Neutralization and Stability of JN.1-derived LB.1, KP.2.3, KP.3 and KP.3.1.1 Subvariants

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

Published: Sept. 5, 2024

SUMMARY During the summer of 2024, COVID-19 cases surged globally, driven by variants derived from JN.1 subvariants SARS-CoV-2 that feature new mutations, particularly in N-terminal domain (NTD) spike protein. In this study, we report on neutralizing antibody (nAb) escape, infectivity, fusion, and stability these subvariants—LB.1, KP.2.3, KP.3, KP.3.1.1. Our findings demonstrate all are highly evasive nAbs elicited bivalent mRNA vaccine, XBB.1.5 monovalent mumps virus-based or infections during BA.2.86/JN.1 wave. This reduction nAb titers is primarily a single serine deletion (DelS31) NTD spike, leading to distinct antigenic profile compared parental other variants. We also found DelS31 mutation decreases pseudovirus infectivity CaLu-3 cells, which correlates with impaired cell-cell fusion. Additionally, protein appears more conformationally stable, as indicated reduced S1 shedding both without stimulation soluble ACE2, increased resistance elevated temperatures. Molecular modeling suggests induces conformational change stabilizes strengthens NTD-Receptor-Binding Domain (RBD) interaction, thus favoring down conformation RBD reducing accessibility ACE2 receptor certain nAbs. introduces an N-linked glycan modification at N30, shields underlying region recognition. data highlight critical role mutations for evasion, stability, viral suggest consideration updating vaccines antigens containing DelS31.

Language: Английский

---

Neutralization and spike stability of JN.1-derived LB.1, KP.2.3, KP.3, and KP.3.1.1 subvariants

mBio, Journal Year: 2025, Volume and Issue: unknown

Published: March 26, 2025

ABSTRACT During the summer of 2024, coronavirus disease 2019 (COVID-19) cases surged globally, driven by variants derived from JN.1 subvariants severe acute respiratory syndrome 2 that feature new mutations, particularly in N-terminal domain (NTD) spike protein. In this study, we report on neutralizing antibody (nAb) escape, infectivity, fusion, and stability these subvariants—LB.1, KP.2.3, KP.3, KP.3.1.1. Our findings demonstrate all are highly evasive nAbs elicited bivalent mRNA vaccine, XBB.1.5 monovalent mumps virus-based or infections during BA.2.86/JN.1 wave. This reduction nAb titers is primarily a single serine deletion (DelS31) NTD spike, leading to distinct antigenic profile compared parental other variants. We also found DelS31 mutation decreases pseudovirus infectivity CaLu-3 cells, which correlates with impaired cell-cell fusion. Additionally, protein appears more conformationally stable, as indicated reduced S1 shedding both without stimulation soluble ACE2 increased resistance elevated temperatures. Molecular modeling suggests enhances NTD-receptor-binding (RBD) interaction, favoring RBD down conformation reducing accessibility specific nAbs. Moreover, introduces an N-linked glycan at N30, shielding recognition. These underscore role mutations immune evasion, stability, viral highlighting need consider DelS31-containing antigens updated COVID-19 vaccines. IMPORTANCE The emergence novel continues pose challenges for global public health, context evasion stability. study identifies key mutation, DelS31, JN.1-derived escape while stabilizes conformation, limits shedding, increases thermal resistance, possibly contribute prolonged persistence. Structural analyses reveal interactions introducing shielding, thus decreasing accessibility. emphasize critical shaping evolution underscoring urgent vaccines account adaptive changes.

Language: Английский

---

From Wuhan to Omicron K.P2 strain: A comprehensive review of SARS-CoV-2 phylogeny and public health implications of the latest booster vaccine

Human Vaccines & Immunotherapeutics, Journal Year: 2025, Volume and Issue: 21(1)

Published: April 11, 2025

The SARS-CoV-2 virus continues to evolve, with the Omicron KP.2 variant, a descendant of BA.2.86, emerging as public health concern due its rapid spread and resistance existing immunity. This review examines phylogenetic evolution SARS-CoV-2, focusing on key mutations (R346T, F456L, V1104L), alongside epidemiological implications. It also discusses development approval KP.2-adapted booster vaccine, shown in clinical trials significantly enhance immune responses protect against symptomatic severe disease, particularly vulnerable groups. Despite vaccine advancements, challenges global distribution inequity persist, especially low- middle-income countries, increasing risk vaccine-resistant variants. manuscript underscores importance equitable access control pandemic prevent future outbreaks, while highlighting need for continuous surveillance broader-spectrum research evolves.

Language: Английский

---

An engineered miniACE2 protein secreted by mesenchymal stromal cells effectively neutralizes multiple SARS-CoV- 2 variants in vitro

Molecular Medicine, Journal Year: 2025, Volume and Issue: 31(1)

Published: April 23, 2025

Abstract SARS-CoV- 2 continues to evolve, producing novel Omicron subvariants through recombinant lineages that acquire new mutations, undermining existing antiviral strategies. The viral fitness and adaptive potential of present significant challenges emergency treatments, particularly monoclonal antibodies, which demonstrate reduced efficacy with the emergence each variant. Consequently, immunocompromised individuals, who are more susceptible severe manifestations COVID- 19 face heightened risks critical complications mortality, remain vulnerable in absence effective treatments. To develop translational approaches can benefit this at-risk population establish broader therapeutic strategies applicable across variants, we previously designed engineered silico miniACE2 decoys (designated BP2, BP9, BP11). These demonstrated promising neutralizing subvariants. In study, leveraged mesenchymal stromal cells (MSCs) for tissue repair immunomodulation lung injuries used these as a platform secretion BP2. Our innovative assays, were conducted BP2 protein secreted into culture supernatant BP2-MSCs, 2, including development advanced platforms holds promise scalability effectively mitigate impact 19, contributing resilient treatment against evolving landscape variants.

Language: Английский

---

In Silico Design of miniACE2 Decoys with In Vitro Enhanced Neutralization Activity against SARS-CoV-2, Encompassing Omicron Subvariants

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(19), P. 10802 - 10802

Published: Oct. 8, 2024

The COVID-19 pandemic has overwhelmed healthcare systems and triggered global economic downturns. While vaccines have reduced the lethality rate of SARS-CoV-2 to 0.9% as October 2024, continuous evolution variants remains a significant public health challenge. Next-generation medical therapies offer hope in addressing this threat, especially for immunocompromised individuals who experience prolonged infections severe illnesses, contributing viral evolution. These cases increase risk new emerging. This study explores miniACE2 decoys novel strategy counteract variants. Using silico design molecular dynamics, blocking proteins (BPs) were developed with stronger binding affinity receptor-binding domain multiple than naturally soluble human ACE2. BPs expressed E. coli tested vitro, showing promising neutralizing effects. Notably, BP9 exhibited an average IC50 4.9 µg/mL across several variants, including Wuhan strain, Mu, Omicron BA.1, BA.2 low demonstrates potent ability BP9, indicating its efficacy at concentrations.Based on these findings, emerged therapeutic candidate combating evolving thereby positioning it potential emergency biopharmaceutical.

Language: Английский

---

SARS-CoV-2 Infection and Alpha-Synucleinopathies: Potential Links and Underlying Mechanisms

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(22), P. 12079 - 12079

Published: Nov. 10, 2024

Alpha-synuclein (α-syn) is a 140-amino-acid, intrinsically disordered, soluble protein that abundantly present in the brain. It plays crucial role maintaining cellular structures and organelle functions, particularly supporting synaptic plasticity regulating neurotransmitter turnover. However, for reasons not yet fully understood, α-syn can lose its physiological begin to aggregate. This altered disrupts dopaminergic transmission causes both presynaptic postsynaptic dysfunction, ultimately leading cell death. A group of neurodegenerative diseases known as α-synucleinopathies characterized by intracellular accumulation deposits specific neuronal glial cells within certain brain regions. In addition Parkinson's disease (PD), these conditions include dementia with Lewy bodies (DLBs), multiple system atrophy (MSA), pure autonomic failure (PAF), REM sleep behavior disorder (RBD). Given disorders are associated α-syn-related neuroinflammation-and considering SARS-CoV-2 infection has been shown affect nervous system, COVID-19 patients experiencing neurological symptoms-it proposed may contribute neurodegeneration PD other promoting misfolding aggregation. this review, we focus on whether could act an environmental trigger facilitates onset or progression α-synucleinopathies. Specifically, new evidence potential modulating function discuss causal relationship between development parkinsonism-like symptoms.

Language: Английский

---