Convergent evolution of SARS-CoV-2 XBB lineages on receptor-binding domain 455–456 synergistically enhances antibody evasion and ACE2 binding

PLoS Pathogens, Год журнала: 2023, Номер 19(12), С. e1011868 - e1011868

Опубликована: Дек. 20, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) XBB lineages have achieved dominance worldwide and keep on evolving. Convergent evolution of the receptor-binding domain (RBD) L455F F456L is observed, resulting in variants with substantial growth advantages, such as EG.5, FL.1.5.1, XBB.1.5.70, HK.3. Here, we show that neutralizing antibody (NAb) evasion drives convergent F456L, while epistatic shift caused by enables subsequent convergence through ACE2 binding enhancement further immune evasion. evade RBD-targeting Class 1 public NAbs, reducing neutralization efficacy breakthrough infection (BTI) reinfection convalescent plasma. Importantly, single substitution significantly dampens receptor binding; however, combination forms an adjacent residue flipping, which leads to enhanced NAbs resistance affinity. The perturbed mode exceptional NAb evasion, revealed structural analyses. Our results indicate flexibility contributed epistasis cannot be underestimated, potential SARS-CoV-2 RBD remains high.

Язык: Английский

---

Spike deep mutational scanning helps predict success of SARS-CoV-2 clades

Nature, Год журнала: 2024, Номер 631(8021), С. 617 - 626

Опубликована: Июль 3, 2024

SARS-CoV-2 variants acquire mutations in the spike protein that promote immune evasion

Язык: Английский

---

Mutations in the SARS-CoV-2 spike receptor binding domain and their delicate balance between ACE2 affinity and antibody evasion

Protein & Cell, Год журнала: 2024, Номер 15(6), С. 403 - 418

Опубликована: Март 4, 2024

Intensive selection pressure constrains the evolutionary trajectory of SARS-CoV-2 genomes and results in various novel variants with distinct mutation profiles. Point mutations, particularly those within receptor binding domain (RBD) spike (S) protein, lead to functional alteration both engagement monoclonal antibody (mAb) recognition. Here, we review data RBD point mutations possessed by major discuss their individual effects on ACE2 affinity immune evasion. Many single amino acid substitutions epitopes crucial for evasion capacity may conversely weaken affinity. However, this weakened effect could be largely compensated specific epistatic such as N501Y, thus maintaining overall protein all variants. The predominant direction evolution lies neither promoting nor evading mAb neutralization but a delicate balance between these two dimensions. Together, interprets how efficiently resist meanwhile is maintained, emphasizing significance comprehensive assessment mutations.

Язык: Английский

---

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

---

Evolution of the SARS-CoV-2 Omicron spike

Cell Reports, Год журнала: 2023, Номер 42(12), С. 113444 - 113444

Опубликована: Ноя. 18, 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern, first identified in November 2021, rapidly spread worldwide and diversified into several subvariants. spike (S) protein accumulated an unprecedented number sequence changes relative to previous variants. In this review, we discuss how S structural features modulate host cell receptor binding, virus entry, immune evasion highlight these differentiate from We also examine key properties track across the still-evolving subvariants importance continuing surveillance evolution over time.

Язык: Английский

---

Deep mutational scanning of SARS-CoV-2 Omicron BA.2.86 and epistatic emergence of the KP.3 variant

Virus Evolution, Год журнала: 2024, Номер 10(1)

Опубликована: Янв. 1, 2024

Deep mutational scanning experiments aid in the surveillance and forecasting of viral evolution by providing prospective measurements effects on traits, but epistatic shifts impacts mutations can hinder when were made outdated strain backgrounds. Here, we report impact all single amino acid ACE2-binding affinity protein folding expression SARS-CoV-2 Omicron BA.2.86 spike receptor-binding domain. As with other variants, find a plastic evolvable basis for receptor binding, many at ACE2 interface maintaining or even improving affinity. Despite its large genetic divergence, have not diverged greatly from those measured BA.2 ancestor. However, do identify strong positive epistasis among subsequent that accrued descendants. Specifically, Q493E mutation decreased previous backgrounds is reversed sign to enhance human coupled L455S F456L currently emerging KP.3 variant. Our results point modest degree drift during recent highlight how these small important consequences emergence new variants.

Язык: Английский

---

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

---

A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification

Cell, Год журнала: 2024, Номер unknown

Опубликована: Окт. 1, 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing sufficiently potent clinical development and retain activity despite remain elusive. We identified human mAb, designated VIR-7229, which targets the receptor-binding motif (RBM) with unprecedented cross-reactivity all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently SARS-CoV-2 variants since 2019, recent EG.5, BA.2.86, JN.1. VIR-7229 tolerates extraordinary variability, partly attributed its high binding affinity, receptor molecular mimicry, interactions RBM backbone atoms. Consequently, features barrier selection of mutants, rare associated reduced fitness, underscoring potential be future evolution. is strong candidate become next-generation medicine.

Язык: Английский

---

Epistatic hotspots organize antibody fitness landscape and boost evolvability

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(2)

Опубликована: Янв. 8, 2025

The course of evolution is strongly shaped by interaction between mutations. Such epistasis can yield rugged sequence–function maps and constrain the availability adaptive paths. While theoretical intuition often built on global statistics large, homogeneous model landscapes, mutagenesis measurements necessarily probe a limited neighborhood reference genotype. It unclear to what extent local topography real epistatic landscape represents its shape. Here, we demonstrate that landscapes be heterogeneously this heterogeneity may render biomolecules more evolvable. By characterizing multipeaked fitness SARS-CoV-2 antibody mutant library, show heterogeneous ruggedness arises from sparse hotspots, whose mutation impacts effect numerous sequence sites. Surprisingly, mutating an hotspot enhance, rather than reduce, accessibility fittest genotype, while increasing overall ruggedness. Further, migratory constraints in space alleviate mutational space, which not only diversify direct paths taken but also turn road-blocking peak into stepping stone leading toward optimum. Our results suggest hierarchy hotspots organize such way path-orienting confers smoothness.

Язык: Английский

---

Full-spike deep mutational scanning helps predict the evolutionary success of SARS-CoV-2 clades

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Ноя. 14, 2023

SARS-CoV-2 variants acquire mutations in spike that promote immune evasion and impact other properties contribute to viral fitness such as ACE2 receptor binding cell entry. Knowledge of how affect these phenotypes can provide insight into the current potential future evolution virus. Here we use pseudovirus deep mutational scanning measure >9,000 across full XBB.1.5 BA.2 spikes binding, entry, or escape from human sera. We find outside receptor-binding domain (RBD) have meaningfully impacted during evolution. also neutralization by serum individuals who recently had infections. The strongest are RBD at sites 357, 420, 440, 456, 473-however, antigenic impacts vary individuals. identify strong RBD; however many them decrease suggesting they act modulating conformation. Notably, growth rates clades be explained substantial part measured effects on phenotypes, our data could enable better prediction

Язык: Английский

---