Population Immunity to Hemagglutinin Head, Stalk and Neuraminidase of Highly Pathogenic Avian Influenza 2.3.4.4b A(H5N1) viruses in the United States and the Impact of Seasonal Influenza on A(H5N1) Immunity

The unprecedented 2.3.4.4b A(H5N1) outbreak in dairy cattle, poultry, and spillover to humans in the United States (US) poses a major public health threat. Population immunity is a critical component of influenza pandemic risk assessment. We conducted a comprehensive assessment of the population immunity to 2.3.4.4b A(H5N1) viruses and analyzed 1794 sera from 723 people (0.5-88 yrs) in multiple US geographic regions during 2021-2024. Low pre-existing neutralizing and hemagglutinin (HA) head binding antibodies and substantial cross reactive binding antibodies to N1 neuraminidase (NA) of 2.3.4.4b A(H5N1) were detected in US population. Antibodies to group 1 HA stalk were also prevalent with an age-related pattern. A(H1N1)pdm09 infection and influenza vaccination did not induce neutralizing antibodies but induced significant rise of NA inhibition (NAI) antibodies to N1 of 2.3.4.4b A(H5N1), and group 1 HA stalk antibodies. Understanding population susceptibility to novel influenza is essential for pandemic preparedness.