The Doctrine of Original Antigenic Sin: Separating Good From Evil

Arnold S. Monto, Ryan E. Malosh, Joshua G. Petrie, Emily T. Martin

The term "Original Antigenic Sin" was coined approximately 60 years ago to describe the imprinting by first influenza type A infection on later antibody response to vaccination. These studies did not suggest reduction in response to current antigens, but instead anamnestic recall of antibody to earlier strains. Then, approximately 40 years ago, it was observed that sequential influenza vaccination might lead to reduced vaccine effectiveness. This conclusion was largely dismissed after an experimental study involving sequential administration of then standard influenza vaccines. Recent observations have revived the sequential vaccination issue and provide convincing evidence that the phenomenon is real. We propose that such reduction in vaccine effectiveness be termed negative "antigenic interaction" given that there is no age cohort effect. In contrast, the potentially positive protective effect of early influenza infection later in life continues to be observed. It is essential that we understand better the immunologic factors underlying both original antigenic sin and negative antigenic interaction to support development of improved influenza vaccines and vaccination strategies.