Convalescent plasma is currently one of the leading treatments for COVID-19, but there is a paucity of data identifying therapeutic efficacy. A comprehensive analysis of the antibody responses in potential plasma donors and an understanding of the clinical and demographic factors that drive variant antibody responses is needed. Among 126 potential convalescent plasma donors, the humoral immune response was evaluated by a SARS-CoV-2 virus neutralization assay using Vero-E6-TMPRSS2 cells, commercial IgG and IgA ELISA to Spike (S) protein S1 domain (Euroimmun), IgA, IgG and IgM indirect ELISAs to the full-length S or S-receptor binding domain (S-RBD), and an IgG avidity assay. Multiple linear regression and predictive models were utilized to assess the correlations between antibody responses with demographic and clinical characteristics. IgG titers were greater than either IgM or IgA for S1, full length S, and S-RBD in the overall population. Of the 126 plasma samples, 101 (80%) had detectable neutralizing titers. Using neutralization titer as the reference, the sensitivity of the IgG ELISAs ranged between 95-98%, but specificity was only 20-32%. Male sex, older age, and hospitalization with COVID-19 were all consistently associated with increased antibody responses across the serological assays. Neutralizing antibody titers were reduced over time in contrast to overall antibody responses. There was substantial heterogeneity in the antibody response among potential convalescent plasma donors, but sex, age and hospitalization emerged as factors that can be used to identify individuals with a high likelihood of having strong antiviral antibody levels.

Conflict of interest: EMB reports receiving personal fees and nonfinancial support from Terumo BCT and personal fees and nonfinancial support from Grifols Diagnostic Solutions. EMB is a member of the United States FDA Blood Products Advisory Committee. Any views or opinions that are expressed in this manuscript are those of the authors, based on their own scientific expertise and professional judgment; they do not necessarily represent the views of either the Blood Products Advisory Committee or the formal position of the FDA, and also do not bind or otherwise obligate or commit either the advisory committee or the agency to the views expressed.

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Background Convalescent plasma therapy is a leading treatment for conferring temporary immunity to COVID-19 susceptible individuals or for use as post-exposure prophylaxis. However, not all recovered patients develop adequate antibody titers for donation and the relationship between avidity and neutralizing titers is currently not well understood. Methods SARS-CoV-2 anti-spike and anti-nucleocapsid IgG titers and avidity were measured in a longitudinal cohort of COVID-19 hospitalized patients (n=16 individuals) and a cross-sectional sample of convalescent plasma donors (n=130). Epidemiologic correlates of avidity were examined in donors by linear regression. The association of avidity and a high neutralizing titer (NT) were also assessed in donors using modified Poisson regression. Results Antibody avidity increased over duration of infection and remained elevated. In convalescent plasma donors, higher levels of anti-spike avidity was associated with older age, male sex, and hospitalization. Higher NTs had a stronger positive correlation with anti-spike IgG avidity (spearman’s rho=0.386;p&0.001), than with anti-nucleocapsid IgG avidity (spearman’s rho=0.211;p=0.026). Increasing levels of anti-spike IgG avidity were associated with high NT(≥160) (adjusted prevalence ratio=1.58[95%CI=1.19-2.12]), independent of age, sex, and hospitalization. Conclusions SARS-CoV-2 antibody avidity correlated with duration of infection and higher neutralizing titers, suggesting a potential alternative screening parameter for identifying optimal convalescent plasma donors.

Convalescent plasma is a promising therapy for coronavirus disease 2019 (COVID-19), but the antibody characteristics that contribute to efficacy remain poorly understood. This study analyzed plasma samples from 126 eligible convalescent blood donors in addition to 15 naive individuals, as well as an additional 20 convalescent individuals as a validation cohort. Multiplexed Fc Array binding assays and functional antibody response assays were utilized to evaluate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody composition and activity. Donor convalescent plasma samples contained a range of antibody cell- and complement-mediated effector functions, indicating the diverse antiviral activity of humoral responses observed among recovered individuals. In addition to viral neutralization, convalescent plasma samples contained antibodies capable of mediating such Fc-dependent functions as complement activation, phagocytosis, and antibody-dependent cellular cytotoxicity against SARS-CoV-2. Plasma samples from a fraction of eligible donors exhibited high activity across all activities evaluated. These polyfunctional plasma samples could be identified with high accuracy with even single Fc Array features, whose correlation with polyfunctional activity was confirmed in the validation cohort. Collectively, these results expand understanding of the diversity of antibody-mediated antiviral functions associated with convalescent plasma, and the polyfunctional antiviral functions suggest that it could retain activity even when its neutralizing capacity is reduced by mutations in variant SARS-CoV-2. IMPORTANCE Convalescent plasma has been deployed globally as a treatment for COVID-19, but efficacy has been mixed. Better understanding of the antibody characteristics that may contribute to its antiviral effects is important for this intervention as well as offer insights into correlates of vaccine-mediated protection. Here, a survey of convalescent plasma activities, including antibody neutralization and diverse effector functions, was used to define plasma samples with broad activity profiles. These polyfunctional plasma samples could be reliably identified in multiple cohorts by multiplex assay, presenting a widely deployable screening test for plasma selection and investigation of vaccine-elicited responses.