The SARS-CoV-2 antibody-dependent enhancement façade

Abstract

Antibody-dependent enhancement (ADE) is an immunological paradox whereby sensitization following a primary viral infection results in the subsequent enhancement of a similar secondary infection. This idiosyncratic immune response has been established in dengue virus infections, driven by four antigenically related serotypes co-circulating in endemic regions. Several coronaviruses exhibit antibody-mediated mechanisms of viral entry, which has led to speculation of an ADE capacity for SARS-CoV-2, though in vivo and epidemiological evidence do not currently support this phenomenon. Three distinct antibody-dependent mechanisms for SARS-CoV-2 entry have recently been demonstrated: 1. FcR-dependent, 2. ACE2-FcR-interdependent, and 3. FcR-independent. These mechanisms of viral entry may be dependent on SARS-CoV-2 antibody specificity; antibodies targeting the receptor binding domain (RBD) typically result in Fc-dependent and ACE2-FcR-interdependent entry, whereas antibodies targeting the N-terminal domain can induce a conformational change to the RBD that optimizes ACE2-receptor binding domain interactions independent of Fc receptors. Whether these antibody-dependent entry mechanisms of SARS-CoV-2 result in the generation of infectious progenies and enhancement of infection has not been robustly demonstrated. Furthermore, ADE of SARS-CoV-2 mediated by antigenic seniority remains a theoretical concern, as no evidence suggests that SARS-CoV-2 imprinting blunts a subsequent immune response, contributing to severe COVID-19 disease.