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2.
PLoS One ; 17(5): e0267725, 2022.
Article in English | MEDLINE | ID: covidwho-1869199

ABSTRACT

BACKGROUND: We aimed to study whether social patterns of exposure to SARS-CoV-2 infection changed in France throughout the year 2020, in light to the easing of social contact restrictions. METHODS: A population-based cohort of individuals aged 15 years or over was randomly selected from the national tax register to collect socio-economic data, migration history, and living conditions in May and November 2020. Home self-sampling on dried blood was proposed to a 10% random subsample in May and to all in November. A positive anti-SARS-CoV-2 ELISA IgG result against the virus spike protein (ELISA-S) was the primary outcome. The design, including sampling and post-stratification weights, was taken into account in univariate and multivariate analyses. RESULTS: Of the 134,391 participants in May, 107,759 completed the second questionnaire in November, and respectively 12,114 and 63,524 were tested. The national ELISA-S seroprevalence was 4.5% [95%CI: 4.0%-5.1%] in May and 6.2% [5.9%-6.6%] in November. It increased markedly in 18-24-year-old population from 4.8% to 10.0%, and among second-generation immigrants from outside Europe from 5.9% to 14.4%. This group remained strongly associated with seropositivity in November, after controlling for any contextual or individual variables, with an adjusted OR of 2.1 [1.7-2.7], compared to the majority population. In both periods, seroprevalence remained higher in healthcare professions than in other occupations. CONCLUSION: The risk of Covid-19 infection increased among young people and second-generation migrants between the first and second epidemic waves, in a context of less strict social restrictions, which seems to have reinforced territorialized socialization among peers.


Subject(s)
COVID-19 , SARS-CoV-2 , Adolescent , Adult , Antibodies, Viral , COVID-19/epidemiology , France/epidemiology , Humans , Immunoglobulin G , Seroepidemiologic Studies , Young Adult
3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-337653

ABSTRACT

ABSTRACT Background Variant-adaptated vaccines against coronavirus disease 2019 (COVID-19) as boosters are needed to increase a broader protection against SARS CoV-2 variants. New adjuvanted recombinant protein vaccines as heterologous boosters could maximize the response. Methods In this randomized, single-blinded, multicenter trial, adults who had received two doses of Pfizer-BioNTech mRNA vaccine (BNT162b2) 3 to7 months before were randomly assigned to receive a boost of BNT162b2, Sanofi/GSK SARS-CoV-2 adjuvanted recombinant protein MV D614 (monovalent parental formulation) or SARS-CoV-2 adjuvanted recombinant protein MV B.1.351 vaccine (monovalent Beta formulation). The primary endpoint was the percentage of subjects with a ≥10-fold increase in neutralizing antibody titers for the Wuhan (D614) and B.1.351 (Beta) SARS-CoV-2 viral strains between day 0 and day 15. Findings The percentages of participants whose neutralizing antibody titers against the Wuhan (D614) SARS-CoV-2 strain increased by a factor ≥10 between day 0 and day 15 was 55.3% (95% CI 43.4-66.7) in MV D614 group (n=76), 76.1% (64.5-85.4) in MV B.1.351 (Beta) group (n=71) and 63.2% (51.3-73.9) in BNT162b2 group (n=76). These percentages were 44.7% (33.3-56.6), 84.5% (74.0-92.0) and 51.3% (39.6-63.0) for the B.1.351 (Beta) viral strain, respectively. Higher neutralizing antibodies rates against Delta and Omicron BA.1 variants were also elicited after Sanofi/GSK MV Beta vaccine compared to the other vaccines. Comparable reactogenicity profile was observed with the three vaccines. Interpretation Heterologous boosting with the Sanofi/GSK Beta formulation vaccine resulted in a higher neutralizing antibody response against Beta variant but also the original strain and Delta and Omicron BA.1 variants, compared with mRNA BNT162b2 vaccine or the Sanofi/GSK MVD614 formulation. New vaccines containing Beta spike protein may represent an interesting strategy for broader protection against SARS CoV-2 variants. Funding French Ministries of Solidarity and Health and Research and Sanofi Trial registration number ClinicalTrials.gov identifier NCT05124171 ;EudraCT identifier 2021-004550-33.

4.
Sci Rep ; 12(1): 8622, 2022 May 21.
Article in English | MEDLINE | ID: covidwho-1852493

ABSTRACT

Assessment of the intensity, dynamics and determinants of the antibody response after SARS-CoV-2 infection or vaccination in the general population is critical to guide vaccination policies. This study characterized the anti-spike IgG titers in 13,971 participants included in a French multicohort population-based serological survey on COVID-19 between April and October 2020 and followed-up with serological testing between May and October 2021. Eight follow-up profiles were defined depending on SARS-CoV-2 infection (0, 1 or 2) and COVID-19 vaccination (0, 1, 2 or 3). The anti-spike titer was lower in adults with no vaccination even in case of infection or reinfection, while it was higher in adults with infection followed by vaccination. The anti-spike titer was negatively correlated with age in vaccinated but uninfected adults, whereas it was positively correlated with age in unvaccinated but infected adults. In adults with 2 vaccine injections and no infection, the vaccine protocol, age, gender, and time since the last vaccine injection were independently associated with the anti-spike titer. The decrease in anti-spike titer was much more rapid in vaccinated than in infected subjects. These results highlight the strong heterogeneity of the antibody response against SARS-CoV-2 in the general population depending on previous infection and vaccination.


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , Antibodies, Viral , Antibody Formation , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Vaccination
5.
J Geriatr Oncol ; 2022 May 16.
Article in English | MEDLINE | ID: covidwho-1851497

ABSTRACT

PURPOSE: The COVID-19 vaccination campaign began in December 2020, in France, and primarily targeted the oldest people. Our study aimed to determine the level of acceptance of vaccination in a population of older patients with cancer. METHODS: From January 2021, we offered vaccination with the BNT162b2 COVID-19 vaccine to all patients 70 years and older referred to our geriatric oncology center in Marseille University Hospital (AP-HM) for geriatric assessment before initiation of an oncological treatment. Objectives were to evaluate acceptance rate of COVID-19 vaccination and to assess vaccine safety, reactogenicity, and efficacy two months after the first dose. RESULTS: Between January 18, 2021 and May 7, 2021, 150 older patients with cancer were offered vaccination after a geriatric assessment. The majority were men (61.3%), with a mean age of 81 years. The two most frequent primary tumors were digestive (29.4%) and thoracic (18%). The vaccine acceptance rate was 82.6% and the complete vaccination rate (2 doses) reached 75.3%. Among the vaccinated patients, 15.9% reported mild side effects after the first dose and 23.4% after the second dose, mostly arm pain and fatigue. COVID-19 cases were observed in 5.1% of vaccinated patients compared with 16.7% in unvaccinated patients. Of the 22 vaccinated patients who agreed to have their serum tested, 15 had antibodies against the spike protein at day 21 after the first dose. CONCLUSION: Our study showed a high acceptance rate of COVID-19 vaccination, with good tolerance in this frail population. These results highlight the benefits of organizing vaccination campaigns at the very beginning of oncological management in older patients. CLINICAL TRIAL REGISTRATION: This study was registered May 23, 2019 in ClinicalTrials.gov (NCT03960593).

6.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-336877

ABSTRACT

The binding of the SARS-CoV-2 spike to angiotensin-converting enzyme 2 (ACE2) promotes virus entry into the cell. Targeting this interaction represents a promising strategy to generate antivirals. By screening a phage-display library of biosynthetic protein sequences build on a rigid alpha-helicoidal HEAT-like scaffold (named αReps), we selected candidates recognizing the spike receptor binding domain (RBD). Two of them (F9 and C2) bind the RBD with affinities in the nM range, displaying neutralisation activity in vitro and recognizing distinct sites, F9 overlapping the ACE2 binding motif. The F9-C2 fusion protein and a trivalent αRep form (C2-foldon) display 0.1 nM affinities and EC 50 of 8-18 nM for neutralization of SARS-CoV-2. In hamsters, F9-C2 instillation in the nasal cavity before or during infections effectively reduced the replication of a SARS-CoV-2 strain harbouring the D614G mutation in the nasal epithelium. Furthermore, F9-C2 and/or C2-foldon effectively neutralized SARS-CoV-2 variants (including delta and omicron variants) with EC 50 values ranging from 13 to 32 nM. With their high stability and their high potency against SARS-CoV-2 variants, αReps provide a promising tool for SARS-CoV-2 therapeutics to target the nasal cavity and mitigate virus dissemination in the proximal environment. Author Summary The entry of SARS-CoV-2 in permissive cells is mediated by the binding of its spike to angiotensin-converting enzyme 2 (ACE2) on the cell surface. To select ligands able to block this interaction, we screened a library of phages encoding artificial proteins (named αReps) for binding to its receptor binding domain (RBD). Two of them were able to bind the RBD with high affinity and block efficiently the virus entry in cultured cells. Assembled αReps through covalent or non-covalent linkages blocked virus entry at lower concentration than their precursors (with around 20-fold activity increase for a trimeric αRep). These αReps derivates neutralize efficiently SARS-CoV-2 β, γ, δ and Omicron virus variants. Instillation of an αRep dimer in the nasal cavity effectively reduced virus replication in the hamster model of SARS-CoV-2 and pathogenicity.

7.
Vox Sang ; 2022 May 16.
Article in English | MEDLINE | ID: covidwho-1846310

ABSTRACT

BACKGROUND AND OBJECTIVE: The SARS-CoV-2 Omicron variant displays increased infectiveness as well as mutations resulting in reduced neutralizing activity of antibodies acquired after vaccination or infection involving earlier strains. To assess the ability of vaccinated COVID-19 convalescent plasma (CCP-V) collected before November 2021 to seroneutralize Omicron, we compared neutralizing antibody (nAb) titres of 63 samples against Omicron and earlier B.1 (D614G) strains. METHODS AND FINDINGS: Relationship between anti-Omicron titres and IgG anti-S1 levels (binding arbitrary unit: BAU/ml) was studied. Although correlated, anti-Omicron titres were significantly lower than anti-B.1 titres (median = 80 [10-1280] vs. 1280 [160-10,240], p < 0.0001). Omicron nAb titres and IgG anti-S1 levels were correlated (Spearman's rank correlation coefficient = 0.67). Anti-S1 IgG threshold at 7000 BAU/ml may allow to discard CCP-V without anti-Omicron activity (nAb titre <40). Conversely, only those with highest titres (≥160) had systematically anti-S1 IgG levels >7000 BAU/ml. CONCLUSION: A fraction of CCP-V collected before November 2021 retains anti-Omicron seroneutralizing activity that may be selected by quantitative anti-IgG assays, but such assays do not easily allow the identification of 'high-titre' CCP-V. However, collecting plasma from vaccinated donors recently infected with Omicron may be the best option to provide optimal CCP-V for immunocompromised patients infected with this variant.

8.
EClinicalMedicine ; 48:101444-101444, 2022.
Article in English | EuropePMC | ID: covidwho-1842851

ABSTRACT

Background Although effective mRNA vaccines for SARS-CoV-2 infection have been deployed worldwide, their interchangeability could facilitate the scale-up of vaccination programs. The objective of the trial was to assess whether the immune response induced by a heterologous SARS-CoV-2 mRNA primo vaccination is non-inferior to that of a homologous mRNA vaccination. Methods We conducted a multicenter, randomized, open-label trial in adults 18 years of age and older who received a first dose of SARS-CoV-2 mRNA vaccine. Participants were randomly assigned in a 1:1 ratio to receive a second dose of BNT162b2 or mRNA-1273, 28 to 49 days after the first dose. Randomization was stratified on the vaccine received at the first vaccination. The primary endpoint was the anti-spike IgG antibodies titer measured 28 days after the second vaccine dose. This study is registered with ClinicalTrials.gov, Trial, NCT04900467. Findings Of the 414 randomized participants recruited from May 28 to July 2, 2021, 390 were included in the per protocol analysis: 94 participants in group 1 (BNT162b2/BNT162b2), 96 in group 2 (BNT162b2/mRNA-1273), 97 in group 3 (mRNA-1273/mRNA-1273), and 103 in group 4 (mRNA-1273/BNT162b2). The geometric mean titers ratios of anti-spike IgG antibodies for each heterologous regimen relative to the corresponding homologous regimen were 1·37 (two-sided 95% CI, 1·10 to 1·72) in the groups 1 and 2 and 0·67 (two-sided 95% CI, 0·55 to 0·82) in the groups 3 and 4. Levels of neutralizing antibodies to the main circulating SARS-Cov-2 viral strains were higher with the vaccine regimen containing mRNA-1273. Participants who received mRNA-1273 as a second dose experienced a higher rate of local adverse reactions and general symptoms than those who received BNT162b2 (p < 0·0001). Interpretation The two SARS-CoV-2 mRNA vaccines could be used with flexibility for the second dose of COVID-19 primo vaccination. Tolerance remains good regardless of vaccine sequence although mRNA-1273 was more reactogenic. Funding French Ministries of Solidarity and Health and Research. BNT162b2 was provided by Pfizer/BioNTech. mRNA-1273 was provided by Moderna.

11.
Open forum infectious diseases ; 2022.
Article in English | EuropePMC | ID: covidwho-1823878

ABSTRACT

The potential preventive efficacy of tenofovir/emtricitabine on SARS-CoV-2 infection was assessed in HIV pre-exposition prophylaxis (PrEP) users. Prevalence of SARS-CoV-2 IgG between May and October 2020 was similar in PrEP users and in a matched population-based cohort suggesting that tenofovir/emtricitabine has no role in reducing the risk of SARS-CoV-2 acquisition.

12.
Viruses ; 14(5)2022 May 03.
Article in English | MEDLINE | ID: covidwho-1820419

ABSTRACT

We aimed to investigate the immunoglobulin G response and neutralizing activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) among primary health care workers (PHCW) in France and assess the association between the neutralizing activity and several factors, including the coronavirus disease 2019 (COVID-19) vaccination scheme. A cross-sectional survey was conducted between 10 May 2021 and 31 August 2021. Participants underwent capillary blood sampling and completed a questionnaire. Sera were tested for the presence of antibodies against the nucleocapsid (N) protein and the S-1 portion of the spike (S) protein and neutralizing antibodies. In total, 1612 PHCW were included. The overall seroprevalences were: 23.6% (95% confidence interval (CI) 21.6-25.7%) for antibodies against the N protein, 94.7% (93.6-95.7%) for antibodies against the S protein, and 81.3% (79.4-83.2%) for neutralizing antibodies. Multivariate regression analyses showed that detection of neutralizing antibodies was significantly more likely in PHCW with previous SARS-CoV-2 infection than in those with no such history among the unvaccinated (odds ratio (OR) 16.57, 95% CI 5.96-59.36) and those vaccinated with one vaccine dose (OR 41.66, 95% CI 16.05-120.78). Among PHCW vaccinated with two vaccine doses, the detection of neutralizing antibodies was not significantly associated with previous SARS-CoV-2 infection (OR 1.31, 95% CI 0.86-2.07), but was more likely in those that received their second vaccine dose within the three months before study entry than in those vaccinated more than three months earlier (OR 5.28, 95% CI 3.51-8.23). This study highlights that previous SARS-CoV-2 infection and the time since vaccination should be considered when planning booster doses and the design of COVID-19 vaccine strategies.


Subject(s)
COVID-19 , Viral Vaccines , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines , Cross-Sectional Studies , Humans , Immunoglobulin G , Primary Health Care , SARS-CoV-2 , Seroepidemiologic Studies , Vaccination , Viral Envelope Proteins
13.
Vox Sang ; 117(4): 606-610, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1784756

ABSTRACT

Quantitation of anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) neutralizing antibodies (Nabs) is a key parameter in determining the effective dose for treatment with COVID-19 convalescent plasma (CCP). Interpretation of results from clinical trials conducted worldwide requires comparison of Nabs titres obtained from different methods. As virus neutralization tests (VNTs) are not standardized scalable or commercially available, strategies based on intensity of ELISA (Enzyme Linked Immunosorbent Assay) or chemiluminescent binding serological tests were implemented to allow comparisons and establish criteria for determining 'high-titres' of anti-SARS-CoV-2 antibodies (Abs). To this end, the FDA (Food and Drug Administration) has proposed criteria to define high-titre plasmas using different serological assays, including the one used in France for the CCP SARS-CoV-2 Abs screening (Euroimmun anti-S1 IgG). A retrospective study revealed that when using the FDA criteria (ELISA signal-to-cut-off [S/C ratio] ≥3.5), 91% of CCP had Nabs titres ≥40 as assessed with an in-house VNT. French strategy to ensure sufficient stocks of CCP of increasing titre has evolved over time. Recently, we improved our strategy by collecting only plasma from vaccinated convalescent donors as we confirmed that the mean IgG antibody level (ELISA S/C ratio) was significantly higher in plasma from vaccinated convalescent donors compared to donations from unvaccinated convalescent donors: 9.31 (CI 95%: 8.46-10.16) versus 3.22 (CI 95%: 3.05-3.39) (p < 0.001).


Subject(s)
COVID-19 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/diagnosis , COVID-19/therapy , Humans , Immunization, Passive , Retrospective Studies , SARS-CoV-2
14.
Lancet Reg Health Eur ; 17: 100363, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1783618

ABSTRACT

Background: Many patients report persistent symptoms after COVID-19. Our aim was to determine whether some of these symptoms were more associated with past SARS-CoV-2 infection compared to other conditions. Methods: This prospective survey was nested in CONSTANCES, a randomly selected French population-based cohort, started in 2012. All participants being followed-up by internet completed 2 questionnaires during the first wave of the pandemic focusing on the acute symptoms of their COVID-19-like illness. Serological tests for SARS-CoV-2 were then performed (May-Nov 2020). Between December 2020 and January 2021, participants completed a third questionnaire about symptoms that had lasted more than 2 months. Participants were classified into four groups according to both European Center for Diseases Control (ECDC) criteria for COVID-19 (ECDC+ or ECDC-) and serological SARS-CoV-2 test results (Sero+ or Sero-). To compare the risk of each persistent symptom among the groups, logistic regression models were adjusted for age, sex, educational level, comorbidities, and the number of acute symptoms declared during the first wave of the epidemic. A mediation analysis was performed to estimate the direct effect of the infection on persistent symptoms and its indirect effect via the initial clinical presentation. Findings: The analysis was performed in 25,910 participants. There was a higher risk of persistent dysgeusia/anosmia, dyspnea and asthenia in the ECDC+/Sero+ group than in the ECDC+/Sero- group (OR: 6.83 [4.47-10.42], 1.69 [1.07-2.6] and 1.48 [1.05-2.07], respectively). Abdominal pain, sensory symptoms or sleep disorders were at lower risk in the ECDC+/Sero+ group than in the ECDC+/Sero- group (0.51 [0.24-0.96], 0.40 [0.16-0.85], and 0.69 [0.49-0.95], respectively). The mediation analysis revealed that the association of the serological test results with each symptom was mainly mediated by ECDC symptoms (proportion mediated range 50-107%). Conclusion: A greater risk of persistent dysgeusia/anosmia, dyspnea and asthenia was observed in SARS-CoV-2 infected people. The initial clinical presentation substantially drives the association of positive serological test results with persistent symptoms. Funding: French National Research Agency.

15.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332623

ABSTRACT

Recombination is a crucial process in the evolution of many organisms. Although the evolutionary reasons behind its occurrence in RNA viruses are debated, this phenomenon has been associated with major epidemiological events such as virus host range expansion, antigenic shift or variation in virulence 1,2, and this process occurs frequently in positive strand RNA viruses such as coronaviruses. The SARS-CoV-2 pandemic has been associated with the repeated emergence of variants of concern presenting increased transmissibility, severity or immune escape 3. The recent extensive circulation of Delta worldwide and its subsequent replacement by viruses of the Omicron lineage 4 (BA.1 then BA.2), have created conditions for genetic exchanges between viruses with both genetic diversity and phenotypic specificities 5-7. Here we report the identification and in vitro and in vivo characterization of a Delta-Omicron recombinant in Europe. This recombinant exhibits immune escape properties similar to Omicron, while its behavior in mice expressing the human ACE2 receptor is more similar to Delta. This recombinant provides a unique and natural opportunity to better understand the genotype to phenotype links in SARS-CoV-2.

16.
Sci Rep ; 12(1): 4683, 2022 03 18.
Article in English | MEDLINE | ID: covidwho-1751758

ABSTRACT

The emergence and rapid spread of the Omicron variant of SARS-CoV-2, which has more than 30 substitutions in the spike glycoprotein, compromises the efficacy of currently available vaccines and therapeutic antibodies. Using a clinical strain of the Omicron variant, we analyzed the neutralizing power of eight currently used monoclonal antibodies compared to the ancestral B.1 BavPat1 D614G strain. We observed that six of these antibodies have lost their ability to neutralize the Omicron variant. Of the antibodies still having neutralizing activity, Sotrovimab/Vir-7831 shows the smallest reduction in activity, with a factor change of 3.1. Cilgavimab/AZD1061 alone shows a reduction in efficacy of 15.8, resulting in a significant loss of activity for the Evusheld cocktail (42.6-fold reduction) in which the other antibody, Tixagevimab, does not retain significant activity against Omicron. Our results suggest that the clinical efficacy of the initially proposed doses should be rapidly evaluated and the possible need to modify doses or propose combination therapies should be considered.


Subject(s)
COVID-19 , Viral Envelope Proteins , Antibodies, Monoclonal , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , Antibodies, Viral/therapeutic use , COVID-19/drug therapy , Humans , Membrane Glycoproteins , Neutralization Tests , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
17.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329966

ABSTRACT

The replacement of the Omicron BA.1 variant of SARS-CoV-2 by the BA.2 sub lineage, which has a different set of mutations in the spike glycoprotein, alters the spectrum of activity of therapeutic antibodies. In this study, we compared the neutralising power of monoclonal antibodies against the Omicron BA.1 and BA.2 variants, with an ancestral strain (D614G) and a Delta variant as reference. Sotrovimab is less active against BA.2 than against BA.1 (fold change reduction ~1,5). Within the Evusheld/ AZD744 cocktail, Cilgavimab is more active against BA.2 than against BA.1 (fold change increase ~32), whilst activity of Tixagevimab remains very low. In total, the activity of Evusheld is significantly improved (fold change increase ~10 compared to BA.1).

18.
Commun Biol ; 5(1): 225, 2022 03 10.
Article in English | MEDLINE | ID: covidwho-1740485

ABSTRACT

Late 2020, SARS-CoV-2 Alpha variant emerged in United Kingdom and gradually replaced G614 strains initially involved in the global spread of the pandemic. In this study, we use a Syrian hamster model to compare a clinical strain of Alpha variant with an ancestral G614 strain. The Alpha variant succeed to infect animals and to induce a pathology that mimics COVID-19. However, both strains replicate to almost the same level and induced a comparable disease and immune response. A slight fitness advantage is noted for the G614 strain during competition and transmission experiments. These data do not corroborate the epidemiological situation observed during the first half of 2021 in humans nor reports that showed a more rapid replication of Alpha variant in human reconstituted bronchial epithelium. This study highlights the need to combine data from different laboratories using various animal models to decipher the biological properties of newly emerging SARS-CoV-2 variants.


Subject(s)
COVID-19 , Disease Models, Animal , Mesocricetus , SARS-CoV-2/physiology , Animals , Antibodies, Neutralizing/blood , COVID-19/blood , COVID-19/immunology , COVID-19/virology , Cytokines/genetics , Female , Gastrointestinal Tract/virology , Genome, Viral , Lung/virology , Nasal Lavage Fluid/virology , SARS-CoV-2/genetics , Virus Replication
19.
Clin Microbiol Infect ; 28(7): 1010-1016, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1739639

ABSTRACT

OBJECTIVES: To assess the efficacy of inhaled ciclesonide in reducing the risk of adverse outcomes in COVID-19 outpatients at risk of developing severe illness. METHODS: COVERAGE is an open-label, randomized controlled trial. Outpatients with documented COVID-19, risk factors for aggravation, symptoms for ≤7 days, and absence of criteria for hospitalization are randomly allocated to either a control arm or one of several experimental arms, including inhaled ciclesonide. The primary efficacy endpoint is COVID-19 worsening (hospitalization, oxygen therapy at home, or death) by Day 14. Other endpoints are adverse events, maximal follow-up score on the WHO Ordinal Scale for Clinical Improvement, sustained alleviation of symptoms, cure, and RT-PCR and blood parameter evolution at Day 7. The trial's Safety Monitoring Board reviewed the first interim analysis of the ciclesonide arm and recommended halting it for futility. The results of this analysis are reported here. RESULTS: The analysis involved 217 participants (control 107, ciclesonide 110), including 111 women and 106 men. Their median age was 63 years (interquartile range 59-68), and 157 of 217 (72.4%) had at least one comorbidity. The median time since first symptom was 4 days (interquartile range 3-5). During the 28-day follow-up, 2 participants died (control 2/107 [1.9%], ciclesonide 0), 4 received oxygen therapy at home and were not hospitalized (control 2/107 [1.9%], ciclesonide 2/110 [1.8%]), and 24 were hospitalized (control 10/107 [9.3%], ciclesonide 14/110 [12.7%]). In intent-to-treat analysis of observed data, 26 participants reached the composite primary endpoint by Day 14, including 12 of 106 (11.3%, 95% CI: 6.0%-18.9%) in the control arm and 14 of 106 (13.2%; 95% CI: 7.4-21.2%) in the ciclesonide arm. Secondary outcomes were similar for both arms. DISCUSSION: Our findings are consistent with the European Medicines Agency's COVID-19 task force statement that there is currently insufficient evidence that inhaled corticosteroids are beneficial for patients with COVID-19.

20.
EMBO Rep ; 23(5): e53820, 2022 05 04.
Article in English | MEDLINE | ID: covidwho-1726972

ABSTRACT

Engineering recombinant viruses is a pre-eminent tool for deciphering the biology of emerging viral pathogens such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the large size of coronavirus genomes renders the current reverse genetics methods challenging. Here, we describe a simple method based on "infectious subgenomic amplicons" (ISA) technology to generate recombinant infectious coronaviruses with no need for reconstruction of the complete genomic cDNA and apply this method to SARS-CoV-2 and also to the feline enteric coronavirus. In both cases we rescue wild-type viruses with biological characteristics similar to original strains. Specific mutations and fluorescent red reporter genes can be readily incorporated into the SARS-CoV-2 genome enabling the generation of a genomic variants and fluorescent reporter strains for in vivo experiments, serological diagnosis, and antiviral assays. The swiftness and simplicity of the ISA method has the potential to facilitate the advance of coronavirus reverse genetics studies, to explore the molecular biological properties of the SARS-CoV-2 variants, and to accelerate the development of effective therapeutic reagents.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antiviral Agents , COVID-19/genetics , Cats , Reverse Genetics , SARS-CoV-2/genetics
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