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It has been known that the influenza A virus infection induces a cross-protective immunity against infection by viruses with different subtypes of viral envelope proteins, hemagglutinin and neuraminidase. This heterosubtypic immunity is generally mediated by cytotoxic T lymphocytes (CTL) reactive to specific epitopes in the viral internal proteins, such as nucleoprotein and matrix protein. By contrast, immunization with inactivated virus antigens has been thought to be unable to generate heterosubtypic immunity, since inactivated antigens do not usually induce CTL responses. However, we show that intranasal immunization with formalin-inactivated intact virus, but not ether-split vaccines, induced a broad spectrum of heterosubtypic protective immunity in mice. The protection may be mediated by the mucosal immune response, most likely secretory IgA antibodies to the viral proteins. This approach may overcome limitations in the efficacy of inactivated influenza vaccines and confer potent immunity to humans against viruses with new pandemic potential. [Copyright &y& Elsevier]

An influenza A virus with a chimeric HA segment comprising the entire coding sequence of the type B HA, flanked by the noncoding sequence of the type A HA, was rescued, but it replicated only marginally. Chimeric viruses containing HAs possessing the type A noncoding region, together with either the signal peptide or transmembrane/cytoplasmic region of the type A virus or both, with remaining regions derived from the type B HA, were generated. All of these chimeric viruses were attenuated in mice. All animals intranasally immunized with a chimeric virus survived upon challenge with a lethal dose of wild-type B and A viruses, suggesting a framework for the design of a novel live vaccine virus. [Copyright &y& Elsevier]

In order to determine the role of neuraminidase (NA) in host range restriction, we studied a reassortant virus that replicated with poor efficiency in ducks. The reassortant virus, in which NA of an avian virus, A/duck/Hong Kong/278/78 (H2N9), was replaced with that from a human virus, A/England/12/62 (H2N2), was rectally inoculated into ducks. The viruses recovered were then orally inoculated into new ducks and a variant that replicated efficiently in the intestinal tract was isolated. Sequence analysis showed that the variant virus NA contained two amino acid substitutions at positions 165 (Val to Ile) and 431 (Gln to Pro). Differences in low pH resistance of the NAs were also assessed to identify differences in the NAs possibly related to the restriction of viral growth in ducks. The NA activity of the parental reassortant virus almost disappeared after low pH treatment (pH 3.0), while that of the variant was conserved under the same conditions. These results indicate that the amino acids, at positions 165 and/or 431 on the NA molecule, correlate with the ability to support viral growth in ducks, contributing to the low pH stability of NA activity. [Copyright &y& Elsevier]