Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies

Abstract

Antibody-based drugs and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being expedited through preclinical and clinical development. Data from the study of SARS-CoV and other respiratory viruses suggest that anti-SARS-CoV-2 antibodies could exacerbate COVID-19 through antibody-dependent enhancement (ADE). Previous respiratory syncytial virus and dengue virus vaccine studies revealed human clinical safety risks related to ADE, resulting in failed vaccine trials. Here, we describe key ADE mechanisms and discuss mitigation strategies for SARS-CoV-2 vaccines and therapies in development. We also outline recently published data to evaluate the risks and opportunities for antibody-based protection against SARS-CoV-2.

Figure 1

The two major established ADE mechanisms in viral diseases. (A) For macrophage-tropic viruses (e.g., dengue virus and FIPV), non-neutralizing or sub-neutralizing antibodies cause enhanced viral infection of monocytes or macrophages via FcγRII-mediated endocytosis, leading to more severe human clinical disease. (B) For non-macrophage-tropic respiratory viruses (e.g., RSV and measles), non-neutralizing antibodies can form immune complexes with viral antigens inside airway tissues, leading to the secretion of pro-inflammatory cytokines, immune cell recruitment, and activation of the complement cascade within lung tissue. The ensuing inflammation can lead to airway obstruction and cause acute respiratory distress syndrome in severe cases. While COVID-19 immunopathology studies are still ongoing and not yet conclusive, the latest available data suggest that human macrophage infection by SARS-CoV-2 is unproductive. Currently available data therefore suggests that immune complex formation, complement deposition, and local immune activation present the most likely ADE mechanisms that can impact COVID-19 immunopathology and medical intervention risks.