The Wages of Original Antigenic Sin

was thinking when pondering certain inexplicable serologic data from a 1946 infl uenza vaccine trial may never be known. Whether in religious reverence for the beauty of science or impish delight fueled by the martini breaks of which he was so fond, Francis coined the term " original antigenic sin " to describe a curious new immunologic phenomenon. Elsewhere in this issue, Adalja and Henderson propose that original antigenic sin has altered the population age–specifi c incidence of infection and disease caused by infl uenza A pandemic (H1N1) 2009 virus and that public health responses must account for the disruption (1). What is original antigenic sin, what is its immunologic basis, and into what sort of trouble is it getting us? Discovery of infl uenza viruses in the early 1930s ignited a search to understand the epidemiology of pandemic/ endemic infl uenza. Serologic data showed that decendents of the 1918 pandemic infl uenza virus were still circulating and were changing antigenically (we would now say drifting and undergoing intrasubtypic reassortment); that contemporary human and swine viruses were closely related; and that over a lifetime of repeated exposures, different human birth cohorts were acquiring fundamentally different infl uenza infection experiences. The surprise appearance in 1946 of a new and antigenically different infl uenza A virus (designated infl uenza A′ and recently shown to be a subtype H1N1 intrasubtypic reassortant) provided Francis a unique opportunity. College students participating in a 1946 trial of the old 1946 virus vaccine were infected in March 1947 with the new A′ virus. Surprisingly, these students developed low serologic titers to the new infecting virus and higher seroconverting titers to old viruses with which they previously had been infected. Moreover, recent recipients of the old virus vaccine had the highest serocon-verting titers of all to the old—but not to the new—virus (2,3). Absorption studies, in which various viruses were used to selectively remove serum antibodies, suggested that repeat exposures to dominant antigens of fi rst-infecting viruses , when seen later as lesser or secondary antigens on subsequently infecting viruses, somehow reinforced anti-body responses to the original strains at the apparent expense of responses to newer strains (4). Francis announced " the doctrine of original antigenic sin " (5,6): " [t]he anti-body-forming mechanisms appear to be oriented by the initial infections of childhood so that exposures later in life to antigenically related strains result in a progressive reinforcement …