Sotrovimab: A Review of Its Efficacy against SARS-CoV-2 Variants

Viruses, Год журнала: 2024, Номер 16(2), С. 217 - 217

Опубликована: Янв. 31, 2024

Among the anti-Spike monoclonal antibodies (mAbs), S-309 derivative sotrovimab was most successful in having longest temporal window of clinical use, showing a high degree resiliency to SARS-CoV-2 evolution interrupted only by appearance BA.2.86* variant interest (VOI). This success undoubtedly reflects rational selection target highly conserved epitope coronavirus Spike proteins. We review here efficacy against different variants outpatients and inpatients, discussing both randomized controlled trials real-world evidence. Although it could not be anticipated at time its development introduction, sotrovimab's use immunocompromised individuals who harbor large populations viruses created conditions for eventual demise, as antibody viral led withdrawal due inefficacy later lineages. Despite this, based on observational data, some authorities have continued promote sotrovimab, but lack binding newer strongly argues futility use. The story highlights power modern biomedical science generate novel therapeutics while also providing cautionary tale need devise strategies minimize emergence resistance antibody-based therapeutics.

Язык: Английский

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Target-based drug design strategies to overcome resistance to antiviral agents: opportunities and challenges

Drug Resistance Updates, Год журнала: 2024, Номер 73, С. 101053 - 101053

Опубликована: Янв. 26, 2024

Язык: Английский

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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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COVID-19 therapeutics

Clinical Microbiology Reviews, Год журнала: 2024, Номер 37(2)

Опубликована: Май 21, 2024

SUMMARYSince the emergence of COVID-19 in 2020, an unprecedented range therapeutic options has been studied and deployed. Healthcare providers have multiple treatment approaches to choose from, but efficacy those often remains controversial or compromised by viral evolution. Uncertainties still persist regarding best therapies for high-risk patients, drug pipeline is suffering fatigue shortage funding. In this article, we review antiviral activity, mechanism action, pharmacokinetics, safety therapies. Additionally, summarize evidence from randomized controlled trials on various antivirals discuss unmet needs which should be addressed.

Язык: Английский

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SARS-CoV-2 evolution during prolonged infection in immunocompromised patients

mBio, Год журнала: 2024, Номер 15(3)

Опубликована: Фев. 16, 2024

ABSTRACT Prolonged infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in immunocompromised patients provides an opportunity for viral evolution, potentially leading to the generation of new pathogenic variants. To investigate pathways we carried out a study on five experiencing prolonged SARS-CoV-2 (quantitative polymerase chain reaction-positive 79–203 days) who were due treatment lymphoma or solid organ transplantation. For each timepoint analyzed, generated at least two independent genome sequences assess heterogeneity and control sequencing error. Four likely had infection; fifth apparently experienced reinfection. The rates accumulation substitutions per day higher hospitalized than those estimated community background. spike coding region accumulated significantly greater number unique mutations other regions, mutation density was higher. Two treated monoclonal antibodies (bebtelovimab sotrovimab); by next sampled timepoint, virus population showed associated antibody resistance as dominant forms ( K444N E340D). All received remdesivir, but remdesivir-resistant not detected. These data thus help elucidate trends emergence, selection mutational variants within long-term infected individuals. IMPORTANCE is responsible global pandemic, driven part emergence Where do these come from? One model that persistence individuals allows evolution response host pressures, resulting viruses more replicate efficiently humans. In this study, characterize replication several individuals, documenting efficient evolution.

Язык: Английский

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Clinical and Virological Outcome of Monoclonal Antibody Therapies Across SARS-CoV-2 Variants in 245 Immunocompromised Patients: A Multicenter Prospective Cohort Study

Clinical Infectious Diseases, Год журнала: 2024, Номер 78(6), С. 1514 - 1521

Опубликована: Март 6, 2024

Abstract Background Immunocompromised patients (ICPs) have an increased risk for a severe and prolonged COVID-19. SARS-CoV-2 monoclonal antibodies (mAbs) were extensively used in these patients, but data from randomized trials that focus on ICPs are lacking. We evaluated the clinical virological outcome of COVID-19 treated with mAbs across variants. Methods In this multicenter prospective cohort study, we enrolled B-cell– and/or T-cell–deficient casirivimab/imdevimab, sotrovimab, or tixagevimab/cilgavimab. RNA was quantified sequenced weekly, time to viral clearance, genome mutations, hospitalization, death rates registered. Results Two hundred forty five infected Delta (50%) Omicron BA.1, 2, 5 variant enrolled. Sixty-seven percent vaccinated; 78 as outpatients, whom 2 required hospital admission, both survived. Of 159 hospitalized at treatment, 43 (27%) mechanical ventilation died. The median clearance 14 days (interquartile range, 7–22); however, it took >30 15%. Resistance-associated spike mutations emerged 9 63 (95% confidence interval, 57–69; P < .001). Spike observed 1 42 (2.4%) after treatment active mAbs, 34 (14.7%) actual monotherapy (sotrovimab), 3 20 (12%) functional (ie, tixagevimab/cilgavimab against tixagevimab-resistant variant). Conclusions Despite morbidity mortality remained substantial. Combination antiviral therapy should be further explored may preferred severely ICPs.

Язык: Английский

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Deep mutational scanning reveals functional constraints and antibody-escape potential of Lassa virus glycoprotein complex

Immunity, Год журнала: 2024, Номер 57(9), С. 2061 - 2076.e11

Опубликована: Июль 15, 2024

Lassa virus is estimated to cause thousands of human deaths per year, primarily due spillovers from its natural host, Mastomys rodents. Efforts create vaccines and antibody therapeutics must account for the evolutionary variability virus's glycoprotein complex (GPC), which mediates viral entry into cells target neutralizing antibodies. To map space accessible GPC, we used pseudovirus deep mutational scanning measure how nearly all GPC amino-acid mutations affected cell neutralization. Our experiments defined functional constraints throughout GPC. We quantified neutralization with a panel monoclonal All antibodies tested were escaped by that existed among lineages. Overall, our work describes biosafety-level-2 method elucidate shows prospective characterization antigenic variation could aid design vaccines.

Язык: Английский

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Estimates of actual and potential lives saved in the United States from the use of COVID-19 convalescent plasma

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(41)

Опубликована: Окт. 1, 2024

In the Spring of 2020, United States America (USA) deployed COVID-19 convalescent plasma (CCP) to treat hospitalized patients. Over 500,000 patients were treated with CCP during first year pandemic. this study, we estimated number actual inpatient lives saved by treatment in based on weekly use, national mortality data, and reduction data from meta-analyses randomized controlled trials real-world data. We also estimate potential if had been for 100% or used 15 75% outpatients. Depending assumptions modeled stratified analyses, that between 16,476 66,296 lives. The ideal use might have as many 234,869 prevented 1,136,133 hospitalizations. deployment was a successful strategy ameliorating impact pandemic USA. This experience has important implications future infectious disease emergencies.

Язык: Английский

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Compositional features analysis by machine learning in genome represents linear adaptation of monkeypox virus

Frontiers in Genetics, Год журнала: 2024, Номер 15

Опубликована: Март 1, 2024

Introduction: The global headlines have been dominated by the sudden and widespread outbreak of monkeypox, a rare endemic zoonotic disease caused monkeypox virus (MPXV). Genomic composition based machine learning (ML) methods recently shown promise in identifying host adaptability evolutionary patterns virus. Our study aimed to analyze genomic characteristics MPXV using ML methods. Methods: open reading frame (ORF) regions full-length genomes were filtered 165 ORFs selected as clusters with highest homology. Unsupervised t-distributed stochastic neighbor embedding (t-SNE), Principal Component Analysis (PCA), hierarchical clustering performed observe DCR ORF clusters. Results: results showed that sequences post-2022 an obvious linear adaptive evolution, indicating it has become more adapted human after accumulating mutations. For further accurate analysis, larger variations out on ranking homology difference narrow down key clusters, which drew same conclusion adaptability. Then differential protein structures predicted AlphaFold 2, meant main domains might be one internal reasons for evolution. Discussion: Understanding process adaptation is critical constant struggle between viruses their hosts, playing significant role crafting effective measures tackle viral diseases. Therefore, present provides valuable insights into 2022 from perspective analysis through

Язык: Английский

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Potent and broadly neutralizing antibodies against sarbecoviruses elicited by single ancestral SARS-CoV-2 infection

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

Опубликована: Июнь 7, 2024

Abstract Monoclonal antibody (mAb) therapeutics hold promise for both preventing and treating infectious diseases, especially among vulnerable populations. However, the emergence of various variants severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents challenges current mAb treatments, emphasizing need more potent broadly neutralizing antibodies. In this study, we employed an unbiased screening approach to discover antibodies successfully isolated two mAbs from individuals with only exposure ancestral SARS-CoV-2. One these antibodies, CYFN1006-1, exhibited robust cross-neutralization against a spectrum SARS-CoV-2 variants, including latest JN.1 KP.2 consistent IC 50 values ranging ∼1 5 ng/mL. Notably, it also displayed broad neutralization activity SARS-CoV related sarbecoviruses, such as WIV1, SHC014, RaTG13, GD-Pangolin. Structural analysis revealed that target shared hotspot but mutation-resistant epitopes, their Fabs locking RBD in “down” conformation through interactions adjacent RBDs, cross-linking Spike trimers into di-trimers block viral infection. vivo studies conducted JN.1-infected hamster model validated protective efficacy its therapeutic potential. These findings suggest that, meticulous approaches, rare activities sarbecoviruses can be identified exclusively virus exposure.

Язык: Английский

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