In 1957, the HA, NA and PB1 proteins of an H2N2 avian influenza virus were introduced in the previously circulating H1N1 human strain. In 1968, the HA and

PB1 proteins of an H3 avian influenza virus were introduced in the previously circulating H2N2 strain. The host species, whether avian or mammalian, that sustained these reassortment events are unknown. The first pandemic of the 21st century was caused in 2009 by an influenza virus H1N1 of swine origin, resulting from reassortment events between swine, avian and human influenza virus strains [173]. The HA, NP, NS and polymerase genes emerged from a triple-reassortant RG7204 ic50 virus circulating in North American swine. The source triple-reassortant

itself comprised genes derived from avian (PB2 and PA), human H3N2 (PB1) and classical swine Volasertib (HA, NP and NS) lineages. The NA and M genes of the pandemic virus originated from the Eurasian avian-like swine H1N1 lineage. Reassortment may represent the most efficient adaptive avenue leading to the generation of pandemic influenza viruses, allowing antigenic shift by acquisition of novel surface glycoproteins on the one hand, and better fitness associated with the maintenance of viral segments adapted to mammalian hosts on the other. Remarkably, in all pandemic viruses except the aminophylline recent H1N1 strain, the PB1 gene was of avian origin, and in all pandemic viruses, the HA gene was of animal and non-human origin. Introductions of HA and PB1 proteins of animal origin were the minimal changes that ever triggered an influenza pandemic in humans. The association of a mammalian PB2 gene segment with an avian PB1 gene segment resulted in

high levels of viral replication in mammalian cells in vitro [174], and may provide adaptive advantages to reassortants harbouring such combination of genes in a pandemic context. Reassortant viruses carrying only the HA and NA surface proteins of LPAIV H9N2 in a human H3N2 or 2009 pandemic H1N1 backbone were transmissible via aerosols in ferrets [175] and [176]. These studies demonstrate that novel surface proteins, and notably novel HA protein, with only minimal changes associated with adaptation to the mammalian host, may be sufficient to generate influenza viruses with pandemic potential. Following influenza pandemics, antigenic drift allows the viruses to recurrently circulate in the human population, causing annual seasonal influenza epidemics. Localized antigenic changes in the HA protein allow seasonal influenza viruses to escape pre-existing humoral immunity in a punctuated way [177]. Such escape from pre-existing immunity results in more extensive epidemic waves and more severe disease [178] and [179].