The 1918 influenza pandemic was the deadliest respiratory pandemic of the 20th century and determined the genomic make-up of subsequent human influenza A viruses (IAV). Here, we analyze both the first 1918 IAV genomes from Europe and the first from samples prior to the autumn peak. 1918 IAV genomic diversity is consistent with a combination of local transmission and long-distance dispersal events. Comparison of genomes before and during the pandemic peak shows variation at two sites in the nucleoprotein gene associated with resistance to host antiviral response, pointing at a possible adaptation of 1918 IAV to humans. Finally, local molecular clock modeling suggests a pure pandemic descent of seasonal H1N1 IAV as an alternative to the hypothesis of origination through an intrasubtype reassortment.
For archival pathogens, like pH1N1 Influenza A virus the causative agent of 1918/19 pandemic, only few whole genome sequences exist. Here, Patrono et al. provide one complete and two partial genomes from Germany and find variation in two sites in the nucleoprotein gene in pandemic samples compared to pre-pandemic samples, that are associated with resistance to host antiviral response, pointing at a possible viral adaptation to humans.