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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.

Background: COVID-19 convalescent plasma (CCP) is an important therapeutic option for outpatients at high risk of hospitalization from SARS-CoV-2 infection. We assessed the safety of outpatient CCP transfusions administered during clinical trials., Study Design and Methods: We analyzed data pertaining to transfusion-related reactions from two randomized controlled trials in the U.S. that evaluated the efficacy of CCP versus control plasma in various ambulatory settings. Multivariable logistic regression was used to assess whether CCP was associated with transfusion reactions, after adjusting for potential confounders., Results: The combined study reported 79/1351 (5.9%) adverse events during the transfusion visit, with the majority 62/1351 (4.6%) characterized by mild, allergic-type findings of urticaria, and/or pruritus consistent with minor allergic transfusion reactions; the other reported events were attributed to the patients' underlying disease, COVID-19, or vasovagal in nature. We found no difference in the likelihood of allergic transfusion reactions between those receiving CCP versus control plasma (adjusted odds ratio [AOR], 0.75; 95% CI, 0.43-1.31). Risk of urticaria and/or pruritus increased with a pre-existing diagnosis of asthma (AOR, 2.33; 95% CI, 1.16-4.67). We did not observe any CCP-attributed antibody disease enhancement in participants with COVID-19 or increased risk of infection. There were no life-threatening severe transfusion reactions and no patients required hospitalization related to transfusion-associated complications., Discussion: Outpatient plasma administration was safely performed for nearly 1400 participants. CCP is a safe therapeutic option for outpatients at risk of hospitalization from COVID-19., (© 2023 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Background: Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) reduces hospitalizations among outpatients treated early after symptom onset. It is unknown whether CCP reduces time to symptom resolution among outpatients., Methods: We evaluated symptom resolution at day 14 by trial arm using an adjusted subdistribution hazard model, with hospitalization as a competing risk. We also assessed the prevalence of symptom clusters at day 14 between treatments. Clusters were defined based on biologic clustering, impact on ability to work, and an algorithm., Results: Among 1070 outpatients followed up after transfusion, 381 of 538 (70.8%) receiving CCP and 381 of 532 (71.6%) receiving control plasma were still symptomatic (P = .78) at day 14. Associations between CCP and symptom resolution by day 14 did not differ significantly from those in controls after adjustment for baseline characteristics (adjusted subdistribution hazard ratio, 0.99; P = .62). The most common cluster consisted of cough, fatigue, shortness of breath, and headache and was found in 308 (57.2%) and 325 (61.1%) of CCP and control plasma recipients, respectively (P = .16)., Conclusions: In this trial of outpatients with early COVID-19, CCP was not associated with faster resolution of symptoms compared with control. Overall, there were no differences by treatment in the prevalence of each symptom or symptom clusters at day 14., Clinical Trials Registration: NCT04373460., Competing Interests: Potential conflicts of interest. E. M. B. is a member of the Food and Drug Administration's Blood Products Advisory Committee. (All opinions in this manuscript are of the authors and do not reflect the Blood Products Advisory Committee or the position of the Food and Drug Administration; this arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict-of-interest policies.) A. C. serves on the Scientific Advisory Board of Sabtherapeutics, which is developing cow-derived human immunoglobulins for the treatment of coronavirus disease 2019 and other infectious diseases. K. A. G. is a paid consultant for UpToDate, Teach for America, and the Aspen Institute. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection., Methods: This double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection., Results: In total, 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs 25.2 days; P = .49) and COVID-19 (26.3 vs 25.9 days; P = .35) was similar for both groups., Conclusions: Administration of high-titer CCP as post-exposure prophylaxis, although appearing safe, did not prevent SARS-CoV-2 infection., Clinical Trials Registration: NCT04323800., Competing Interests: Potential conflicts of interests . The authors report the following: K. G.reports grants or contracts unrelated to this work and paid to institution from NIHI, personal fees from Aspen Institute, Teach for America and UpToDate. T. G. reports paid consultant for Fresenius Kabi USA and reports <$5000 of JNJ stock. A. C. reports Scientific Advisory Board of Sabtherapeutics (cow-derived human immunoglobulins COVID-19 treatment and other infectious diseases) and Ortho Diagnostics Speakers Bureau, and consulting fees from Ortho Diagnostics and Pfizer, and payment for expert testimony from King & Spalding LLP, and leadership or fiduciary role with American Society for Microbiology, and part owner of Melatech. E. B.’s time is funded in part by National Heart Lung and Blood Institute (NHLBI) through grant number 1K23HL151826, is a member of the FDA Blood Products Advisory Committee, Abbot Laboratories, Grifols Diagnostic Solutions, personal fee for invited educational presentations for Terumo BCT (honoraria for educational webinar), and advisor for California Institute for Regenerative Medicine (convalescent plasma program), and unpaid participation as invited member for a Data Safety Monitoring Board for the following trial: ‘Assessment of safety and efficacy of COVID-19 Convalescent Plasma for treatment of COVID-19 in adults in Uganda; A Phase III randomized controlled trial. S. S. reports research grants from Ansun, Astellas, Cidara, Emergent Biosolutions, F2G, Gilead, Merck, Scynexis, Zeteo, Shionogi and Shire, personal fees from Adagio, Adamis, Celltrion, Immunome, Intermountain Health and Karyopharm (consultant, advisory board and data safety monitoring board member), participation on a Data Safety Monitoring Board or Advisory Board for Adagio, Adamis, Amplyx, Immunome, Intermountain Health, Janssen, Karyopharm, Reviral, and stock options from Immunome. D. Su. reports grants or contracts unrelated to this work from NIH/NIAID (R01AI150763 Dual artemisinin action combats resistance; NIH R21TR001737 Quantum model repurposing of cethromycin for liver stage malaria; NIH R01AI111962 Optimized Combination Antimalarial Drug Therapy), founder, board member, and stock options from AliquantumRx, DSMB member NIAID SMC/ISM Intramural 2018, medical royalties for malaria test (Binax Inc/D/B/A Inverness), consultant on malaria diagnosis for Masimo and Hemex Health and consulting fees for legal malaria case (Mabrey Firm 2019 and Ressler and Ressler 2018), and patents (Issued-USP 9,642,865 9 May 2017 New angiogenesis inhibitors; Issued-USP 9,568,471 14 February 2017 Malaria Diagnosis in Urine; Issued-USP 7,270,948 18 September 2007 Detection of malaria parasites by laser desorption mass spectrometry; Pending SALTS AND POLYMORPHS OF CETHROMYCIN FOR THE TREATMENT OF DISEASE Patent Application (Application number 20210163522); and Pending- Macrolide compounds and their use in liver stage malaria and related disease (Application number PCT/US2015/046665). E. C. reports research grants from Gilead Sciences and Merck Sharp and Dohme (funds paid to UC Regents), payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead Sciences, and advisory board member for Gilead Sciences. J. C. is aconsultant for Merck and Co. and Resverlogix. S. Ka. reports educational product development for Integritas Communications Group. G. M. reports research grants from Teva, Sanofi Regeneron, Astra Zeneca, Alk Abello, Genentech, Propeller Health, GlaxoSmithKline, and Novartis, and honoraria paid to author for HCPLive educational presentation, and position as Secretary/Treasurer (March 2019 to February 2020), President-Elect (March 2020 to February 2021), President (March 2021 to February 2022) of the American Academy of Allergy, Asthma, and Immunology (payments made to institution during term as President), and Director of American Board of Allergy and Immunology (2020–2025), Co-Chair of American Board of Allergy and Immunology Continuous Assessment Program Examination Committee (2020–2022) (honoraria paid to author). C. S. reports research grants from Centers for Disease Control and Prevention, Merck and Pfizer. D. J. reports grants or contracts unrelated to this work from National Eye Institute, National Institutes of Health, and National Center for Advancing Translational Research, National Institutes of Health; Board of Directors of the American Uveitis Society, speaking honoraria from Retina Society, Controversies in Ophthalmology, University of Rochester, Wills Eye Hospital, LSU School of Medicine and Icahn School of Medicine at Mt. Sinai, and participation on a Data Safety Monitoring Board or Advisory Board for National Eye Institute Intramural Branch. D. Sh. reports numerous grants supporting ongoing and completed research unrelated to this article from the NIH; and is a member of DSMB for the Pelvic Floor Disorders Network (stipend support for meeting activities 4/year). D. H. reports consulting fees from Neurotrope. M. H. reports grants or contracts unrelated to this work from NIH National Center of Advancing Translational Sciences (NCATS) (grant number KL2TR001426), NIH National Institute of Allergy and Infectious Diseases (NIAID) (grant number UM1AI069501), and Insmed Inc, and is a member of the AIDS Clinical Trials Group (ACTG) Tuberculosis Transformative Science Group (TB TSG) Study Monitoring Committee. O. L. reports grants or contracts unrelated to this work from Division of Intramural Research, NIAID, NIH. V. C. reports stock/stock options from spouse’s employer and under spouse’s name from Pfizer. D. T. reports board membership with Excision Bio and board membership (DSMB) with Merck and Co (paid to author); employment with JHU; various expert testimony paid to author; honoraria for CME programs only, paid to author (no service on corporate speaker’s bureau); royalties from UpToDate; and stock/stock options with Excision Bio. N. M. reports participation as HyazOUT and UtahONE combined DSMB member for NIH National Center for Advancing Translational Sciences (NCATS) U24TR001609-S3.All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants severely limits available effective monoclonal antibody therapies. Effective drugs are also supply limited. COVID-19 convalescent plasma (CCP) qualified for high antibody levels effectively reduces immunocompetent outpatient hospitalization. The Food and Drug Administration currently allows outpatient CCP for the immunosuppressed. Viral-specific antibody levels in CCP can range 10- to 100-fold between donors, unlike the uniform viral-specific monoclonal antibody dosing. Limited data are available on the efficacy of polyclonal CCP to neutralize variants. We examined 108 pre-δ/pre-ο donor units obtained before March 2021, 20 post-δ COVID-19/postvaccination units, and 1 pre-δ/pre-ο hyperimmunoglobulin preparation for variant-specific virus (vaccine-related isolate [WA-1], δ, and ο) neutralization correlated to Euroimmun S1 immunoglobulin G antibody levels. We observed a two- to fourfold and 20- to 40-fold drop in virus neutralization from SARS-CoV-2 WA-1 to δ or ο, respectively. CCP antibody levels in the upper 10% of the 108 donations as well as 100% of the post-δ COVID-19/postvaccination units and the hyperimmunoglobulin effectively neutralized all 3 variants. High-titer CCP neutralizes SARS-CoV-2 variants despite no previous donor exposure to the variants., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain., Methods: In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion., Results: Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized., Conclusions: In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.)., (Copyright © 2022 Massachusetts Medical Society.)

Convalescent plasma, collected from donors who have recovered from a pathogen of interest, has been used to treat infectious diseases, particularly in times of outbreak, when alternative therapies were unavailable. The COVID-19 pandemic revived interest in the use of convalescent plasma. Large observational studies and clinical trials that were executed during the pandemic provided insight into how to use convalescent plasma, whereby high levels of antibodies against the pathogen of interest and administration early within the time course of the disease are critical for optimal therapeutic effect. Several studies have shown outpatient administration of COVID-19 convalescent plasma (CCP) to be both safe and effective, preventing clinical progression in patients when administered within the first week of COVID-19. The United States Food and Drug Administration expanded its emergency use authorization (EUA) to allow for the administration of CCP in an outpatient setting in December 2021, at least for immunocompromised patients or those on immunosuppressive therapy. Outpatient transfusion of CCP and infusion of monoclonal antibody therapies for a highly transmissible infectious disease introduces nuanced challenges related to infection prevention. Drawing on our experiences with the clinical and research use of CCP, we describe the logistical considerations and workflow spanning procurement of qualified products, infrastructure, staffing, transfusion, and associated management of adverse events. The purpose of this description is to facilitate the efforts of others intent on establishing outpatient transfusion programs for CCP and other antibody-based therapies., (© 2022 AABB.)

INTRODUCTION: In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety. METHODS: A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites. RESULTS: We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites. CONCLUSION: The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies.

BackgroundThe efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection.MethodsThis double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection.ResultsIn total, 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs 25.2 days; P = .49) and COVID-19 (26.3 vs 25.9 days; P = .35) was similar for both groups.ConclusionsAdministration of high-titer CCP as post-exposure prophylaxis, although appearing safe, did not prevent SARS-CoV-2 infection.Clinical trials registrationNCT04323800.