Enhanced potency of an IgM-like nanobody targeting conserved epitope in SARS-CoV-2 spike N-terminal domain

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Май 13, 2024

Abstract Almost all the neutralizing antibodies targeting receptor-binding domain (RBD) of spike (S) protein show weakened or lost efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged emerging variants, such as Omicron and its sub-variants. This suggests that highly conserved epitopes are crucial for development antibodies. Here, we present one nanobody, N235, displaying broad neutralization SARS-CoV-2 prototype multiple including newly Cryo-electron microscopy demonstrates N235 binds a novel, conserved, cryptic epitope in N-terminal (NTD) S protein, which interferes with RBD neighboring protein. The mechanism interpreted via flow cytometry Western blot shows appears to induce S1 subunit shedding from trimeric complex. Furthermore, nano-IgM construct (MN235), engineered by fusing human IgM Fc region, displays prevention inducing cross-linking virus particles. Compared MN235 exhibits varied enhancement pseudotyped authentic viruses vitro. intranasal administration low doses can effectively prevent infection sub-variant BA.1 XBB vivo, suggesting it be developed promising prophylactic antibody cope ongoing future infection.

Язык: Английский

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Deciphering a reliable synergistic bispecific strategy of rescuing antibodies for SARS-CoV-2 escape variants, including BA.2.86, EG.5.1, and JN.1

Cell Reports, Год журнала: 2024, Номер 43(6), С. 114338 - 114338

Опубликована: Июнь 1, 2024

The game between therapeutic monoclonal antibodies (mAbs) and continuously emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has favored the virus, as most mAbs have been evaded. Addressing this challenge, we systematically explored a reproducible bispecific antibody (bsAb)-dependent synergistic effect in study. It could effectively restore neutralizing activity of bsAb when any its single is escaped by variants. This synergy primarily attributed to binding angle receptor-binding domain (RBD)-5, facilitating inter-spike cross-linking promoting cryptic epitope exposure that classical cocktails cannot achieve. Furthermore, RBD-5 with RBD-2, RBD-6, RBD-7, alongside RBD-8, also exhibit significantly enhanced effects. study not only shifts paradigm understanding interactions but paves way for developing more effective against rapidly mutating SARS-CoV-2, Dia-19 already showing promise like BA.2.86, EG.5.1, JN.1.

Язык: Английский

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SARS-CoV-2 Vaccines: The Advantage of Mucosal Vaccine Delivery and Local Immunity

Vaccines, Год журнала: 2024, Номер 12(7), С. 795 - 795

Опубликована: Июль 18, 2024

Immunity against respiratory pathogens is often short-term, and, consequently, there an unmet need for the effective prevention of such infections. One infectious disease coronavirus 19 (COVID-19), which caused by novel Beta SARS-CoV-2 that emerged around end 2019. The World Health Organization declared illness a pandemic on 11 March 2020, and since then it has killed or sickened millions people globally. development COVID-19 systemic vaccines, impressively led to significant reduction in severity, hospitalization, mortality, contained pandemic’s expansion. However, these vaccines have not been able stop virus from spreading because restricted mucosal immunity. As result, breakthrough infections frequently occurred, new strains emerging. Furthermore, will likely continue circulate like influenza virus, co-exist with humans. upper tract nasal cavity are primary sites infection thus, mucosal/nasal vaccination induce response virus’ transmission warranted. In this review, we present status both approved those under evaluation clinical trials. our approach B-cell peptide-based applied prime-boost schedule elicit

Язык: Английский

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Mosaic RBD nanoparticle elicits immunodominant antibody responses across sarbecoviruses

Cell Reports, Год журнала: 2024, Номер 43(5), С. 114235 - 114235

Опубликована: Май 1, 2024

Nanoparticle vaccines displaying mosaic receptor-binding domains (RBDs) or spike (S) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) other sarbecoviruses are used in preparedness against potential zoonotic outbreaks. Here, we describe a self-assembling nanoparticle using lumazine synthase (LuS) as the scaffold to display RBDs different sarbecoviruses. Mosaic nanoparticles induce sarbecovirus cross-neutralizing antibodies comparable cocktail. We find elicit B cell receptor repertoire an immunodominant germline gene pair of IGHV14-3:IGKV14-111. Most tested IGHV14-3:IGKV14-111 monoclonal (mAbs) broadly cross-reactive clade 1a, 1b, and 3 Using mAb competition cryo-electron microscopy, determine that representative mAb, M2-7, binds conserved epitope on RBD, largely overlapping with pan-sarbecovirus S2H97. This suggests expand recognition common epitopes shared by clades These results provide immunological insights into responses elicited

Язык: Английский

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The D Gene in CDR H3 Determines a Public Class of Human Antibodies to SARS-CoV-2

Vaccines, Год журнала: 2024, Номер 12(5), С. 467 - 467

Опубликована: Апрель 27, 2024

Public antibody responses have been found against many infectious agents. Structural convergence of public antibodies is usually determined by immunoglobulin V genes. Recently, a human class SARS-CoV-2 was reported, where the D gene (IGHD3-22) encodes common YYDxxG motif in heavy-chain complementarity-determining region 3 (CDR H3), which determines specificity for receptor-binding domain (RBD). In this review, we discuss isolation, structural characterization, and genetic analyses antibodies, isolated from various cohorts COVID-19 convalescents vaccinees. All eleven with available structures target RBD similar binding mode, CDR H3 dominates interaction antigen. The conserved site on that does not overlap site, but their particular angle approach results direct steric hindrance to receptor binding, enables both neutralization potency breadth. We also review properties H3-dominant other viruses. Overall, unlike most are identified usage, newly discovered dominated D-gene-encoded uncovers further opportunities germline-targeting vaccine design.

Язык: Английский

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