Two Different Antibody-Dependent Enhancement (ADE) Risks for SARS-CoV-2 Antibodies

Abstract

COVID-19 (SARS-CoV-2) disease severity and stages varies from asymptomatic, mild flu-like symptoms, moderate, severe, critical, and chronic disease. COVID-19 disease progression include lymphopenia, elevated proinflammatory cytokines and chemokines, accumulation of macrophages and neutrophils in lungs, immune dysregulation, cytokine storms, acute respiratory distress syndrome (ARDS), etc. Development of vaccines to severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome coronavirus (MERS-CoV), and other coronavirus has been difficult to create due to vaccine induced enhanced disease responses in animal models. Multiple betacoronaviruses including SARS-CoV-2 and SARS-CoV-1 expand cellular tropism by infecting some phagocytic cells (immature macrophages and dendritic cells) via antibody bound Fc receptor uptake of virus. Antibody-dependent enhancement (ADE) may be involved in the clinical observation of increased severity of symptoms associated with early high levels of SARS-CoV-2 antibodies in patients. Infants with multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 may also have ADE caused by maternally acquired SARS-CoV-2 antibodies bound to mast cells. ADE risks associated with SARS-CoV-2 has implications for COVID-19 and MIS-C treatments, B-cell vaccines, SARS-CoV-2 antibody therapy, and convalescent plasma therapy for patients. SARS-CoV-2 antibodies bound to mast cells may be involved in MIS-C and multisystem inflammatory syndrome in adults (MIS-A) following initial COVID-19 infection. SARS-CoV-2 antibodies bound to Fc receptors on macrophages and mast cells may represent two different mechanisms for ADE in patients. These two different ADE risks have possible implications for SARS-CoV-2 B-cell vaccines for subsets of populations based on age, cross-reactive antibodies, variabilities in antibody levels over time, and pregnancy. These models place increased emphasis on the importance of developing safe SARS-CoV-2 T cell vaccines that are not dependent upon antibodies.

Keywords: ADE; COVID-19; MIS-C; SARS-CoV-2; antibody dependent enhancement; multisystem inflammatory syndrome.

Figure 1

SARS-CoV-2 Spike protein variation results. Amino acid residue color code: dark green (critical residues—V1), light green (critical residues with conservative substitutions or variant in <10 sequences—V2, yellow (three variants—V3), light blue (four variants—V4; likely spacer residues), and blue (5+ variants—V5+; spacer residues).

Figure 2

Disease progression model with normal immune responses during the initial mild symptoms phase (see 1–3). Antigen presenting cells migrate to the lymph nodes to activate T cells (2a). The progression gate to moderate and server disease is the infection of phagocytic immune cells (3a) leading to immune dysregulation (4b). In the lungs, chemokines attract additional dendritic cells and immature macrophages that are subsequently infected in an positive feedback-loop infection cascade (4b). Infected phagocytic immune cells disseminate throughout the body infecting additional organs (5 & 6). Levels of chemokine and cytokines in the lungs from infected cells can create a cytokine storm (6).