H5N1 influenza viral lineages beginning to evade human immunological defenses, UNC Charlotte research finds

New computational modeling of avian influenza variants’ immunoprotein interactions – developed by a research team at the University of North Carolina at Charlotte – reveals the H5N1 influenza virus is evolving to escape immunological defenses raised by previous infection or vaccination in mammals.

Published on March 17 in eBioMedicine, part of The Lancet, the team’s new research provides urgent findings as avian influenza poses an ongoing threat to global agricultural interests and raises increasing alarms for human health. 

Discovery of “an overall worsening in antibody affinity to more recent H5N1 isolates” indicates current and future H5N1 viral lineages pose a greater risk to human health – including the possibility of increased transmission in humans, researchers explain in their recent publication.

The lead author is Colby T. Ford, Ph.D., a visiting scholar in data science at UNC Charlotte’s Center for Computational Intelligence to Predict Health and Environmental Risks (CIPHER) and founder of Charlotte-based biotechnology consulting firm Tuple, LLC.

Crucially, Ford explains, this rapid adaptation means that “if one makes an H5N1 vaccine with a previous vaccine candidate virus, the vaccine will have less efficacy, based on our measurements of how much the virus has evolved in recent years” As such, the team’s research approach provides guidance for keeping pace with a rapidly adapting viral threat.

The team from UNC Charlotte’s Department of Bioinformatics and Genomics includes students Shirish Yasa, Khaled Obeid, and Sayal Guirales-Medrano, led by Bioinformatics Assistant Professor Richard Allen White III, Ph.D., and CIPHER Co-Director Daniel Janies, Ph.D. who is the Carol Grotnes Belk Distinguished Professor of Bioinformatics and Genomics. The UNC Charlotte team collaborated with researchers from the Massachusetts Institute of Technology: Rafael Jaimes III, Ph.D., and Phillip J. Tomezsko, Ph.D. 

H5N1 antigenic drift, binding affinity

By examining the virus’ rampant host-shifting and recent mutations comprehensively, researchers find “the continuous transmission of H5N1 from birds to mammals and the increase in strains with immuno-evasive HA in mammals sampled over time suggest that antigenic drift is a source of zoonotic risk.”

In the paper, “Large-scale computational modelling of H5 influenza variants against HA1-neutralising antibodies,” the UNC Charlotte research team shares their results from analysis of 1,804 viral protein-host antibody comparisons. The experiments consisted of current hemagglutinin domain 1 viral proteins computationally bound in physics models to neutralizing antibodies obtained from infected hosts and vaccine recipients from 1996 to 2018. 

Using high-performance computational modeling, CIPHER researchers documented “a trend of weakening binding affinity of a wide variety of existing antibodies, collected from vaccinated and or infected hosts, against H5 viral isolates over time.”

Due to the public health importance, the findings were available via preprint publication in July 2024 prior to successful peer review.   Due to the computational tools they had assembled during the SARS-CoV-2 pandemic, the team was able to complete this work on H5N1 just three months after the first reported cow-to-human transmission of H5N1, which was reported in a farmworker in Texas.  

In assessing the possible pandemic risk spurred by H5 bird flu spread and mutation, global researchers agree that “the avian virus (remains) high on lists of potential pandemic agents,” as reported in Science in December 2024.

As of this writing, no human-to-human transmission has been reported. However, cattle in at least 17 states have tested positive for H5N1 in addition to millions of cases among wild birds, small mammals, commercial chickens, and other flocks. Between January 2022 and March 2025, the Centers for Disease Control reported:

• 12,510 outbreaks among wild birds in the U.S.
• 51 jurisdictions with bird flu among wild birds.
• 166,417,923 poultry affected
• 70 human cases of H5N1, one fatal, in the U.S.

The H5N1 virus, according to the World Health Organization, has killed 466 people worldwide since January 2003.

Speed important to respond to fast-evolving viral threat

Vaccines, many experts say, will likely be a crucial tool in controlling a bird flu pandemic, as mutations of viral lineages adapt to new mammal hosts.

In eBioMedicine, the research team from Charlotte writes that their findings “indicate that the virus has potential to move from epidemic to pandemic status in the near future.”

The study – along with other research that confirms worsening antibody binding over time alongside increased avian-to-mammalian transmission – indicates “there is an impending danger to human health for highly pathogenic strains of H5 influenza that can infect avian and mammalian livestock and jump to humans.”

Avian Influenza can already be considered a pandemic among wild and domesticated animals due to the virus’ pervasive spread across geography and species. Likewise, the spread of H5N1 from wild birds to chickens, dairy cattle, and farm workers illustrates the opportunism of infections across species.

Now, UNC Charlotte’s computational modeling results “specifically assert that the worsening trend of the antibody performance along with the already present animal pandemic is a cause for concern for an eventual human pandemic.”

Further, the authors write that high-performance computing – which in this case included AI-based protein folding and physics-based simulations of viral protein-antibody interactions – provides rapid and reliable results to inform leaders in preparedness. 

Janies, in a recent interview, explained the utility of computational modeling as a means of understanding viral mutation as well as predictive thinking concerning how a virus is evolving. 

High-performance computational modeling, Janies said, is a pathway for “chipping away at multiple angles of biological variation at speed and scale” to “tune our intuition to the right approaches” for vaccine efficacy and infection control as viruses evolve.

The protein modeling research on H5N1 viral lineages conducted at UNC Charlotte was funded by an Ignite grant from the UNC Charlotte Division of Research. Research used genetic data and metadata from GISAID, the Global Initiative on Sharing All Influenza Data, and the United States National Institutes of Health’s GenBank.