ANTIBODY DEPENDENT ENHANCEMENT (ADE) - CAUSE OF DISEASE SEVERITY IN CORONAVIRUS INFECTED AND/OR VACCINATED INDIVIDUALS

Abstract

Aim: This study evaluated the potential for ADE in serum samples from patients exposed to SARS-CoV-2 (Severe acute respiratory syndrome-coronavirus-2) and MERS-CoV (Middle East Respiratory Syndrome-coronavirus). For SARS-CoV-2 exposed samples we included samples from both infected and/or vaccinated individuals. Further, we evaluated the effect of SARS-CoV-2 vaccination on ADE in individuals with a MERS infection history. We then tested the level of neutralizing IgG levels in ADE positive serum samples and evaluated the association of IgG levels and neutralization to ADE. Study Design We performed ADE assay in sera from patients with SARS-CoV-2 infection (n=210) of different disease severity, including patients admitted to ICU with severe infection (severe-ICU) (n=75) and patients with severe infection but not admitted to ICU (severe- non-ICU) (n=70). We evaluated ADE in serum samples from individuals administrated differently with any SARS-CoV-2 vaccine regiments (n=225) including, Adenovirus vector (n=75), inactivated virus (n=75), and mRNA vaccines. We also evaluated the role of pre-existing immunity in ADE using samples from MERS-recovered individuals and patients with acute infection before and after SARS-CoV-2 vaccination (n=16). We used BHK cells expressing FcgRIIa, SARS-CoV-2 (Wuhan and Omicron), MERS-CoV, and NL63 pseudoviruses (PVs) to assess ADE. Further, we analyzed the association of ADE to complements and serum IgG levels using ELISA and neutralization with PV neutralization assay. Results: Out of 210 patient's samples with SARS-CoV-2 infection, only 6.2% demonstrated ADE; however, out of 225 samples from SARS-CoV-2 vaccination individuals, 5.3% showed ADE against SARS-CoV-2 PV. Strikingly out of 16 MERS patients, nine demonstrated ADE for SARS-CoV-2 PV, however, none of the samples demonstrated ADE for MERS-CoV PV. Interestingly, out of the seven patients exposed to SARS-CoV-2 vaccination after MERS-CoV infection, only one patient (acutely infected with MERS-CoV) showed ADE. Further flow cytometric antigen bead analysis of serum IgG levels in MERS-infected patients indicated that IgG1, IgG2, and IgG3 against SARS-CoV-2 S1 and RBD subunits, IgG1 and IgG2 against the MERS-CoV S1subunit, and serum neutralizing activity were low in ADE-positive samples. However, serum IgG levels in SARS-CoV-2 infected and/or vaccinated patients using ELISA didn't show significant difference in total IgG and IgG subclass levels in ADE positive and negative samples. Complement analysis in serum samples with SARS-CoV-2 infection showed increased complement activation in severe-ICU and non-ICU samples compared to mild infection. However, a significant complement activation associated to ADE is not clear. Conclusion: In Summary, sera samples from SARS-CoV-2 infected, vaccinated and, MERS-CoV-infected individuals elicited ADE activity against SARS-CoV-2 PV. Nevertheless, a higher percentage of MERS recovered individuals elicited ADE; however, subsequent exposure to SARS-CoV-2 vaccination resulted in diminished the ADE activity. In MERS patient samples ADE and was significantly associated with low levels of neutralizing antibodies. Further studies in larger cohort of MERS recovered and other human CoV infected individuals is essential to understand the role pre-existing immunity in ADE.