wrote the paper. == Competing interests == R.R. of 482 human monoclonal antibodies (nAbs) neutralizing the original Wuhan virus, expressed as recombinant IgG1. Our study confirmed that nAbs no longer neutralizing SARS-CoV-2 Omicron variants can retain their Fc functions. Surprisingly, we found that nAbs with the most potent Fc function recognize the N-terminal domain, followed by those targeting class 3 epitopes in the receptor binding domain. Interestingly, nAbs direct against the class 1/2 epitopes in the receptor binding motif, which are the most potent in neutralizing the virus, were the weakest in Fc functions. The divergent properties of the neutralizing and Fc functionmediating antibodies were confirmed by the use of different B cell germlines and by the observation that Fc functions of polyclonal sera differ from the profile observed with nAbs, suggesting that non-neutralizing antibodies also contribute to Fc functions. These data provide a high-resolution picture of the Fc-antibody response to SARS-CoV-2 and suggest that the Fc contribution should be considered for the design of improved vaccines, the selection of therapeutic antibodies, and the evaluation of correlates of protection. The coronavirus disease 2019 (COVID-19) pandemic has been responsible for more than 768 million infections and nearly 7 million deaths reported worldwide (1). Significant progress in the fight against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) KL1333 has been achieved with the approval and the administration of vaccines and monoclonal antibodies (mAbs). Antibodies administrated or elicited by vaccination neutralize viral entry into host cells by the interaction between the antigen-binding fragment (Fab) region of the antibodies and KL1333 the SARS-CoV-2 Spike (S) protein (2,3). KL1333 Early predictive models suggested that neutralizing levels of anti-S protein antibodies elicited by vaccination correlate with protection from infection with SARS-CoV-2 (4). These studies were conducted when the S protein antigen encoded by COVID-19 vaccines KL1333 was the same as the circulating virus. Unfortunately, during the COVID-19 pandemic, SARS-CoV-2 variants developed progressively several mutations mainly placed in the receptor binding domain (RBD) and the N-terminal domain (NTD) of the S protein (5). These SARS-CoV-2 variants, and especially the Omicron lineages, show resistance against the majority of monoclonal antibodies and the ability to evade infection and vaccination-induced immunity (6,7). As a result, higher neutralizing antibody titers are necessary to induce protection from SARS-CoV-2 variants (8). Despite elevated resistance to neutralization, individuals infected with recently emerged variants showed lower severity of disease, suggesting that additional components of the immune system play a role in protection from severe COVID-19 (9). Fragment crystallizable (Fc)-dependent antibodies effector MAP3K5 functions are emerging as key players in determining the outcome of severe infection (10,11). Several pieces of evidence report that the Fc functions provide protection from COVID-19 diseases even in the absence of neutralization (1012). Indeed, Addetia et al. demonstrated that the FDA-approved mAb S309 (sotrovimab) triggers antibody-dependent cell cytotoxicity (ADCC) in vitro and protects mice against BQ.1.1 challenge in vivo despite loss of neutralization activity (12). In addition, Mackin et al. reported that mice lacking expression of activating FcRs, especially murine FcR III (CD16), or depleted of alveolar macrophages, lose the antiviral activity of passively transferred immune serum against multiple SARS-CoV-2 variants (10). Recent serology data have also demonstrated that SARS-CoV-2 vaccine induced higher Fc-receptor binding antibody levels and consequently higher humoral and cellular immune responses in subjects with previous SARS-CoV-2 infection compared to infection of.