Dairy cattle herds mount a characteristic antibody response to highly pathogenic H5N1 avian influenza viruses

An unprecedented outbreak of a highly pathogenic avian influenza virus, H5 clade 2.3.4.4b, was reported in United States dairy cattle during the spring of 2024. It has now spread to hundreds of herds across multiple states. In humans, antibodies to the hemagglutinin (HA) protein confer the strongest protection against infection. Human herd immunity limits viral spread but also drives the emergence of antigenic variants that escape dominant antibody responses. We used store-bought milk to profile the collective H5N1 antibody response of dairy cattle herds. We detected HA binding antibodies in specific samples from states with recent/ongoing outbreaks. These antibodies present in milk neutralized replicating virus expressing dairy cattle HA and neuraminidase (NA). Despite originating from independent vendors, dairies/plants, geographic regions, and time, antibodies present in these samples are remarkably similar in activity and HA binding specificity. The dominant antibody response was clade 2.3.4.4b HA specific, followed by cross-reactivity with other H5s. Whether the uniformity of the response is a pathway to achieve herd immunity or an avenue for antigenic variants to rapidly escape remains to be seen. SIGNIFICANCEEstablishing human herd immunity ends pandemics. For influenza viruses, this immunity drives continued antigenic evolution that enables viruses to infect once-immune individuals. An outbreak of highly pathogenic avian influenza virus was detected in dairy cattle in 2024 and has spread rapidly across herds and states. We report approaches to assess dairy cattle herd immunity using store-bought milk samples. Across samples separated by geography and time we find dairy cattle mount a strikingly similar antibody response that is strongest to the dairy cattle virus. Benchmarking immunity at this phase of the outbreak is important to understand either eradication or the emergence of antigenic variants that enable reinfection.