Patient and donor antibody profiles in early COVID-19 convalescent plasma therapy in the COnV-ert trial

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Introduction: The negative efficacy results of coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) as early treatment in the COnV-ert trial have been attributed to the use of methylene blue (MB). We characterized immune responses after MB-treated CCP infusion and the impact of MB on antibodies of the infused CCP units. Methods: We measured antibody isotypes (IgG, IgM, and IgA) and IgG subclasses (IgG1, IgG2, IgG3, and IgG4) against SARS-CoV-2 nucleocapsid and spike (S) antigens, neutralizing antibody titers, and IgG avidity in 128 participants of the COnV-ert trial 7 and 60 days after infusion and in paired CCP units before and after MB treatment. Results: Treatment with CCP significantly increased the levels of IgG and IgG1 to receptor-binding domain (RBD) and S, IgG3 to S and S2, and IgG avidity in recipients 7 days after infusion, without an increase in IgA, IgM, IgG2, IgG4, or neutralization. At day 7 post-infusion, recipients exhibited lower IgG, all IgG subclasses, and avidity; higher IgA and IgM; and comparable neutralization relative to paired CCP units. MB was associated with a significant decrease in cytophilic subclasses IgG1 and IgG3 to S and S2, and IgA to RBD, S and S2 in CCP units, without a reduction in neutralization titer and with a modest increase in IgG2 to RBD and S. Discussion: Our study shows a modest impact of a single intravenous infusion of MB-treated high-titer CCP on circulating antibody levels compared to those generated by the host by day 7 and an adverse effect of MB on IgG1 and IgG3, which are essential for effector functions. Clinical trial registration: https://www.clinicaltrials.gov/, identifier NCT04621123.

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