Vaccination against rapidly evolving pathogens and the entanglements of memory

Immune memory determines infection risk and responses to future infections and vaccinations over potentially decades of life. Despite its centrality, the dynamics of memory to antigenically variable pathogens remains poorly understood. This Review examines how past exposures shape B cell responses to vaccinations with influenza and SARS-CoV-2. An overriding feature of vaccinations with these pathogens is the recall of primary responses, often termed 'imprinting' or 'original antigenic sin'. These recalled responses can inhibit the generation of new responses unless some incompletely defined conditions are met. Depending on the context, immune memory can increase or decrease the total neutralizing antibody response to variant antigens, with apparent consequences for protection. These effects are easier to measure experimentally than epidemiologically, but there is evidence that both early and recent exposures influence vaccine effectiveness. A few immunological interactions between adaptive immune responses and antigens might explain the seemingly discrepant effects of memory. Overall, the complex observations point to a need for more quantitative approaches to integrate high-dimensional immune data from populations with diverse exposure histories. Such approaches could help identify optimal vaccination strategies against antigenically diverse pathogens.