Antibody-dependent enhancement of SARS-CoV-2, the impact of variants and vaccination

This study characterized antibody-dependent enhancement (ADE) in serum samples from individuals exposed to SARS-CoV-2 via infection or vaccination and evaluated its association with SARS-CoV-2 variants (Wuhan and Omicron), MERS-CoV, and NL63. ADE assays were performed on sera from SARS-CoV-2-infected patients (<i>n</i> = 210) with varying disease severity and vaccinated individuals (<i>n</i> = 225) who received adenovirus vector, inactivated virus or mRNA vaccines. ADE was assessed using pseudoviruses (PVs) in BHK cells expressing FcgRIIa. Neutralizing antibody levels, total IgG, IgG subclasses, and complement activation were analyzed using ELISA and neutralization assays. ADE was observed in 6.2% of infection samples (primarily severe cases) and 5.3% of vaccinated samples (adenovirus-vector and inactivated virus groups). ADE-positive samples showed reduced neutralizing activity, while total IgG and IgG subclasses did not differ significantly between ADE-positive and negative samples. Complement activation was elevated in severe cases but did not correlate clearly with ADE. Notably, MERS-CoV PV induced ADE in a subset of infected samples, but no ADE was detected for NL63. ADE was observed in SARS-CoV-2-infected individuals, particularly in severe cases, and in those vaccinated with adenovirus-vector and inactivated virus vaccines, but not with mRNA vaccines. Cross-reactivity leading to ADE was detected for MERS-CoV but not for NL63. ADE was associated with reduced neutralizing antibody activity and elevated complement activation in severe infections, though the specific role of complement in ADE remains unclear. These findings highlight the need to investigate the mechanisms underlying ADE and its implications for vaccine design and post-infection immunity against respiratory viruses.