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1.
Clinical Microbiology and Infection ; 2022.
Article in English | ScienceDirect | ID: covidwho-1996084

ABSTRACT

Objectives The potential benefit of convalescent plasma (CP) therapy for COVID-19 is highest when given early after symptom onset. Our objective was to determine the effectiveness of CP in improving the disease course of COVID-19 in high-risk outpatients. Methods A multicentre double blind randomized trial was conducted comparing 300mL of CP with non-CP. Patients were 50 years or older, symptomatic for <8 days, had PCR or antigen-test confirmed COVID-19 and at least 1 risk factor for severe COVID-19. The primary endpoint was the highest score on a 5-point ordinal scale ranging from fully recovered (score=1) or not (2) on day 7, over hospital admission (3), ICU admission (4) and death (5) in the 28 days following randomization. Secondary endpoints were hospital admission, symptom duration and viral RNA excretion. Results After enrolment of 421 patients and the transfusion of 416, recruitment was discontinued when the countrywide vaccination uptake in those aged >50 years was 80%. Patients had a median age of 60, symptoms for 5 days and 207 of 416 received CP. During the 28 days of follow-up, 28 patients were hospitalized and 2 died. The odds ratio (OR) for an improved disease severity score with CP was 0.86 (95%credible interval 0.59-1.22). The OR was 0.58 (95%confidence interval 0.33–1.02) for patients with ≤5 days of symptoms. The hazard ratio for hospital admission was 0.61 (95%confidence interval 0.28-1.34). No difference was found in viral RNA excretion nor in the duration of symptoms. Conclusions In patients with early COVID-19, CP did not improve the 5-point disease severity score. Clinical registry number NCT04589949.

2.
J Infect Dis ; 2022 Aug 04.
Article in English | MEDLINE | ID: covidwho-1973177

ABSTRACT

The aim of this randomized, controlled trial is to determine whether anti-SARS-CoV-2 hyperimmune globulin protects against severe COVID-19 in severely immunocompromised, hospitalized, COVID-19 patients. Patients were randomly assigned to receive anti-SARS-CoV-2 hyperimmune globulin (COVIG) or intravenous immunoglobulin without SARS-CoV-2 antibodies. Severe COVID-19 was observed in two out of ten (20%) patients treated with COVIG compared to seven out of eight (88%) in the IVIG control group (p = 0.015, Fisher's exact test). COVIG may be a valuable treatment in severely immunocompromised, hospitalized, COVID-19 patients and should be considered when no monoclonal antibody therapies are available. The trial was registered at www.trialregister.nl (#NL9436).

3.
Front Immunol ; 13: 821721, 2022.
Article in English | MEDLINE | ID: covidwho-1902983

ABSTRACT

Many studies already reported on the association between patient characteristics on the severity of COVID-19 disease outcome, but the relation with SARS-CoV-2 antibody levels is less clear. To investigate this in more detail, we performed a retrospective observational study in which we used the IgG antibody response from 11,118 longitudinal antibody measurements of 2,082 unique COVID convalescent plasma donors. COVID-19 symptoms and donor characteristics were obtained by a questionnaire. Antibody responses were modelled using a linear mixed-effects model. Our study confirms that the SARS-CoV-2 antibody response is associated with patient characteristics like body mass index and age. Antibody decay was faster in male than in female donors (average half-life of 62 versus 72 days). Most interestingly, we also found that three symptoms (headache, anosmia, nasal cold) were associated with lower peak IgG, while six other symptoms (dry cough, fatigue, diarrhoea, fever, dyspnoea, muscle weakness) were associated with higher IgG concentrations.


Subject(s)
Age Factors , COVID-19/immunology , COVID-19/therapy , SARS-CoV-2/physiology , Adult , Antibodies, Viral/blood , Antibody Formation , Blood Donors , Body Mass Index , COVID-19/epidemiology , COVID-19/physiopathology , Convalescence , Female , Humans , Immunization, Passive/methods , Immunoglobulin G/blood , Male , Middle Aged , Netherlands/epidemiology , Retrospective Studies
4.
Nat Commun ; 13(1): 2583, 2022 05 11.
Article in English | MEDLINE | ID: covidwho-1839524

ABSTRACT

Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when <20% of recruitment target was achieved. A Bayesian-adaptive individual patient data meta-analysis was implemented. Outpatients aged ≥50 years and symptomatic for ≤7days were included. The intervention consisted of 200-300mL of CP with a predefined minimum level of antibodies. Primary endpoints were a 5-point disease severity scale and a composite of hospitalization or death by 28 days. Amongst the 797 patients included, 390 received CP and 392 placebo; they had a median age of 58 years, 1 comorbidity, 5 days symptoms and 93% had negative IgG antibody-test. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of CP for improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311); OR for hospitalization or death was 0.919 (CI 0.592-1.416). CP effect on hospital admission or death was largest in patients with ≤5 days of symptoms (OR 0.658, 95%CI 0.394-1.085). CP did not decrease the time to full symptom resolution. TRIAL REGISTRATION: Clinicaltrials.gov NCT04621123 and NCT04589949. REGISTRATION: NCT04621123 and NCT04589949 on https://www. CLINICALTRIALS: gov.


Subject(s)
COVID-19 , Bayes Theorem , COVID-19/therapy , Humans , Immunization, Passive , Middle Aged , Multicenter Studies as Topic , Outpatients , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome
5.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332301

ABSTRACT

Background: Severely immunocompromised patients are at risk for severe COVID-19. Benefit from convalescent plasma in these patients is suggested but data from randomised trials are lacking. The aim of this study is to determine efficacy of SARS-CoV-2 hyperimmune globulin (COVIG) in treatment of severely immunocompromised, hospitalised COVID-19 patients. Methods: In this randomised, controlled, double-blind, multicentre, phase 3 trial, severely immunocompromised patients who were hospitalised with symptomatic COVID-19 were randomly assigned (1:1) to receive 15 grams of COVIG or 15 grams of intravenous immunoglobulin without SARS-CoV-2 antibodies (IVIG, control). Patients included were solid organ transplant patients with three drugs from different immunosuppressive classes or patient with disease or treatment severely affecting B-cell function. Patients that required mechanical ventilation or high flow nasal oxygen were excluded. All investigators, research staff, and participants were masked to group allocation. The primary endpoint was occurrence of severe COVID-19 evaluated up until day 28 after treatment, defined as the need for mechanical ventilation, high-flow nasal oxygen, readmission for COVID-19 after hospital discharge or lack of clinical improvement on day seven or later. This trial is registered with Netherlands Trial Register (NL9436). Findings: From April, 2021, to July, 2021, 18 participants were enrolled at three sites in the Netherlands;18 patients were analysed. Recruitment was halted prematurely when casirivimab/imdevimab became the recommended therapy in the Dutch COVID-19 treatment guideline for seronegative, hospitalised COVID-19 patients. Median age was 58 years and all but two were negative for SARS-CoV-2 spike IgG at baseline. Severe COVID-19 was observed in two out of ten (20%) patients treated with COVIG compared to seven of eight (88%) in the IVIG control group (p = 0.015, Fisher′s exact test). Interpretation: COVIG reduced the incidence of severe COVID-19 in severely immunocompromised patients, hospitalised with COVID-19. COVIG may be a valuable treatment in this patient group and can be used when no monoclonal antibody therapies are available. Funding: The Netherlands Organisation for Health Research and Development, Sanquin Blood Supply Foundation.

6.
Clin Infect Dis ; 74(7): 1271-1274, 2022 04 09.
Article in English | MEDLINE | ID: covidwho-1706426

ABSTRACT

Twenty-five B-cell-depleted patients (24 following anti-CD19/20 therapy) diagnosed with coronavirus disease 2019 had been symptomatic for a median of 26 days but remained antibody negative. All were treated with convalescent plasma with high neutralizing antibody titers. Twenty-one (84%) recovered, indicating the potential therapeutic effects of this therapy in this particular population.


Subject(s)
COVID-19 , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral , COVID-19/therapy , Humans , Immunization, Passive , SARS-CoV-2
7.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-311075

ABSTRACT

Convalescent plasma could be an inexpensive and widely available treatment for COVID-19 patients but reports on effectiveness are inconclusive. We collected convalescent plasma from donors with high titers of neutralizing anti-SARS-CoV-2 antibodies effectively blocking SARS-CoV-2 infection in vitro. In a randomized clinical trial of 86 COVID-19 patients, no overall clinical benefit of 300 mL convalescent plasma was found in patients hospitalized for COVID-19 in the Netherlands. Using a comprehensive translational approach, we unraveled the virological and immunological responses following plasma treatment which helps to understand which COVID-19 patients may benefit from this therapy and should be the focus of future studies. Convalescent plasma treatment in this patient group did not improve survival, had no effect on the clinical course of disease, nor did plasma enhance viral clearance in the respiratory tract, influence anti-SARS-CoV-2 antibody development or serum proinflammatory cytokines levels. The vast majority of patients already had potent neutralizing anti-SARS-CoV-2 antibodies at hospital admission and at comparable titers as the carefully selected plasma donors. Together, these data indicate that the variable effectivity observed in trials on convalescent plasma for COVID-19 may be explained by the timing of treatment and varying levels of preexisting anti-SARS-CoV-2 immunity in patients. It also substantiates that convalescent plasma should be studied as early as possible in the disease course or at least preceding the start of an autologous humoral response. Trial registration : Clinicaltrials.gov: NCT04342182

8.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-293378

ABSTRACT

Background: Convalescent plasma (CP) for hospitalized patients with COVID-19 has not demonstrated clear benefits. However, data on outpatients with early symptoms are scarce. We aimed to assess whether treatment with CP administered during the first 7 days of symptoms reduced the disease progression or risk of hospitalization of outpatients. Methods: Two double-blind randomized trials ( NCT04621123 , NCT04589949 ) were merged with data pooling starting when <20% of their predefined sample size had been recruited. A Bayesian adaptive individual patient data meta-analysis was implemented. Analyses were done with Bayesian proportional odds and logistic models, where odds ratios (OR)<1.0 indicate a favorable outcome for CP. Fourteen study sites across the Netherlands and Catalonia in Spain participated in the trial. The two studies included outpatients aged ≥50 years and diagnosed with COVID-19 and symptomatic for ≤7days. The intervention consisted of one unit (200-300mL) of CP with a predefined minimum level of antibodies. The two primary endpoints were (a) a 5-point disease severity scale (fully recovered by day 7 or not, hospital or ICU admission and death) and (b) a composite of hospitalization or death. Results: Of 797 patients included, 390 received CP and 392 placebo. At baseline, they had a median age of 58 years, 1 comorbidity, symptoms for 5 days and 93% tested negative for SARS-CoV-2 S-protein IgG antibodies. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The OR of CP for an improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311). The OR for hospitalization or death was 0.919 (CI 0.592-1.416). The effect of CP on hospital admission or death was largest in patients with ≤5 days of symptoms (OR 0.658, 95% CI 0.394-1.085). CP did not decrease the time to full symptom resolution (p=0.62). Conclusion: Treatment with CP of outpatients in the first 7 days of symptoms did not improve the outcome of COVID-19. The possible beneficial effect in patients with ≤5 days of symptoms requires further study.   Registration: NCT04621123 and NCT04589949 on https://www.clinicaltrials.gov

9.
Clin Infect Dis ; 74(7): 1271-1274, 2022 04 09.
Article in English | MEDLINE | ID: covidwho-1320296

ABSTRACT

Twenty-five B-cell-depleted patients (24 following anti-CD19/20 therapy) diagnosed with coronavirus disease 2019 had been symptomatic for a median of 26 days but remained antibody negative. All were treated with convalescent plasma with high neutralizing antibody titers. Twenty-one (84%) recovered, indicating the potential therapeutic effects of this therapy in this particular population.


Subject(s)
COVID-19 , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral , COVID-19/therapy , Humans , Immunization, Passive , SARS-CoV-2
10.
Nat Commun ; 12(1): 3189, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1246368

ABSTRACT

In a randomized clinical trial of 86 hospitalized COVID-19 patients comparing standard care to treatment with 300mL convalescent plasma containing high titers of neutralizing SARS-CoV-2 antibodies, no overall clinical benefit was observed. Using a comprehensive translational approach, we unravel the virological and immunological responses following treatment to disentangle which COVID-19 patients may benefit and should be the focus of future studies. Convalescent plasma is safe, does not improve survival, has no effect on the disease course, nor does plasma enhance viral clearance in the respiratory tract, influence SARS-CoV-2 antibody development or serum proinflammatory cytokines levels. Here, we show that the vast majority of patients already had potent neutralizing SARS-CoV-2 antibodies at hospital admission and with comparable titers to carefully selected plasma donors. This resulted in the decision to terminate the trial prematurely. Treatment with convalescent plasma should be studied early in the disease course or at least preceding autologous humoral response development.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/therapy , Cytokines/blood , SARS-CoV-2/immunology , Aged , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Blood Donors , COVID-19/blood , COVID-19/virology , Disease Progression , Female , Hospitalization , Humans , Immunization, Passive , Immunoglobulin G/blood , Kaplan-Meier Estimate , Male , Middle Aged , Spike Glycoprotein, Coronavirus/immunology , Treatment Outcome
11.
Clin Transl Immunology ; 10(5): e1285, 2021.
Article in English | MEDLINE | ID: covidwho-1233184

ABSTRACT

OBJECTIVES: Characterisation of the human antibody response to SARS-CoV-2 infection is vital for serosurveillance purposes and for treatment options such as transfusion with convalescent plasma or immunoglobulin products derived from convalescent plasma. In this study, we longitudinally and quantitatively analysed antibody responses in RT-PCR-positive SARS-CoV-2 convalescent adults during the first 250 days after onset of symptoms. METHODS: We measured antibody responses to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and the nucleocapsid protein in 844 longitudinal samples from 151 RT-PCR-positive SARS-CoV-2 convalescent adults. With a median of 5 (range 2-18) samples per individual, this allowed quantitative analysis of individual longitudinal antibody profiles. Kinetic profiles were analysed by mixed-effects modelling. RESULTS: All donors were seropositive at the first sampling moment, and only one donor seroreverted during follow-up analysis. Anti-RBD IgG and anti-nucleocapsid IgG levels declined with median half-lives of 62 and 59 days, respectively, 2-5 months after symptom onset, and several-fold variation in half-lives of individuals was observed. The rate of decline of antibody levels diminished during extended follow-up, which points towards long-term immunological memory. The magnitude of the anti-RBD IgG response correlated well with neutralisation capacity measured in a classic plaque reduction assay and in an in-house developed competitive assay. CONCLUSION: The result of this study gives valuable insight into the long-term longitudinal response of antibodies to SARS-CoV-2.

12.
J Immunol ; 205(12): 3491-3499, 2020 12 15.
Article in English | MEDLINE | ID: covidwho-895432

ABSTRACT

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infections often cause only mild disease that may evoke relatively low Ab titers compared with patients admitted to hospitals. Generally, total Ab bridging assays combine good sensitivity with high specificity. Therefore, we developed sensitive total Ab bridging assays for detection of SARS-CoV-2 Abs to the receptor-binding domain (RBD) and nucleocapsid protein in addition to conventional isotype-specific assays. Ab kinetics was assessed in PCR-confirmed, hospitalized coronavirus disease 2019 (COVID-19) patients (n = 41) and three populations of patients with COVID-19 symptoms not requiring hospital admission: PCR-confirmed convalescent plasmapheresis donors (n = 182), PCR-confirmed hospital care workers (n = 47), and a group of longitudinally sampled symptomatic individuals highly suspect of COVID-19 (n = 14). In nonhospitalized patients, the Ab response to RBD is weaker but follows similar kinetics, as has been observed in hospitalized patients. Across populations, the RBD bridging assay identified most patients correctly as seropositive. In 11/14 of the COVID-19-suspect cases, seroconversion in the RBD bridging assay could be demonstrated before day 12; nucleocapsid protein Abs emerged less consistently. Furthermore, we demonstrated the feasibility of finger-prick sampling for Ab detection against SARS-CoV-2 using these assays. In conclusion, the developed bridging assays reliably detect SARS-CoV-2 Abs in hospitalized and nonhospitalized patients and are therefore well suited to conduct seroprevalence studies.


Subject(s)
Antibodies, Viral/immunology , Antibody Formation , COVID-19/immunology , Nucleocapsid Proteins/immunology , SARS-CoV-2/immunology , Adult , COVID-19/diagnosis , COVID-19 Nucleic Acid Testing , COVID-19 Serological Testing , Convalescence , Female , Humans , Immunologic Tests , Male , Middle Aged
13.
Eur J Immunol ; 50(12): 1998-2012, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-871354

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. Understanding the immune response that provides specific immunity but may also lead to immunopathology is crucial for the design of potential preventive and therapeutic strategies. Here, we characterized and quantified SARS-CoV-2-specific immune responses in patients with different clinical courses. Compared to individuals with a mild clinical presentation, CD4+ T-cell responses were qualitatively impaired in critically ill patients. Strikingly, however, in these patients the specific IgG antibody response was remarkably strong. Furthermore, in these critically ill patients, a massive influx of circulating T cells into the lungs was observed, overwhelming the local T-cell compartment, and indicative of vascular leakage. The observed disparate T- and B-cell responses could be indicative of a deregulated immune response in critically ill COVID-19 patients.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immunoglobulin G/immunology , SARS-CoV-2/immunology , Adult , Aged , B-Lymphocytes/pathology , CD4-Positive T-Lymphocytes/pathology , COVID-19/pathology , Female , Humans , Male , Middle Aged , Severity of Illness Index
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