Immune Imprinting Across Respiratory Virus Infection, Vaccination, and Passive Immunization: Rethinking 'Original Antigenic Sin' in Influenza, SARS-CoV-2, and RSV

Immune imprinting shapes every subsequent response to antigenically related pathogens and is now central to designing updated vaccines for influenza, SARS-CoV-2, and respiratory syncytial virus (RSV). The label "Original Antigenic Sin" has framed imprinting as a fixed liability, but recent germinal-center, B-cell repertoire, and epidemiological data show that the effect is neither uniformly harmful nor irreversible. This review distinguishes cross-reactive immune memory from immune imprinting, defined here as a preferential bias toward the first-encountered antigen. Prior exposure can provide useful cross-reactive memory, but available evidence generally does not show that first-antigen bias itself improves protection relative to an equivalent unbiased memory response. We therefore use a hypothesis-generating conceptual framework to examine how antigenic distance, conserved-epitope accessibility, and exposure interval may influence both the usefulness of recalled memory and the extent to which imprinting restricts recruitment of responses to later antigens. The framework organizes existing observations and is not intended to predict imprinting outcomes ex ante. We discuss recent quantitative models that explicitly formalize competition between memory and de novo responses as complementary, pathogen-specific approaches. Across influenza and SARS-CoV-2, early exposure can establish cross-reactive memory associated with subsequent heterologous protection, while preferential recall of the priming antigen may limit responses to novel epitopes. For RSV, the effects of maternal vaccination and passive antibodies on subsequent active immune memory remain uncertain. Immunogen engineering, schedule adjustment, adjuvant selection, and cohort-tailored strategies may broaden pre-existing memory toward conserved protective epitopes and reduce restrictive first-antigen bias.