Diversity of immunization strongly impacts SARS-CoV-2 antibody function surrogates

System serology offers a comprehensive approach to evaluate the humoral immune response by evaluating multiple parameters. In the present study, based on four groups of individuals with a different history of SARS-CoV-2 immunization, we analyzed the serum of 180 individuals based on six serological methods to better decipher their immunity. Through our analysis, against different SARS-CoV-2 antigens or variants, we report the importance of system serology to better decipher population immunity. Fc-dependent parameters are key factors underlying the variability of humoral immune response triggered by different schemes of SARS-CoV-2 immunization. With an evolving exposure to new variants, the acquisition of robust cross-reactive Fc-dependent effector functions are likely to be key to control viral replication when neutralizing antibodies are poorly cross-reactive. As booster vaccination remains a useful tool in periodically bolstering humoral immunity, particularly in vulnerable populations, studies should continue to evaluate the humoral immune response using system serology approach.