Neutralization and antibody-dependent cellular cytotoxicity functions of SARS-CoV-2 Spike-IgG in vaccinated individuals

Abstract

Background: Following the world-wide spread of the SARS-CoV-2 virus during the COVID-19 pandemic, several types of vaccines were rolled out in various countries including Uganda. Studies elsewhere revealed significant variation in immune response kinetics to vaccines within and among populations, but there is limited understanding as to why some individuals and populations have better neutralizing and Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) effector functions that others. Investigating the full extent of this variation across different diverse populations is important for improving the next generations of vaccines.

Aim: This study evaluated the neutralization and ADCC effector function profiles of spike protein-IgG in the plasma samples of SARS-CoV-2 vaccine recipients in Uganda and correlated the response dynamics with binding patterns to the spike RBD, NTD and S2 subunits

Hypothesis: The study hypothesized that differential binding of spike-IgG to the RBD, NTD and S2 subdomains would influence neutralization and ADCC effector functions.

Methods: Pseudotyped-Virus neutralization assays, Enzyme-linked Immunosorbent Assays and flow cytometry-based Natural Killer cell degranulation experiments were used to measure spike-IgG antibody responses in longitudinal plasma samples collected from participants who received the BNT162b2, CoronaVac and ChAdOx1-S SARS-CoV-2 vaccines.

Results: The findings of this study revealed remarkable intra-population diversity in binding, neutralization and ADCC functions of antibodies in vaccinated individuals. The most potent, broad and diversified binding and neutralizing antibodies were elicited by the BNT162b2 vaccine. There were substantially elevated S2-IgG binding antibodies across all participant groups even before vaccination, and this was the predominant antibody response elicited by CoronaVac. Elevated S2-IgG heavily influenced and contributed to the ADCC responses, which was particularly greater among those vaccinated with CoronaVac. Neutralization was mostly influenced by RBD-IgG and to a less extent NTD-IgG. However, individuals with diversified antibody responses across all spike protein domains including the S2 sub-domain had the broadest neutralizing antibody responses. Polyfunctionality of effector functions with both neutralization and ADCC was identified in several individuals with diversified spike-IgG binding, supporting the hypothesized functional synergy.

Conclusion: The variability of vaccine-induced antibodies revealed by this study, points to unique underlying immunogenetic patterns within this population that would be of great impact to investigate for the benefit of future population-optimized vaccine design efforts.