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1.
Immunity ; 55(6): 1096-1104.e4, 2022 Jun 14.
Article in English | MEDLINE | ID: covidwho-1778211

ABSTRACT

The SARS-CoV-2 Omicron variant can escape neutralization by vaccine-elicited and convalescent antibodies. Memory B cells (MBCs) represent another layer of protection against SARS-CoV-2, as they persist after infection and vaccination and improve their affinity. Whether MBCs elicited by mRNA vaccines can recognize the Omicron variant remains unclear. We assessed the affinity and neutralization potency against the Omicron variant of several hundred naturally expressed MBC-derived monoclonal IgG antibodies from vaccinated COVID-19-recovered and -naive individuals. Compared with other variants of concern, Omicron evaded recognition by a larger proportion of MBC-derived antibodies, with only 30% retaining high affinity against the Omicron RBD, and the reduction in neutralization potency was even more pronounced. Nonetheless, neutralizing MBC clones could be found in all the analyzed individuals. Therefore, despite the strong immune escape potential of the Omicron variant, these results suggest that the MBC repertoire generated by mRNA vaccines still provides some protection against the Omicron variant in vaccinated individuals.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Humans , RNA, Messenger/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccination
2.
Nat Med ; 28(6): 1297-1302, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1758268

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 Omicron BA.1 sublineage has been supplanted in many countries by the BA.2 sublineage. BA.2 differs from BA.1 by about 21 mutations in its spike. In this study, we first compared the sensitivity of BA.1 and BA.2 to neutralization by nine therapeutic monoclonal antibodies (mAbs). In contrast to BA.1, BA.2 was sensitive to cilgavimab, partly inhibited by imdevimab and resistant to adintrevimab and sotrovimab. We then analyzed sera from 29 immunocompromised individuals up to 1 month after administration of Ronapreve (casirivimab and imdevimab) and/or Evusheld (cilgavimab and tixagevimab) antibody cocktails. All treated individuals displayed elevated antibody levels in their sera, which efficiently neutralized the Delta variant. Sera from Ronapreve recipients did not neutralize BA.1 and weakly inhibited BA.2. Neutralization of BA.1 and BA.2 was detected in 19 and 29 out of 29 Evusheld recipients, respectively. As compared to the Delta variant, neutralizing titers were more markedly decreased against BA.1 (344-fold) than BA.2 (nine-fold). We further report four breakthrough Omicron infections among the 29 individuals, indicating that antibody treatment did not fully prevent infection. Collectively, BA.1 and BA.2 exhibit noticeable differences in their sensitivity to therapeutic mAbs. Anti-Omicron neutralizing activity of Ronapreve and, to a lesser extent, that of Evusheld is reduced in patients' sera.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral , COVID-19/drug therapy , Humans , Membrane Glycoproteins/genetics , Neutralization Tests , Spike Glycoprotein, Coronavirus , Viral Envelope Proteins
3.
EClinicalMedicine ; 46: 101362, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1757291

ABSTRACT

Background: In moderate-to-severe COVID-19 pneumonia, dexamethasone (DEX) and tocilizumab (TCZ) reduce the occurrence of death and ventilatory support. We investigated the efficacy and safety of DEX+TCZ in an open randomized clinical trial. Methods: From July 24, 2020, through May 18, 2021, patients with moderate-to-severe COVID-19 pneumonia requiring oxygen (>3 L/min) were randomly assigned to receive DEX (10 mg/d 5 days tapering up to 10 days) alone or combined with TCZ (8 mg/kg IV) at day 1, possibly repeated with a fixed dose of 400 mg i.v. at day 3. The primary outcome was time from randomization to mechanical ventilation support or death up to day 14, analysed on an intent-to-treat basis using a Bayesian approach. ClinicalTrials.gov number, NCT04476979. Findings: A total of 453 patients were randomized, 3 withdrew consent, 450 were analysed, of whom 226 and 224 patients were assigned to receive DEX or TCZ+DEX, respectively. At day 14, mechanical ventilation or death occurred in 32/226 (14%) and 27/224 (12%) in the DEX and TCZ+DEX arms, respectively (hazard ratio [HR] 0·85, 90% credible interval [CrI] 0·55 to 1·31). At day 14, the World health Organization (WHO) clinical progression scale (CPS) was significantly improved in the TCZ+DEX arm (OR 0·69, 95% CrI, 0·49 to 0.97). At day 28, the cumulative incidence of oxygen supply independency was 82% in the TCZ+DEX arms and 72% in the DEX arm (HR 1·36, 95% CI 1·11 to 1·67). On day 90, 24 deaths (11%) were observed in the DEX arm and 18 (8%) in the TCZ+DEX arm (HR 0·77, 95% CI 0·42-1·41). Serious adverse events were observed in 25% and 21% in DEX and TCZ+DEX arms, respectively. Interpretation: Mechanical ventilation need and mortality were not improved with TCZ+DEX compared with DEX alone. The safety of both treatments was similar. However, given the wide confidence intervals for the estimate of effect, definitive interpretation cannot be drawn. Funding: Programme Hospitalier de Recherche Clinique [PHRC COVID-19-20-0151, PHRC COVID-19-20-0029], Fondation de l'Assistance Publique - Hôpitaux de Paris (Alliance Tous Unis Contre le Virus) and from Fédération pour la Recherche Médicale" (FRM). Tocilizumab was provided by Roche.

4.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330085

ABSTRACT

The SARS-CoV-2 Omicron BA.1 variant has been supplanted in many countries by the BA.2 sub-lineage. BA.2 differs from BA.1 by about 21 mutations in its spike. Human anti-spike monoclonal antibodies (mAbs) are used for prevention or treatment of COVID-19. However, the capacity of therapeutic mAbs to neutralize BA.1 and BA.2 remains poorly characterized. Here, we first compared the sensitivity of BA.1 and BA.2 to neutralization by 9 therapeutic mAbs. In contrast to BA.1, BA.2 was sensitive to Cilgavimab, partly inhibited by Imdevimab and resistant to Adintrevimab and Sotrovimab. Two combinations of mAbs, Ronapreve (Casirivimab + Imdevimab) and Evusheld (Cilgavimab + Tixagevimab), are indicated as a pre-exposure prophylaxis in immunocompromised persons at risk of severe disease. We analyzed sera from 29 such individuals, up to one month after administration of Ronapreve and/or Evusheld. After treatment, all individuals displayed elevated antibody levels in their sera and neutralized Delta with high titers. Ronapreve recipients did not neutralize BA.1 and weakly impaired BA.2. With Evusheld, neutralization of BA.1 and BA.2 was detected in 19 and 29 out of 29 patients, respectively. As compared to Delta, titers were more severely decreased against BA.1 (344-fold) than BA.2 (9-fold). We further report 4 breakthrough Omicron infections among the 29 participants. Therefore, BA.1 and BA.2 exhibit noticeable differences in their sensitivity to therapeutic mAbs. Anti-Omicron activity of Ronapreve, and to a lesser extent that of Evusheld, is reduced in patients’ sera, a phenomenon associated with decreased clinical efficacy.

5.
Ann Rheum Dis ; 81(5): 720-728, 2022 05.
Article in English | MEDLINE | ID: covidwho-1622018

ABSTRACT

OBJECTIVES: The emergence of strains of SARS-CoV-2 exhibiting increase viral fitness and immune escape potential, such as the Delta variant (B.1.617.2), raises concerns in immunocompromised patients. We aimed to evaluate seroconversion, cross-neutralisation and T-cell responses induced by BNT162b2 in immunocompromised patients with systemic inflammatory diseases. METHODS: Prospective monocentric study including patients with systemic inflammatory diseases and healthcare immunocompetent workers as controls. Primary endpoints were anti-spike antibodies levels and cross-neutralisation of Alpha and Delta variants after BNT162b2 vaccine. Secondary endpoints were T-cell responses, breakthrough infections and safety. RESULTS: Sixty-four cases and 21 controls not previously infected with SARS-CoV-2 were analysed. Kinetics of anti-spike IgG after BNT162b2 vaccine showed lower and delayed induction in cases, more pronounced with rituximab. Administration of two doses of BNT162b2 generated a neutralising response against Alpha and Delta in 100% of controls, while sera from only one of rituximab-treated patients neutralised Alpha (5%) and none Delta. Other therapeutic regimens induced a partial neutralising activity against Alpha, even lower against Delta. All controls and cases except those treated with methotrexate mounted a SARS-CoV-2 specific T-cell response. Methotrexate abrogated T-cell responses after one dose and dramatically impaired T-cell responses after two doses of BNT162b2. Third dose of vaccine improved immunogenicity in patients with low responses. CONCLUSION: Rituximab and methotrexate differentially impact the immunogenicity of BNT162b2, by impairing B-cell and T-cell responses, respectively. Delta fully escapes the humoral response of individuals treated with rituximab. These findings support efforts to improve BNT162b2 immunogenicity in immunocompromised individuals (ClinicalTrials.gov number, NCT04870411).


Subject(s)
COVID-19 , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunocompromised Host , Immunogenicity, Vaccine , Methotrexate , Prospective Studies , Rituximab , SARS-CoV-2
7.
Immunity ; 54(12): 2893-2907.e5, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1433403

ABSTRACT

In addition to serum immunoglobulins, memory B cell (MBC) generation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is another layer of immune protection, but the quality of MBC responses in naive and coronavirus disease 2019 (COVID-19)-recovered individuals after vaccination remains ill defined. We studied longitudinal cohorts of naive and disease-recovered individuals for up to 2 months after SARS-CoV-2 mRNA vaccination. We assessed the quality of the memory response by analysis of antibody repertoires, affinity, and neutralization against variants of concern (VOCs) using unbiased cultures of 2,452 MBCs. Upon boosting, the MBC pool of recovered individuals expanded selectively, matured further, and harbored potent neutralizers against VOCs. Although naive individuals had weaker neutralizing serum responses, half of their RBD-specific MBCs displayed high affinity toward multiple VOCs, including delta (B.1.617.2), and one-third retained neutralizing potency against beta (B.1.351). Our data suggest that an additional challenge in naive vaccinees could recall such affinity-matured MBCs and allow them to respond efficiently to VOCs.


Subject(s)
/immunology , COVID-19/immunology , Precursor Cells, B-Lymphoid/immunology , RNA, Messenger/genetics , SARS-CoV-2/physiology , Animals , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Antibody Affinity , Cells, Cultured , Convalescence , Humans , Immunization, Secondary , Immunologic Memory , Mass Vaccination , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology
9.
Med Image Anal ; 67: 101860, 2021 01.
Article in English | MEDLINE | ID: covidwho-866975

ABSTRACT

Coronavirus disease 2019 (COVID-19) emerged in 2019 and disseminated around the world rapidly. Computed tomography (CT) imaging has been proven to be an important tool for screening, disease quantification and staging. The latter is of extreme importance for organizational anticipation (availability of intensive care unit beds, patient management planning) as well as to accelerate drug development through rapid, reproducible and quantified assessment of treatment response. Even if currently there are no specific guidelines for the staging of the patients, CT together with some clinical and biological biomarkers are used. In this study, we collected a multi-center cohort and we investigated the use of medical imaging and artificial intelligence for disease quantification, staging and outcome prediction. Our approach relies on automatic deep learning-based disease quantification using an ensemble of architectures, and a data-driven consensus for the staging and outcome prediction of the patients fusing imaging biomarkers with clinical and biological attributes. Highly promising results on multiple external/independent evaluation cohorts as well as comparisons with expert human readers demonstrate the potentials of our approach.


Subject(s)
Artificial Intelligence , COVID-19/diagnostic imaging , Pneumonia, Viral/diagnostic imaging , Biomarkers/analysis , Disease Progression , Humans , Neural Networks, Computer , Prognosis , Radiographic Image Interpretation, Computer-Assisted , SARS-CoV-2 , Triage
10.
J Infect ; 81(6): e4-e6, 2020 12.
Article in English | MEDLINE | ID: covidwho-728706

ABSTRACT

OBJECTIVE: To assess post-discharge persistent symptoms and health-related quality of life (HRQoL) of patients hospitalized in a COVID-19 ward unit more than 100 days after their admission. METHODS: All eligible patients were contacted by phone by trained physicians and were asked to answer to a dedicated questionnaire. Patients managed in hospital ward without needing intensive care were compared with those who were transferred in intensive care units (ICU). RESULTS: We included 120 patients after a mean (±SD) of 110.9 (±11.1) days following admission. The most frequently reported persistent symptoms were fatigue (55%), dyspnoea (42%), loss of memory (34%), concentration and sleep disorders (28% and 30.8%, respectively). Comparisons between ward- and ICU patients led to no statistically significant differences regarding those symptoms. In both group, EQ-5D (mobility, self-care, pain, anxiety or depression, usual activity) was altered with a slight difference in pain in the ICU group. CONCLUSION: Most patients requiring hospitalization for COVID-19 still have persistent symptoms. While there were few differences between HRQoL between ward and ICU patients, our findings must be confirmed in larger cohorts, including more severe patients.


Subject(s)
COVID-19/epidemiology , Hospitalization , Patient Discharge , Quality of Life , Aged , Aged, 80 and over , Anxiety/epidemiology , Fatigue/epidemiology , Female , Humans , Intensive Care Units , Male , Middle Aged , Pain/epidemiology , SARS-CoV-2 , Surveys and Questionnaires
11.
Ann Med ; 52(7): 367-375, 2020 11.
Article in English | MEDLINE | ID: covidwho-684538

ABSTRACT

OBJECTIVE: To identify predictive factors of unfavourable outcome among patients hospitalized for COVID-19. METHODS: We conducted a monocentric retrospective cohort study of COVID-19 patients hospitalized in Paris area. An unfavourable outcome was defined as the need for artificial ventilation and/or death. Characteristics at admission were analysed to identify factors predictive of unfavourable outcome using multivariable Cox proportional hazard models. Based on the results, a nomogram to predict 14-day probability of poor outcome was proposed. RESULTS: Between March 15th and April 14th, 2020, 279 COVID-19 patients were hospitalized after a median of 7 days after the first symptoms. Among them, 88 (31.5%) patients had an unfavourable outcome: 48 were admitted to the ICU for artificial ventilation, and 40 patients died without being admitted to ICU. Multivariable analyses retained age, overweight, polypnoea, fever, high C-reactive protein, elevated us troponin-I, and lymphopenia as risk factors of an unfavourable outcome. A nomogram was established with sufficient discriminatory power (C-index 0.75), and proper consistence between the prediction and the observation. CONCLUSION: We identified seven easily available prognostic factors and proposed a simple nomogram for early detection of patients at risk of aggravation, in order to optimize clinical care and initiate specific therapies. KEY MESSAGES Since novel coronavirus disease 2019 pandemic, a minority of patients develops severe respiratory distress syndrome, leading to death despite intensive care. Tools to identify patients at risk in European populations are lacking. In our series, age, respiratory rate, overweight, temperature, C-reactive protein, troponin and lymphocyte counts were risk factors of an unfavourable outcome in hospitalized adult patients. We propose an easy-to-use nomogram to predict unfavourable outcome for hospitalized adult patients to optimize clinical care and initiate specific therapies.


Subject(s)
Coronavirus Infections/physiopathology , Critical Care , Hospitalization , Nomograms , Pneumonia, Viral/physiopathology , Aged , Aged, 80 and over , COVID-19 , Cohort Studies , Coronavirus Infections/mortality , Coronavirus Infections/therapy , Female , Humans , Male , Middle Aged , Pandemics , Paris , Pneumonia, Viral/mortality , Pneumonia, Viral/therapy , Predictive Value of Tests , Prognosis , Proportional Hazards Models , Retrospective Studies , Risk Factors
13.
J Infect ; 81(4): 614-620, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-635718

ABSTRACT

OBJECTIVES: To determine the frequency of SARS-CoV-2 positive samples in a subset of patients consulting for primarily isolated acute (<7 days) loss of smell and to assess the diagnostic accuracy of olfactory/gustatory dysfunction for COVID-19 diagnosis in the overall population tested for COVID-19 in the same period. METHODS: Prospective multicentric cohort study in four olfactory ENT units and a screening center for COVID-19. RESULTS: i) Among a subset of 55 patients consulting for primarily recent loss of smell, we found that 51 (92.7%) had a COVID-19 positive test (median viral load of 28.8 cycle threshold). Loss of smell was mostly total (anosmia), rarely associated with nasal obstruction but associated with a taste disorder in 80%. Olfactory dysfunction occurred suddenly, either as first complaint or preceded by mild symptoms occurring a median of 3 days. The majority of patients (72.9%) partially recovered the sense of smell within 15 days. ii) In a population of 1824 patients tested for COVID-19, the positive predictive value and the specificity of loss of smell and/or taste were 78.5% and 90.3% respectively (sensitivity (40.8%), negative predictive value (63.6%)). CONCLUSIONS: Self-reported loss of smell had a high predictive positive value to identify COVID-19. Making this sign well known publicly could help to adopt isolation measures and inform potential contacts.


Subject(s)
Coronavirus Infections/diagnosis , Olfaction Disorders/virology , Pneumonia, Viral/diagnosis , Taste Disorders/virology , Adult , Betacoronavirus , COVID-19 , Female , Humans , Male , Pandemics , Prospective Studies , SARS-CoV-2 , Self Report , Smell/physiology , Taste Perception/physiology
14.
J Infect ; 81(3): e96-e98, 2020 09.
Article in English | MEDLINE | ID: covidwho-401340

ABSTRACT

OBJECTIVES: The CURB-65 is a severity score to predict mortality secondary to community acquired pneumonia and is widely used to identify patients who can be managed as outpatients. However, whether CURB-65 can be applicable to COVID-19 patients for the decision of outpatient treatment is still unknown. METHODS: We conducted a retrospective single-centre study assessing the performance of the CURB-65 to predict the risk of poor outcome, defined as the need for mechanical ventilation and/or death, among patients hospitalized for COVID-19. The association between the CURB-65 and the outcome was assessed by a univariable Cox proportional hazard regression model. RESULTS: A total of 279 patients were hospitalized between March 15th and April 14th, 2020. According to the CURB-65, 171 (61.3%) patients were considered at low risk (CURB-65 01), 66 (23.7%) at intermediate risk (CURB-65=2), and 42 (15.1%) had high risk of 30-day mortality (CURB-65 35). During the study period, 88 (31.5%) patients had a poor outcome. The CURB-65 was strongly associated with a poor outcome (Pfor linear trend <0.001). However, among patients with a CURB-65 of 01, thus considered at low risk, 36/171 (21.1%) had a poor outcome. CONCLUSIONS: Our study suggests that the applicability of CURB-65 to guide the decision of inpatient or outpatient care is scarce, as it does not safely identify patients who could be managed as outpatients.


Subject(s)
Community-Acquired Infections , Coronavirus Infections , Coronavirus , Pandemics , Pneumonia, Viral , Pneumonia , Ambulatory Care , Betacoronavirus , COVID-19 , Humans , Outpatients , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , United Kingdom
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