Outpatient COVID-19 convalescent plasma recipient antibody thresholds correlated to reduced hospitalizations within a randomized trial
Han-Sol Park, et al.
Han-Sol Park, et al.
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Clinical Research and Public Health COVID-19

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

Abstract

BACKGROUND COVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined.METHODS This 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.RESULTS SARS-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).CONCLUSION In 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 REGISTRATION ClinicalTrials.gov NCT04373460.FUNDING Department 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.

Authors

Han-Sol Park, Anna Yin, Caelan Barranta, John S. Lee, Christopher A. Caputo, Jaiprasath Sachithanandham, Maggie Li, Steve Yoon, Ioannis Sitaras, Anne Jedlicka, Yolanda Eby, Malathi Ram, Reinaldo E. Fernandez, Owen R. Baker, Aarthi G. Shenoy, Giselle S. Mosnaim, Yuriko Fukuta, Bela Patel, Sonya L. Heath, Adam C. Levine, Barry R. Meisenberg, Emily S. Spivak, Shweta Anjan, Moises A. Huaman, Janis E. Blair, Judith S. Currier, James H. Paxton, Jonathan M. Gerber, Joann R. Petrini, Patrick B. Broderick, William Rausch, Marie Elena Cordisco, Jean Hammel, Benjamin Greenblatt, Valerie C. Cluzet, Daniel Cruser, Kevin Oei, Matthew Abinante, Laura L. Hammitt, Catherine G. Sutcliffe, Donald N. Forthal, Martin S. Zand, Edward R. Cachay, Jay S. Raval, Seble G. Kassaye, Christi E. Marshall, Anusha Yarava, Karen Lane, Nichol A. McBee, Amy L. Gawad, Nicky Karlen, Atika Singh, Daniel E. Ford, Douglas A. Jabs, Lawrence J. Appel, David M. Shade, Bryan Lau, Stephan Ehrhardt, Sheriza N. Baksh, Janna R. Shapiro, Jiangda Ou, Yu Bin Na, Maria D. Knoll, Elysse Ornelas-Gatdula, Netzahualcoyotl Arroyo-Curras, Thomas J. Gniadek, Patrizio Caturegli, Jinke Wu, Nelson Ndahiro, Michael J. Betenbaugh, Alyssa Ziman, Daniel F. Hanley, Arturo Casadevall, Shmuel Shoham, Evan M. Bloch, Kelly A. Gebo, Aaron A.R. Tobian, Oliver Laeyendecker, Andrew Pekosz, Sabra L. Klein, David J. Sullivan

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Figure 2

CCP donor neutralizing antibody and anti–S-RBD levels establish a functional cutoff associated with hospitalization protection in screened seronegative recipients.

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CCP donor neutralizing antibody and anti–S-RBD levels establish a functi...
(A) Here, we use the 1:40 dilutional titer for the neutralizing antibody (nAb) to identify the upper limit of donor anti–S-RBD IgG 2,728 AUC associated with protection from hospitalization. A dilutional titer of 1:10 is the limit of detection for the nAb. (B) The ratio of matched donor anti–S-RBD IgG AUC to that of their respective CCP seronegative recipients that was used to infer the functional cutoff in recipients was determined to be 21.3. Red dots correspond to those hospitalized and black dots are those not hospitalized. (C) Anti–S-RBD IgG AUC levels among donors and posttransfusion recipients segregated by screen vaccination status and serostatus compared by Kruskall-Wallis with Dunn’s post hoc correction. **P < 0.002, ***P < 0.001. Unvaccinated subsequently hospitalized (red dots) posttransfusion recipients in screen seronegative (n = 15) and screen seropositive (n = 2). Black dots are donors and blue dots are nonhospitalized participants. (D) Screen seronegative, unvaccinated recipient D0 (posttransfusion) antibody (n = 361) segregated by recipient days from symptom onset to transfusion and high (>128 AUC) or low (≤128 AUC) anti–S-RBD IgG levels. Recipient high and low cutoffs were calculated using a 21.3-fold drop from donor anti–S-RBD AUC (upper value of the 95% confidence interval) at a 1:40 nAb titer associated with protection. Subsequently hospitalized (red dots) and nonhospitalized (blue dots) recipients are shown. The n values and percentages in each quadrant are the proportion hospitalized among quadrant total. (E) Predicted probabilities of hospitalization across early versus late and high (>128 AUC) versus low (≤128 AUC) anti–S-RBD IgG categories of screen seronegative, unvaccinated CCP recipients were compared using Firth’s logistic regression model adjusted for age, sex, BMI, and variant. P values that the predicted probability is greater than 0% (horizontal dashed line) are shown, with P < 0.05 considered significant.