Improved control of SARS-CoV-2 by treatment with a nucleocapsid-specific monoclonal antibody

Journal of Clinical Investigation, Год журнала: 2022, Номер 132(23)

Опубликована: Окт. 11, 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main antigen in all approved COVID-19 vaccines and also only target for monoclonal antibody (mAb) therapies. Immune responses to other viral antigens are generated after SARS-CoV-2 infection, but their contribution antiviral response remains unclear. Here, we interrogated whether nucleocapsid-specific antibodies can improve protection against SARS-CoV-2. We first immunized mice with a nucleocapsid-based vaccine then transferred sera from these into naive mice, followed by challenge show that received or mAb exhibited enhanced control of Nucleocapsid-specific elicited NK-mediated, antibody-dependent cellular cytotoxicity (ADCC) infected cells. To our knowledge, findings provide demonstration literature specific nucleocapsid clearance, providing rationale clinical evaluation therapies treat COVID-19.

Язык: Английский

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Pre-existing immunity modulates responses to mRNA boosters

Cell Reports, Год журнала: 2023, Номер 42(3), С. 112167 - 112167

Опубликована: Фев. 15, 2023

mRNA vaccines are effective in preventing severe COVID-19, but breakthrough infections, emerging variants, and waning immunity warrant the use of boosters. Although boosters being implemented, extent to which pre-existing influences efficacy remains unclear. In a cohort individuals primed with mRNA-1273 or BNT162b2 vaccines, we report that lower antibody levels before boost associated higher fold-increase after boost, suggesting modulates immunogenicity vaccines. Our studies mice show antibodies accelerate clearance vaccine antigen via Fc-dependent mechanisms, limiting amount available prime B cell responses These data demonstrate "tug war" between de novo following vaccination, they suggest transient downmodulation effector function may improve

Язык: Английский

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Treatments for COVID-19

Annual Review of Medicine, Год журнала: 2023, Номер 75(1), С. 145 - 157

Опубликована: Сен. 19, 2023

The treatment for COVID-19 has evolved rapidly since the start of pandemic and now consists mainly antiviral immunomodulatory agents. Antivirals, such as remdesivir nirmatrelvir-ritonavir, have proved to be most useful earlier in illness (e.g., outpatient therapy) less severe disease. Immunomodulatory therapies, dexamethasone interleukin-6 or Janus kinase inhibitors, are disease critical illness. role anti-SARS-CoV-2 monoclonal antibodies diminished because emergence viral variants that not anticipated susceptible these treatments, there still is a consensus on use convalescent plasma. been associated with increased rates venous thromboembolism, but antithrombotic therapy limited. Multiple investigational agents continue studied, which will alter current paradigms new data released.

Язык: Английский

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Protective mechanisms of nonneutralizing antiviral antibodies

PLoS Pathogens, Год журнала: 2023, Номер 19(10), С. e1011670 - e1011670

Опубликована: Окт. 5, 2023

Antibodies that can bind to viruses but are unable block infection in cell culture known as "nonneutralizing antibodies." Such antibodies nearly universally elicited following viral and have been characterized infections such influenza, rotavirus, cytomegalovirus, HIV, SARS-CoV-2. It has widely assumed these nonneutralizing do not function a protective way vivo therefore desirable targets of antiviral interventions; however, increasing evidence now shows this be true. Several virus-specific antibody responses correlated with protection human studies also shown significantly reduce virus replication animal models. The mechanisms by which many is only coming light. While cannot prevent entering their host cell, work the extracellular space recruit effector proteins or cells destroy antibody-virus complex. Other exert effects inside cells, either blocking life cycle directly recruiting intracellular Fc receptor TRIM21. In review, we will discuss multitude ways against range infections.

Язык: Английский

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The preference signature of the SARS-CoV-2 Nucleocapsid NTD for its 5’-genomic RNA elements

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июнь 7, 2023

Abstract The nucleocapsid protein (N) of SARS-CoV-2 plays a pivotal role during the viral life cycle. It is involved in RNA transcription and accounts for packaging large genome into virus particles. N manages enigmatic balance bulk RNA-coating versus precise RNA-binding to designated cis-regulatory elements. Numerous studies report involvement its disordered segments non-selective RNA-recognition, but how organizes inevitable recognition specific motifs remains unanswered. We here use NMR spectroscopy systematically analyze interactions N’s N-terminal domain (NTD) with individual cis elements clustering regulatory 5’-genomic end. Supported by broad solution-based biophysical data, we unravel NTD preferences natural context. show that domain’s flexible regions read intrinsic signature preferred selective stable complex formation within pool available motifs.

Язык: Английский

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OVX033, a nucleocapsid-based vaccine candidate, provides broad-spectrum protection against SARS-CoV-2 variants in a hamster challenge model

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Июнь 19, 2023

Spike-based COVID-19 vaccines induce potent neutralizing antibodies but their efficacy against SARS-CoV-2 variants decreases. OVX033 is a recombinant protein composed of the full-length nucleocapsid (N) genetically fused to oligoDOM ® , self-assembling domain which improves antigen immunogenicity. including N as an antigenic target proposed new vaccine candidate providing broad-spectrum protection sarbecoviruses. demonstrated its ability trigger cross-reactive T cell responses and cross-protection three (B.1 Europe, Delta B.1.617.2, Omicron B.1.1.529) in hamster challenge model, evidenced by lower weight loss, lung viral loads, reduced histopathological lesions.

Язык: Английский

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The role of SARS-CoV-2 nucleocapsid protein in antiviral immunity and vaccine development

Emerging Microbes & Infections, Год журнала: 2022, Номер 12(1)

Опубликована: Дек. 30, 2022

ABSTRACTThe coronavirus disease 2019 (COVID-19) has caused enormous health risks and global economic disruption. This is by the severe acute respiratory syndrome 2 (SARS-CoV-2). The SARS-CoV-2 nucleocapsid protein a structural involved in viral replication assembly. There accumulating evidence indicating that multi-functional, playing key role pathogenesis of COVID-19 antiviral immunity against SARS-CoV-2. Here, we summarize its potential application prevention COVID-19, which based on inflammation, cell death, innate immunity, adaptive immunity.

Язык: Английский

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Importance, Applications and Features of Assays Measuring SARS-CoV-2 Neutralizing Antibodies

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5352 - 5352

Опубликована: Март 10, 2023

More than three years ago, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused unforeseen COVID-19 pandemic with millions of deaths. In meantime, SARS-CoV-2 has become endemic and is now part repertoire viruses causing seasonal severe respiratory infections. Due to several factors, among them development immunity through natural infection, vaccination current dominance seemingly less pathogenic strains belonging omicron lineage, situation stabilized. However, challenges remain possible new occurrence highly variants remains a threat. Here we review development, features importance assays measuring neutralizing antibodies (NAbs). particular focus on in vitro infection molecular interaction studying binding receptor domain (RBD) its cognate cellular ACE2. These assays, but not measurement SARS-CoV-2-specific per se, can inform us whether produced by convalescent or vaccinated subjects may protect against thus have potential predict risk becoming newly infected. This information extremely important given fact that considerable number subjects, vulnerable persons, respond poorly production antibodies. Furthermore, these allow determine evaluate virus-neutralizing capacity induced vaccines administration plasma-, immunoglobulin preparations, monoclonal antibodies, ACE2 synthetic compounds be used for therapy assist preclinical evaluation vaccines. Both types relatively quickly adapted emerging virus about magnitude cross-neutralization, which even estimate infected appearing variants. Given paramount discuss their specific features, advantages disadvantages, technical aspects yet fully resolved issues, such as cut-off levels predicting degree vivo protection.

Язык: Английский

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The role of SARS-CoV-2 N protein in diagnosis and vaccination in the context of emerging variants: present status and prospects

Frontiers in Microbiology, Год журнала: 2023, Номер 14

Опубликована: Авг. 14, 2023

Despite many countries rapidly revising their strategies to prevent contagions, the number of people infected with Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues surge. The emergent variants that can evade immune response significantly affect effectiveness mainstream vaccines and diagnostic products based on original spike protein. Therefore, it is essential focus highly conserved nature nucleocapsid protein as a potential target in field diagnostics. In this regard, our review initially discusses structure, function, mechanism action N Based discussion, we summarize relevant research in-depth development application methods protein, such serology nucleic acid detection. Such valuable information aid designing more efficient vaccine tools could help end SARS-CoV-2 pandemic.

Язык: Английский

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Modulation of biophysical properties of nucleocapsid protein in the mutant spectrum of SARS-CoV-2

eLife, Год журнала: 2024, Номер 13

Опубликована: Фев. 6, 2024

Genetic diversity is a hallmark of RNA viruses and the basis for their evolutionary success. Taking advantage uniquely large genomic database SARS-CoV-2, we examine impact mutations across spectrum viable amino acid sequences on biophysical phenotypes highly expressed multifunctional nucleocapsid protein. We find variation in physicochemical parameters its extended intrinsically disordered regions (IDRs) sufficient to allow local plasticity, but also observe functional constraints that similarly occur related coronaviruses. In experiments with several N-protein species carrying associated major variants, point IDRs can have nonlocal modulate thermodynamic stability, secondary structure, protein oligomeric state, particle formation, liquid-liquid phase separation. Omicron variant, distant different compensatory effects shifting delicate balance interactions controlling assembly properties, include creation new protein-protein interaction interface N-terminal IDR through defining P13L mutation. A picture emerges where genetic accompanied by significant characteristics species, particular IDRs.

Язык: Английский

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