In that case, it must have had some intermediate host. Pigs are a widely suggested possibility because they are known to be susceptible to both human and avian viruses. Indeed, simultaneous outbreaks of influenza were seen in humans and swine during the 1918 pandemic, but we believe that the direction of transmission was most probably from humans to pigs. There are numerous examples of human influenza A virus strains infecting swine since 1918, but swine influenza strains have been isolated only sporadically from humans. Nevertheless, to explore the possibility that the 1918 HA may have started as an avian form that gradually adapted to mammalian hosts in swine, we looked at a current example of how avian viruses evolve in pigs—an avian H1N1 influenza lineage that has become established in European swine over the past 25 years. We found that even 20 years of evolution in swine has not resulted in the number of changes from avian sequences exhibited by the 1918 pandemic strain.
When we applied these types of analyses to four other 1918 virus genes, we came to the same conclusion: the virus that sparked the 1918 pandemic could well have been an avian strain that was evolutionarily isolated from the typical wild waterfowl influenza gene pool for some time—one that, like the SARS coronavirus, emerged into circulation among humans from an as yet unknown animal host.
Our analyses of five RNA segments from the 1918 virus have shed some light on its origin and strongly suggest that the pandemic virus was the common ancestor of both subsequent human and swine H1N1 lineages, rather than having emerged from swine. To date, analyzing the viral genes has offered no definitive clue to the exceptional virulence of the 1918 virus strain. But experiments with engineered viruses containing 1918 genes indicate that certain of the 1918 viral proteins could promote rapid virus replication and provoke an intensely destructive host immune response.
In future work, we hope that the 1918 pandemic virus strain can be placed in the context of influenza viruses that immediately preceded and followed it. The direct precursor of the pandemic virus, the first or spring wave virus strain, lacked the autumn wave's exceptional virulence and seemed to spread less easily. At present, we are seeking influenza RNA samples from victims of the spring wave to identify any genetic differences between the two strains that might help elucidate why the autumn wave was more severe. Similarly, finding pre-1918 human influenza RNA samples would clarify which gene segments in the 1918 virus were completely novel to humans. The unusual mortality among young people during the 1918 pandemic might be explained if the virus shared features with earlier circulating strains to which older people had some immunity. And finding samples of H1N1 from the 1920s and later would help us understand the 1918 virus's subsequent evolution into less virulent forms.
We must remember that the mechanisms by which pandemic flu strains originate are not yet fully understood. Because the 1957 and 1968 pandemic strains had avian-like HA proteins, it seems most likely that they originated in the direct reassortment of avian and human virus strains. The actual circumstances of those reassortment events have never been identified, however, so no one knows how long it took for the novel strains to develop into human pandemics.
The 1918 pandemic strain is even more puzzling, because its gene sequences are consistent neither with direct reassortment from a known avian strain nor with adaptation of an avian strain in swine. If the 1918 virus should prove to have acquired novel genes through a different mechanism than subsequent pandemic strains, this could have important public health implications. An alternative origin might even have contributed to the 1918 strain's exceptional virulence. Sequencing of many more avian influenza viruses and research into alternative intermediate hosts other than swine, such as poultry, wild birds or horses, may provide more clues to the 1918 pandemic's source. Until the origins of such strains are better understood, detection and prevention efforts may overlook the beginning of the next pandemic.