COVID-19 Severity Is Associated with Differential Antibody Fc-Mediated Innate Immune Functions

Abstract

Beyond neutralization, antibodies binding to their Fc receptors elicit several innate immune functions including antibody-dependent complement deposition (ADCD), antibody-dependent cell-mediated phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). These functions are beneficial, as they contribute to pathogen clearance; however, they also can induce inflammation. We tested the possibility that qualitative differences in SARS-CoV-2-specific antibody-mediated innate immune functions contribute to coronavirus disease 2019 (COVID-19) severity. We found that anti-S1 and anti-RBD antibodies from hospitalized COVID-19 patients elicited higher ADCD but lower ADCP compared to antibodies from nonhospitalized COVID-19 patients. Consistently, higher ADCD was associated with higher systemic inflammation, whereas higher ADCP was associated with lower systemic inflammation during COVID-19. Our study points to qualitative, differential features of anti-SARS-CoV-2 specific antibodies as potential contributors to COVID-19 severity. Understanding these qualitative features of natural and vaccine-induced antibodies will be important in achieving optimal efficacy and safety of SARS-CoV-2 vaccines and/or COVID-19 therapeutics. IMPORTANCE A state of hyperinflammation and increased complement activation has been associated with coronavirus disease 2019 (COVID-19) severity. However, the pathophysiological mechanisms that contribute to this phenomenon remain mostly unknown. Our data point to a qualitative, rather than quantitative, difference in SARS-CoV-2-specific antibodies’ ability to elicit Fc-mediated innate immune functions as a potential contributor to COVID-19 severity and associated inflammation. These data highlight the need for further studies to understand these qualitative features and their potential contribution to COVID-19 severity. This understanding could be essential to develop antibody-based COVID-19 therapeutics and SARS-CoV-2 vaccines with an optimal balance between efficacy and safety.

Comparing Immunoassays for SARS-CoV-2 Antibody Detection in Patients with and without Laboratory-Confirmed SARS-CoV-2 Infection

“…Further, we could not evaluate the contribution of the detection platform, instrumentation, or automation of ECLIA, CLIA, or ELISA in addition to the differences in the choice and preparation of recombinant antigen, all of which were used in the analyzed assays. We focused on total antibody and IgG antibody responses in blood and did not evaluate the impact of different immunoglobulin classes or IgG subclasses with respect to microneutralization ( 33 ) or functionality ( 34 ). Exploratory data from our center and the available literature suggest that detection of IgA is too variable and cannot be used reliably in approximately 1% of patients with selective or partial IgA deficiency ( 35 ).…”

Boosting of Cross-Reactive Antibodies to Endemic Coronaviruses by SARS-CoV-2 Infection but not Vaccination with Stabilized Spike

“…To this end, a subset of monoclonal antibodies isolated from SARS-CoV patients that were able to cross-react with, but not neutralize SARS-CoV-2 were able to confer protection in a mouse model 42 . Indeed, both passive transfer experiments of monoclonal antibodies [43][44][45][46][47] and evaluation of polyclonal antibodies raised in the context of vaccination or infection [48][49][50] have shown that effector mechanisms contribute to antiviral activity in vivo. This evidence extends beyond correlative observations 45,48 to include mechanistic 1 evidence of in vivo contributions via Fc sequence engineering to knockout or enhance these activities 44,46 , as well as on the basis of depletion of effector cells 46 .…”

Intravenous immunoglobulin as an important adjunct in the prevention and therapy of coronavirus 2019 disease

“…It is important to understand how these antibodies or antibodies contained in IVIg preparations, interplay between them and thus can modify disease's severity. 47 …”