COVID-19: Significance of Fc properties and functions in antibody responses against SARS-CoV-2

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Project Summary/Abstract The COVID-19 pandemic, which is caused by SARS-CoV-2, a novel coronavirus first detected in November-December 2019, has inflicted millions of deaths worldwide. In the US, the outbreak is affecting millions of lives. The VA hospitals, including the James J. Peters VA Medical Center (JJP VAMC) in the Bronx, NY, have responded promptly to provide care to Veterans and employees. Veterans are typically older than the general US population, making them highly susceptible to severe disease. COVID-19 vaccines are also distributed initially to the elderly and other high-risk individuals. This provides the VA a unique opportunity to study SARS-CoV-2 infection and vaccination in the most vulnerable individuals. This VA Merit application proposes to investigate the protective role of antibodies (Abs) elicited against the SARS-CoV-2 spike protein and its receptor-binding domain (RBD) following vaccination or infection. In particular, we will examine the Ab Fc properties and functions that are not well understood and the Abs that are present in blood and in saliva as a proxy of Abs at the mucosal site of virus entry. The proposed study is built upon our published and preliminary results showing the detection of different immunoglobulin (Ig) isotypes against SARS-CoV-2 spike and RBD in saliva vs plasma of convalescent COVID-19 patients and vaccine recipients. Interestingly, our preliminary data indicate a lack of correlation of spike-specific Ig isotypes in saliva vs plasma from infected and vaccinated subjects. The data further show the binding of C1q, the first component in the classical complement cascade, to Abs from both infected and vaccinated subjects. Notably, the C1q binding activities of Abs in saliva vs plasma correlated poorly, offering the initial evidence for differential Fc functions of mucosal vs circulating anti-spike Abs elicited by infection and vaccination. To investigate further the Fc properties and functions of Abs against SARS-CoV-2, we hypothesize that Fc isotype and glycosylation are the key determinants of Fc-dependent Ab functions in protection against COVID-19. A research team that include research specialists with expertise in Abs and viral immunology (PI: Catarina Hioe at JJP VAMC; collaborators: Susan Zolla-Pazner, Chitra Upadhyay, Ray Alvarez at Mount Sinai School of Medicine/MSSM), an expert in mass spectrometry and glycan biology (Hui Zhang at Johns Hopkins Univ), and an infectious disease clinician (Co-I: Juan Bandres at JJP VAMC) will work together to test this hypothesis. We will leverage our extensive expertise in Abs against HIV envelope glycoprotein and our experience investigating Ab responses against SARS-CoV-2 in the past year. In Aim 1, we will collect longitudinal plasma and saliva samples to determine the isotypes and durability of Abs against spike and RBD in different bodily fluids of ambulatory and hospitalized COVID-19 patients and healthy uninfected recipients of COVID-19 RNA vaccines. Aim 2 will evaluate the glycan structures on the Fc regions of Abs against spike from SARS-CoV-2-infected and vaccinated subjects. Aim 3 will assess the Fc-mediated activities that these Abs mediate to destroy virus particles and virus-infected cells, i.e. complement binding/activation and FcɣR-mediated signaling, cytotoxicity, and phagocytosis. Abs of different Ig isotypes and with experimentally modified Fc glycans will also be examined for their Fc-dependent activities. The proposed study will produce data critical to advance the development of improved Ab-based arsenals for diagnostics, prophylactics, and therapeutics against COVID-19.