Influenza virus exposure shapes the B cell response to influenza vaccination fifty years later

Pre-existing immunity impacts vaccine responses to endemic respiratory viruses such as 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 vaccinate individuals born before (H2 Exposed) or after (H2 Naïve) 1968 with an H2 HA DNA plasmid and/or a ferritin nanoparticle vaccine. H2 Exposed individuals generated a rapid B cell recall response that differed in potency, cross-reactivity, immunoglobulin repertoire, epitope targeting and phenotype from the de novo response in H2 Naïve individuals. Furthermore, vaccinating with a DNA versus a protein nanoparticle vaccine altered the response in H2 Naïve but not H2 Exposed individuals. This study clearly establishes and describes the life-long impact of influenza HA-specific memory B cells formed early in life on vaccine responses decades later.