on an S2 region spanning authentic in different cell lines presence antibodies. We identify mutations residue 813 that reduced TMPRSS2-mediated with decreased virulence. addition, show F823Y mutation, present bat betacoronavirus HKU9 protein, confers resistance to Our findings provide mechanistic insights into also highlight potential challenge developing protective S2-based coronavirus vaccines.

Язык: Английский

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