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Vaccination-primed immunity in poultry has been suggested for selection of antigenically drifted highly pathogenic avian influenza viruses (HPAIVs). In this study, we performed two consecutive passage studies of an H5N1 HPAIV in vaccinated chickens, namely, study-I and study-II, to select antigenic variants under immune pressure from the vaccination. In study-I, nine consecutive passages of a wild-type H5N1 HPAIV were carried out in chickens vaccinated with the homologous challenge strain. Antigenically drifted variants with mutations at position 179 in the hemagglutinin (HA) were selected after three passages. Similarly, in study-II, a vaccination-mediated antigenic variant isolated in study-I was used as the vaccine and challenge strain to confirm further antigenic drift after updating the vaccine; after the third passage, additional antigenic variants with a mutation at position 256 in the HA were selected. Thus, our study demonstrated the contribution of vaccination in the selection of antigenic variants of H5 HPAIVs in chickens.

Avian influenza viruses possess hemagglutinin (HA) which preferentially bind to the sialic acid α2,3-galactose sialyloligosaccharides (SAα2,3Gal) receptor. In contrast, human influenza viruses bind to sialic acid α2,6-galactose sialyloligosaccharides (SAα2,6Gal). The A/Hong Kong/68 (H3N2) virus preferentially binds to SAα2,6Gal, although its HA gene was derived from an avian influenza virus strain. To elucidate the mechanisms behind acquisition of binding specificity for the human-type receptor, the avian influenza virus, A/duck/Hokkaido/5/77 (H3N2), which carries the HA with SAα2,3Gal receptor specificity, was consecutively passaged in pigs. Viruses that preferentially bind to the SAα2,6Gal receptor were predominantly recovered from the nasal swabs of pigs after three passages. The present results indicate that avian influenza viruses can acquire the potential to infect humans after multiple infections in a pig population. Intensive surveillance of swine influenza is, thus, important for the preparedness for the future pandemics.

The outbreak of H7N9 low pathogenic avian influenza viruses in China has attracted attention to H7 influenza virus infection in humans. Since we have shown that the pathogenicity of H1N1 and H5N1 influenza viruses in macaques was almost the same as that in humans, we compared the pathogenicities of H7 avian influenza viruses in cynomolgus macaques via intranasal and conjunctival inoculation, which mimics natural infection in humans. H7N9 virus, as well as H7N7 highly pathogenic avian influenza virus, showed more efficient replication and higher pathogenicity in macaques than did H7N1 and H7N3 highly pathogenic avian influenza viruses. These results are different from pathogenicity in chickens as reported previously. Therefore, our results obtained in macaques help to estimate the pathogenicity of H7 avian influenza viruses in humans.