An update on the anti-spike monoclonal antibody pipeline for SARS-CoV-2

Clinical Microbiology and Infection, Год журнала: 2024, Номер 30(8), С. 999 - 1006

Опубликована: Апрель 24, 2024

Язык: Английский

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Molecular insights into the adaptive evolution of SARS-CoV-2 spike protein

Journal of Infection, Год журнала: 2024, Номер 88(3), С. 106121 - 106121

Опубликована: Фев. 16, 2024

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has substantially damaged global economy and human health. spike (S) protein of coronaviruses plays a pivotal role in viral entry binding to host cell receptors. Additionally, it acts as primary target for neutralizing antibodies those infected is central focus currently utilized or researched vaccines. During virus's adaptation host, S SARS-CoV-2 undergone significant evolution. As pandemic unfolded, new mutations have arisen vanished, giving rise distinctive amino acid profiles within variant concern strains SARS-CoV-2. Notably, many these changes been positively selected, leading substantial alterations characteristics, such heightened transmissibility immune evasion capabilities. This review aims provide an overview our current understanding structural implications associated with key These research findings shed light on intricate dynamic nature evolution, underscoring importance continuous monitoring analysis genomes. Through molecular-level investigations, we can attain deeper insights into adaptive offering valuable guidance designing vaccines developing antiviral drugs combat ever-evolving threats.

Язык: Английский

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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), Год журнала: 2024, Номер unknown

Опубликована: Сен. 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.

Язык: Английский

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Spike N354 glycosylation augments SARS-CoV-2 fitness for human adaptation through structural plasticity

National Science Review, Год журнала: 2024, Номер 11(7)

Опубликована: Июнь 13, 2024

ABSTRACT Selective pressures have given rise to a number of SARS-CoV-2 variants during the prolonged course COVID-19 pandemic. Recently evolved differ from ancestors in additional glycosylation within spike protein receptor-binding domain (RBD). Details how acquisition impacts viral fitness and human adaptation are not clearly understood. Here, we dissected role N354-linked glycosylation, acquired by BA.2.86 sub-lineages, as RBD conformational control element attenuating infectivity. The reduced infectivity is recovered presence heparin sulfate, which targets ‘N354 pocket’ ease restrictions transition resulting ‘RBD-up’ state, thereby conferring an adjustable Furthermore, N354 improved cleavage cell–cell fusion, particular escaped one subset ADCC antibodies. Together with immunogenicity hybrid immunity background, these indicate single amino acid event provides selective advantage humans through multiple mechanisms.

Язык: Английский

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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

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Structural basis for the evolution and antibody evasion of SARS-CoV-2 BA.2.86 and JN.1 subvariants

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Сен. 4, 2024

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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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

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Tracking the genetic diversity of SARS-CoV-2 variants in Nicaragua throughout the COVID-19 pandemic

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Фев. 9, 2025

Abstract The global circulation of SARS-CoV-2 has been extensively documented; however, the dynamics within Central America, particularly Nicaragua, remain underexplored. This study characterizes genomic diversity in Nicaragua from March 2020 through December 2022, utilizing 1064 genomes obtained via next-generation sequencing. These sequences were selected nationwide and analyzed for variant classification, lineage predominance, phylogenetic diversity. We employed both Illumina Oxford Nanopore Technologies all sequencing procedures. Results indicated a temporal spatial shift dominant lineages, initially B.1 A.2 early to various Omicron subvariants toward study’s end. Significant shifts correlated with changes COVID-19 positivity rates, underscoring epidemiological impact dissemination. Comparative analysis regional data underscored low circulating lineages their delayed introduction compared other countries American region. also linked specific viral mutations hospitalization emphasizing clinical relevance surveillance. research advances understanding evolution provides valuable information regarding its genetic public health officials America. highlight critical role ongoing surveillance identifying emergent informing strategies.

Язык: Английский

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