Low levels of influenza H5N1 HA and NA antibodies in the human population are boosted by seasonal H1N1 infection but not by H3N2 infection or influenza vaccination

An increase in the number of human cases of influenza A/H5N1 infection in the USA has raised concerns about the pandemic potential of the virus. Pre-existing population immunity is a key determinant for risk assessment and pandemic potential for any virus. Antibody responses against the bovine A/H5N1 hemagglutinin (HA) and neuraminidase (NA) proteins were measured among a population of influenza-vaccinated or influenza-infected individuals. Modest titers of bovine A/H5N1 HA-binding antibodies and low to undetectable neutralizing antibody titers were detected in a cohort of 73 individuals. Conversely, bovine A/H5N1 NA-binding and neuraminidase-inhibiting antibody titers were comparable to those against a human A/H1N1 NA at baseline. Seasonal influenza vaccination failed to significantly increase antibody titers against both HA and NA glycoproteins of bovine A/H5N1. Recent infection with human A/H1N1 but not A/H3N2 viruses induced significant increases in bovine A/H5N1-neutralizing antibody, as well as increases in NA-binding and NA-inhibiting antibodies to bovine A/H5N1 NA. While the degree of protection afforded by these A/H5N1 cross-reactive antibodies is not known, incorporating NA or enhancing current seasonal vaccine formulations to increase NA-specific antibody titers may increase antibody breadth and protection against both seasonal and pandemic influenza viruses.IMPORTANCEA/H5N1 influenza A viruses continue to pose a pandemic threat to humans. Recent infection of dairy cattle and poultry with A/H5N1 in the USA has magnified that concern. We determined the level of antibodies that recognize A/H5N1 hemagglutinin (HA) and neuraminidase (NA) proteins in a population in Baltimore, MD. We show that while low levels of H5 HA-binding and A/H5N1-neutralizing antibodies are present, there is a significantly stronger recognition of bovine N1 NA. Vaccines that target the N1 NA protein may induce protective antibody responses in humans due to the presence of cross-reactive human N1 NA antibodies.