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Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults

Killingley et al., Nature Medicine, doi:10.1038/s41591-022-01780-9, NCT04865237
Mar 2022  
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Peak symptom score -60% Improvement Relative Risk Remdesivir  Killingley et al.  EARLY TREATMENT Is early treatment with remdesivir beneficial for COVID-19? Prospective study of 18 patients in the United Kingdom (Mar - Jul 2021) Higher progression with remdesivir (not stat. sig., p=0.43) c19early.org Killingley et al., Nature Medicine, Mar 2022 Favorsremdesivir Favorscontrol 0 0.5 1 1.5 2+
SARS-CoV-2 challenge study in 36 low-risk young adults. Infected participants had high viral loads peaking around 5 days post-exposure, mild-to-moderate upper respiratory symptoms, and anosmia, but no severe disease. Remdesivir had no significant effect on viral kinetics or symptoms. There was a 1-2 day delay before significant viral spread. A majority of patients reported symptoms prior to significant viral spread, supporting the use of early treatment targeted at the upper respiratory tract as a promising approach to limit progression of SARS-CoV-2.
Gérard, Zhou, Wu, Kamo, Choi, Kim show significantly increased risk of acute kidney injury with remdesivir.
peak symptom score, 60.1% higher, RR 1.60, p = 0.43, treatment mean 8.48 (±8.1) n=6, control mean 5.3 (±7.7) n=12, relative peak symptom score.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Killingley et al., 31 Mar 2022, prospective, United Kingdom, peer-reviewed, mean age 21.8, 31 authors, study period March 2021 - July 2021, trial NCT04865237 (history). Contact: c.chiu@imperial.ac.uk.
This PaperRemdesivirAll
Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults
Ben Killingley, Alex J Mann, Mariya Kalinova, Alison Boyers, Niluka Goonawardane, Jie Zhou, Kate Lindsell, Samanjit S Hare, Jonathan Brown, Rebecca Frise, Emma Smith, Claire Hopkins, Nicolas Noulin, Brandon Löndt, Tom Wilkinson, Stephen Harden, Helen Mcshane, Mark Baillet, Anthony Gilbert, Michael Jacobs, Christine Charman, Priya Mande, Jonathan S Nguyen-Van-Tam, Malcolm G Semple, Robert C Read, Neil M Ferguson, Peter J Openshaw, Garth Rapeport, Wendy S Barclay, Andrew P Catchpole, Christopher Chiu
Nature Medicine, doi:10.1038/s41591-022-01780-9
oronavirus disease 2019 (COVID-19) is a complex clinical syndrome caused by SARS-CoV-2. Despite extensive research into severe disease of hospitalized patients 1 and many large studies leading to approval of vaccines and antivirals 2-4 , the global spread of SARS-CoV-2 continues and is, indeed, accelerating in many regions. Infections are typically mild or asymptomatic in younger people, but these likely drive community transmission 5 , and the detailed time course of infection and infectivity in this context has not been fully elucidated 6, 7 . Deliberate human infection of low-risk volunteers enables the exact longitudinal measurement of viral kinetics, immunological responses, transmission dynamics and duration of infectious shedding after a fixed dose of Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults
Online content Any methods, additional references, Nature Research reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at https://doi.org/10.1038/ s41591-022-01780-9 . Articles Nature MediciNe V-Spot image analyzer, with virus titer determined by calculating the average spot number and subtraction of background spot count from the negative control wells. Serum antibody assays. Serum samples were analyzed at Nexelis to determine SARS-CoV-2 anti-spike IgG concentrations by ELISA (reported as ELU ml -1 ). Neutralizing antibody titers for live SARS-CoV-2 virus (lineage Victoria/01/2020) were determined by microneutralization assay at the UK Health Security Agency and reported as the 50% neutralizing antibody titer (NT 50 ). For the microneutralization assay, lower limit of detection (LLOD) was 58, and undetectable samples were assigned a value of 29. For the spike protein IgG ELISA, LLOD was 50.2 ELU ml -1 , and undetectable samples were assigned a value of 25 ELU ml -1 . Lateral flow rapid antigen assays. LFAs were performed using the Innova SARS-CoV-2 antigen rapid quantitative test kit (BT1309) as per the manufacturer's recommendations with adaptations as follows. This commercially available kit is designed to detect the presence of the SARS-CoV-2 nucleocapsid protein through in vitro..
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' 'and hold shares in Open Orphan and Poolbeg Pharma. A.G. is previous employee at ' 'hVIVO Services Ltd. and holds shares in Open Orphan and Poolbeg Pharma. G.R. is ' 'a co-founder of SubIntro Ltd. M.G.S. is Director of MedEx Solutions Ltd., ' 'chairs the Infectious Disease Scientific Advisory Board of Integrum Scientific ' 'LLC and holds shares in Integrum Scientific LLC and MedEx Solutions Ltd. T.W. ' 'has received research grants and/or fees from AstraZeneca, UCB, Bergenbio, ' 'Synairgen, Valneva and my mhealth (MMH) in the field of COVID-19 research. T.W. ' 'owns shares in Open Orphan and MMH. T.W. is a director of MMH. J.S.N.-V.-T. is ' 'seconded to the Department of Health and Social Care, England.', 'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}, { 'value': 'This content has been made available to all.', 'name': 'free', 'label': 'Free to read'}]}
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