Abstract The ongoing COVID-19 pandemic represents a public health emergency of global concern, due to the high levels of morbidity and mortality, as well as the ease of transmission. Intensive research efforts are currently focused in the development of antibody-based therapeutics that would neutralize SARS-CoV-2 and provide robust antiviral activity. In addition, several vaccine candidates are currently being tested, as an effort to provide long- lasting immunity against SARS-CoV-2. However, a major concern about the safety of these approaches stems from the capacity of antibodies -either administered passively or elicited upon vaccination- to enhance viral infection, a phenomenon that is termed as antibody-dependent enhancement (ADE). Although ADE has been primarily demonstrated for flaviviruses, like dengue, it is unknown whether this phenomenon also extends to coronaviruses. Like dengue disease, COVID-19 patients exhibit a wide range of clinical disease severity, ranging from asymptomatic to severe symptomatic disease, which is often fatal. This suggests that host immune factors likely determine disease susceptibility and are critical for progression to severe disease. Additionally, SARS- CoV-2, the causative agent for COVID-19, shares high degree of sequence similarity with other human and bat coronaviruses, including SARS-CoV and MERS-CoV. Similar to what has been shown for dengue, it is likely that pre-existing immunity against other coronaviruses might predispose for SARS-CoV-2 infection and development of severe COVID-19 disease. Likewise, active or passive immunization against SARS-CoV-2 might increase the susceptibility to infection with other coronaviruses via the presence of non-neutralizing, cross-reactive antibodies. Although there is limited evidence on the capacity of anti-SARS-CoV-2 antibodies to mediate ADE, several prior studies on SARS-CoV have provided some preliminary evidence that under specific conditions, anti-SARS-CoV antibodies might enhance infection of FcγR-expressing cells. Given the ongoing clinical development efforts for antibody-based therapeutics and vaccines to control SARS-CoV-2 infection, it is important to assess whether anti-SARS-CoV-2 antibodies have the capacity to mediate ADE and if so, determine the precise molecular mechanisms and the role of FcγRs in this process. Our proposed studies aim to: (i) determine the ADE activity of IgG antibodies purified from recovered COVID-19 patients with variable degree of disease severity, (ii) generate and evaluate the ADE activity of anti-SARS-CoV-2 and anti-SARS-CoV mAbs with variable cross- reactivity and neutralization potency, and (iii) compare the ADE activity of Fc domain variants of these mAbs with selectively enhanced binding to specific human FcγRs to determine the role for human FcγRs in mediating ADE activity. We anticipate that these studies will address a significance safety concern about the capacity of antibodies to mediate ADE of coronaviruses, acce...