Researchers have discovered that a previous infection with the 2009 H1N1 influenza virus can dramatically reduce the risk of serious illness from H5N1 bird flu. This protection was evident even when ferrets, a common model for human influenza, were exposed through close contact with an H5N1 strain originating from dairy cattle.

The study, published in *Science Translational Medicine*, investigated how prior exposure to different influenza A virus subtypes impacts susceptibility to H5N1. The findings are crucial for public health officials and frontline workers dealing with the increasing spread of avian flu among mammals, including a notable outbreak in U.S. dairy herds.

In the research, ferrets were pre-conditioned with immunity from either the 2009 H1N1, seasonal H3N2, or influenza B viruses. Those pre-exposed to the 2009 H1N1 strain showed markedly less viral shedding and no signs of illness when later challenged with H5N1. They maintained their body weight and all survived the ordeal.

Conversely, ferrets with only seasonal H3N2 immunity experienced partial protection, with intermediate viral titers and some weight loss, though they also survived. The study highlighted that the H1N1 immunity generated robust cross-reactive antibodies, particularly targeting the neuraminidase enzyme, which effectively inhibited H5N1 neuraminidase activity.

The order of prior infections also proved significant. Any ferret group that had encountered the 2009 H1N1 virus, regardless of sequence, exhibited minimal to no H5N1 shedding and did not develop disease. This suggests that the presence of H1N1 immunity was more critical than the timing of exposure.

In a critical direct contact experiment, ferrets naive to any influenza strain transmitted H5N1 to all their cage mates, resulting in universally fatal disease. Prior H3N2 immunity failed to prevent infection, with all contacts shedding virus and only half surviving. However, prior H1N1 immunity significantly improved outcomes. Only half of the H1N1-immune contacts experienced low, transient shedding, none developed clinical disease, and all survived.

These findings strongly indicate that immunity acquired from the 2009 H1N1 pandemic virus acts as a robust defense against contemporary H5N1 strains, suppressing replication and preventing severe disease, even in high-dose exposure scenarios.

The study suggests that the superior protection observed in H1N1-primed animals stems from cross-reactive antibodies, specifically those targeting the N1 neuraminidase found in both H1N1 and H5N1 viruses. Low levels of antibodies targeting the H5 hemagglutinin stem were also present but did not neutralize H5.

Immunity to internal viral proteins appeared comparable between H1N1 and H3N2 groups, implying that the enhanced defense against H5N1 is likely linked to hemagglutinin or neuraminidase cross-reactivity rather than broader immune responses.

The Centers for Disease Control and Prevention reported that as of June 2024, there have been 41 laboratory-confirmed human infections with H5N1 avian influenza in the United States, primarily linked to dairy cattle. Most of these cases have been mild, a trend this study’s findings may help to explain.

The research concludes that preexisting immunity to the 2009 H1N1 pandemic influenza virus offers substantial protection against H5N1 infection, replication, and illness in ferrets, even following direct, high-dose exposure. Immunity to seasonal H3N2 provided some attenuation of illness but did not reliably prevent infection.

The authors noted limitations, including the controlled infection intervals in ferrets and the inability to assess cellular immunity. Nevertheless, these insights are invaluable for developing future preparedness strategies, designing effective vaccines, and informing risk assessment and clinical surveillance policies, particularly emphasizing the role of neuraminidase-focused cross-reactivity.