Recently approved vaccines have shown remarkable efficacy in limiting SARS-CoV-2-associated disease. However, with the variety of vaccines, immunization strategies, and waning antibody titers, defining the correlates of immunity across a spectrum of antibody titers is urgently required. Thus, we profiled the humoral immune response in a cohort of non-human primates immunized with a recombinant SARS-CoV-2 spike glycoprotein (NVX-CoV2373) at two doses, administered as a single- or two-dose regimen. Both antigen dose and boosting significantly altered neutralization titers and Fc-effector profiles, driving unique vaccine-induced antibody fingerprints. Combined differences in antibody effector functions and neutralization were associated with distinct levels of protection in the upper and lower respiratory tract. Moreover, NVX-CoV2373 elicited antibodies that functionally targeted emerging SARS-CoV-2 variants. Collectively, the data presented here suggest that a single dose may prevent disease via combined Fc/Fab functions but that two doses may be essential to block further transmission of SARS-CoV-2 and emerging variants. Display omitted NVX-CoV2373 vaccine elicits neutralizing and Fc-effector functional antibodiesThe vaccine protects against respiratory tract infection in non-human primatesBoth neutralizing and Fc-effector functions contribute to protectionHuman vaccine-induced antibodies exhibit altered Fc-receptor binding to CoV-2 variants Gorman et al. demonstrate that both neutralization and Fc-effector functions are important in controlling SARS-CoV-2 infection in the respiratory tract after NVX-CoV2373 vaccination in non-human primates. In addition, the authors profile the humoral response in humans after NVX-CoV2373 vaccination and demonstrate altered Fc-receptor binding to emerging SARS-CoV-2 variants.