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1.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-316224

ABSTRACT

COVID-19 has become a pandemic that has caused over 200,000 deaths worldwide, with no antiviral drug or vaccine yet available. Several clinical studies are ongoing to evaluate the efficacy of repurposed drugs that have demonstrated antiviral efficacy in vitro . Among these candidates, hydroxychloroquine (HCQ) has been given to thousands of individuals worldwide but definitive evidence for HCQ efficacy in treatment of COVID-19 is still missing.We evaluated the antiviral activity of HCQ both in vitro and in SARS-CoV-2-infected macaques. HCQ showed antiviral activity in monkey African green monkey kidney (VeroE6) cells but not in a model of reconstituted human airway epithelium. In macaques, we tested different treatment strategies in comparison to placebo, before and after peak viral load, alone or in combination with azithromycin (AZTH). Neither HCQ nor HCQ+AZTH showed a significant effect on the viral load levels in any of the tested compartments. When the drug was used as a pre-exposure prophylaxis (PrEP), HCQ did not confer protection against acquisition of infection.Our findings do not support the use of HCQ, either alone or in combination with AZTH, as an antiviral treatment for COVID-19 in humans.

2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-311331

ABSTRACT

Non-human primates infected with SARS-CoV-2 exhibit mild clinical signs. Here we used a mathematical model to characterize in detail the viral dynamics in 31 cynomolgus macaques infected with 10 6 pfu of SARS-CoV-2 for which nasopharyngeal and tracheal viral load were frequently assessed. We identified that infected cells had a large daily viral production (>10 4 virus) and a within-host reproductive basic number of 6 and 4 in nasopharyngeal and tracheal compartment, respectively. After peak viral load, infected cells were rapidly cleared with a half-life of 9 hours, with no significant association between cytokine elevation and clearance. Translating our model to the context of human-to-human infection, human mild infection may be characterized by a peak occurring 4 days after infection, a viral shedding of ~11 days and a generation time of 4 days. These results improve the understanding of SARS-CoV-2 viral replication and better understand the infection to SARS-CoV-2 in humans.

3.
PLoS One ; 16(12): e0260958, 2021.
Article in English | MEDLINE | ID: covidwho-1546973

ABSTRACT

SARS-CoV-2 variants are emerging with potential increased transmissibility highlighting the great unmet medical need for new therapies. Niclosamide is a potent anti-SARS-CoV-2 agent that has advanced in clinical development. We validate the potent antiviral efficacy of niclosamide in a SARS-CoV-2 human airway model. Furthermore, niclosamide remains its potency against the D614G, Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) variants. Our data further support the potent anti-SARS-CoV-2 properties of niclosamide and highlights its great potential as a therapeutic agent for COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Niclosamide/therapeutic use , SARS-CoV-2/drug effects , Animals , Caco-2 Cells , Chlorocebus aethiops , Humans , Inhibitory Concentration 50 , Respiratory Mucosa/virology , Vero Cells
4.
J Infect Dis ; 224(9): 1489-1499, 2021 11 16.
Article in English | MEDLINE | ID: covidwho-1522216

ABSTRACT

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a complex antibody response that varies by orders of magnitude between individuals and over time. METHODS: We developed a multiplex serological test for measuring antibodies to 5 SARS-CoV-2 antigens and the spike proteins of seasonal coronaviruses. We measured antibody responses in cohorts of hospitalized patients and healthcare workers followed for up to 11 months after symptoms. A mathematical model of antibody kinetics was used to quantify the duration of antibody responses. Antibody response data were used to train algorithms for estimating time since infection. RESULTS: One year after symptoms, we estimate that 36% (95% range, 11%-94%) of anti-Spike immunoglobulin G (IgG) remains, 31% (95% range, 9%-89%) anti-RBD IgG remains, and 7% (1%-31%) of anti-nucleocapsid IgG remains. The multiplex assay classified previous infections into time intervals of 0-3 months, 3-6 months, and 6-12 months. This method was validated using data from a seroprevalence survey in France, demonstrating that historical SARS-CoV-2 transmission can be reconstructed using samples from a single survey. CONCLUSIONS: In addition to diagnosing previous SARS-CoV-2 infection, multiplex serological assays can estimate the time since infection, which can be used to reconstruct past epidemics.


Subject(s)
Antibodies, Viral/blood , COVID-19/blood , COVID-19/immunology , Serologic Tests/methods , Adolescent , Adult , Aged , Aged, 80 and over , Antibody Formation , Antibody Specificity , COVID-19/epidemiology , Female , France/epidemiology , Humans , Immunoglobulin G/blood , Kinetics , Male , Middle Aged , SARS-CoV-2/immunology , Sensitivity and Specificity , Seroepidemiologic Studies , Young Adult
5.
EBioMedicine ; 70: 103495, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1322073

ABSTRACT

BACKGROUND: Children are underrepresented in the COVID-19 pandemic and often experience milder disease than adolescents and adults. Reduced severity is possibly due to recent and more frequent seasonal human coronaviruses (HCoV) infections. We assessed the seroprevalence of SARS-CoV-2 and seasonal HCoV specific antibodies in a large cohort in north-eastern France. METHODS: In this cross-sectional seroprevalence study, serum samples were collected from children and adults requiring hospital admission for non-COVID-19 between February and August 2020. Antibody responses to SARS-CoV-2 and seasonal HCoV (229E, HKU1, NL63, OC43) were assessed using a bead-based multiplex assay, Luciferase-Linked ImmunoSorbent Assay, and a pseudotype neutralisation assay. FINDINGS: In 2,408 individuals, seroprevalence of SARS-CoV-2-specific antibodies was 7-8% with three different immunoassays. Antibody levels to seasonal HCoV increased substantially up to the age of 10. Antibody responses in SARS-CoV-2 seropositive individuals were lowest in adults 18-30 years. In SARS-CoV-2 seronegative individuals, we observed cross-reactivity between antibodies to the four HCoV and SARS-CoV-2 Spike. In contrast to other antibodies to SARS-CoV-2, specific antibodies to sub-unit 2 of Spike (S2) in seronegative samples were highest in children. Upon infection with SARS-CoV-2, antibody levels to Spike of betacoronavirus OC43 increased across the whole age spectrum. No SARS-CoV-2 seropositive individuals with low levels of antibodies to seasonal HCoV were observed. INTERPRETATION: Our findings underline significant cross-reactivity between antibodies to SARS-CoV-2 and seasonal HCoV, but provide no significant evidence for cross-protective immunity to SARS-CoV-2 infection due to a recent seasonal HCoV infection. In particular, across all age groups we did not observe SARS-CoV-2 infected individuals with low levels of antibodies to seasonal HCoV. FUNDING: This work was supported by the « URGENCE COVID-19 ¼ fundraising campaign of Institut Pasteur, by the French Government's Investissement d'Avenir program, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases (Grant No. ANR-10-LABX-62-IBEID), and by the REACTing (Research & Action Emerging Infectious Diseases), and by the RECOVER project funded by the European Union's Horizon 2020 research and innovation programme under grant agreement No. 101003589, and by a grant from LabEx IBEID (ANR-10-LABX-62-IBEID).


Subject(s)
COVID-19/immunology , Immunity, Humoral/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Viral/immunology , Child , Child, Preschool , Clinical Trials as Topic , Cross Reactions/immunology , Cross-Sectional Studies , Female , France , Humans , Infant , Infant, Newborn , Male , Middle Aged , Pandemics/prevention & control , Seasons , Seroepidemiologic Studies , Spike Glycoprotein, Coronavirus/immunology , Young Adult
6.
J Infect Dis ; 224(9): 1489-1499, 2021 11 16.
Article in English | MEDLINE | ID: covidwho-1317919

ABSTRACT

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a complex antibody response that varies by orders of magnitude between individuals and over time. METHODS: We developed a multiplex serological test for measuring antibodies to 5 SARS-CoV-2 antigens and the spike proteins of seasonal coronaviruses. We measured antibody responses in cohorts of hospitalized patients and healthcare workers followed for up to 11 months after symptoms. A mathematical model of antibody kinetics was used to quantify the duration of antibody responses. Antibody response data were used to train algorithms for estimating time since infection. RESULTS: One year after symptoms, we estimate that 36% (95% range, 11%-94%) of anti-Spike immunoglobulin G (IgG) remains, 31% (95% range, 9%-89%) anti-RBD IgG remains, and 7% (1%-31%) of anti-nucleocapsid IgG remains. The multiplex assay classified previous infections into time intervals of 0-3 months, 3-6 months, and 6-12 months. This method was validated using data from a seroprevalence survey in France, demonstrating that historical SARS-CoV-2 transmission can be reconstructed using samples from a single survey. CONCLUSIONS: In addition to diagnosing previous SARS-CoV-2 infection, multiplex serological assays can estimate the time since infection, which can be used to reconstruct past epidemics.


Subject(s)
Antibodies, Viral/blood , COVID-19/blood , COVID-19/immunology , Serologic Tests/methods , Adolescent , Adult , Aged , Aged, 80 and over , Antibody Formation , Antibody Specificity , COVID-19/epidemiology , Female , France/epidemiology , Humans , Immunoglobulin G/blood , Kinetics , Male , Middle Aged , SARS-CoV-2/immunology , Sensitivity and Specificity , Seroepidemiologic Studies , Young Adult
7.
Neuroepidemiology ; 55(5): 381-386, 2021.
Article in English | MEDLINE | ID: covidwho-1290486

ABSTRACT

INTRODUCTION: Olfactory and taste disorders (OTDs) have been reported in COVID-19 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the mechanisms of which remain unclear. We conducted a detailed analysis of OTDs as part of 2 seroepidemiological investigations of COVID-19 outbreaks. METHODS: Two retrospective cohort studies were conducted in a high school and primary schools of Northern France following a COVID-19 epidemic in February-March 2020. Students, their relatives, and school staff were included. Anti-SARS-CoV-2 antibodies were identified using a flow-cytometry-based assay detecting anti-S IgG. RESULTS: Among 2,004 participants (median [IQR] age: 31 [11-43] years), 303 (15.2%) tested positive for SARS-CoV-2 antibodies. OTDs were present in 91 (30.0%) and 92 (30.3%) of them, respectively, and had 85.1 and 78.0% positive predictive values for SARS-CoV-2 infection, respectively. In seropositive participants, OTDs were independently associated with an age above 18 years, female gender, fatigue, and headache. CONCLUSION: This study confirms the higher frequency of OTDs in females than males and adults than children. Their high predictive value for the diagnosis of COVID-19 suggests that they should be systematically searched for in patients with respiratory symptoms, fever, or headache. The association of OTDs with headache, not previously reported, suggests that they share a common mechanism, which deserves further investigation.


Subject(s)
COVID-19/complications , Olfaction Disorders/etiology , Taste Disorders/etiology , Adolescent , Adult , Antibodies, Viral/analysis , Child , Humans , Retrospective Studies , Risk Factors , Young Adult
9.
Cell Rep Med ; 2(5): 100275, 2021 05 18.
Article in English | MEDLINE | ID: covidwho-1193507

ABSTRACT

Many SARS-CoV-2-infected individuals remain asymptomatic. Little is known about the extent and quality of their antiviral humoral response. Here, we analyze antibody functions in 52 asymptomatic infected individuals, 119 mildly symptomatic, and 21 hospitalized patients with COVID-19. We measure anti-spike immunoglobulin G (IgG), IgA, and IgM levels with the S-Flow assay and map IgG-targeted epitopes with a Luminex assay. We also evaluate neutralization, complement deposition, and antibody-dependent cellular cytotoxicity (ADCC) using replication-competent SARS-CoV-2 or reporter cell systems. We show that COVID-19 sera mediate complement deposition and kill infected cells by ADCC. Sera from asymptomatic individuals neutralize the virus, activate ADCC, and trigger complement deposition. Antibody levels and functions are lower in asymptomatic individuals than they are in symptomatic cases. Antibody functions are correlated, regardless of disease severity. Longitudinal samplings show that antibody functions follow similar kinetics of induction and contraction. Overall, asymptomatic SARS-CoV-2 infection elicits polyfunctional antibodies neutralizing the virus and targeting infected cells.


Subject(s)
Antibodies, Viral/blood , COVID-19/pathology , Spike Glycoprotein, Coronavirus/immunology , Adolescent , Adult , Antibodies, Viral/immunology , Antibody-Dependent Cell Cytotoxicity , Antigen-Antibody Reactions , Asymptomatic Diseases , COVID-19/virology , Complement System Proteins/metabolism , Epitopes/immunology , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Killer Cells, Natural/immunology , Male , Middle Aged , Neutralization Tests , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Severity of Illness Index , Young Adult
10.
Euro Surveill ; 26(15)2021 04.
Article in English | MEDLINE | ID: covidwho-1190261

ABSTRACT

BackgroundChildren's role in SARS-CoV-2 epidemiology remains unclear. We investigated an initially unnoticed SARS-CoV-2 outbreak linked to schools in northern France, beginning as early as mid-January 2020.AimsThis retrospective observational study documents the extent of SARS-CoV-2 transmission, linked to an affected high school (n = 664 participants) and primary schools (n = 1,340 study participants), in the context of unsuspected SARS-CoV-2 circulation and limited control measures.MethodsBetween 30 March and 30 April 2020, all school staff, as well as pupils and their parents and relatives were invited for SARS-CoV-2 antibody testing and to complete a questionnaire covering symptom history since 13 January 2020.ResultsIn the high school, infection attack rates were 38.1% (91/239), 43.4% (23/53), and 59.3% (16/27), in pupils, teachers, and non-teaching staff respectively vs 10.1% (23/228) and 12.0% (14/117) in the pupils' parents and relatives (p < 0.001). Among the six primary schools, three children attending separate schools at the outbreak start, while symptomatic, might have introduced SARS-CoV-2 there, but symptomatic secondary cases related to them could not be definitely identified. In the primary schools overall, antibody prevalence in pupils sharing classes with symptomatic cases was higher than in pupils from other classes: 15/65 (23.1%) vs 30/445 (6.7%) (p < 0.001). Among 46 SARS-CoV-2 seropositive pupils < 12 years old, 20 were asymptomatic. Whether past HKU1 and OC43 seasonal coronavirus infection protected against SARS-CoV-2 infection in 6-11 year olds could not be inferred.ConclusionsViral circulation can occur in high and primary schools so keeping them open requires consideration of appropriate control measures and enhanced surveillance.


Subject(s)
COVID-19 , Child , Cohort Studies , France/epidemiology , Humans , Retrospective Studies , SARS-CoV-2 , Schools
11.
PLoS Comput Biol ; 17(3): e1008785, 2021 03.
Article in English | MEDLINE | ID: covidwho-1181165

ABSTRACT

Non-human primates infected with SARS-CoV-2 exhibit mild clinical signs. Here we used a mathematical model to characterize in detail the viral dynamics in 31 cynomolgus macaques for which nasopharyngeal and tracheal viral load were frequently assessed. We identified that infected cells had a large burst size (>104 virus) and a within-host reproductive basic number of approximately 6 and 4 in nasopharyngeal and tracheal compartment, respectively. After peak viral load, infected cells were rapidly lost with a half-life of 9 hours, with no significant association between cytokine elevation and clearance, leading to a median time to viral clearance of 10 days, consistent with observations in mild human infections. Given these parameter estimates, we predict that a prophylactic treatment blocking 90% of viral production or viral infection could prevent viral growth. In conclusion, our results provide estimates of SARS-CoV-2 viral kinetic parameters in an experimental model of mild infection and they provide means to assess the efficacy of future antiviral treatments.


Subject(s)
COVID-19/virology , Macaca fascicularis/virology , SARS-CoV-2/physiology , Animals , Antiviral Agents/pharmacology , Basic Reproduction Number , COVID-19/blood , COVID-19/prevention & control , Cytokines/blood , Disease Models, Animal , Nasopharynx/virology , SARS-CoV-2/drug effects , Trachea/virology , Viral Load , Virus Replication/drug effects
12.
EBioMedicine ; 59: 102915, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-691414

ABSTRACT

BACKGROUND: The serologic response of individuals with mild forms of SARS-CoV-2 infection is poorly characterized. METHODS: Hospital staff who had recovered from mild forms of PCR-confirmed SARS-CoV-2 infection were tested for anti-SARS-CoV-2 antibodies using two assays: a rapid immunodiagnostic test (99.4% specificity) and the S-Flow assay (~99% specificity). The neutralizing activity of the sera was tested with a pseudovirus-based assay. FINDINGS: Of 162 hospital staff who participated in the investigation, 160 reported SARS-CoV-2 infection that had not required hospital admission and were included in these analyses. The median time from symptom onset to blood sample collection was 24 days (IQR: 21-28, range 13-39). The rapid immunodiagnostic test detected antibodies in 153 (95.6%) of the samples and the S-Flow assay in 159 (99.4%), failing to detect antibodies in one sample collected 18 days after symptom onset (the rapid test did not detect antibodies in that patient). Neutralizing antibodies (NAbs) were detected in 79%, 92% and 98% of samples collected 13-20, 21-27 and 28-41 days after symptom onset, respectively (P = 0.02). INTERPRETATION: Antibodies against SARS-CoV-2 were detected in virtually all hospital staff sampled from 13 days after the onset of COVID-19 symptoms. This finding supports the use of serologic testing for the diagnosis of individuals who have recovered from SARS-CoV-2 infection. The neutralizing activity of the antibodies increased overtime. Future studies will help assess the persistence of the humoral response and its associated neutralization capacity in recovered patients. FUNDINGS: The funders had no role in study design, data collection, interpretation, or the decision to submit the work for publication.


Subject(s)
Antibodies, Viral/blood , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Adult , Antibodies, Neutralizing/blood , Betacoronavirus/genetics , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/virology , Female , France , Health Personnel , Hospitals , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , RNA, Viral/metabolism , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Serologic Tests , Severity of Illness Index
13.
Nature ; 585(7826): 584-587, 2020 09.
Article in English | MEDLINE | ID: covidwho-664587

ABSTRACT

Coronavirus disease 2019 (COVID-19) has rapidly become a global pandemic and no antiviral drug or vaccine is yet available for the treatment of this disease1-3. Several clinical studies are ongoing to evaluate the efficacy of repurposed drugs that have demonstrated antiviral efficacy in vitro. Among these candidates, hydroxychloroquine (HCQ) has been given to thousands of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-the virus that causes COVID-19-worldwide but there is no definitive evidence that HCQ is effective for treating COVID-194-7. Here we evaluated the antiviral activity of HCQ both in vitro and in SARS-CoV-2-infected macaques. HCQ showed antiviral activity in African green monkey kidney cells (Vero E6) but not in a model of reconstituted human airway epithelium. In macaques, we tested different treatment strategies in comparison to a placebo treatment, before and after peak viral load, alone or in combination with azithromycin (AZTH). Neither HCQ nor the combination of HCQ and AZTH showed a significant effect on viral load in any of the analysed tissues. When the drug was used as a pre-exposure prophylaxis treatment, HCQ did not confer protection against infection with SARS-CoV-2. Our findings do not support the use of HCQ, either alone or in combination with AZTH, as an antiviral drug for the treatment of COVID-19 in humans.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Animals , Azithromycin/pharmacology , Azithromycin/therapeutic use , COVID-19 , Chlorocebus aethiops , Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , Cytokines/blood , Disease Models, Animal , Female , Humans , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/pharmacology , In Vitro Techniques , Kinetics , Macaca fascicularis , Male , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/physiopathology , Pre-Exposure Prophylaxis , Respiratory Mucosa/cytology , Respiratory Mucosa/drug effects , Respiratory Mucosa/virology , SARS-CoV-2 , Time Factors , Treatment Failure , Vero Cells , Viral Load/drug effects
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