eBioMedicine: Large-Scale Computational Modelling of H5 Influenza Variants Against HA1-Neutralising Antibodies

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While it is pretty easy to look back over the events of the past few years and say - with reasonable certainty - that the public health threat from HPAI H5 has increased, understanding why it has increased is a bit more challenging. 

Last August we looked at a preprint (see Preprint: Large-Scale Computational Modeling of H5 Influenza Variants Against HA1-Neutralizing Antibodies) from the University of North Carolina at Charlotte which attempted to answer that question using in silico analysis, which found more recent H5 isolates have mutated to better evade our existing antibody defenses. 

This week the full study has been peer-reviewed, accepted, and published in eBioMedicine, and while much of the study is highly technical, the bottom line is pretty easy to grasp; 

In recent years the H5N1 virus has evolved to better evade existing human immune defenses. This decline suggests an increased zoonotic risk and greater potential for human transmission. 

First, a few brief excerpts from the open access study (follow the link to read it in its entirety), after which I'll return with a brief postscript.

Large-scale computational modelling of H5 influenza variants against HA1-neutralising antibodies

Colby T. Forda,b,c,d ∙ Shirish Yasaa,b ∙ Khaled Obeida,b ∙ Rafael Jaimes, IIIe ∙ Phillip J. Tomezskoe ∙ Sayal Guirales-Medranoa,b∙ et al. Show more

Summary

Background

The United States Department of Agriculture has recently released reports that show samples collected from 2022 to 2025 of highly pathogenic avian influenza (H5N1) have been detected in mammals and birds. Up to February 2025, the United States Centres for Disease Control and Prevention reports that there have been 67 humans infected with H5N1 since 2024 with 1 death. The broader potential impact on human health remains unclear.

Methods

In this study, we computationally model 1804 protein complexes consisting of various H5 isolates from 1959 to 2024 against 11 haemagglutinin domain 1 (HA1)-neutralising antibodies. This was performed using AI-based protein folding and physics-based simulations of the antibody-antigen interactions. We analysed binding affinity changes over time and across various antibodies using multiple biochemical and biophysical binding metrics.

Findings

This study shows a trend of weakening binding affinity of existing antibodies against H5 isolates over time, indicating that the H5N1 virus is evolving immune escape from our therapeutic and immunological defences. We also found that based on the wide variety of host species and geographic locations in which H5N1 was observed to have been transmitted from birds to mammals, there is not a single central reservoir host species or location associated with H5N1's spread.

Interpretation

These results indicate that the virus has potential to move from epidemic to pandemic status. This study illustrates the value of high-performance computing to rapidly model protein–protein interactions and viral genomic sequence data at-scale for functional insights into medical preparedness.

Research in context

Evidence before this study

The United States Department of Agriculture has recently released reports that show samples collected from 2022 to 2025 of highly pathogenic avian influenza (H5N1) have been detected in mammals and birds.1 Up to February 2025, the United States Centres for Disease Control and Prevention reports that there have been 67 humans infected with H5N1 since 2024 with 1 death.2 The broader potential impact on human health remains unclear.

Previous studies have shown that cases of avian influenza transmissions to mammals are increasing in frequency, which is of concern to human health. Since 1997, nearly a thousand H5N1 cases have been reported in humans, with a 52% fatality rate. Previous analyses have indicated specific mutations in the haemagglutinin protein that allow for this “host jumping” between birds and mammals.3 There is also existing evidence of recent viral strains with reduced neutralisation by sera.4

Added value of this study

This study provides a comprehensive look at the mutational space of haemagglutinin of H5N1 influenza and presents computational predictions of the binding between various HA1-neutralising antibodies derived from infected vaccinated patients and humanised mice, and 1804 representative H5 HA1 proteins. These analyses show a weakening trend of existing antibodies. We also confirm that the mutations found in other studies that enable zoonosis also affect binding affinities of the antibodies tested.

Furthermore, through phylogenetic analyses, we quantify the avian-to-mammalian transmissions from 1959 to 2024 and show a persistent circulation of isolates between North America and Europe. Taken together, 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 spillover risk.

Implications of all the available evidence

Our findings indicate that the worsening in antibody binding, along with the increase in avian-to-mammalian H5N1 influenza transmissions, are risks to public health.

Through the findings of previous studies along with the predictions reported in this study, we can now monitor specific mutations of interest, quantified by their potential impact on antibody evasion, and inform public health monitoring of circulating isolates in 2024 and beyond. In addition, these findings may help to guide future vaccine and therapeutic development in the fight against H5N1 influenza infections in humans.

         (Continue . . . )

What started nearly 3 decades ago as an obscure, and geographically limited, viral infection in Chinese poultry has grown into a global threat, with billions of birds (both wild and captive) lost, hundreds of thousands of mammals killed, and almost certainly more than 1,000 humans infected. 

Over time, the virus became better adapted for carriage in wild and migratory birds (see DEFRA: The Unprecedented `Order Shift' In Wild Bird H5N1 Positives In Europe & The UK), which has facilitated its international spread.  

Starting in 2022, we began to see a huge shift in its impact on mammals (see 2022's PrePrint: HPAI H5N1 Infections in Wild Red Foxes Show Neurotropism and Adaptive Virus Mutations).  While cats and cattle have taken the brunt of the impact thus far, the virus continues to expand its host range. 

So far, we've been spared an H5 pandemic due to a nebulous, and poorly understood species barrier; one that keeps avian viruses from adapting well enough to humans to allow for efficient transmission.  

But HPAI H5 has both time, and growing genetic diversity, on its side.  Which means we shouldn't be too comforted by what it hasn't managed to do in the past.