Original Antigenic Sin: How Original? How Sinful?

We review the phenomenon of "original antigenic sin" (OAS) in antibody responses to influenza A virus (IAV) infection or vaccination. OAS refers to the preferential induction of antibodies with higher affinity to priming versus boosting immunogens. We emphasize its mechanistic basis and origins in the basic immunobiology of B-cell responses to myriad immunogens. We tabulate 23 studies in animals and humans to show that the magnitude of OAS depends on many variables. We discuss a number of misconceptions about OAS, examine the extent to which OAS is sinful, and argue that OAS is evolutionary selected and not a deleterious by-product of selection for other features of the immune response. We end by raising questions regarding the mechanistic basis of OAS whose answers could contribute to improving influenza virus vaccines on the road to the holy grail of a "universal" influenza vaccine.