The study sponsors did not contribute to the study design, the collection, analysis, and interpretation of data, and the decision to submit the paper for publication. Abbreviations: CCPCOVID-19 convalescent plasmaRCTrandomized controlled trial Footnotes Conflict of Interest Statement TG-Paid consultant and employee of Fenwal, a Fresenius Kabi company; AC-Scientific Advisory Board of Sabtherapeutics (cow-derived human immunoglobulins COVID-19 treatment and other infectious diseases) and Ortho Diagnostics Speakers Bureau; MAH-contracts from Gilead Sciences, Insmed, AN2 Therapeutics, AstraZeneca to the University of Cincinnati, outside the submitted Nelonicline work. 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 significant association with Fishers exact test between early and high antibodies versus all other CCP recipients (or control plasma) with antibody cutoffs established by both methods-donor virus neutralization-based cutoff: (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. CONCLUSION In unvaccinated, seronegative CCP recipients, Rabbit polyclonal to SR B1 early transfusion of plasma units corresponding to the upper 30% of all study donors reduced outpatient hospitalizations. These high antibody level plasma units, given early, should be reserved for therapeutic use. Trial registration: “type”:”clinical-trial”,”attrs”:”text”:”NCT04373460″,”term_id”:”NCT04373460″NCT04373460 FUNDING Defense Health Agency and others. Nelonicline Keywords: convalescent plasma, hospitalization, COVID-19, outpatients, randomized controlled trial, viral load INTRODUCTION The SARS-CoV-2 specific antibody levels necessary to prevent infection or reduce hospitalization from mild outpatient COVID-19 or reduce deaths in those already hospitalized are likely to be different. For hospitalized patients, effective CCP antibody levels have been estimated from registries(1, 2), but comparable information is not Nelonicline available for outpatient usage. The high inter-laboratory variability with diverse SARS-CoV-2 serologic assays for binding or virus neutralization antibody levels creates further challenges(3, 4). Dilutional live or pseudovirus neutralization measures from 27 separate pre-alpha convalescent plasma collections varied in geometric means for 50% inhibition from 19 to 4,344 with a mean of 311(5). Separating protective antibody metrics in vaccinated people or COVID-19 convalescent plasma donors that are still therapeutic after dilution further adds to complexity. For example, influenza vaccinees in the 1970s with dilutional virus hemagglutination inhibition titer 1:40 prevented infection(6, 7), such that the World Health Organization set the threshold of protection at 1:40(8). Infants with Respiratory Syncytial Virus in two separate studies with neutralizing antibody titers over 1:256 are protected from hospitalizations(9, 10). However, therapeutic convalescent plasma would need to have 10C20 times the protective neutralization titer after a small plasma volume is diluted into a seronegative recipient. We previously reported that outpatient transfusion randomized to CCP or control plasma in 1181 participants with pre-delta CCP reduced the risk of hospitalization by 54%(11). A prespecified analysis from the parent outpatient CCP RCT aimed to compare antibody levels in donor-recipient pairs to explore the association between antibody levels and prevention of hospitalizations in recipients. With 88% of post-transfusion COVID-19 hospitalizations (15 of 17 total) occurring among unvaccinated, seronegative outpatient recipients, we analyzed hospitalization risk among this group by comparing CCP recipients stratified by early or late treatment (i.e., 5 versus >5 days from symptom onset) with antibody levels to demarcate pre-delta CCP for pre-omicron recipient thresholds for efficacy to reduce mild CoVID-19 hospitalizations. RESULTS Trial population This secondary analysis includes the unvaccinated at screening subgroup to correlate donor and post-transfusion antibody levels with hospitalization. Transfusions spanned 16 months from June 3, Nelonicline 2020 to Oct 1, 2021 with last three month follow up after transfusion in January 2022. The unvaccinated seropositive rate was 21%. Among the seronegative, unvaccinated patients analyzed, 368 received control plasma and 366 received CCP with an average age of 44 years old. Both control and CCP arms were predominately female, obese (44% with BMI 30), and had at least one pre-existing comorbidity (41%). All COVID-19-related hospitalizations in the CCP arm recipients (17 total) were among unvaccinated recipients15 seronegative (88%) and 2 seropositive recipients (12%; Figure 1, Table 1). Excluded from this analysis were the 159 fully vaccinated with no hospitalizations, 58 partly vaccinated with one hospitalization and 199 unvaccinated seropositive with 7 hospitalizations. Open in a separate window Figure 1. CONSORT diagram depicting enrollment, allocation, and analysis flow of recipients. Table 1. Unvaccinated control Nelonicline and convalescent.