Understanding the correlates of protection against SARS-CoV-2 is essential for evaluating vaccine efficacy, elucidating pathogenesis, and preparing for future pandemics. Neutralizing antibodies are often the primary focus of such studies. However, antibody-dependent cellular cytotoxicity (ADCC), primarily mediated by NK cells, plays an important role in clearing infected cells. Despite this, the factors influencing ADCC activity in SARS-CoV-2 antibodies remain poorly understood.

In this study, we isolated ~150 monoclonal SARS-CoV-2 antibodies from two longitudinal blood samples of a unique donor repeatedly exposed to SARS-CoV-2 antigens. Using CD107a expression as a marker of primary human NK cell activation, we assessed how ADCC functions of these antibodies are influenced by factors such as epitope target, antigen binding density, neutralization potency, degree of somatic hypermutation, and repeated antigen exposure.

By integrating these analyses, we provide a comprehensive framework for understanding the molecular and functional determinants of ADCC. These findings offer novel insights into the mechanisms driving ADCC functions, with important implications for vaccine design and therapeutic antibody development.