Is Antigenic Sin Always “Original?” Re-examining the Evidence Regarding Circulation of a Human H1 Influenza Virus Immediately Prior to the 1918 Spanish Flu

What makes the 1918 Spanish influenza pandemic stand out from all the others is its wellknownW-shaped mortality signature, which was caused by unusually high mortality among adults aged 20 to 40 [1]. Much debate remains as to the exact reason for this atypical pattern [2]. A contribution by Worobey et al. [3] published recently in the Proceedings of the National Academy of Sciences (PNAS) is no doubt adding important information to this debate. In agreement with previous work [4–7], Worobey et al. propose that the very high mortality experienced by young adults during the 1918 H1N1 virus pandemic was primarily due to their childhood exposure to the heterosubtypic H3-like virus that is thought to have caused the earlier 1889–1890 Russian flu pandemic [3]. As is generally accepted, the authors also presume that older adults had immunological cross-protection from earlier exposures to a putative H1-like virus, which circulated prior the 1890 pandemic. As for the lower mortality of children and adolescents, however, a new and compelling hypothesis is put forward: this pattern may be attributed to the appearance of a new H1 influenza variant in the early 1900s, which would have provided protection in 1918 for individuals born at the turn of the century, presumably exposed early in life (or “primed”) to this new variant. They propose that this H1N8 virus arose from reassortment between an H1 lineage virus and an avian influenza virus sometime between 1901 and 1907, replacing the H3N8 virus of the 1889–1890 pandemic. This phylogenetic reconstitution appears to be supported by (often forgotten) seroarcheological and mortality evidence.