Project 2: Characterizing humoral responses to SARS-CoV-2, and the immunological and biological effects of plasma therapy for severe Covid-19

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Abstract This SeroNet Center of Excellence in SARS-CoV2 basic and applied research will use human clinical samples and small animal models to illuminate the molecular mechanisms driving serological and humoral immune responses to this pandemic pathogen. Here we outline Project 2, which will investigate the influence of polyclonal antibodies present in convalescent plasma on the virologic and immunobiological outcomes, and immune responses in patients treated with convalescent plasma for severe SARS-CoV-2 infection, the agent of Covid-19. This project leverages the robust infrastructure for collection and infusion of CCP as therapy at our institution. Serum and mucosal samples collected from CCP donors and CCP recipients provide a comprehensive and longitudinal biorepository to examine the fundamental immunobiological properties of antibodies in CCP. Samples are provided by participants enrolled in an integrated but separately funded, investigator-initiated trial of convalescent plasma therapy at our institution. Project 2, Aim 1 will provide an in-depth analysis that addresses whether neutralizing and/or non-neutralizing antibodies in CCP accelerate viral clearance and resolve inflammation in blood and mucosal compartments. CCP containing different concentrations of neutralizing antibodies will also be tested in a novel translational model of SARS-CoV-2 mouse challenge with Project 1. In Project 2 Aim 2, we will employ novel recombinant antigen development technologies and systems serology (Core B) and Ig seq (Core C) to define the isotype-specific properties of antibodies in donor CCP units, and measure the trafficking of these antibodies in CCP recipients. Project 2 Aim 3 will longitudinally follow CCP recipients to evaluate the influence of CCP therapy on de novo development of long lived plasma blasts and memory B cells. This project contributes critically to Project 1 in the serocenter by the provision of a robust clinical-immunobiological repository of CCP donors and recipients. Interactions with Project 3 allow for comparisons between these cohorts and other observational cohorts of patients with SARS-CoV-2 infection who did not receive CCP. Facilitated by Core A, Cores B and C provide innovative assays necessary to address long-standing questions regarding differential antiviral and immunomodulatory properties of specific antibodies in convalescent plasma. The virological and immunobiological data generated in this proposal can be linked to a granular database of individual demographics and clinical variables in patients with SARS-CoV-2 infection. The integration of this Project within the serocenter, and the potential to link biological observations to clinical outcomes in our parallel, randomized therapeutic study in which hospitalized COVID- 19 patients receive either standard or high-neutralizing titer CCP, will allow this Project to contribute substantially to the understanding of the immune response to SARS-CoV2.