Serologic studies have detected protective immunity against 2009 pandemic H1N1 influenza virus (H1N1-2009) in some people. However, further study of preexisting immunity has been complicated by the complexity of the human immunological background. Here, we immunized mice with HA- and NA-encoding plasmids. The cross-neutralizing activity of the anti-HA antisera and the effect of the anti-NA antisera on viral infectivity were evaluated using H1N1-1918- and 2009-pseudotyped particles (pps) and an H1N1-2009 isolate. Antibodies to H1N1-2009 HA (09HA) neutralized pps harboring 09HA or H1N1-1918 HA (18HA); similarly, antibodies to 18HA neutralized pps harboring 18HA or 09HA. Antibodies to 09HA and 18HA also neutralized the H1N1-2009 virus with high efficiency. Antibodies to H1N1-1918 NA (18NA) or H1N1-2009 NA (09NA) both enhanced the infectivity of pps harboring 09NA and 18NA. Although anti-09NA and -18NA antibodies significantly reduced cytopathic effects in multiple-cycle infection assays, conversely, these antibodies enhanced the infectivity of H1N1-2009 in single-cycle infection assays. Our study demonstrates the existence of cross-protection between antibodies against these two antigenically related virus strains and shows that anti-NA antibodies have a dual effect that requires reexamination of their role in human immunity.
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