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Avian influenza A viruses of the H5 and H7 subtypes periodically cause severe outbreaks of disease in poultry. The question we wished to address in this study is whether these highly pathogenic strains constitute unique lineages or whether they and related nonpathogenic viruses are derived from common ancestors in the wild bird reservoir. We therefore compared the nucleotide and amino acid sequences of the hemagglutinin (HA) genes of 15 H5 and 26 H7 influenza A viruses isolated over 91 years from a variety of host species in Eurasia, Africa, Australia, and North America. Phylogenetic analysis indicated that the HA genes of H5 and H7 viruses that cause severe disease in domestic birds do not form unique lineages but share common ancestors with nonpathogenic H5 and H7 viruses. These findings predict that highly pathogenic avian H5 and H7 influenza A viruses will continue to emerge from wild bird reservoirs. Another important question is whether H7 influenza viruses found in mammalian species are derived from avian strains. We included eight equine influenza viruses and one seal isolate in the phylogenetic analysis of H7 HA genes. We could show that the HA genes of both, the equine and the seal viruses, shared ancestors with avian H7 HA genes. This indicates that currently circulating H7 viruses with an avian HA gene may have the potential to adapt to mammalian species and to cause an influenza outbreak in the new host.

Pigs have been proposed to act as the intermediate hosts in the generation of pandemic human influenza strains by reassortment of genes from avian and human influenza virus strains. The circulation of avian-like H1N1 influenza viruses in European pigs since 1979 and the detection of human-avian reassortants in pigs raises the question of whether these viruses actually have the potential to transmit and cause disease in humans. We now report the serologic and genetic characterization of two human influenza A viruses (A/Netherlands/5/93 [H3N2] and A/Netherlands/35/93 [H3N2]) that caused influenza in children in The Netherlands in 1993. The results show that these viruses are human-avian ressortants that were generated and currently still are circulating in European swine. This shows the pivotal role that pigs can play in the generation and transmission of avian influenza virus genes to humans and their potential to generate a new human pandemic strain.

H2N2 influenza A viruses caused the Asian pandemic of 1957 and then disappeared from the human population 10 years later. To assess the potential for similar outbreaks in the future, we determined the antigenicity of H2 hemagglutinins (HAs) from representative human and avian H2 viruses and then analyzed the nucleotide and amino acid sequences to determine their evolutionary characteristics in different hosts. The results of longitudinal virus surveillance studies were also examined to estimate the prevalence of avian H2 isolates among samples collected from wild ducks and domestic poultry. Reactivity patterns obtained with a large panel of monoclonal antibodies indicated antigenic drift in the HA of human H2 influenza viruses, beginning in 1962. Amino acid changes were clustered in two regions of HA1 that correspond to antigenic sites A and D of the H3 HA. By contrast, the antigenic profiles of the majority of avian H2 HAs were remarkably conserved through 1991, resembling the prototype Japan 57 (H2N2) strain. Amino acid changes were distributed throughout HA1, indicating that antibodies do not play a major role in the selection of avian H2 viruses. Phylogenetic analysis revealed two geographic site-specific lineages of avian H2 HAs: North American and Eurasian. Evidence is presented to support interregion transmission of gull H2 viruses. The human H2 HAs that circulated in 1957-1968 form a separate phylogenetic lineage, most closely related to the Eurasian avian H2 HAs. There was an increased prevalence of H2 influenza viruses among wild ducks in 1988 in North America, preceding the appearance of H2N2 viruses in domestic fowl. As the prevalence of avian H2N2 influenza viruses increased on turkey farms and in live bird markets in New York City and elsewhere, greater numbers of these viruses have come into direct contact with susceptible humans. We conclude that antigenically conserved counterparts of the human Asian pandemic strain of 1957 continue to circulate in the avian reservoir and are coming into closer proximity to susceptible human populations.