Pooled intravenous immunoglobulins exhibit broad binding and Fc-mediated activity against diverse SARS-CoV-2 variants

During the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), antibody-based therapies such as COVID-19 convalescent plasma (CCP) and monoclonal antibodies (mAbs) emerged rapidly. However, many CCP clinical trials failed to show consistent benefits, and mAbs lost effectiveness as new SARS-CoV-2 variants emerged. These studies consistently indicated that antibody therapies are effective when given very early in disease and in patients with delayed or suppressed immune responses. Intravenous immunoglobulin (IVIG), which is pooled IgGs from thousands of donors, has been explored as an additional source of anti-SARS-CoV-2 antibodies to treat acutely ill patients because IVIG was shown to prevent disease and death in animal models against variants even without neutralizing activity. As antibodies can also protect via Fc-mediated activation of innate immune effector functions, in this study, we compared the qualitative and quantitative properties of CCP and IVIG to determine if IVIG might serve as a clinical therapeutic alternative to CCP. We measured SARS-CoV-2 spike (S)- and nucleocapsid (N)- specific antibody-binding titers across variants and evaluated their ability to induce antibody-dependent effector functions. We found that IVIG and CCP had comparable binding and Fc-effector activity against ancestral SARS-CoV-2. Remarkably, IVIG manufactured before the emergence of XBB.1.5, JN.1, KP.2, XEC, and XFG demonstrated strong binding and Fc-effector activity against these newer variants. IMPORTANCE Despite the availabilities of vaccines for SARS-CoV-2 for most individuals, there remain vulnerable populations for which vaccination is ineffective. As the emergence of SARS-CoV-2 variants has rendered many monoclonal antibody therapies ineffective, there remains a need to understand the role of polyclonal antibody therapies for SARS-CoV-2, such as COVID-19 convalescent plasma (CCP) and intravenous immunoglobulin (IVIG). While CCP is variable and donor-dependent, IVIG is pooled from thousands of donors with a range of vaccine- and natural infection-derived antibody responses and may represent a consistent source of polyclonal antibodies. We compared high neutralizing antibody titer CCP, previously shown to be associated with reduced time to hospital discharge, with IVIG produced post-2021. We find that IVIG offers expanded antibody binding to SARS-CoV-2 variants, including those that emerged after the IVIG was collected, and enhanced induction of Fc-mediated innate immune effector functions, highlighting the potential utility of IVIG as an adjunct treatment of SARS-CoV-2. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT04524507 .