Building better antibody responses: The interplay of infection, vaccination, and immune imprinting

Antibodies are critical for protection against a range of viral respiratory diseases, including SARS-CoV-2, but the induction of durable and potent antibody responses continues to be a challenge. Beyond neutralization, there is growing appreciation for the potential protective role of Fc-mediated functions, especially against immune-evasive variants. Induction of polyfunctional antibody responses is a complex multifactorial process that is shaped by interactions between various antibody features, viral properties, and host factors. Here, we review lessons learned from the COVID-19 pandemic regarding how prior infection and different vaccination strategies can modulate plasma and mucosal antibody profiles, including isotypes, immunoglobulin G subclasses, Fc glycosylation, and consequently, antibody functions. Additionally, we discuss the challenges of immune imprinting and its effects upon antibody responses to viral variants. This review provides insights into optimizing antibody-based strategies for COVID-19 prevention and treatment, emphasizing the need for further research to understand the mechanisms behind effective antibody responses and their impact upon clinical outcomes.