Evolving antibody response to SARS-CoV-2 antigenic shift from XBB to JN.1

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

Опубликована: Апрель 22, 2024

Abstract The continuous evolution of SARS-CoV-2, particularly the emergence BA.2.86/JN.1 lineage replacing XBB lineages, necessitates re-evaluation current vaccine compositions. Here, we provide a comprehensive analysis humoral immune response to and JN.1 human exposures, emphasizing need for JN.1-lineage-based boosters. We demonstrate antigenic distinctiveness lineages in SARS-CoV-2-naive individuals but not those with prior vaccinations or infections, infection elicits superior plasma neutralization titers against its subvariants. highlight strong evasion receptor binding capability KP.3, supporting foreseeable prevalence. Extensive BCR repertoire, isolating ∼2000 RBD-specific monoclonal antibodies (mAbs) their targeting epitopes characterized by deep mutational scanning (DMS), underscores systematic superiority JN.1-elicited memory B cells (MBCs). Notably, Class 1 IGHV3-53/3-66-derived neutralizing (NAbs) contribute majorly within wildtype (WT)-reactive NAbs JN.1. However, KP.2 KP.3 evade substantial subset them, even induced JN.1, advocating booster updates optimized enrichment. JN.1-induced Omicron-specific also high potency across all Omicron lineages. Escape hotspots these have mainly been mutated RBD, resulting higher barrier escape, considering probable recovery previously escaped NAbs. Additionally, prevalence broadly reactive IGHV3-53/3-66- encoding MBCs, competing suggests inhibitory role on de novo activation naive cells, potentially explaining heavy imprinting mRNA-vaccinated individuals. These findings delineate evolving antibody shift from importance developing lineage, especially KP.3-based boosters, enhance immunity future SARS-CoV-2 variants.

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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SARS-CoV-2 JN.1 variant evasion of IGHV3-53/3-66 B cell germlines

Science Immunology, Год журнала: 2024, Номер 9(98)

Опубликована: Авг. 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.

Язык: Английский

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Comprehensive Overview of Broadly Neutralizing Antibodies against SARS-COV-2 Variants

Опубликована: Апрель 10, 2024

Currently, SARS-CoV-2 has evolved into various variants, including the numerous highly mutated Omicron sub-lineages, significantly increasing immune evasion ability. The development raises concerns about possibly diminished effectiveness of available vaccines and antibody-based therapeutics. Here, we describe those representative categories broadly neutralizing antibodies (bnAbs) that retain prominent against emerging variants sub-lineages. molecular characteristics, epitope conservation, resistance mechanisms these are further detailed, aiming to offer suggestion or direction for therapeutic antibodies, facilitate vaccine design with broad-spectrum potential.

Язык: Английский

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Comprehensive Overview of Broadly Neutralizing Antibodies against SARS-CoV-2 Variants

Viruses, Год журнала: 2024, Номер 16(6), С. 900 - 900

Опубликована: Июнь 1, 2024

Currently, SARS-CoV-2 has evolved into various variants, including the numerous highly mutated Omicron sub-lineages, significantly increasing immune evasion ability. The development raises concerns about possibly diminished effectiveness of available vaccines and antibody-based therapeutics. Here, we describe those representative categories broadly neutralizing antibodies (bnAbs) that retain prominent against emerging variants sub-lineages. molecular characteristics, epitope conservation, resistance mechanisms these are further detailed, aiming to offer suggestion or direction for therapeutic antibodies, facilitate design with broad-spectrum potential.

Язык: Английский

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Antigenic sin and multiple breakthrough infections drive converging evolution of COVID-19 neutralizing responses

Cell Reports, Год журнала: 2024, Номер 43(9), С. 114645 - 114645

Опубликована: Авг. 27, 2024

Understanding the evolution of B cell response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is fundamental design next generation vaccines and therapeutics. We longitudinally analyze at single-cell level almost 900 neutralizing human monoclonal antibodies (nAbs) isolated from vaccinated people individuals with hybrid super immunity (SH), developed after three mRNA vaccine doses two breakthrough infections. The most potent neutralization Fc functions against highly mutated belong SH cohort. Repertoire analysis shows that original Wuhan antigenic sin drives convergent expansion same germlines in cohorts. Only Omicron infections expand previously unseen germ lines generate broadly nAbs by restoring IGHV3-53/3-66 lines. Our analyses find cells initially expanded continue play a role immune toward an evolving virus.

Язык: Английский

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Rethinking Optimal Immunogens to Face SARS‐CoV‐2 Evolution Through Vaccination

Influenza and Other Respiratory Viruses, Год журнала: 2025, Номер 19(1)

Опубликована: Янв. 1, 2025

ABSTRACT SARS‐CoV‐2, which originated in China late 2019, quickly fueled the global COVID‐19 pandemic, profoundly impacting health and economy worldwide. A series of vaccines, mostly based on full SARS‐CoV‐2 Spike protein, were rapidly developed, showing excellent humoral cellular responses high efficacy against both symptomatic infection severe disease. However, viral evolution waning neutralizing strongly challenged vaccine long term effectiveness, mainly infection, making necessary a strategy repeated updated booster shots. In this vaccination context, antibody repertoire diversification was evidenced, although immune imprinting after doses or reinfection also demonstrated identified as major determinant immunological to antigen exposures. Considering that small domain receptor binding (RBD), is target antibodies concentrates most mutations, following text aims provide insights into ongoing debate over best strategies for boosters. We address relevance developing new vaccines evolving RBD, thus focusing relevant antigenic sites variants. combination with immunofusing computerized approaches could minimize imprinting, therefore optimizing efficacy.

Язык: Английский

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Preemptive optimization of a clinical antibody for broad neutralization of SARS-CoV-2 variants and robustness against viral escape

Science Advances, Год журнала: 2025, Номер 11(13)

Опубликована: Март 28, 2025

Most previously authorized clinical antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have lost neutralizing activity to recent variants due rapid viral evolution. To mitigate such escape, we preemptively enhance AZD3152, an antibody for prophylaxis in immunocompromised individuals. Using deep mutational scanning (DMS) on the SARS-CoV-2 antigen, identify AZD3152 vulnerabilities at antigen positions F456 and D420. Through two iterations of computational design that integrates structure-based modeling, machine-learning, experimental validation, co-optimize 24 contemporary previous variants, as well 20 potential future escape variants. Our top candidate, 3152-1142, restores full potency (100-fold improvement) more recently emerged XBB.1.5+F456L variant escaped maintains concern, shows no additional vulnerability assessed by DMS. This preemptive mitigation demonstrates a generalizable approach optimizing existing escape.

Язык: Английский

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Public antibodies: convergent signatures in human humoral immunity against pathogens

mBio, Год журнала: 2025, Номер unknown

Опубликована: Апрель 16, 2025

ABSTRACT The human humoral immune system has evolved to recognize a vast array of pathogenic threats. This ability is primarily driven by the immense diversity antibodies generated gene rearrangement during B cell development. However, different people often produce strikingly similar when exposed same antigen—known as public antibodies. Public not only reflect system’s consistently select for optimal cells but can also serve signatures responses triggered infection and vaccination. In this Minireview, we examine compare antibody identification methods, including criteria used based on V(D)J usage similarity in complementarity-determining region three sequences, explore molecular features elicited against common pathogens, viruses, protozoa, bacteria. Finally, discuss evolutionary significance potential applications informing design germline-targeting vaccines, predicting escape mutations emerging providing insights into process affinity maturation. ongoing discovery response pathogens holds improve pandemic preparedness, accelerate vaccine efforts, deepen our understanding biology.

Язык: Английский

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Structural Immunology of SARS‐CoV‐2

Immunological Reviews, Год журнала: 2024, Номер unknown

Опубликована: Дек. 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.

Язык: Английский

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