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Influenza immunostimulating complexes (flu-ISCOMs) and a monovalent subvirion vaccine prepared with an H1N1 strain of influenza virus were compared in mice for immunogenicity and protection against challenge with homologous and heterotypic influenza viruses. flu-ISCOMs but not subvirion vaccine fully protected mice against homologous virus challenge after one immunization as assessed by measurement of virus lung titers. The improved protection induced by flu-ISCOMs was associated with a 10-fold higher prechallenge serum hemagglutination inhibition titer. Furthermore, only flu-ISCOMs fully protected mice against mortality and reduced morbidity following challenge with an influenza virus of the serologically distinct H2N2 subtype. This cross-protection correlated with the induction of virus cross-reactive cytotoxic T lymphocytes that recognized a known major histocompatibility class I (H2-Kd)-restricted epitope within the hemagglutinin of influenza virus that is conserved among the H1 and H2 influenza virus subtypes. flu-ISCOMs may offer significant advantages over current commercial formulations as an improved influenza vaccine.

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