Protection against numerous infectious diseases correlates with the quantity and quality of pathogen-specific antibody (Ab) molecules secreted by B cells. Seasonal flu vaccines contain hemagglutinin (HA) proteins designed to elicit anti-HA Abs capable of conferring protective immunity against influenza infection, but the current annual flu vaccines confer protection only in ~60% of the population. Recent studies have focused on designing new HA-based immunogens that can elicit broadly-protective Abs (bpAbs) capable of protecting against diverse influenza strains, but bpAbs elicited by these strategies are often short-lived. A gap in our knowledge regarding the molecular features, functionalities, and longevity of influenza Abs, specifically related to the impact of pre-existing humoral memory from prior exposure, impedes the design of vaccines capable of generating long-lasting bpAbs. Due to the ubiquitous nature of influenza and recommended seasonal vaccinations, most of the population is exposed to influenza at a young age, and many studies have made observations that suggest Ab repertoire generated from the childhood exposure is ‘imprinted’ in the immune system and persists in circulation through ensuing exposures to drifted strains. Despite these observations, information on the clinical relevance and impact of imprinted serum Ab repertoire on subsequent vaccine responses is lacking. Here, we propose to apply cutting edge transcriptomic and proteomic tools to matched pre- and post-vaccination samples to distinguish the imprinted influenza Ab repertoire from newly elicited (de novo) Abs to define the biophysical and functional features of imprinted Abs. Identifying various avenues for overcoming potential restrictions imposed by the imprinted Ab repertoire could be key for the design of a universal flu vaccine that can confer long-lasting protection against diverse influenza strains.