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.

Dysregulation of Pulmonary Responses in Severe COVID-19

“…Besides the dysregulation in the T cell compartment, severe cases had increased frequencies of IgA1 (IGHA1 + )-expressing B cells (and a trend of increasing IgG1 (IGHG1 + )) ( Figure 1 D), in agreement with Chen et al’s observation that higher virus-specific antibody titers correlate with disease severity [ 19 ]. Generally, antibodies, if they possess a neutralizing capability, confer favorable humoral immunity; however, the neutralizing capability of antibodies in the severe cases, at least in part, is questionable, and massive immune complexes can be a driving force of tissue permeability, known as antibody-dependent disease enhancement [ 20 , 21 ]. In summary, decreased TH17-type T cells and increased IgA-secreting B cells may augment the disease severity.…”

Factors influencing on development of COVID-19 pneumonia and association with oral anti-diabetic drugs in hospitalized patients with diabetes mellitus

“…The mast cell degranulation is regulated by stromal cell-derived factor-1 (SDF-1) which is inactivated by DPP-4 [ 12 ]. However, growing evidence shows mast cells release bioactive molecules which exacerbate clinical course of disease while neutralizing these pathogens [ 11 , 13 ]. The dual activity of mast cells in viral infection has led debates about COVID-19 pneumonia and DPP-4 inhibitors [ [14] , [15] , [16] , [17] ].…”

What we know and still ignore on COVID-19 immune pathogenesis and a proposal based on experience of allergic disorders.

“…This might look like what happens in recovered patients at six months from primary infection where a robust SARS-CoV-2-specific T cell response is maintained and prevents reinfection [18]. The pre-existing memory T cells induced by CCC previous infections might, however, be harmful, through an antibody-mediated disease enhancement mechanism [19]. High pre-existing T cell response may be detrimental if associated to a parallel dysfunction of naive-and induced-T regulatory (Treg) cells [20].…”