Abstract
Pre-existing immunity impacts vaccine responses to influenza, but directly connecting influenza infections early in life with immune responses decades later is difficult. However, H2N2 stopped circulating in the human population in 1968, creating the opportunity to directly evaluate the impact of early H2N2 exposure on vaccine responses 50 years later. Here, we vaccinated individuals born before (H2 exposed) or after (H2 naive) 1968 with an H2 hemagglutinin (HA) DNA plasmid and/or a ferritin nanoparticle vaccine. H2-exposed individuals generated a rapid B cell recall response that was more potent, targeted more conserved epitopes, and differed phenotypically from the de novo response in H2-naive individuals. Furthermore, vaccinating with a DNA versus a protein nanoparticle vaccine altered the response in H2-naive but not H2-exposed individuals. This study establishes and describes the lifelong impact of influenza HA-specific memory B cells formed early in life on vaccine responses decades later.