Figure 1 Influenza A and influenza B. The figure represents an influenza A virus particle or virion. Both influenza A and influenza B viruses are enveloped negative- sense RNA viruses with genomes comprising eight single- stranded RNA segments located inside the virus particle. Although antigenically different, the viral proteins encoded by the viral genome of influenza A and influenza B viruses have similar functions: the three largest RNA
segments encode the three subunits of the viral RNA- dependent RNA polymerases (PB1, PB2 and PA) that are responsible for RNA synthesis and replication in infected cells; two RNA segments encode the viral glycoproteins haemagglutinin (HA , which has a ‘stalk’ domain and a ‘head’ domain), which mediates binding to sialic acid- containing receptors and viral entry , and neuraminidase (NA), which is responsible for releasing viruses bound to non- functional receptors and helping viral spread. The RNA genome is bound by the viral nucleoprotein (NP), which is encoded by RNA segment 5. RNA
segments 6 and 8 encode more than one protein, namely , the matrix protein (M1) and membrane protein (M2) — BM2 in the case of influenza B — and the nonstructural protein NS1 (not shown) and nuclear export protein (NEP). The M1 protein is thought to provide a scaffold that helps the structure of the virion and that, together with NEP, regulates the trafficking of the viral RNA segments in the cell; the M2 protein is a proton ion channel that is required for viral entry and exit and that, together with the HA and NA glycoproteins, is located on the surface of the virus anchored in a lipid membrane derived from the infected cell. Finally , the NS1 protein is a virulence factor that inhibits host antiviral responses in infected cells. The influenza viruses can also express additional
accessory viral proteins in infected cells, such as PB1–F2 and PA- x (influenza A), that participate in preventing host innate antiviral responses together with the NS1 protein or NB (influenza B), the function of which is unknown. NS1, NEP, PB1–F2 and PA- x are not present in the virus particle or are present in only very small amounts. NB is a unique influenza B virus surface protein anchored in the lipid membrane of the virus particles.
Figure 2 Influenza pandemics. In the past 100 years, four pandemics of human influenza have occurred, with the 1918 pandemic caused by an influenza A H1N1 virus being the most devastating, as it was associated with >40 million deaths. Influenza A H2N2, H3N2 and H1N1 viruses caused the 1957 , 1968 and 2009 pandemics, respectively. In 1977 , influenza A H1N1 restarted circulation in humans without causing a pandemic, as the strain was similar to that which preceded the 1957 influenza A H2N2 pandemic. By contrast, the 2009 pandemic influenza A H1N1 virus was antigenically very different to the previous seasonal influenza A H1N1 viruses and replaced them as the circulating influenza A H1N1 strain. Examples of the spreading of human influenza A viruses in the world are shown for pandemic 1918 and 1957 viruses and for seasonal H3N2 viruses18. For pandemic virus outbreaks, the arrows indicate the first and second waves of transmission. For seasonal influenza A H3N2 spread, the arrows indicate the seeding hierarchy of seasonal influenza A (H3N2) viruses over a 5-year period, starting from a network of major cities in east and southeast Asia; the hierarchy within the city network is unknown. Seasonal influenza B viruses (not shown) are co- circulating in humans with influenza A viruses.
Fig. 3 | Emergence of influenza A virus from aquatic wild bird reservoirs. Influenza A viruses have been found in multiple species all seemingly derived from viral ancestors in wild birds, with the possible exception of bat influenza- like virus, which is of still uncertain origin. Influenza viruses from wild birds can spill over through water or fomites to marine mammals and to domestic free- range ducks. Transmissions to other avian species (for example, poultry) from domestic ducks or directly from wild birds can also occur from contaminated water. Transmission from ducks to other species occurs through ‘backyard’ farming, whereby the animals are raised together, and in live poultry and/or animal markets. Transmission from backyard to commercial farms can occur via lack of biosecurity and via spread through live markets. Humans can be infected with poultry and swine influenza viruses through aerosols, fomites or contaminated water.
However, in most instances these infections do not result in subsequent human- to-human transmission. Human- to-human transmission of seasonal or pandemic human viruses can be mediated by respiratory droplets, aerosols or self- inoculation after touching of fomites. Additional virus adaptations would be required for sustainable human- to-human transmission of animal influenza viruses. Other domestic animals known to be susceptible to influenza virus infections are dogs and cats. Dashed lines represent transmission that bypasses a domestic duck intermediate.
Fig. 4 | Influenza virus life cycle. Influenza virus enters the cell by endosomal uptake and release, and its negative- sense genetic material in the form of viral ribonucleoproteins (vRNPs) is imported to the nucleus for transcription of mRNA and replication through a positive-sense complementary ribonucleoprotein (cRNP) intermediate. Viral mRNA is translated into viral proteins in the cytoplasm, and these are assembled into new virions together with the newly synthesized vRNPs. PB1–F2 is shown here as a dimer, but can also be multimeric. HA , haemagglutinin; M1, matrix protein; M2, membrane protein; NA , neuraminidase; NEP, nuclear export protein; NP, nucleoprotein; NS1, nonstructural protein; PB1, PB2 and PA , viral RNA polymerases.
Fig. 5 | Influenza antigenic shift and antigenic drift. In 1968, co- infections between an avian influenza A H3Nx (where x = 1–9) virus and the seasonal human influenza A H2N2 viruses resulted in the exchange of viral segments (reassortment) and the selection of the pandemic human influenza A H3N2 virus, with the RNA polymerase PB1 and haemagglutinin (HA) RNA segments derived from the avian virus and the rest of the segments derived from the human virus. The lack of pre- existing immunity to the antigenically novel H3 HA in humans facilitated human transmission. Similar reassortment processes have taken place during other influenza A virus pandemics. Once H3N2 became established in humans, the virus began to drift, as is the case with all other human seasonal influenza viruses. During drift, small antigenic changes in the HA protein generated by mutation are selected to increase immune evasion, although not as dramatically as during shift. M, RNA encoding M1, matrix protein, and M2, membrane protein; NA , RNA encoding neuraminidase; NP, RNA encoding nucleoprotein; NS1, RNA encoding nonstructural protein; PB2 and PA , RNA encoding RNA polymerases.
Fig. 7 | Inactivated influenza A virus vaccine manufacture. An antigenically representative circulating strain is reassorted with the high- growth influenza A/Puerto Rico/8/1934 (PR8) virus strain by co- infection in eggs, and a vaccine virus is selected with the high- growth properties of PR8 (conferred by its RNA segments encoding internal viral proteins) and the haemagglutinin (HA) and neuraminidase (NA) derived from the circulating strain. The vaccine virus is amplified in eggs, and the allantoic fluid from the infected eggs containing high titres of the virus is harvested; the virus is inactivated, treated for splitting of individual viral components and subjected to partial purification to enrich for the HA (and NA) viral components in the final injectable vaccine.
Influenza, Nature Reviews, 2018