The True Extent of Avian Influenza Virus Infections: Knowns and Unknowns

While seasonal strains of influenza A viruses (H1N1 and H3N2) are not new to humans and are fairly well known even to the general public, avian influenza viruses (AIVs) and the concerns surrounding them have become familiar to the public only subsequent to the SARS-CoV-2 pandemic. While influenza virologists think about AIVs frequently, keeping many of us awake at night, the general public likely considers AIVs most often when media report large numbers of wild birds found dead, dairy cattle being infected, or the rare human case resulting in hospitalization.

Influenza viruses are classified based on their surface proteins, hemagglutinin (HA) and neuraminidase (NA). To date, 19 HA subtypes and 11 NA subtypes have been identified, with only H1, H2, H3, H5, H6, H7, H9, and H10 viruses known to cause human infections. Reasonably, much of the research to date has focused on AIVs known to cause substantial human disease and/or substantial mortality in poultry (e.g., highly pathogenic avian influenza [HPAI] H5N1 or H7N9). However, it was recently shown that an H13 virus was capable of infecting human cells in vitro (Sun et al., 2023). This highlights two important gaps in knowledge. As scientists, (1) we know very little about which other AIVs have the potential to either infect humans and/or cause substantial disease, and (2) we have no idea to what extent human infections with AIVs have gone unidentified, undiagnosed, or have caused asymptomatic infections. These gaps became more apparent when mild disease was reported by farm workers infected during the H5N1 clade 2.3.4.4b outbreak in dairy cattle in the United States (Centers for Disease Control and Prevention, 2025b; Drehoff et al., 2024; Uyeki et al., 2024). Given that mild “flu-like” symptoms could be indicators of many other infections, there is likely an underreporting of AIV infections.

Prior to the introduction of H5N1 clade 2.3.4.4b into North America in late 2021 (Caliendo et al., 2022), H5N1 outbreaks in wild birds were largely sporadic and finite, without sustained transmission. This changed substantially in the years that have followed, with not only sustained bird-to-bird transmission being reported, but also geographical expansion (including to Antarctica), species expansion, and infections and high fatality rates even among bird species not known to have been negatively impacted by HPAIs historically (Alkie et al., 2023; Avery‐Gomm et al., 2024; Banyard et al., 2024; European Food Safety Authority, 2024; Giacinti et al., 2024; Harvey et al., 2023; Jakobek et al., 2023; Lair et al., 2024; Plaza et al., 2024; Wight et al., 2024). Extensive spread among wild birds has been documented, with 100% of waterfowl tested in Newfoundland, Canada, having anti-H5 antibodies only weeks after the introduction of the virus into the region (Wight et al., 2024). While this has likely remained under the radar for the public, influenza virologists certainly took note. However, when H5N1 infections in dairy cattle in the United States were reported in March 2024, both influenza virologists and the general public took notice (Hu et al., 2024; Nguyen et al., 2024; USDA APHIS, 2024; Wallace et al., 2025). The extensive transmission of H5N1 clade 2.3.4.4b in dairy cattle (925 infected herds in 16 states as of 13 Jan 2025) (USDA APHIS, 2024) (USDA APHIS, 2025) has been accompanied by 66 known human infections in the United States, mostly among poultry/dairy workers (Centers for Disease Control and Prevention, 2025b; Drehoff et al., 2024; Uyeki et al., 2024). While most of these cases have been mild, the recent infection and hospitalization of a teenager in British Columbia, Canada, and the death of a person in Louisiana infected with the wild bird-related H5N1 virus (British Columbia Ministry of Health, 2024; Centers for Disease Control and Prevention, 2025a; Jassem et al., 2024) have again highlighted the need for additional research and prevention.

One of the most important aspects of the desperately needed research is large-scale serosurveys to truly understand the extent of human infections with AIVs, most notably HPAI H5N1. The scale of recent human serosurveys has not been large enough to make general conclusions. A recent study reported 7% of ∼100 dairy workers in Michigan and Colorado were seropositive for H5 (Mellis et al., 2024). Prior to the current outbreak of HPAI H5Nx in North America, in 2014 it was reported that none of the 900+ people surveyed who came in contact with birds in Alaska had anti-H5 antibodies, despite infected birds known to be present in the region during that time (Reed et al., 2014). Some of the people most likely to be infected with these viruses are individuals working on poultry or dairy farms, those who hunt and consume wild game as a food source, and those individuals who interact with wild birds, including scientists and volunteers who perform annual AIV surveillance and bird banding.

Although we are arguably more prepared for a future influenza pandemic than we were for the SARS-CoV-2 pandemic, the growing anti-science movement and rise of anti-vaccine rhetoric, accompanied by the geographic and host expansion of H5N1 clade 2.3.4.4b, increased rates of zoonotic infectious disease outbreaks, and ease of global travel, certainly highlight the need to understand the extent of previous infections with zoonotic viruses, including AIVs. In addition, research on the pandemic potential of all influenza A viruses, whether or not they have previously been reported to cause human infections, will be of utmost importance in the coming years and decades.

Should we be ringing alarm bells at the present moment? No. But are we totally prepared for an avian influenza outbreak in humans? Also no. Given how quickly outbreaks can occur, should we be ready to ring alarm bells at a moment’s notice? Absolutely yes. The time is now to prepare for the future, in part by understanding the past.