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2.
Clin Infect Dis ; 2022 Feb 13.
Article in English | MEDLINE | ID: covidwho-1816034

ABSTRACT

COVID-19 symptom definitions rarely include symptom severity. We collected daily nasal swabs and symptom diaries from contacts of SARS-CoV-2 cases. Requiring ≥1 moderate or severe symptom reduced sensitivity to predict SARS-CoV-2 shedding from 60.0% (CI: 52.9-66.7%) to 31.5% (CI: 25.7-38.0%), but increased specificity from 77.5% (CI:75.3-79.5%) to 93.8% (CI: 92.7-94.8%).

3.
Nat Biotechnol ; 2022 Apr 28.
Article in English | MEDLINE | ID: covidwho-1815566

ABSTRACT

We designed a protein biosensor that uses thermodynamic coupling for sensitive and rapid detection of neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants in serum. The biosensor is a switchable, caged luciferase-receptor-binding domain (RBD) construct that detects serum-antibody interference with the binding of virus RBD to angiotensin-converting enzyme 2 (ACE-2) as a proxy for neutralization. Our coupling approach does not require target modification and can better distinguish sample-to-sample differences in analyte binding affinity and abundance than traditional competition-based assays.

4.
JCI Insight ; 7(10)2022 May 23.
Article in English | MEDLINE | ID: covidwho-1794308

ABSTRACT

BACKGROUNDMeasuring the immune response to SARS-CoV-2 enables assessment of past infection and protective immunity. SARS-CoV-2 infection induces humoral and T cell responses, but these responses vary with disease severity and individual characteristics.METHODSA T cell receptor (TCR) immunosequencing assay was conducted using small-volume blood samples from 302 individuals recovered from COVID-19. Correlations between the magnitude of the T cell response and neutralizing antibody (nAb) titers or indicators of disease severity were evaluated. Sensitivity of T cell testing was assessed and compared with serologic testing.RESULTSSARS-CoV-2-specific T cell responses were significantly correlated with nAb titers and clinical indicators of disease severity, including hospitalization, fever, and difficulty breathing. Despite modest declines in depth and breadth of T cell responses during convalescence, high sensitivity was observed until at least 6 months after infection, with overall sensitivity ~5% greater than serology tests for identifying prior SARS-CoV-2 infection. Improved performance of T cell testing was most apparent in recovered, nonhospitalized individuals sampled > 150 days after initial illness, suggesting greater sensitivity than serology at later time points and in individuals with less severe disease. T cell testing identified SARS-CoV-2 infection in 68% (55 of 81) of samples with undetectable nAb titers (<1:40) and in 37% (13 of 35) of samples classified as negative by 3 antibody assays.CONCLUSIONThese results support TCR-based testing as a scalable, reliable measure of past SARS-CoV-2 infection with clinical value beyond serology.TRIAL REGISTRATIONSpecimens were accrued under trial NCT04338360 accessible at clinicaltrials.gov.FUNDINGThis work was funded by Adaptive Biotechnologies, Frederick National Laboratory for Cancer Research, NIAID, Fred Hutchinson Joel Meyers Endowment, Fast Grants, and American Society for Transplantation and Cell Therapy.

5.
Sci Rep ; 12(1): 5856, 2022 04 07.
Article in English | MEDLINE | ID: covidwho-1784021

ABSTRACT

Rapid dissemination of SARS-CoV-2 sequencing data to public repositories has enabled widespread study of viral genomes, but studies of longitudinal specimens from infected persons are relatively limited. Analysis of longitudinal specimens enables understanding of how host immune pressures drive viral evolution in vivo. Here we performed sequencing of 49 longitudinal SARS-CoV-2-positive samples from 20 patients in Washington State collected between March and September of 2020. Viral loads declined over time with an average increase in RT-QPCR cycle threshold of 0.87 per day. We found that there was negligible change in SARS-CoV-2 consensus sequences over time, but identified a number of nonsynonymous variants at low frequencies across the genome. We observed enrichment for a relatively small number of these variants, all of which are now seen in consensus genomes across the globe at low prevalence. In one patient, we saw rapid emergence of various low-level deletion variants at the N-terminal domain of the spike glycoprotein, some of which have previously been shown to be associated with reduced neutralization potency from sera. In a subset of samples that were sequenced using metagenomic methods, differential gene expression analysis showed a downregulation of cytoskeletal genes that was consistent with a loss of ciliated epithelium during infection and recovery. We also identified co-occurrence of bacterial species in samples from multiple hospitalized individuals. These results demonstrate that the intrahost genetic composition of SARS-CoV-2 is dynamic during the course of COVID-19, and highlight the need for continued surveillance and deep sequencing of minor variants.


Subject(s)
COVID-19 , COVID-19/genetics , Genome, Viral , Humans , Metagenome , Metagenomics , SARS-CoV-2/genetics
6.
J Infect Dis ; 2022 Feb 12.
Article in English | MEDLINE | ID: covidwho-1774394

ABSTRACT

While detection of SARS-CoV-2 by diagnostic RT-PCR is highly sensitive for viral RNA, the nucleic acid amplification of subgenomic RNAs (sgRNA) that are the product of viral replication may more accurately identify replication. We characterized the diagnostic RT-PCR and sgRNA detection from nasal swabs collected daily by participants in post exposure prophylaxis or treatment studies for SARS-CoV-2. Among 1932 RT-PCR-positive swabs with sgRNA tests, 40% (767) had detectable sgRNA. Above a diagnostic PCR viral load threshold of 5.1 log10 copies/mL, 96% of samples had detectable sgRNA with viral loads that followed a linear trend. The trajectories of diagnostic and sgRNA viral loads differed, with 80% peaking on the same day but duration of sgRNA detection being shorter (8 versus 14 days). With a large sample of daily swabs we provide comparative sgRNA kinetics and a diagnostic PCR threshold that correlates with replicating virus independent of symptoms or duration of illness.

8.
Nat Commun ; 13(1): 1547, 2022 03 17.
Article in English | MEDLINE | ID: covidwho-1751715

ABSTRACT

SARS-CoV-2 remdesivir resistance mutations have been generated in vitro but have not been reported in patients receiving treatment with the antiviral agent. We present a case of an immunocompromised patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection. Remdesivir therapy alleviated symptoms and produced a transient virologic response, but her course was complicated by recrudescence of high-grade viral shedding. Whole genome sequencing identified a mutation, E802D, in the nsp12 RNA-dependent RNA polymerase, which was not present in pre-treatment specimens. In vitro experiments demonstrated that the mutation conferred a ~6-fold increase in remdesivir IC50 but resulted in a fitness cost in the absence of remdesivir. Sustained clinical and virologic response was achieved after treatment with casirivimab-imdevimab. Although the fitness cost observed in vitro may limit the risk posed by E802D, this case illustrates the importance of monitoring for remdesivir resistance and the potential benefit of combinatorial therapies in immunocompromised patients with SARS-CoV-2 infection.


Subject(s)
COVID-19 , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , Coronavirus RNA-Dependent RNA Polymerase , Female , Humans , Immunocompromised Host , Mutation , SARS-CoV-2/genetics
9.
Clin Infect Dis ; 74(6): 1089-1092, 2022 03 23.
Article in English | MEDLINE | ID: covidwho-1703666

ABSTRACT

Across 20 vaccine breakthrough cases detected at our institution, all 20 (100%) infections were due to variants of concern (VOCs) and had a median Ct of 20.2 (IQR, 17.1-23.3). When compared with 5174 contemporaneous samples sequenced in our laboratory, VOCs were significantly enriched among breakthrough infections (P < .05).


Subject(s)
COVID-19 , SARS-CoV-2 , Base Sequence , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Washington/epidemiology
10.
Int J Infect Dis ; 117: 287-294, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1670581

ABSTRACT

OBJECTIVES: This study assesses and compares the performance of different swab types and specimen collection sites for SARS-CoV-2 testing, to reference standard real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and viral culture. METHODS: Symptomatic adults with COVID-19 who visited routine COVID-19 testing sites used spun polyester and FLOQSwabs to self-collect specimens from the anterior nares and tongue. We evaluated the self-collected specimen from anterior nares and tongue swabs for the nucleocapsid (N) or spike (S) antigen of SARS-CoV-2 by RT-PCR and then compared these results with results from RT-PCR and viral cultures from nurse-collected nasopharyngeal swabs. RESULTS: Diagnostic sensitivity was highest for RT-PCR testing conducted using specimens from the anterior nares collected on FLOQSwabs (84%; 95% CI 68-94%) and spun polyester swabs (82%; 95% CI 66-92%), compared to RT-PCR tests conducted using specimens from nasopharyngeal swabs. Relative to viral culture from nasopharyngeal swabs, diagnostic sensitivities were higher for RT-PCR and antigen testing of anterior nares swabs (91-100%) than that of tongue swabs (18-81%). Antigen testing of anterior nares swabs had higher sensitivities against viral culture (91%) than against nasopharyngeal RT-PCR (38-70%). All investigational tests had high specificity compared with nasopharyngeal RT-PCR. Spun polyester swabs are equally effective as FLOQSwabs for anterior nasal RT-PCR testing. CONCLUSIONS: We found that anterior nares specimens were more sensitive than tongue swab specimens or antigen testing for detecting SARS-CoV-2 by RT-PCR. Thus, self-collected anterior nares specimens may represent an alternative method for diagnostic SARS-CoV-2 testing in some settings.


Subject(s)
COVID-19 , Nucleic Acids , Adult , COVID-19/diagnosis , COVID-19 Testing , Humans , Nasopharynx , Nucleocapsid/genetics , Polymerase Chain Reaction , SARS-CoV-2/genetics , Sensitivity and Specificity , Specimen Handling/methods , Tongue
11.
Clin Epidemiol ; 14: 115-125, 2022.
Article in English | MEDLINE | ID: covidwho-1666857

ABSTRACT

PURPOSE: To examine associations between male sex and SARS-CoV-2 test positivity, severe COVID-19 disease, and death in a single-site cohort, and assess whether male sex impacts risk for severe COVID-19 disease through socioeconomic status (SES), comorbidities, or inflammation. MATERIALS AND METHODS: We conducted a retrospective cohort study with data collected from University of Washington Medicine EMR from March 1 to September 29, 2020. All persons, regardless of age, were included if they had a conclusive diagnostic COVID-19 PCR test result. Our exposure was sex assigned at birth. We used Poisson regression to assess associations between sex and COVID-19 test positivity, disease severity and COVID-19 related death, and linear regression to compare viral cycle threshold at the first positive test. We conducted mediation analyses to assess interventional indirect effects of male sex on severe COVID-19 risk through socioeconomic status (SES, based on area deprivation and insurance type), comorbidities, and inflammation status. Models controlled for age and race/ethnicity. RESULTS: Of 32,919 males and 34,733 females included, 1469 (4.5%) and 1372 (4.0%) tested positive for SARS-CoV-2, respectively. Males were 14% more likely to test positive (RR = 1.14; 95% CI: 1.06-1.23), had 80% higher risk for severe COVID-19 disease (RR = 1.80; 95% CI: 1.39-2.33) and had 58% higher risk for death (RR = 1.58; 95% CI: 1.10-2.26) compared to females after adjusting for age and race/ethnicity. Mediation analyses indicated non-significant interventional indirect effects of male sex on severe COVID-19 disease through elevated inflammatory markers, SES and comorbidities, but the greatest effect was through the inflammation pathway. CONCLUSION: Males appear to be at higher risk at all steps of the continuum of COVID-19 illness. The strongest mediating signal, albeit non-significant, is with inflammatory pathways. Further elucidation of causal pathways linking sex and COVID-19 severity is needed in larger cohorts.

12.
Proc Natl Acad Sci U S A ; 119(5)2022 02 01.
Article in English | MEDLINE | ID: covidwho-1642084

ABSTRACT

Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants pose a challenge to controlling the COVID-19 pandemic. Previous studies indicate that clinical samples collected from individuals infected with the Delta variant may contain higher levels of RNA than previous variants, but the relationship between levels of viral RNA and infectious virus for individual variants is unknown. We measured infectious viral titer (using a microfocus-forming assay) and total and subgenomic viral RNA levels (using RT-PCR) in a set of 162 clinical samples containing SARS-CoV-2 Alpha, Delta, and Epsilon variants that were collected in identical swab kits from outpatient test sites and processed soon after collection. We observed a high degree of variation in the relationship between viral titers and RNA levels. Despite this, the overall infectivity differed among the three variants. Both Delta and Epsilon had significantly higher infectivity than Alpha, as measured by the number of infectious units per quantity of viral E gene RNA (5.9- and 3.0-fold increase; P < 0.0001, P = 0.014, respectively) or subgenomic E RNA (14.3- and 6.9-fold increase; P < 0.0001, P = 0.004, respectively). In addition to higher viral RNA levels reported for the Delta variant, the infectivity (amount of replication competent virus per viral genome copy) may be increased compared to Alpha. Measuring the relationship between live virus and viral RNA is an important step in assessing the infectivity of novel SARS-CoV-2 variants. An increase in the infectivity for Delta may further explain increased spread, suggesting a need for increased measures to prevent viral transmission.


Subject(s)
COVID-19/epidemiology , Gene Expression Regulation, Viral , Genome, Viral , RNA, Viral/genetics , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Animals , COVID-19/pathology , COVID-19/transmission , COVID-19/virology , Cell Line, Tumor , Chlorocebus aethiops , Coronavirus Envelope Proteins/genetics , Coronavirus Envelope Proteins/metabolism , Hepatocytes/metabolism , Hepatocytes/virology , Humans , RNA, Viral/metabolism , SARS-CoV-2/classification , SARS-CoV-2/metabolism , Vero Cells , Viral Load , Virulence
13.
J Clin Microbiol ; 60(1): e0165921, 2022 01 19.
Article in English | MEDLINE | ID: covidwho-1632827

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged into a world of maturing pathogen genomics, with more than 2 million genomes sequenced at the time of writing. The rise of more transmissible variants of concern that impact vaccine and therapeutic effectiveness has led to widespread interest in SARS-CoV-2 evolution. Clinicians are also eager to take advantage of the information provided by SARS-CoV-2 genotyping beyond surveillance purposes. Here, we review the potential role of SARS-CoV-2 genotyping in clinical care. The review covers clinical use cases for SARS-CoV-2 genotyping, methods of SARS-CoV-2 genotyping, assay validation and regulatory requirements, and clinical reporting for laboratories, as well as emerging issues in clinical SARS-CoV-2 sequencing. While clinical uses of SARS-CoV-2 genotyping are currently limited, rapid technological change along with a growing ability to interpret variants in real time foretells a growing role for SARS-CoV-2 genotyping in clinical care as continuing data emerge on vaccine and therapeutic efficacy.


Subject(s)
COVID-19 , Communicable Diseases , Consensus , Genotype , Humans , SARS-CoV-2 , United States
14.
JAMA Netw Open ; 5(1): e2142796, 2022 01 04.
Article in English | MEDLINE | ID: covidwho-1615909

ABSTRACT

Importance: The SARS-CoV-2 viral trajectory has not been well characterized in incident infections. These data are needed to inform natural history, prevention practices, and therapeutic development. Objective: To characterize early SARS-CoV-2 viral RNA load (hereafter referred to as viral load) in individuals with incident infections in association with COVID-19 symptom onset and severity. Design, Setting, and Participants: This prospective cohort study was a secondary data analysis of a remotely conducted study that enrolled 829 asymptomatic community-based participants recently exposed (<96 hours) to persons with SARS-CoV-2 from 41 US states from March 31 to August 21, 2020. Two cohorts were studied: (1) participants who were SARS-CoV-2 negative at baseline and tested positive during study follow-up, and (2) participants who had 2 or more positive swabs during follow-up, regardless of the initial (baseline) swab result. Participants collected daily midturbinate swab samples for SARS-CoV-2 RNA detection and maintained symptom diaries for 14 days. Exposure: Laboratory-confirmed SARS-CoV-2 infection. Main Outcomes and Measures: The observed SARS-CoV-2 viral load among incident infections was summarized, and piecewise linear mixed-effects models were used to estimate the characteristics of viral trajectories in association with COVID-19 symptom onset and severity. Results: A total of 97 participants (55 women [57%]; median age, 37 years [IQR, 27-52 years]) developed incident infections during follow-up. Forty-two participants (43%) had viral shedding for 1 day (median peak viral load cycle threshold [Ct] value, 38.5 [95% CI, 38.3-39.0]), 18 (19%) for 2 to 6 days (median Ct value, 36.7 [95% CI, 30.2-38.1]), and 31 (32%) for 7 days or more (median Ct value, 18.3 [95% CI, 17.4-22.0]). The cycle threshold value has an inverse association with viral load. Six participants (6%) had 1 to 6 days of viral shedding with censored duration. The peak mean (SD) viral load was observed on day 3 of shedding (Ct value, 33.8 [95% CI, 31.9-35.6]). Based on the statistical models fitted to 129 participants (60 men [47%]; median age, 38 years [IQR, 25-54 years]) with 2 or more SARS-CoV-2-positive swab samples, persons reporting moderate or severe symptoms tended to have a higher peak mean viral load than those who were asymptomatic (Ct value, 23.3 [95% CI, 22.6-24.0] vs 30.7 [95% CI, 29.8-31.4]). Mild symptoms generally started within 1 day of peak viral load, and moderate or severe symptoms 2 days after peak viral load. All 535 sequenced samples detected the G614 variant (Wuhan strain). Conclusions and Relevance: This cohort study suggests that having incident SARS-CoV-2 G614 infection was associated with a rapid viral load peak followed by slower decay. COVID-19 symptom onset generally coincided with peak viral load, which correlated positively with symptom severity. This longitudinal evaluation of the SARS-CoV-2 G614 with frequent molecular testing serves as a reference for comparing emergent viral lineages to inform clinical trial designs and public health strategies to contain the spread of the virus.


Subject(s)
COVID-19/virology , RNA, Viral , SARS-CoV-2 , Severity of Illness Index , Viral Load , Virus Shedding , Adult , COVID-19/complications , Female , Humans , Incidence , Longitudinal Studies , Male , Middle Aged , Molecular Diagnostic Techniques/methods , Polymerase Chain Reaction/methods , Prospective Studies , Serologic Tests
15.
J Pediatric Infect Dis Soc ; 10(Supplement_4): S88-S95, 2021 Dec 24.
Article in English | MEDLINE | ID: covidwho-1593724

ABSTRACT

Hospital outbreak investigations are high-stakes epidemiology. Contacts between staff and patients are numerous; environmental and community exposures are plentiful; and patients are highly vulnerable. Having the best data is paramount to understanding an outbreak in order to stop ongoing transmission and prevent future outbreaks. In the past 5 years, the high-resolution view of transmission offered by analyzing pathogen whole-genome sequencing (WGS) is increasingly part of hospital outbreak investigations. Concerns over speed and actionability, assay validation, liability, cost, and payment models lead to further opportunities for work in this area. Now accelerated by funding for COVID-19, the use of genomics in hospital outbreak investigations has firmly moved from the academic literature to more quotidian operations, with associated concerns involving regulatory affairs, data integration, and clinical interpretation. This review details past uses of WGS data in hospital-acquired infection outbreaks as well as future opportunities to increase its utility and growth in hospital infection prevention.


Subject(s)
COVID-19 , Cross Infection , Cross Infection/epidemiology , Disease Outbreaks , Genomics , Hospitals , Humans , Molecular Epidemiology , SARS-CoV-2
17.
Open forum infectious diseases ; 8(Suppl 1):S345-S345, 2021.
Article in English | EuropePMC | ID: covidwho-1564381

ABSTRACT

Background Antenatal care is a unique opportunity to assess SARS-CoV-2 seroprevalence and antibody response in pregnant people, including those with previously unknown infection. Methods Pregnant people were screened for SARS-CoV-2 IgG during antenatal care or delivery in Seattle, Washington with Abbott Architect chemiluminescent immunoassay which provides quantitative index (positive ≥1.4). Participants with IgG+ results or identified with RT-PCR+ results via medical records were invited to enroll in a longitudinal evaluation of antibody responses. We report preliminary results of an ongoing seroprevalence and longitudinal study with planned 18-month follow-up. Results Between September 9, 2020–May 7, 2021, we screened 1304 pregnant people;62 (4.8%) tested SARS-CoV-2 IgG+, including 28 (45%) with known prior SARS-CoV-2 infection. Among participants testing IgG+, median age was 32 years (interquartile range [IQR] 26–35) and median gestational age was 21 weeks (IQR 12–38) at screening;median IgG index was 3.2 (IQR 2.1–4.9, range 1.4–9.9), including 3.9 (IQR 2.3–5.8) among those with vs. 2.7 (IQR 1.9–4.2) among those without prior RT-PCR+ results (p=0.05 by Wilcoxon rank-sum). Of 30 longitudinal study participants enrolled, 24 tested IgG+ at baseline (75% with prior RT-PCR+ result) and 6 tested IgG- on enrollment but were identified as previously RT-PCR+ via medical records;24/30 (80%) reported previous symptoms. Of 24 participants testing IgG+ at baseline, 14 (58%) had first follow-up IgG results at median of 66 days (IQR 42–104) since initial testing, with median IgG index of 2.0 (IQR 1.0–3.8). 9/14 (64%) participants with repeat IgG testing remained IgG+ at first follow-up (≤280 days after first RT-PCR+ result for those with and ≥104 days after first IgG detection for those without prior RT-PCR+ results), while 5/14 (26%) had a negative Abbott IgG test at a median of 81 days (IQR 75–112) since initial testing. Conclusion Nearly half of pregnant people testing SARS-CoV-2 IgG+ reported no known prior SARS-CoV-2 diagnosis or symptoms. SARS-CoV-2 IgG antibody response and durability in pregnancy has implications for maternal and neonatal protection and susceptibility and highlights potential benefits of vaccination in this population. Disclosures Sylvia LaCourse, MD, Merck (Grant/Research Support) Alisa Kachikis, MD, MS, GlaxoSmithKline (Consultant)Pfizer (Consultant) Alexander L. Greninger, MD, PhD, Abbott (Grant/Research Support)Gilead (Grant/Research Support)Merck (Grant/Research Support) Janet A. Englund, MD, AstraZeneca (Consultant, Grant/Research Support)GlaxoSmithKline (Research Grant or Support)Meissa Vaccines (Consultant)Pfizer (Research Grant or Support)Sanofi Pasteur (Consultant)Teva Pharmaceuticals (Consultant) Alison Drake, PhD, MPH, Merck (Grant/Research Support)

18.
EMBO Mol Med ; 14(2): e15290, 2022 02 07.
Article in English | MEDLINE | ID: covidwho-1551925

ABSTRACT

With the COVID-19 pandemic caused by SARS-CoV-2 now in its second year, there remains an urgent need for diagnostic testing that can identify infected individuals, particularly those who harbor infectious virus. Various RT-PCR strategies have been proposed to identify specific viral RNA species that may predict the presence of infectious virus, including detection of transcriptional intermediates (e.g., subgenomic RNA [sgRNA]) and replicative intermediates (e.g., negative-strand RNA species). Using a novel primer/probe set for detection of subgenomic (sg)E transcripts, we successfully identified 100% of specimens containing culturable SARS-CoV-2 from a set of 126 clinical samples (total sgE CT values ranging from 12.3 to 37.5). This assay showed superior performance compared to a previously published sgRNA assay and to a negative-strand RNA assay, both of which failed to detect target RNA in a subset of samples from which we isolated live virus. In addition, total levels of viral RNA (genome, negative-strand, and sgE) detected with the WHO/Charité primer-probe set correlated closely with levels of infectious virus. Specifically, infectious virus was not detected in samples with a CT above 31.0. Clinical samples with higher levels of viral RNA also displayed cytopathic effect (CPE) more quickly than those with lower levels of viral RNA. Finally, we found that the infectivity of SARS-CoV-2 samples is significantly dependent on the cell type used for viral isolation, as Vero E6 cells expressing TMRPSS2 extended the analytical sensitivity of isolation by more than 3 CT compared to parental Vero E6 cells and resulted in faster isolation. Our work shows that using a total viral RNA Ct cutoff of > 31 or specifically testing for sgRNA can serve as an effective rule-out test for the presence of culturable virus.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Pandemics , Polymerase Chain Reaction , RNA, Viral/genetics
20.
Nat Commun ; 12(1): 6415, 2021 11 05.
Article in English | MEDLINE | ID: covidwho-1503781

ABSTRACT

Remdesivir is an antiviral approved for COVID-19 treatment, but its wider use is limited by intravenous delivery. An orally bioavailable remdesivir analog may boost therapeutic benefit by facilitating early administration to non-hospitalized patients. This study characterizes the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Both GS-621763 and GS-441524 inhibit SARS-CoV-2, including variants of concern (VOC) in cell culture and human airway epithelium organoids. Oral GS-621763 is efficiently converted to plasma metabolite GS-441524, and in lungs to the triphosphate metabolite identical to that generated by remdesivir, demonstrating a consistent mechanism of activity. Twice-daily oral administration of 10 mg/kg GS-621763 reduces SARS-CoV-2 burden to near-undetectable levels in ferrets. When dosed therapeutically against VOC P.1 gamma γ, oral GS-621763 blocks virus replication and prevents transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection.


Subject(s)
Adenosine/analogs & derivatives , Antiviral Agents/pharmacology , COVID-19/drug therapy , Prodrugs/pharmacology , SARS-CoV-2/drug effects , Adenosine/pharmacology , Animals , COVID-19/metabolism , COVID-19/virology , Cell Line , Chlorocebus aethiops , Cricetinae , Disease Models, Animal , Female , Ferrets , Humans , SARS-CoV-2/isolation & purification
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