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1.
Antimicrob Agents Chemother ; 66(7): e0019822, 2022 07 19.
Article in English | MEDLINE | ID: covidwho-1901915

ABSTRACT

In vitro selection of remdesivir-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed the emergence of a V166L substitution, located outside of the polymerase active site of the Nsp12 protein, after 9 passages of a single lineage. V166L remained the only Nsp12 substitution after 17 passages (10 µM remdesivir), conferring a 2.3-fold increase in 50% effective concentration (EC50). When V166L was introduced into a recombinant SARS-CoV-2 virus, a 1.5-fold increase in EC50 was observed, indicating a high in vitro barrier to remdesivir resistance.


Subject(s)
COVID-19 , SARS-CoV-2 , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Alanine/analogs & derivatives , Alanine/metabolism , Antiviral Agents/chemistry , COVID-19/drug therapy , Humans
2.
Can Geriatr J ; 25(2): 183-196, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1893249

ABSTRACT

Background: We report characteristics and outcomes of adults admitted to Canadian Immunization Research Network (CIRN) Serious Outcomes Surveillance (SOS) Network hospitals with COVID-19 in 2020. Methods: Patients with laboratory-confirmed COVID-19 admitted to 11 sites in Ontario, Quebec, Alberta, and Nova Scotia up to December 31, 2020 were enrolled in this prospective observational cohort study. Measures included age, sex, demographics, housing, exposures, Clinical Frailty Scale, comorbidities; in addition, length of stay, intensive care unit (ICU) admission, mechanical ventilation, and survival were assessed. Descriptive analyses and multivariable logistic regressions were conducted. Results: Among 2,011 patients, mean age was 71.0 (range 19-105) years. 29.7% were admitted from assisted living or long-term care facilities. The full spectrum of frailty was represented in both younger and older age groups. 81.8% had at least one underlying comorbidity and 27.2% had obesity. Mortality was 14.3% without ICU admission, and 24.6% for those admitted to ICU. Older age and frailty were independent predictors of lower ICU use and higher mortality; accounting for frailty, obesity was not an independent predictor of mortality, and associations of comorbidities with mortality were weakened. Conclusions: Frailty is a critical clinical factor in predicting outcomes of COVID-19, which should be considered in research and clinical settings.

3.
Influenza Other Respir Viruses ; 16(5): 916-925, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1819906

ABSTRACT

BACKGROUND: Understanding the immune response to natural infection by SARS-CoV-2 is key to pandemic management, especially in the current context of emerging variants. Uncertainty remains regarding the efficacy and duration of natural immunity against reinfection. METHODS: We conducted an observational prospective cohort study in Canadian healthcare workers (HCWs) with a history of PCR-confirmed SARS-CoV-2 infection to (i) measure the average incidence rate of reinfection and (ii) describe the serological immune response to the primary infection. RESULTS: Our cohort comprised 569 HCWs; median duration of individual follow-up was 371 days. We detected six cases of reinfection in absence of vaccination between August 21, 2020, and March 1, 2022, for a reinfection incidence rate of 4.0 per 100 person-years. Median duration of seropositivity was 415 days in symptomatics at primary infection compared with 213 days in asymptomatics (p < 0.0001). Other characteristics associated with prolonged seropositivity for IgG against the spike protein included age over 55 years, obesity, and non-Caucasian ethnicity. CONCLUSIONS: Among unvaccinated healthcare workers, reinfection with SARS-CoV-2 following a primary infection remained rare.


Subject(s)
COVID-19 , COVID-19/diagnosis , COVID-19/epidemiology , Canada/epidemiology , Cohort Studies , Health Personnel , Humans , Middle Aged , Prospective Studies , Reinfection/epidemiology , SARS-CoV-2
4.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327599

ABSTRACT

ABSTRACT Background Understanding the immune response to natural infection by SARS-CoV-2 is key to pandemic management, especially in the current context of emerging variants. Uncertainty remains regarding the efficacy and duration of natural immunity against reinfection. Method We conducted an observational prospective cohort study in Canadian healthcare workers (HCWs) with a history of PCR-confirmed SARS-CoV-2 infection to : (i) measure the average incidence rate of reinfection and (ii), describe the serological immune response to the primary infection. Results We detected 5 cases of reinfection over 14 months of follow-up, for a reinfection incidence rate of 3.3 per 100 person-years. Median duration of seropositivity was 420 days in symptomatics at primary infection compared to 213 days in asymptomatics (p<0.0001). Other variables associated with prolonged seropositivity for IgG against the spike protein included age 55 and above, obesity, and non-Caucasian ethnicity. Summary Among healthcare workers, the incidence of reinfection with SARS-CoV-2 following a primary infection remained rare, although our analysis predates the circulation of the Omicron variant.

5.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327496

ABSTRACT

In vitro selection of remdesivir-resistant SARS-CoV-2 revealed the emergence of a V166L substitution, located outside of the polymerase active site of the nsp12 protein, after 9 passages. V166L remained the only nsp12 substitution after 17 passages at a final concentration of 10 μM RDV, conferring a 2.3-fold increase in EC 50 . When V166L was introduced into a recombinant SARS-CoV-2 virus, a 1.5-fold increase in EC 50 was observed, indicating a high in vitro barrier to RDV resistance.

6.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-325481

ABSTRACT

Background: Montreal was one of the highest COVID-19 burdened cities in Canada during the first and second waves of the pandemic. We estimated the seroprevalence of SARS-CoV-2 in children and teenagers in four neighbourhoods of Montreal, Canada.Methods: All children attending selected schools and daycares within the four neighbourhoods were invited to participate in the study. Study participation included an online questionnaire that parents completed, followed by at-home dried blood spot (DBS) collection. Serological results were analyzed using a research-based ELISA assay. Statistical analyses included multivariable logistic regression models to calculate average marginal effects and robust standard errors to account for clustering by school or daycare. Several different sociodemographic differences were examined between the seronegative and seropositive children.Findings: There were 30 daycares, 22 primary schools, and 11 secondary schools that participated in the study with 1,632 participants having provided a DBS sample that was of sufficient quality for the serological analysis. The average seroprevalence was 5·8% (95%CI 4·6 to 7·0) but increased over time from 3·2% (95% CI 0·7 to 5·8) in October-November 2020 to 8.4% (95% CI 4·4 to 12·4) in March-April 2021. The children of visible minority parents were nearly twice as likely to be seropositive as children of non-visible minority parents (1·93, 95%CI 1·11 to 2·75). Interpretation: Our results provide a benchmark of the seroprevalence status in Canadian children and provide further evidence of COVID-19 inequities. It will be important to continue monitoring the serological status of children, particularly in the context of new COVID-19 variants of concern and in the absence of mass vaccination campaigns targeting young children.Funding Information: Public Health Agency of Canada through the COVID-19 Immunity Task Force.Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: All participants provided informed consent for the survey and ethics approval was received from the research ethics boards of the Université de Montréal and the Centre Hospitalier Universitaire Sainte-Justine.

7.
Viruses ; 14(2)2022 02 15.
Article in English | MEDLINE | ID: covidwho-1687057

ABSTRACT

The types of interactions between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory viruses are not well-characterized due to the low number of co-infection cases described since the onset of the pandemic. We have evaluated the interactions between SARS-CoV-2 (D614G mutant) and influenza A(H1N1)pdm09 or respiratory syncytial virus (RSV) in the nasal human airway epithelium (HAE) infected simultaneously or sequentially (24 h apart) with virus combinations. The replication kinetics of each virus were determined by RT-qPCR at different post-infection times. Our results showed that during simultaneous infection, SARS-CoV-2 interferes with RSV-A2 but not with A(H1N1)pdm09 replication. The prior infection of nasal HAE with SARS-CoV-2 reduces the replication kinetics of both respiratory viruses. SARS-CoV-2 replication is decreased by a prior infection with A(H1N1)pdm09 but not with RSV-A2. The pretreatment of nasal HAE with BX795, a TANK-binding kinase 1 inhibitor, partially alleviates the reduced replication of SARS-CoV-2 or influenza A(H1N1)pdm09 during sequential infection with both virus combinations. Thus, a prior infection of nasal HAE with SARS-CoV-2 interferes with the replication kinetics of A(H1N1)pdm09 and RSV-A2, whereas only A(H1N1)pdm09 reduces the subsequent infection with SARS-CoV-2. The mechanism involved in the viral interference between SARS-CoV-2 and A(H1N1)pdm09 is mediated by the production of interferon.


Subject(s)
Epithelial Cells/virology , Influenza A Virus, H1N1 Subtype/physiology , Nasopharynx/cytology , Respiratory Syncytial Virus, Human/physiology , SARS-CoV-2/physiology , Viral Interference , Virus Replication , Coinfection , Humans , Microbial Interactions , Nasopharynx/virology
8.
Infect Control Hosp Epidemiol ; : 1-4, 2022 Feb 09.
Article in English | MEDLINE | ID: covidwho-1683855

ABSTRACT

We describe 10 patients with severe coronavirus disease 2019 (COVID-19) who received tocilizumab and dexamethasone. We correlated isolation duration with cycle thresholds (Ct) values of nucleic acid amplification tests, clinical state and viral cultures. Isolation duration exceeded 21 days for 7 patients due to positive viral cultures or Ct values <30.

9.
Emerg Infect Dis ; 28(2): 273-281, 2022 02.
Article in English | MEDLINE | ID: covidwho-1651071

ABSTRACT

Multiple respiratory viruses can concurrently or sequentially infect the respiratory tract and lead to virus‒virus interactions. Infection by a first virus could enhance or reduce infection and replication of a second virus, resulting in positive (additive or synergistic) or negative (antagonistic) interaction. The concept of viral interference has been demonstrated at the cellular, host, and population levels. The mechanisms involved in viral interference have been evaluated in differentiated airway epithelial cells and in animal models susceptible to the respiratory viruses of interest. A likely mechanism is the interferon response that could confer a temporary nonspecific immunity to the host. During the coronavirus disease pandemic, nonpharmacologic interventions have prevented the circulation of most respiratory viruses. Once the sanitary restrictions are lifted, circulation of seasonal respiratory viruses is expected to resume and will offer the opportunity to study their interactions, notably with severe acute respiratory syndrome coronavirus 2.


Subject(s)
COVID-19 , Respiratory Tract Infections , Viruses , Animals , Humans , Pandemics , Respiratory Tract Infections/epidemiology , SARS-CoV-2 , Viral Interference
10.
Infect Control Hosp Epidemiol ; 43(1): 102-104, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1634839

ABSTRACT

We performed viral culture of respiratory specimens in 118 severe acute respiratory coronavirus virus 2 (SARS-CoV-2)-infected healthcare workers (HCWs), ∼2 weeks after symptom onset. Only 1 HCW (0.8%) had a positive culture. No factors for prolonged viral shedding were identified. Infectivity is resolved in nearly all HCWs ∼2 weeks after symptom onset.


Subject(s)
COVID-19 , Cross-Sectional Studies , Health Personnel , Humans , SARS-CoV-2 , Virus Shedding
11.
Int J Infect Dis ; 116: 387-390, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1620729

ABSTRACT

OBJECTIVE: A predictive model for hospitalization due to COVID-19 or death was developed in the placebo group (N=2,084) from a large clinical trial of colchicine in COVID-19 patients (N = 4,159). RESULTS: The 7 variables retained in the predictive model were age, gender, body-mass index, history of respiratory disease, use of diabetes drugs, use of anticoagulants, and use of oral steroids at the time of randomization. An optimal threshold value identified from the predictive model was used to classify high-risk patients (those with a predicted probability above the optimal threshold) and low-risk patients (those with a predicted probability below the optimal threshold). The number needed to treat to prevent 1 hospitalization or death with colchicine treatment decreased from 71 in the whole study population (N = 4,159) to 29 in the high-risk subgroup (N=1,692). CONCLUSION: This model could serve to identify high-risk subjects who will particularly benefit from early colchicine therapy.


Subject(s)
COVID-19 , COVID-19/drug therapy , Colchicine/adverse effects , Colchicine/therapeutic use , Hospitalization , Humans , Risk Factors , SARS-CoV-2 , Treatment Outcome
12.
JAMA Netw Open ; 4(11): e2135975, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1527396

ABSTRACT

Importance: Quebec prioritized in-person learning after the first wave of the COVID-19 pandemic, with school closures being implemented temporarily in selected schools or in hot-spot areas. Quebec's decision to keep most schools open was controversial, especially in Montreal, which was the epicenter of Canada's first and second waves; therefore, understanding the extent to which children were infected with SARS-CoV-2 provides important information for decisions about school closures. Objective: To estimate the seroprevalence of SARS-CoV-2 antibodies in children and teenagers in 4 neighborhoods of Montreal, Canada. Design, Setting, and Participants: This cohort study (the Enfants et COVID-19: Étude de séroprévalence [EnCORE] study) enrolled a convenience sample of children aged 2 to 17 years between October 22, 2020, and March 22, 2021, in Montreal, Canada. Exposures: Potential exposure to SARS-CoV-2. Main Outcomes and Measures: The main outcome was seroprevalence of SARS-CoV-2 antibodies, collected using dried blood spots (DBSs) and analyzed with a research-based enzyme-linked immunosorbent assay (ELISA). Parents also completed an online questionnaire that included questions on self-reported COVID-19 symptoms and tests, along with sociodemographic questions. Results: This study included 1632 participants who provided a DBS sample from 30 day cares, 22 primary schools, and 11 secondary schools. The mean (SD) age of the children who provided a DBS sample was 9.0 (4.4) years; 801 (49%) were female individuals, with 354 participants (22%) from day cares, 725 (44%) from primary schools, and 553 (34%) from secondary schools. Most parents had at least a bachelor's degree (1228 [75%]), and 210 (13%) self-identified as being a racial or ethnic minority. The mean seroprevalence was 5.8% (95% CI, 4.6%-7.0%) but increased over time from 3.2% (95% CI, 0.7%-5.8%) in October to November 2020 to 8.4% (95% CI, 4.4%-12.4%) in March to April 2021. Of the 95 children with positive SARS-CoV-2 antibody results, 78 (82%) were not tested or tested negative with reverse transcription-polymerase chain reaction (RT-PCR) testing, and all experienced mild (49 [52%]) or no clinical symptoms (46 [48%]). The children of parents who self-identified as belonging to a racial and ethnic minority group were more likely to be seropositive compared with children of White parents (adjusted seroprevalence ratio, 1.9; 95% CI, 1.1-2.6). Conclusions and Relevance: These results provide a benchmark of the seroprevalence status in Canadian children. The findings suggest that there was more transmission occurring in children compared with what was being detected by RT-PCR, although children experienced few or mild symptoms. It will be important to continue monitoring the serological status of children, particularly in the context of new COVID-19 variants of concern and in the absence of mass vaccination campaigns targeting young children.


Subject(s)
COVID-19 Serological Testing/statistics & numerical data , COVID-19/epidemiology , SARS-CoV-2/isolation & purification , Adolescent , Antibodies, Viral/blood , Child , Child, Preschool , Cross-Sectional Studies , Female , Humans , Male , Prevalence , Quebec , Seroepidemiologic Studies
13.
Lancet Respir Med ; 9(8): 924-932, 2021 08.
Article in English | MEDLINE | ID: covidwho-1413874

ABSTRACT

BACKGROUND: Evidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission. METHODS: The present study is a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre trial. The study was done in Brazil, Canada, Greece, South Africa, Spain, and the USA, and was led by the Montreal Heart Institute. Patients with COVID-19 diagnosed by PCR testing or clinical criteria who were not being treated in hospital were eligible if they were at least 40 years old and had at least one high-risk characteristic. The randomisation list was computer-generated by an unmasked biostatistician, and masked randomisation was centralised and done electronically through an automated interactive web-response system. The allocation sequence was unstratified and used a 1:1 ratio with a blocking schema and block sizes of six. Patients were randomly assigned to receive orally administered colchicine (0·5 mg twice per day for 3 days and then once per day for 27 days thereafter) or matching placebo. The primary efficacy endpoint was the composite of death or hospital admission for COVID-19. Vital status at the end of the study was available for 97·9% of patients. The analyses were done according to the intention-to-treat principle. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682) and is now closed to new participants. FINDINGS: Trial enrolment began in March 23, 2020, and was completed in Dec 22, 2020. A total of 4488 patients (53·9% women; median age 54·0 years, IQR 47·0-61·0) were enrolled and 2235 patients were randomly assigned to colchicine and 2253 to placebo. The primary endpoint occurred in 104 (4·7%) of 2235 patients in the colchicine group and 131 (5·8%) of 2253 patients in the placebo group (odds ratio [OR] 0·79, 95·1% CI 0·61-1·03; p=0·081). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4·6%) of 2075 patients in the colchicine group and 126 (6·0%) of 2084 patients in the placebo group (OR 0·75, 0·57-0·99; p=0·042). Serious adverse events were reported in 108 (4·9%) of 2195 patients in the colchicine group and 139 (6·3%) of 2217 patients in the placebo group (p=0·051); pneumonia occurred in 63 (2·9%) of 2195 patients in the colchicine group and 92 (4·1%) of 2217 patients in the placebo group (p=0·021). Diarrhoea was reported in 300 (13·7%) of 2195 patients in the colchicine group and 161 (7·3%) of 2217 patients in the placebo group (p<0·0001). INTERPRETATION: In community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Given the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients and the benefit of colchicine in patients with PCR-proven COVID-19, this safe and inexpensive anti-inflammatory agent could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of PCR-positive community-treated patients is recommended. FUNDING: The Government of Quebec, the Bill & Melinda Gates Foundation, the National Heart, Lung, and Blood Institute of the US National Institutes of Health, the Montreal Heart Institute Foundation, the NYU Grossman School of Medicine, the Rudin Family Foundation, and philanthropist Sophie Desmarais.


Subject(s)
COVID-19 , Colchicine , Administration, Oral , Ambulatory Care/methods , Ambulatory Care/statistics & numerical data , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/adverse effects , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/epidemiology , Colchicine/administration & dosage , Colchicine/adverse effects , Double-Blind Method , Drug Monitoring/methods , Female , Hospitalization/statistics & numerical data , Humans , Intention to Treat Analysis , Male , Middle Aged , Outcome Assessment, Health Care , Risk Assessment , SARS-CoV-2/isolation & purification
14.
J Biol Chem ; 297(4): 101151, 2021 10.
Article in English | MEDLINE | ID: covidwho-1377741

ABSTRACT

The seasonal nature of outbreaks of respiratory viral infections with increased transmission during low temperatures has been well established. Accordingly, temperature has been suggested to play a role on the viability and transmissibility of SARS-CoV-2, the virus responsible for the COVID-19 pandemic. The receptor-binding domain (RBD) of the Spike glycoprotein is known to bind to its host receptor angiotensin-converting enzyme 2 (ACE2) to initiate viral fusion. Using biochemical, biophysical, and functional assays to dissect the effect of temperature on the receptor-Spike interaction, we observed a significant and stepwise increase in RBD-ACE2 affinity at low temperatures, resulting in slower dissociation kinetics. This translated into enhanced interaction of the full Spike glycoprotein with the ACE2 receptor and higher viral attachment at low temperatures. Interestingly, the RBD N501Y mutation, present in emerging variants of concern (VOCs) that are fueling the pandemic worldwide (including the B.1.1.7 (α) lineage), bypassed this requirement. This data suggests that the acquisition of N501Y reflects an adaptation to warmer climates, a hypothesis that remains to be tested.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/chemistry , COVID-19/pathology , COVID-19/virology , Calorimetry , Humans , Interferometry , Polymorphism, Single Nucleotide , Protein Binding , Protein Structure, Quaternary , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Temperature , Thermodynamics
15.
PLoS One ; 16(7): e0253022, 2021.
Article in English | MEDLINE | ID: covidwho-1308177

ABSTRACT

Influenza and RSV are human viruses responsible for outbreaks in hospitals, long-term care facilities and nursing homes. The present study assessed an air treatment using ozone at two relative humidity conditions (RHs) in order to reduce the infectivity of airborne influenza. Bovine pulmonary surfactant (BPS) and synthetic tracheal mucus (STM) were used as aerosols protectants to better reflect the human aerosol composition. Residual ozone concentration inside the aerosol chamber was also measured. RSV's sensitivity resulted in testing its resistance to aerosolization and sampling processes instead of ozone exposure. The results showed that without supplement and with STM, a reduction in influenza A infectivity of four orders of magnitude was obtained with an exposure to 1.70 ± 0.19 ppm of ozone at 76% RH for 80 min. Consequently, ozone could be considered as a virucidal disinfectant for airborne influenza A. RSV did not withstand the aerosolization and sampling processes required for the use of the experimental setup. Therefore, ozone exposure could not be performed for this virus. Nonetheless, this study provides great insight for the efficacy of ozone as an air treatment for the control of nosocomial influenza A outbreaks.


Subject(s)
Influenza A virus/drug effects , Ozone/pharmacology , Respiratory Syncytial Viruses/drug effects , Virus Inactivation/drug effects , Aerosols , Air Microbiology , Cross Infection/prevention & control , Disinfection/methods , Humans , Influenza, Human/prevention & control , Ozone/administration & dosage , Real-Time Polymerase Chain Reaction , Respiratory Syncytial Virus Infections/prevention & control
16.
BMJ Open ; 11(7): e053245, 2021 07 08.
Article in English | MEDLINE | ID: covidwho-1304235

ABSTRACT

INTRODUCTION: Further evidence is needed to understand the contribution of schools and daycares for the spread of COVID-19 in the context of diverse transmission dynamics and continually evolving public health interventions. The Enfants et COVID-19: Étude de séroprévalence (EnCORE) study will estimate the seroprevalence and seroconversion of SARS-CoV-2 among school and daycare children and personnel. In addition, the study will examine associations between seroprevalence and sociodemographic characteristics and reported COVID-19 symptoms and tests, and investigates changes in health, lifestyle and well-being outcomes. METHODS AND ANALYSIS: This study includes children and personnel from 62 schools and daycares in four neighbourhoods in Montreal, Canada. All children aged 2-17 years attending one of the participating schools or daycares and their parents are invited to participate, as well as a sample of personnel members. Participants respond to brief questionnaires and provide blood samples, collected via dried blood spot, at baseline (October 2020-March 2021) and follow-up (May-June 2021). Questionnaires include sociodemographic and household characteristics, reported COVID-19 symptoms and tests, potential COVID-19 risk factors and prevention efforts and health and lifestyle information. Logistic regression using generalised estimating equations will be used to estimate seroprevalence and seroconversion, accounting for school-level clustering. ETHICS AND DISSEMINATION: This study was approved by the research ethics boards of the Université de Montréal (CERSES) and the Centre Hospitalier Universitaire Sainte-Justine. Results will contribute to our knowledge about SARS-CoV-2 transmission in schools and daycares and will be made available to study participants and their families, school and public health decision-makers and the research community.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Canada , Child , Cohort Studies , Humans , Schools , Seroepidemiologic Studies
17.
ACS Omega ; 6(25): 16584-16591, 2021 Jun 29.
Article in English | MEDLINE | ID: covidwho-1301139

ABSTRACT

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3CL protease is a promising target for inhibition of viral replication by interaction with a cysteine residue (Cys145) at its catalytic site. Dalcetrapib exerts its lipid-modulating effect by binding covalently to cysteine 13 of a cholesteryl ester transfer protein. Because 12 free cysteine residues are present in the 3CL protease, we investigated the potential of dalcetrapib to inhibit 3CL protease activity and SARS-CoV-2 replication. Molecular docking investigations suggested that dalcetrapib-thiol binds to the catalytic site of the 3CL protease with a delta G value of -8.5 kcal/mol. Dalcetrapib inhibited both 3CL protease activity in vitro and viral replication in Vero E6 cells with IC50 values of 14.4 ± 3.3 µM and an EC50 of 17.5 ± 3.5 µM (mean ± SD). Near-complete inhibition of protease activity persisted despite 1000-fold dilution after ultrafiltration with a nominal dalcetrapib-thiol concentration of approximately 100 times below the IC50 of 14.4 µM, suggesting stable protease-drug interaction. The inhibitory effect of dalcetrapib on the SARS-CoV-2 3CL protease and viral replication warrants its clinical evaluation for the treatment of COVID-19.

18.
Sci Rep ; 11(1): 10847, 2021 05 25.
Article in English | MEDLINE | ID: covidwho-1243312

ABSTRACT

We conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical trial. We found a significant association at 5p13.3 (rs1173773; P = 4.94 × 10-8) near the natriuretic peptide receptor 3 gene (NPR3). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331; P = 2.95 × 10-8) in interaction with colchicine (P = 1.19 × 10-5) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.


Subject(s)
COVID-19/drug therapy , Colchicine/therapeutic use , Genome-Wide Association Study , Adult , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Chromosomes, Human, Pair 5/genetics , Chromosomes, Human, Pair 9/genetics , Double-Blind Method , Female , Gene Frequency , Genotype , Humans , Male , Middle Aged , Outpatients , Placebo Effect , Proportional Hazards Models , Remission Induction , Risk Factors , SARS-CoV-2/isolation & purification , Severity of Illness Index
20.
Front Microbiol ; 11: 631736, 2020.
Article in English | MEDLINE | ID: covidwho-1067655

ABSTRACT

The emergence and spread of infectious diseases with pandemic potential occurred regularly throughout history. Major pandemics and epidemics such as plague, cholera, flu, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) have already afflicted humanity. The world is now facing the new coronavirus disease 2019 (COVID-19) pandemic. Many infectious diseases leading to pandemics are caused by zoonotic pathogens that were transmitted to humans due to increased contacts with animals through breeding, hunting and global trade activities. The understanding of the mechanisms of transmission of pathogens to humans allowed the establishment of methods to prevent and control infections. During centuries, implementation of public health measures such as isolation, quarantine and border control helped to contain the spread of infectious diseases and maintain the structure of the society. In the absence of pharmaceutical interventions, these containment methods have still been used nowadays to control COVID-19 pandemic. Global surveillance programs of water-borne pathogens, vector-borne diseases and zoonotic spillovers at the animal-human interface are of prime importance to rapidly detect the emergence of infectious threats. Novel technologies for rapid diagnostic testing, contact tracing, drug repurposing, biomarkers of disease severity as well as new platforms for the development and production of vaccines are needed for an effective response in case of pandemics.

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