Abstract
COVID-19 convalescent plasma (CCP), a passive polyclonal antibody therapeutic, has had mixed clinical results. Though, antibody neutralization is the predominant approach to benchmarking CCP’s efficacy, CCP may also influence the evolution of the endogenous antibody response. Using systems serology to comprehensive profile SARS-CoV-2 functional antibodies of hospitalized COVID-19 participants enrolled in a randomized controlled trial of CCP (ClinicalTrials.gov Identifier NCT04397757), we find the clinical benefit of CCP is associated with both a shift towards reduced inflammatory Spike (S) responses and enhanced Nucleocapsid (N) humoral responses. We find CCP has the greatest clinical benefit in participants with low pre-existing anti-SARS-CoV-2 antibody function and CCP-induced immunomodulatory Fc glycan profiles and N immunodominant profiles persist for at least two months. We highlight a potential mechanism of action of CCP associated with durable immunomodulation, outline optimal patient characteristics for CCP treatment, and provide guidance for the development of a different class of COVID-19 hyperflammation-targeting antibody therapeutics.
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