Immune Escape and Zoonotic Risk in the Evolutionary Trajectory of H5N1 Avian Influenza: Findings from UNC Charlotte
Dr. Majed Hamed Al Saegh / poultry pathologist / Australia
Computational modeling of immune-protein interactions with variants of the H5N1 avian influenza virus has shown that the virus is evolving in a way that may soon allow it to escape immune responses developed from prior infections or vaccinations.
A research team from the University of North Carolina at Charlotte (UNC Charlotte) has presented clear evidence that these evolutionary changes present an ongoing and increasing threat to global agriculture, prompting an urgent call for public health preparedness.
Dr Colby T. Ford, a visiting data science scholar at the Centre for Computational Intelligence to Predict Health and Environmental Risks (CIPHER), stated: “The overall decline in antibody affinity to more recent H5N1 isolates indicates that current and future viral strains pose an increasing risk to human health” (Ford et al., 2024).
This drop in neutralisation capacity may lead to increased susceptibility in humans, particularly given the virus’s rapid evolution. Ford added, “If an H5N1 vaccine is made using an older vaccine candidate virus, the vaccine will be less effective, based on our measurements of how much the virus has evolved in recent years” (Ford et al., 2024).
The findings were published in July 2024 as a preprint due to their urgent public health importance, under the title: “Large-scale Computational Modeling of H5 Influenza Variants against HA1-Neutralising Antibodies”, , in which 1,804 interactions between viral proteins and antibodies were analysed.
The researchers used physics-based computational models to simulate the binding between HA1 proteins from different H5 isolates and antibodies collected from infected or vaccinated individuals between 1996 and 2018.
The results revealed a clear trend of progressively weaker binding affinity between existing antibodies and recent viral isolates, suggesting immune escape due to mutations that reduce the effectiveness of neutralising antibodies—particularly those targeting the HA1 domain (UNC Charlotte, 2024).
The study also highlighted the implications of ongoing cross-species transmission. The report stated: “The continuous transmission of H5N1 from birds to mammals and the increase in strains containing immune-evasive hemagglutinin (HAx) in mammals over time indicate that antigenic drift is a significant source of zoonotic risk.”
This research followed shortly after the first confirmed case of H5N1 transmission from cattle to a human in Texas in 2024. Since then, H5N1-positive cases have been reported in cattle in at least in 17 U.S. states, along with widespread outbreaks in wild birds, poultry, and small mammals (CDC, 2025).
Between January 2022 and March 2025, the Centers for Disease Control and Prevention (CDC) reported: 12,510 confirmed outbreaks in wild birds in the U.S., Over 166 million affected poultry birds, and 70 confirmed human cases, including one fatality.
Although no human-to-human transmission has been reported to date, the virus’s continued adaptation to mammals is alarming. Science magazine noted in December 2024 that the virus remains at the top of the list of potential pandemic threats (Science, 2024).
The research team was led by Dr Richard Allen White III and Dr Daniel Janies, and included students and researchers from UNC Charlotte. They collaborated with researchers from the Massachusetts Institute of Technology (MIT), including Dr Rafael Jaimes III and Dr Phillip Tomezsko.
The team used advanced AI-based protein folding technologies and physics-driven simulations of antibody-viral protein interactions, producing rapid and reliable results to guide policymakers in pandemic preparedness.
The researchers concluded, “The worsening trend in antibody binding affinity is a real cause for concern,” warning that “H5 strains have the potential to move from epidemic to pandemic status in the near future.”
In another development, the United Kingdom recently reported the first case of H5N1 infection in a sheep in Yorkshire during precautionary testing at a farm where avian influenza had previously been found among birds. The infected animal was culled, and no further cases were detected. UK authorities emphasised that the risk to public health and livestock remained low, and strict biosecurity measures were enforced to prevent disease spread.
Avian influenza is already considered a pandemic among wild and domestic animals due to its wide geographical and species spread. The virus’s continued movement from wild birds to poultry, cattle, and now to farmworkers highlights its ability to cross species barriers.
The computational modeling results from the UNC Charlotte team indicate that “this alarming trend is a real cause for concern for human health,” affirming that high-performance computing has become an essential tool for supporting outbreak prediction efforts and strengthening global preparedness.
References:
- Ford, C. T., White, R. A., Janies, D., et al. (2024). Large-scale Computational Modelling of H5 Influenza Variants against HA1-Neutralising Antibodies. UNC Charlotte, CIPHER [Preprint].
- Centers for Disease Control and Prevention (CDC). (2025). Avian Influenza Outbreaks in the United States, 2022–2025. Available online: https://www.cdc.gov/flu/avianflu/
- Science Magazine. (December 2024). H5N1: Still a Leading Pandemic Threat. Available online: https://www.science.org/
