Mechanisms of antibody-dependent enhancement of SARS-CoV-2 infection

The ongoing COVID-19 pandemic represents a public health emergency of global concern, due to the high levelsof morbidity and mortality, as well as the ease of transmission. Intensive research efforts are currently focusedin the development of antibody-based therapeutics that would neutralize SARS-CoV-2 and provide robustantiviral 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 stemsfrom the capacity of antibodies -either administered passively or elicited upon vaccination- to enhance viralinfection, a phenomenon that is termed as antibody-dependent enhancement (ADE). Although ADE has beenprimarily demonstrated for flaviviruses, like dengue, it is unknown whether this phenomenon also extends tocoronaviruses. Like dengue disease, COVID-19 patients exhibit a wide range of clinical disease severity, rangingfrom asymptomatic to severe symptomatic disease, which is often fatal. This suggests that host immune factorslikely 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 batcoronaviruses, including SARS-CoV and MERS-CoV. Similar to what has been shown for dengue, it is likely thatpre-existing immunity against other coronaviruses might predispose for SARS-CoV-2 infection and developmentof severe COVID-19 disease. Likewise, active or passive immunization against SARS-CoV-2 might increase thesusceptibility 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 priorstudies on SARS-CoV have provided some preliminary evidence that under specific conditions, anti-SARS-CoVantibodies might enhance infection of FcγR-expressing cells. Given the ongoing clinical development efforts forantibody-based therapeutics and vaccines to control SARS-CoV-2 infection, it is important to assess whetheranti-SARS-CoV-2 antibodies have the capacity to mediate ADE and if so, determine the precise molecularmechanisms and the role of FcγRs in this process. Our proposed studies aim to: (i) determine the ADE activityof 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 withselectively enhanced binding to specific human FcγRs to determine the role for human FcγRs in mediating ADEactivity. We anticipate that these studies will address a significance safety concern about the capacity ofantibodies to mediate ADE of coronaviruses, accelerating our efforts for the development of vaccine ortherapeutic interventions for the control of SARS-CoV-2 infection.