A potent, broadly neutralizing human monoclonal antibody that efficiently protects hACE2-transgenic mice from infection with the Wuhan, BA.5, and XBB.1.5 SARS-CoV-2 variants DOI Creative Commons

Sergey V. Guselnikov,

Konstantin O. Baranov, Sergey V. Kulemzin

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: July 19, 2024

The COVID-19 pandemic has uncovered the high genetic variability of SARS-CoV-2 virus and its ability to evade immune responses that were induced by earlier viral variants. Only a few monoclonal antibodies have been reported date are capable neutralizing broad spectrum Here, we report isolation new broadly human antibody, iC1. antibody was identified through sorting SARS-CoV-1 RBD-stained individual B cells isolated from blood vaccinated donor following breakthrough infection. In vitro , iC1 potently neutralizes pseudoviruses expressing wide range Spike variants, including those XBB sublineage. an hACE2-transgenic mouse model, provided effective protection against Wuhan strain as well BA.5 XBB.1.5 Therefore, can be considered potential component cocktails resisting mutation escape.

Language: Английский

SARS-CoV-2 JN.1 variant evasion of IGHV3-53/3-66 B cell germlines DOI Open Access
Ida Paciello, Giuseppe Maccari, Giulio Pierleoni

et al.

Science Immunology, Journal Year: 2024, Volume and Issue: 9(98)

Published: Aug. 9, 2024

The severe acute respiratory syndrome coronavirus 2 variant JN.1 recently emerged as the dominant despite having only one amino acid change on spike (S) protein receptor binding domain (RBD) compared with ancestral BA.2.86, which never represented more than 5% of global variants. To define at molecular level ability to spread globally, we interrogated a panel 899 neutralizing human monoclonal antibodies. Our data show that single leucine-455-to-serine mutation in RBD unleashed JN.1, likely occurring by elimination 70% antibodies mediated IGHV3-53/3-66 germlines. However, resilience class 3 low neutralization potency but strong Fc functions may explain absence disease.

Language: Английский

Citations

8
Quantitative Characterization and Prediction of the Binding Determinants and Immune Escape Hotspots for Groups of Broadly Neutralizing Antibodies Against Omicron Variants: Atomistic Modeling of the SARS-CoV-2 Spike Complexes with Antibodies DOI Creative Commons
Mohammed Alshahrani, Vedant Parikh, Brian Foley

et al.

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 249 - 249

Published: Feb. 8, 2025

A growing body of experimental and computational studies suggests that the cross-neutralization antibody activity against Omicron variants may be driven by balance tradeoff between multiple energetic factors interaction contributions evolving escape hotspots involved in antigenic drift convergent evolution. However, dynamic details quantifying contribution these factors, particularly balancing nature specific interactions formed antibodies with epitope residues, remain largely uncharacterized. In this study, we performed molecular dynamics simulations, an ensemble-based deep mutational scanning SARS-CoV-2 spike binding free energy computations for two distinct groups broadly neutralizing antibodies: E1 group (BD55-3152, BD55-3546, BD5-5840) F3 (BD55-3372, BD55-4637, BD55-5514). Using approaches, examined determinants which potent can evade immune resistance. Our analysis revealed emergence a small number positions correspond to R346 K444 strong van der Waals act synchronously, leading large contribution. According our results, Abs effectively exploit hotspot clusters hydrophobic sites are critical functions along selective complementary targeting positively charged important ACE2 binding. Together conserved epitopes, lead expand breadth resilience neutralization shifts associated viral The results study demonstrate excellent qualitative agreement predicted mutations respect latest experiments on average scores. We argue epitopes leverage stability binding, while tend emerge synergistically electrostatic interactions.

Language: Английский

Citations

0
Mutational Scanning and Binding Free Energy Computations of the SARS-CoV-2 Spike Complexes with Distinct Groups of Neutralizing Antibodies: Energetic Drivers of Convergent Evolution of Binding Affinity and Immune Escape Hotspots DOI Open Access
Mohammed Alshahrani, Vedant Parikh, Brian Foley

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1507 - 1507

Published: Feb. 11, 2025

The rapid evolution of SARS-CoV-2 has led to the emergence variants with increased immune evasion capabilities, posing significant challenges antibody-based therapeutics and vaccines. In this study, we conducted a comprehensive structural energetic analysis spike receptor-binding domain (RBD) complexes neutralizing antibodies from four distinct groups (A–D), including group A LY-CoV016, B AZD8895 REGN10933, C LY-CoV555, D AZD1061, REGN10987, LY-CoV1404. Using coarse-grained simplified simulation models, energy-based mutational scanning, rigorous MM-GBSA binding free energy calculations, elucidated molecular mechanisms antibody escape mechanisms, identified key hotspots, explored evolutionary strategies employed by virus evade neutralization. residue-based decomposition revealed thermodynamic factors underlying effect mutations on binding. results demonstrate excellent qualitative agreement between predicted hotspots latest experiments escape. These findings provide valuable insights into determinants viral escape, highlighting importance targeting conserved epitopes leveraging combination therapies mitigate risk evasion.

Language: Английский

Citations

0
Omicron-specific ultra-potent SARS-CoV-2 neutralizing antibodies targeting the N1/N2 loop of Spike N-terminal domain DOI Creative Commons
Xiaofeng Niu, Zhiqiang Li, Jing Wang

et al.

Emerging Microbes & Infections, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 3, 2024

A multitude of functional mutations continue to emerge on the N-terminal domain (NTD) spike protein in SARS-CoV-2 Omicron subvariants. Understanding immunogenicity NTD and properties antibodies elicited by it is crucial for comprehending impact viral fitness guiding vaccine design. In this study, we find that most NTD-targeting isolated from individuals with BA.5/BF.7 breakthrough infection (BTI) are ancestral (wildtype or WT)-reactive non-neutralizing. Surprisingly, identified five ultra-potent neutralizing (NAbs) can only bind but not WT NTD. Structural analysis revealed they a unique epitope N1/N2 loop interact receptor-binding (RBD) via light chain. These Omicron-specific NAbs achieve neutralization through ACE2 competition blockage ACE2-mediated S1 shedding. However, BA.2.86 BA.2.87.1, which carry insertions deletions loop, evade these antibodies. Together, provided detailed map antibody repertoire post-Omicron era, demonstrating their vulnerability enabled its evolutionary flexibility, despite potent neutralization. results function indels BA.2.86/JN.1 sublineage evading highlighted importance considering

Language: Английский

Citations

3
Structural Immunology of SARS‐CoV‐2 DOI Creative Commons
Meng Yuan, Ian A. Wilson

Immunological Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 27, 2024

The SARS-CoV-2 spike (S) protein has undergone significant evolution, enhancing both receptor binding and immune evasion. In this review, we summarize ongoing efforts to develop antibodies targeting various epitopes of the S protein, focusing on their neutralization potency, breadth, escape mechanisms. Antibodies receptor-binding site (RBS) typically exhibit high neutralizing potency but are frequently evaded by mutations in variants. contrast, conserved regions, such as S2 stem helix fusion peptide, broader reactivity generally lower potency. However, several broadly have demonstrated exceptional efficacy against emerging variants, including latest omicron subvariants, underscoring potential vulnerable sites RBS-A RBS-D/CR3022. We also highlight public classes different protein. targeted present opportunities for germline-targeting vaccine strategies. Overall, developing escape-resistant, potent effective vaccines remains crucial combating future This review emphasizes importance identifying key utilizing antibody affinity maturation inform therapeutic design.

Language: Английский

Citations

2
Structural and Functional Insights into the Evolution of SARS-CoV-2 KP.3.1.1 Spike Protein DOI Creative Commons
Zi‐Qi Feng, Jiachen Huang, Sabyasachi Baboo

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 10, 2024

Summary The JN.1-sublineage KP.3.1.1 recently emerged as the globally prevalent SARS-CoV-2 variant, demonstrating increased infectivity and antibody escape. We investigated how mutations a deletion in spike protein (S) affect ACE2 binding Mass spectrometry revealed new glycan site at residue N30 altered glycoforms neighboring N61. Cryo-EM structures showed that rearrangement of adjacent residues did not significantly change overall structure, up-down ratio receptor-binding domains (RBDs), or binding. Furthermore, S structure with hACE2 further confirmed an epistatic effect between F456L Q493E on Our analysis shows variants after late 2023 are now incorporating reversions to found other sarbecoviruses, including glycan, Q493E, others. Overall, these results inform structural functional consequences mutations, current evolutionary trajectory, immune evasion.

Language: Английский

Citations

2
Omicron-specific ultra-potent SARS-CoV-2 neutralizing antibodies targeting the N1/N2 loop of Spike N-terminal domain DOI
Xiaofeng Niu, Zhiqiang Li, Jing Wang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 10, 2024

Abstract A multitude of functional mutations continue to emerge on the N-terminal domain (NTD) spike protein in SARS-CoV-2 Omicron subvariants. Understanding immunogenicity NTD and properties antibodies elicited by it is crucial for comprehending impact viral fitness guiding vaccine design. In this study, we find that most NTD-targeting isolated from individuals with BA.5/BF.7 breakthrough infection (BTI) are ancestral (wildtype or WT)-reactive non-neutralizing. Surprisingly, identified five ultra-potent neutralizing (NAbs) can only bind but not WT NTD. Structural analysis revealed they a unique epitope N1/N2 loop interact receptor-binding (RBD) via light chain. These Omicron-specific NAbs achieve neutralization through ACE2 competition blockage ACE2-mediated S1 shedding. However, BA.2.86 BA.2.87.1, which carry insertions deletions loop, evade these antibodies. Together, provided detailed map antibody repertoire post-Omicron era, demonstrating their vulnerability enabled its evolutionary flexibility, despite potent neutralization. results highlighted importance considering Author Summary COVID-19 pandemic caused severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues be major global public health concern four years after emergence. The critical component glycoprotein, pivotal cellular entry serves as primary target therapeutics development. Characterizing sublineages understanding evolution Here, show vaccination induces majorly non-neutralizing Still, class specifically sublineages. neutralize virus competing blocking analyses reveal NTD, intriguingly glycoprotein. This special binding pattern, escaped BA.2.87.1 sublineages, shedding role recently emerged Our findings provide fresh insights into highlighting capacity evasion due flexibility. underscores carefully

Language: Английский

Citations

0
A potent, broadly neutralizing human monoclonal antibody that efficiently protects hACE2-transgenic mice from infection with the Wuhan, BA.5, and XBB.1.5 SARS-CoV-2 variants DOI Creative Commons

Sergey V. Guselnikov,

Konstantin O. Baranov, Sergey V. Kulemzin

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: July 19, 2024

The COVID-19 pandemic has uncovered the high genetic variability of SARS-CoV-2 virus and its ability to evade immune responses that were induced by earlier viral variants. Only a few monoclonal antibodies have been reported date are capable neutralizing broad spectrum Here, we report isolation new broadly human antibody, iC1. antibody was identified through sorting SARS-CoV-1 RBD-stained individual B cells isolated from blood vaccinated donor following breakthrough infection. In vitro , iC1 potently neutralizes pseudoviruses expressing wide range Spike variants, including those XBB sublineage. an hACE2-transgenic mouse model, provided effective protection against Wuhan strain as well BA.5 XBB.1.5 Therefore, can be considered potential component cocktails resisting mutation escape.

Language: Английский

Citations

0