Outpatient COVID-19 convalescent plasma recipient antibody thresholds correlated to reduced hospitalizations within a randomized trial.

BACKGROUNDCOVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined.METHODSThis secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization-equivalent anti-Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis.RESULTSSARS-CoV-2 anti-S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01).CONCLUSIONIn unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors' antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use.TRIAL REGISTRATIONClinicalTrials.gov NCT04373460.FUNDINGDepartment of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

Charting a path forward: Promising outcomes of convalescent plasma therapy in the care of severely B-cell depleted patients with persistent COVID-19.

BACKGROUND: Patients with severe B-cell depletion related to hematological malignancies or B-cell targeted therapy suffer from impaired antibody responses to SARS-CoV-2 and are at risk for prolonged COVID-19. In this population, COVID-19 convalescent plasma (CCP) may provide passive immunity, enhance immune response, and promote virus neutralization. This study evaluated outcomes of B-cell depleted patients with persistent COVID-19 treated with CCP. STUDY DESIGN AND METHODS: This analysis included all consecutive severely B-cell depleted patients with persistent COVID-19, receiving CCP at Rambam between 01.2022-02.2023. Persistent COVID-19 was defined as the presence of symptoms for ≥14 days in patients with negative SARS-CoV-2 nucleocapsid antibody test results. RESULTS: Twenty patients met inclusion criteria, 17 of whom had hematological malignancies, two suffered from rheumatoid arthritis and one had both. Twelve patients received anti-CD-20 treatment, one - CAR-T cells and three underwent stem cell transplantation. The median duration of COVID-19 symptoms was 27.5 days (range 14-97); 12 patients had mild-to-moderate COVID-19 and 8 had severe infection. Sixteen patients required hospitalization. The majority of patients received other COVID-19 therapies before CCP. Within a median of two days (range 1-16) post-infusion, 19/20 patients clinically improved. No CCP-associated adverse events were documented. COVID-19 symptoms recurred in 3 of the improved patients. Two patients died from COVID-19 on days 1 and 90 following the first CCP infusion. DISCUSSION: In severely B-cell depleted patients with persistent COVID-19, CCP is safe and associated with rapid clinical improvement. This subset of immunocompromised patients could particularly benefit from CCP administration.

Factors related to the development of high antibody titres against SARS-CoV-2 in convalescent plasma donors from the ConPlas-19 trial.

BACKGROUND AND OBJECTIVES: The efficacy of COVID-19 convalescent plasma (CP) associates with high titres of antibodies. ConPlas-19 clinical trial showed that CP reduces the risk of progression to severe COVID-19 at 28 days. Here, we aim to study ConPlas-19 donors and characteristics that associate with high anti-SARS-CoV-2 antibody levels. MATERIALS AND METHODS: Four-hundred donors were enrolled in ConPlas-19. The presence and titres of anti-SARS-CoV-2 antibodies were evaluated by EUROIMMUN anti-SARS-CoV-2 S1 IgG ELISA. RESULTS: A majority of 80.3% of ConPlas-19 donor candidates had positive EUROIMMUN test results (ratio ≥1.1), and of these, 51.4% had high antibody titres (ratio ≥3.5). Antibody levels decline over time, but nevertheless, out of 37 donors tested for an intended second CP donation, over 90% were still EUROIMMUN positive, and nearly 75% of those with high titres maintained high titres in the second sample. Donors with a greater probability of developing high titres of anti-SARS-CoV-2 antibodies include those older than 40 years of age (RR 2.06; 95% CI 1.24-3.42), with more than 7 days of COVID-19 symptoms (RR 1.89; 95% CI 1.05-3.43) and collected within 4 months from infection (RR 2.61; 95% CI 1.16-5.90). Male donors had a trend towards higher titres compared with women (RR 1.67; 95% CI 0.91-3.06). CONCLUSION: SARS-CoV-2 CP candidate donors' age, duration of COVID-19 symptoms and time from infection to donation associate with the collection of CP with high antibody levels. Beyond COVID-19, these data are relevant to inform decisions to optimize the CP donor selection process in potential future outbreaks.

Fc-mediated functions and the treatment of severe respiratory viral infections with passive immunotherapy - a balancing act.

Passive immunotherapies have been used to treat severe respiratory infections for over a century, with convalescent blood products from recovered individuals given to patients with influenza-related pneumonia as long ago as the Spanish flu pandemic. However, passive immunotherapy with convalescent plasma or hyperimmune intravenous immunoglobulin (hIVIG) has not provided unequivocal evidence of a clinical benefit for severe respiratory infections including influenza and COVID-19. Efficacy trials, primarily conducted in late-stage disease, have demonstrated inconsistent efficacy and clinical benefit for hIVIG treatment of severe respiratory infections. To date, most serological analyses of convalescent plasma and hIVIG trial samples have focused on the measurement of neutralizing antibody titres. There is, however, increasing evidence that baseline antibody levels and extra-neutralizing antibody functions influence the outcome of passive immunotherapy in humans. In this perspective, findings from convalescent plasma and hIVIG trials for severe influenza, COVID-19 and respiratory syncytial virus (RSV) will be described. Clinical trial results will be discussed in the context of the potential beneficial and deleterious roles of antibodies with Fc-mediated effector functions, with a focus on natural killer cells and antibody-dependent cellular cytotoxicity. Overall, we postulate that treating respiratory viral infections with hIVIG represents a delicate balance between protection and immunopathology.

Eficacia y seguridad de la administración de plasma de convaleciente en pacientes con COVID-19 / Efficacy and safety of convalescent plasma administration in patients with COVID-19 infection

Introducción Durante la pandemia de COVID-19 surgieron diversas estrategias para el manejo de la enfermedad, incluidos los tratamientos farmacológicos y no farmacológicos como el plasma convaleciente (PC). El uso de PC se sugirió debido a los resultados benéficos mostrados al tratar otras enfermedades virales. Objetivo Determinar la eficacia y la seguridad de la administración de PC obtenido de sangre total en pacientes con COVID-19. Métodos Ensayo clínico piloto en pacientes con COVID-19 de un hospital general. Los sujetos se separaron en 3 grupos que recibieron la transfusión de 400ml de PC (n=23) o 400ml de plasma estándar (PE) (n=19) y un grupo no transfundido (NT) (n=37). Los pacientes recibieron además, el tratamiento médico estándar disponible para COVID-19. El seguimiento de los sujetos se llevó a cabo diariamente desde el ingreso hasta el día 21. Resultados El PC no mejoró la curva de supervivencia en las variantes moderadas y graves de COVID-19, ni disminuyó el grado de severidad de la enfermedad evaluado con la escala de progresión clínica COVID-19, OMS y SOFA. Ningún paciente presentó una reacción postransfusional severa al PC. Conclusiones El tratamiento con PC no disminuye la mortalidad de los pacientes, aun cuando su administración tiene un alto grado de seguridad (AU)

Introduction During the COVID-19 pandemic, several strategies were suggested for the management of the disease, including pharmacological and non-pharmacological treatments such as convalescent plasma (CP). The use of CP was suggested due to the beneficial results shown in treating other viral diseases. Objective To determine the efficacy and safety of CP obtained from whole blood in patients with COVID-19. Methods Pilot clinical trial in patients with COVID-19 from a general hospital. The subjects were separated into three groups that received the transfusion of 400ml of CP (n=23) or 400ml of standard plasma (SP) (n=19) and a non-transfused group (NT) (n=37). Patients also received the standard available medical treatment for COVID-19. Subjects were followed up daily from admission to day 21. Results The CP did not improve the survival curve in moderate and severe variants of COVID-19, nor did it reduce the degree of severity of the disease evaluated with the COVID-19 WHO and SOFA clinical progression scale. No patient had a severe post-transfusion reaction to CP. Conclusions Treatment with CP does not reduce the mortality of patients even when its administration has a high degree of safety (AU)

Igniting the slow burn of post-COVID conditions.

Post-COVID conditions (PCCs) are persistent new patient symptoms occurring after acute COVID-19 infection and are an increasingly appreciated dimension of the COVID-19 pandemic. The factors that cause PCCs are not well understood. In recent work, Gebo et al. identify a connection between acute IL-6 levels, early COVID-19 convalescent plasma (CP) administration, and later PCCs in subjects from a randomized controlled trial of acutely ill subjects enrolled in 2020 to 2021 (K. A. Gebo, S. L. Heath, Y. Fukuta, X. Zhu, et al., mBio e00618-23, 2023, https://doi.org/10.1128/mbio.00618-23). These results may be viewed as part of an emerging picture linking the intensity of inflammatory responses during acute infection to later PCCs.

Convalescent plasma and all-cause mortality of COVID-19 patients: systematic review and meta-analysis.

Insight into the clinical potential of convalescent plasma in patients with coronavirus disease (COVID-19) is important given the severe clinical courses in unvaccinated and seronegative individuals. The aim of the study was to investigate whether there is a survival benefit of convalescent plasma therapy in COVID-19 patients. The authors independently assessed randomized controlled trials (RCTs) identified by the search strategy for inclusion, extracted data, and assessed risk of bias. The binary primary outcome was all-cause mortality. Risk ratio (RR) of the convalescent plasma treatment (vs. best standard care) and its associated standard error (effect size) were calculated. A random-effects model was employed to statistically pool the effect sizes of the selected studies. We included 19 RCTs with 17,021 patients. The random-effects model resulted in an estimated pooled RR of 0.94 (95% CI 0.81-1.08, p = 0.33), showing no statistical evidence of the benefit of convalescent plasma therapy on all-cause mortality. Convalescent plasma therapy was not found to be effective in reducing all-cause mortality in COVID-19 patients. Further studies are needed to determine in which patients convalescent plasma therapy may lead to a reduction in mortality.

Convalescent Plasma Therapy in Late-State, Severe COVID-19 Infection.

OBJECTIVES: Current evidence favors plasma to be effective against coronavirus disease 2019 (COVID-19) in critically ill patients in the early stages of infection. We investigated the safety and efficacy of convalescent plasma in specifically late-stage (designated as after 2 weeks of hospital admission) severe COVID-19 infection. We also conducted a literature review on the late-stage use of plasma in COVID-19. METHODS: This case series examined eight COVID-19 patients admitted to the intensive care unit (ICU) who met criteria for severe or life-threatening complications. Each patient received one dose (200 mL) of plasma. Clinical information was gathered in intervals of 1 day pretransfusion and 1 hour, 3 days, and 7 days posttransfusion. The primary outcome was effectiveness of plasma transfusion, measured by clinical improvement, laboratory parameters, and all-cause mortality. RESULTS: Eight ICU patients received plasma late in the course of COVID-19 infection, on average at 16.13 days postadmission. On the day before transfusion, the averaged initial Sequential Organ Failure Assessment (SOFA) score, PaO2:FiO2 ratio, Glasgow Coma Scale (GCS), and lymphocyte count were 6.5, 228.03, 8.63, and 1.19, respectively. Three days after plasma treatment, the group averages for the SOFA score (4.86), PaO2:FiO2 ratio (302.73), GCS (9.29), and lymphocyte count (1.75) improved. Although the mean GCS improved to 10.14 by posttransfusion day 7, the other means marginally worsened with an SOFA score of 5.43, a PaO2:FiO2 ratio of 280.44, and a lymphocyte count of 1.71. Clinical improvement was noted in six patients who were discharged from the ICU. CONCLUSIONS: This case series provides evidence that convalescent plasma may be safe and effective in late-stage, severe COVID-19 infection. Results showed clinical improvement posttransfusion as well as decreased all-cause mortality in comparison to pretransfusion predicted mortality. Randomized controlled trials are needed to conclusively determine benefits, dosage, and timing of treatment.

COVID-19 Serology Data Provide Guidance for Future Deployments of Convalescent Plasma.

Measurement of antibody content and function after a viral illness is important for diagnosis and selection of the best convalescent plasma (CP) units for passive immunization. Zhang et al. (mBio 14:e03523-22, 2013, https://doi.org/10.1128/mbio.03523-22) analyzed over 19,000 coronavirus disease 2019 (COVID-19) CP (CCP) samples from the early days of the COVID-19 pandemic and reported a moderately strong correlation between antibody amount and neutralizing titer. Strikingly, about one-third of the samples had little or no neutralizing activity. The results provide a detailed glimpse of the humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in immunologically naive humans and reveal major differences in the quality of CP units collected for passive therapy before antibody screening. Heterogeneity in CCP quality undoubtedly contributed to the variable therapeutic efficacy. Analysis of the COVID-19 serology data suggest that, for the next infectious disease emergency, the best approach after quick establishment of methods for robust antibody-level stratification would be to use CP units in the top quintile of antibody content and neutralizing capacity.

Early, very high-titre convalescent plasma therapy in clinically vulnerable individuals with mild COVID-19 (COVIC-19): protocol for a randomised, open-label trial.

INTRODUCTION: COVID-19 convalescent plasma (CCP) is a possible treatment option for COVID-19. A comprehensive number of clinical trials on CCP efficacy have already been conducted. However, many aspects of CCP treatment still require investigations: in particular (1) Optimisation of the CCP product, (2) Identification of the patient population in need and most likely to benefit from this treatment approach, (3) Timing of administration and (4) CCP efficacy across viral variants in vivo. We aimed to test whether high-titre CCP, administered early, is efficacious in preventing hospitalisation or death in high-risk patients. METHODS AND ANALYSIS: COVIC-19 is a multicentre, randomised, open-label, adaptive superiority phase III trial comparing CCP with very high neutralising antibody titre administered within 7 days of symptom onset plus standard of care versus standard of care alone. We will enrol patients in two cohorts of vulnerable patients [(1) elderly 70+ years, or younger with comorbidities; (2) immunocompromised patients]. Up to 1020 participants will be enrolled in each cohort (at least 340 with a sample size re-estimation after reaching 102 patients). The primary endpoint is the proportion of participants with (1) Hospitalisation due to progressive COVID-19, or (2) Who died by day 28 after randomisation. Principal analysis will follow the intention-to-treat principle. ETHICS AND DISSEMINATION: Ethical approval has been granted by the University of Ulm ethics committee (#41/22) (lead ethics committee for Germany), Comité de protection des personnes Sud-Est I (CPP Sud-Est I) (#2022-A01307-36) (ethics committee for France), and ErasmusMC ethics committee (#MEC-2022-0365) (ethics committee for the Netherlands). Signed informed consent will be obtained from all included patients. The findings will be published in peer-reviewed journals and presented at relevant stakeholder conferences and meetings. TRIAL REGISTRATION: Clinical Trials.gov (NCT05271929), EudraCT (2021-006621-22).

Post-hospitalization rehabilitation alleviates long-term immune repertoire alteration in COVID-19 convalescent patients.

The global pandemic of Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an once-in-a-lifetime public health crisis. Among hundreds of millions of people who have contracted with or are being infected with COVID-19, the question of whether COVID-19 infection may cause long-term health concern, even being completely recovered from the disease clinically, especially immune system damage, needs to be addressed. Here, we performed seven-chain adaptome immune repertoire analyses on convalescent COVID-19 patients who have been discharged from hospitals for at least 6 months. Surprisingly, we discovered lymphopenia, reduced number of unique CDR3s, and reduced diversity of the TCR/BCR immune repertoire in convalescent COVID-19 patients. In addition, the BCR repertoire appears to be activated, which is consistent with the protective antibody titres, but serological experiments reveal significantly lower IL-4 and IL-7 levels in convalescent patients compared to those in healthy controls. Finally, in comparison with convalescent patients who did not receive post-hospitalization rehabilitation, the convalescent patients who received post-hospitalization rehabilitation had attenuated immune repertoire abnormality, almost back to the level of healthy control, despite no detectable clinic demographic difference. Overall, we report the potential long-term immunological impairment for COVID-19 infection, and correction of this impairment via post-hospitalization rehabilitation may offer a new prospect for COVID-19 recovery strategy.

[Value of convalescent plasma in the therapy of COVID-19]. / Zum Stellenwert von Rekonvaleszentenplasma bei der Therapie von COVID-19.

Convalescent plasma was discussed as a therapeutic option early in the course of the COVID-19 pandemic. However, until the onset of the pandemic, only the results of mostly small single-arm studies in other infectious diseases were available, which did not prove efficacy. In the meantime, the results of more than 30 randomized trials of COVID-19 convalescent plasma (CCP) for treatment of COVID-19 are available 1. Despite the heterogeneity of the results, conclusions for an optimal use are possible.

Convalescent Plasma Therapy for COVID-19: A Systematic Review and Meta-Analysis on Randomized Controlled Trials.

Background: While passive immunotherapy has been considered beneficial for patients with severe respiratory viral infections, the treatment of COVID-19 cases with convalescent plasma produced mixed results. Thus, there is a lack of certainty and consensus regarding its effectiveness. This meta-analysis aims to assess the role of convalescent plasma treatment on the clinical outcomes of COVID-19 patients enrolled in randomized controlled trials (RCTs). Methods: A systematic search was conducted in the PubMed database (end-of-search: 29 December 2022) for RCTs on convalescent plasma therapy compared to supportive care\standard of care. Pooled relative risk (RR) and 95% confidence intervals were calculated with random-effects models. Subgroup and meta-regression analyses were also performed, in order to address heterogeneity and examine any potential association between the factors that varied, and the outcomes reported. The present meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: A total of 34 studies were included in the meta-analysis. Per overall analysis, convalescent plasma treatment was not associated with lower 28-day mortality [RR = 0.98, 95% CI (0.91, 1.06)] or improved 28-day secondary outcomes, such as hospital discharge [RR = 1.00, 95% CI (0.97, 1.03)], ICU-related or score-related outcomes, with effect estimates of RR = 1.00, 95% CI (0.98, 1.05) and RR = 1.06, 95% CI (0.95, 1.17), respectively. However, COVID-19 outpatients treated with convalescent plasma had a 26% less risk of requiring hospital care, when compared to those treated with the standard of care [RR = 0.74, 95% CI (0.56, 0.99)]. Regarding subgroup analyses, COVID-19 patients treated with convalescent plasma had an 8% lower risk of ICU-related disease progression when compared to those treated with the standard of care (with or without placebo or standard plasma infusions) [RR = 0.92, 95% CI (0.85, 0.99)] based on reported outcomes from RCTs carried out in Europe. Finally, convalescent plasma treatment was not associated with improved survival or clinical outcomes in the 14-day subgroup analyses. Conclusions: Outpatients with COVID-19 treated with convalescent plasma had a statistically significantly lower risk of requiring hospital care when compared to those treated with placebo or the standard of care. However, convalescent plasma treatment was not statistically associated with prolonged survival or improved clinical outcomes when compared to placebo or the standard of care, per overall analysis in hospitalized populations. This hints at potential benefits, when used early, to prevent progression to severe disease. Finally, convalescent plasma was significantly associated with better ICU-related outcomes in trials carried out in Europe. Well-designed prospective studies could clarify its potential benefit for specific subpopulations in the post-pandemic era.

Simple prediction of COVID-19 convalescent plasma units with high levels of neutralization antibodies.

BACKGROUND: Hyperimmune convalescent COVID-19 plasma (CCP) containing anti-SARS-CoV-2 neutralizing antibodies (NAbs) was proposed as a therapeutic option for patients early in the new coronavirus disease pandemic. The efficacy of this therapy depends on the quantity of neutralizing antibodies (NAbs) in the CCP units, with titers ≥ 1:160 being recommended. The standard neutralizing tests (NTs) used for determining appropriate CCP donors are technically demanding and expensive and take several days. We explored whether they could be replaced by high-throughput serology tests and a set of available clinical data. METHODS: Our study included 1302 CCP donors after PCR-confirmed COVID-19 infection. To predict donors with high NAb titers, we built four (4) multiple logistic regression models evaluating the relationships of demographic data, COVID-19 symptoms, results of various serological testing, the period between disease and donation, and COVID-19 vaccination status. RESULTS: The analysis of the four models showed that the chemiluminescent microparticle assay (CMIA) for the quantitative determination of IgG Abs to the RBD of the S1 subunit of the SARS-CoV-2 spike protein was enough to predict the CCP units with a high NAb titer. CCP donors with respective results > 850 BAU/ml SARS-CoV-2 IgG had a high probability of attaining sufficient NAb titers. Including additional variables such as donor demographics, clinical symptoms, or time of donation into a particular predictive model did not significantly increase its sensitivity and specificity. CONCLUSION: A simple quantitative serological determination of anti-SARS-CoV-2 antibodies alone is satisfactory for recruiting CCP donors with high titer NAbs.

COVID 19 convalescent plasma: Is there still a place for CCP?

BACKGROUND: Convalescent plasma has been used for a long time for the treatment of various infectious diseases. The principle is to collect antibody-containing plasma from recovered patients and to transfuse the plasma to infectious patients thereby modifying their immune system. This approach was also used in the SARS-CoV-2 pandemic when no specific drugs were available for the treatment of the disease. DESIGN AND METHODS: This short narrative review reports on relevant studies of collection and transfusion of Covid-19 convalescent plasma (CCP) from 2020 until August 2022. Clinical patients' outcome parameters such as need for ventilation, length of hospital stay and mortality were analysed. RESULTS: Heterogenous patient groups were studied resulting in difficult comparability of the studies. High titer of transfused neutralizing antibodies, early onset of CCP treatment and moderate disease activity were identified as key parameters for effective treatment. Special subgroups of patients were identified to benefit from CCP treatment. No relevant side effects were observed during and after collection and transfusion of CCP. CONCLUSIONS: Transfusion of CCP plasma is an option for the treatment of special subgroups of patients suffering from SARS-CoV-2 infection. CCP can be easily used in low-to-middle income countries where no specific drugs are available for treatment of the disease. Further clinical trials are necessary to define the role of CCP in the treatment of SARS-CoV-2 disease.

Pathogen reduction with methylene blue does not have an impact on the clinical effectiveness of COVID-19 convalescent plasma.

BACKGROUND AND OBJECTIVES: There is a concern about a possible deleterious effect of pathogen reduction (PR) with methylene blue (MB) on the function of immunoglobulins of COVID-19 convalescent plasma (CCP). We have evaluated whether MB-treated CCP is associated with a poorer clinical response compared to other inactivation systems at the ConPlas-19 clinical trial. MATERIALS AND METHODS: This was an ad hoc sub-study of the ConPlas-19 clinical trial comparing the proportion of patients transfused with MB-treated CCP who had a worsening of respiration versus those treated with amotosalen (AM) or riboflavin (RB). RESULTS: One-hundred and seventy-five inpatients with SARS-CoV-2 pneumonia were transfused with a single CCP unit. The inactivation system of the CCP units transfused was MB in 90 patients (51.4%), RB in 60 (34.3%) and AM in 25 (14.3%). Five out of 90 patients (5.6%) transfused with MB-treated CCP had worsening respiration compared to 9 out of 85 patients (10.6%) treated with alternative PR methods (p = 0.220). Of note, MB showed a trend towards a lower rate of respiratory progressions at 28 days (risk ratio, 0.52; 95% confidence interval, 0.18-1.50). CONCLUSION: Our data suggest that MB-treated CCP does not provide a worse clinical outcome compared to the other PR methods for the treatment of COVID-19.

Reduced Mortality among COVID-19 ICU Patients after Treatment with HemoClear Convalescent Plasma in Suriname.

Convalescent plasma is a promising therapy for coronavirus disease 2019 (COVID-19), but its efficacy in intensive care unit (ICU) patients in low- and middle-income country settings such as Suriname is unknown. Bedside plasma separation using the HemoClear device made convalescent plasma therapy accessible as a treatment option in Suriname. Two hundred patients with severe SARS-CoV-2 infection requiring intensive care were recruited. Fifty eight patients (29%) received COVID-19 convalescent plasma (CCP) treatment in addition to standard of care (SOC). The CCP treatment and SOC groups were matched by age, sex, and disease severity scores. Mortality in the CCP treatment group was significantly lower than that in the SOC group (21% versus 39%; Fisher's exact test P = 0.0133). Multivariate analysis using ICU days showed that CCP treatment reduced mortality (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.18 to 0.66; P = 0.001), while complication of acute renal failure (creatinine levels, >110 mol/L; HR, 4.45; 95% CI, 2.54 to 7.80; P < 0.0001) was independently associated with death. Decrease in chest X-ray score in the CCP treatment group (median -3 points, interquartile range [IQR] -4 to -1) was significantly greater than that in the SOC group (median -1 point, IQR -3 to 1, Mann-Whitney test P = 0.0004). Improvement in the PaO2/FiO2 ratio was also significantly greater in the CCP treatment group (median 83, IQR 8 to 140) than in the SOC group (median 35, IQR -3 to 92, Mann-Whitney P = 0.0234). Further research is needed for HemoClear-produced CCP as a therapy for SARS-CoV-2 infection together with adequately powered, randomized controlled trials. IMPORTANCE This study compares mortality and other endpoints between intensive care unit COVID-19 patients treated with convalescent plasma plus standard of care (CCP), and a control group of patients hospitalized in the same medical ICU facility treated with standard of care alone (SOC) in a low- and middle-income country (LMIC) setting using bedside donor whole blood separation by gravity (HemoClear) to produce the CCP. It demonstrates a significant 65% survival improvement in HemoClear-produced CCP recipients (HR, 0.35; 95% CI, 0.19 to 0.66; P = 0.001). Although this is an exploratory study, it clearly shows the benefit of using the HemoClear-produced CCP in ICU patients in the Suriname LMIC setting. Additional studies could further substantiate our findings and their applicability for both LMICs and high-income countries and the use of CCP as a prepared readiness method to combat new viral pandemics.

Mid-titer human convalescent plasma administration results in suboptimal prophylaxis against SARS-CoV-2 infection in rhesus macaques.

Introduction: ARS-CoV-2 is a respiratory pathogen currently causing a worldwide pandemic, with resulting pathology of differing severity in humans, from mild illness to severe disease and death. The rhesus macaque model of COVID-19 was utilized to evaluate the added benefit of prophylactic administration of human post-SARS-CoV-2 infection convalescent plasma (CP) on disease progression and severity. Methods: A pharmacokinetic (PK) study using CP in rhesus monkeys preceded the challenge study and revealed the optimal time of tissue distribution for maximal effect. Thereafter, CP was administered prophylactically three days prior to mucosal SARS-CoV-2 viral challenge. Results: Results show similar viral kinetics in mucosal sites over the course of infection independent of administration of CP or normal plasma, or historic controls with no plasma. No changes were noted upon necropsy via histopathology, although there were differences in levels of vRNA in tissues, with both normal and CP seemingly blunting viral loads. Discussion: Results indicate that prophylactic administration with mid-titer CP is not effective in reducing disease severity of SARS-CoV-2 infection in the rhesus COVID-19 disease model.

Lessons learned from the CONCOR-1 trial.

Faced with an evolving pandemic and a lack of clarity of the role of convalescent plasma for patients with COVID-19, the CONCOR-1 trial was launched. In 14 months the trial was designed, launched, completed, and submitted for publication. In total, 72 sites in three countries served by four blood suppliers randomised 940 patients. Many enablers facilitated the trial including: three study principal investigators to distribute the trial workload, diverse steering committee members, an international data safety monitoring committee, multiple statisticians and methodologists, virtual meeting platforms, REDCap data platform, pausing of non-COVID-19 trials, rapid approval pathways for institutional review boards and regulators, centralised institutional review boards in many locations, restriction of use of convalescent plasma to trial participants and the incredible dedication by research personnel. In future pandemics, we need to be prepared for rapid launch of trials. The protocols, consent forms, data collection tools, and procedures need to be in draft form ready for use at all times. We were well-prepared for blood shortages but should have anticipated the need to conduct trials with convalescent plasma. In this short article, we detail our lessons learned to inform researchers faced with the next pandemic pathogen.