Flu Virus binding to Receptor Cells – Credit CDC
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As humans, we like to believe that tomorrow will be pretty much like today, or the day before (aka the `Normalcy Bias '). We tend to discount bad things happening in the future in favor of enjoying more immediate rewards.
In the 5 years prior to the emergence of COVID, the world was warned repeatedly about our continued lack of preparedness for a severe pandemic. While I could cite dozens of examples, a few include:So we put on blinders, or simply procrastinate, thinking we have plenty of time to prepare for future threats.
- In 2015, we looked at an 84-page Bipartisan Report of The Blue Ribbon Study Panel On Biodefense that looked at our nation’s vulnerability to the triple threat of a biological attack, an accidental release, or naturally occurring pandemic with a highly pathogenic biological agent.
- Their conclusion? We weren't anywhere near ready.
- in 2017, in World Bank: World Ill-Prepared For A Pandemic, we looked at a 131-page working paper from The World Bank, that warned that far too many nations have let pandemic preparedness slide, and that the world remains unprepared to face even a moderately severe pandemic.
- Johns Hoplins held two major table-top exercies involving coronaviruses: 2018's day-long CLADE X pandemic tabletop exercise and 2019's JHCHS Pandemic Table Top Exercise (EVENT 201).
- In August of 2019, in WHO: Survey Of Pandemic Preparedness In Member States, we saw the dismal results of a two-year survey of global pandemic preparedness.
- only just over half (n=104, or 54%) of member states responded. And of those, just 92 stated they had a national pandemic plan. Nearly half (48%) of those plans were created prior to the 2009 pandemic, and have not been updated since.
While governments, agencies, and health organizations all promised remedial action - when COVID finally emerged in January of 2020 - it was obvious that far too little had been done to prepare.
Today we find ourselves watching another virus (HPAI H5Nx) which circulates in many genetically distinct forms (subclades, subtypes, genotypes, variants, etc.) around the globe; one that has the potential of being even more impactful than SARS-CoV-2.
While we see new warnings almost daily from scientists (see here, here, here, here, . . . ad nauseum), few appear to be listening (see Two Surveys (UK & U.S.) Illustrating The Public's Lack of Concern Over Avian Flu).
Today we've yet another cautionary report - this time from the University of North Carolina - which argues that contemporary clade 2.3.4.4b H5N1 viruses have undergone a functional shift - from being primarily avian-adapted - to actively evolving in mammalian hosts as well.
They cite both explosive spread and changing seasonality since H5's arrival in late 2021, and the emergence of two mammalian-linked linages:
- B3.13 in cattle (with spillovers into humans, cats, and other mammals)
- and D1.x in wild birds, and poultry (with spillover into humans)
Add in PB2 mutations (E249K/G/D/V, E627K/V, I463M/V, V344M, A588T/V) which are associated with mammalian adaptation, and scattered reports of antiviral resistance (see Emerg. Microbes & Inf: Oseltamivir Resistant H5N1 (Genotype D1.1) found On 8 Canadian Poultry Farms), and you have a worrisome trend.
The following report is both lenghty and at times technical. It is computational analysis based on existing data, which - as we know - hasn't always been robust or released in a timely fashion.
Despite its limitations, it paints a picture of a family of viruses that are actively evolving towards becoming a greater mammalian threat.
I've only posted the abstract and a couple of excerpts. Follow the link to read it in its entirety. I'll have a brief postscript after you return.
H5N1 Influenza A is now promiscuous in host range and has improved replication in mammals
Sayal Guirales-Medrano, Kary Ocaña, Khaled Obeid, Rachel Alexander, Colby T Ford, Daniel Janies
doi: https://doi.org/10.1101/2025.03.15.641219
This article is a preprint and has not been certified by peer review
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Abstract
Influenza A virus has been circulating in birds from Eurasia for more than 146 years, but human infection has been sporadic. H5N1 (clade 2.3.4.4b) has recently infected hundreds of species of wild and domestic birds and mammals in North America. Infections include 70 people with two fatalities. We have developed an analytical bioinformatics, genomics, and structural workflow to understand better how H5N1 is circulating in North America and adapting to new host species.Our time-series analysis reveals that the circulation of H5N1 (clade 2.3.4.4b) in North America follows a distinct annual pattern, with cases in the United States consistently peaking each December. Separate from this seasonal cycle, our analysis also documents an increase in the total number of cases reported since 2021.We also show that H5N1 (clade 2.3.4.4b) spreads in North America as two distinct subclades of interest for human and animal health. These viral lineages have achieved a vast host range by efficiently binding the viral surface protein Hemagglutinin to both mammalian and avian cell surface receptors.This novel promiscuity of host range is concomitant with the additional strengthening of the Polymerase basic 2 viral proteins' binding for mammalian and avian immune proteins. Once bound, the immune proteins will have diminished ability to fight the virus, thus allowing for more efficient replication of H5N1 in mammalian and avian cells than seen in the recent past.Finally, structural docking analyses predict that while most current antivirals remain effective, a fatal human isolate showed significantly reduced binding to multiple drugs from different classes.In conclusion, the H5N1 virus is causing an animal pandemic through promiscuity of host rage and strengthening ability to evade the innate immune systems of both mammalian and avian cells.
(SNIP)
ConclusionOur results indicate that HA has achieved broad receptor-binding capability on both avian and mammalian cells, Moreover, we find that PB2 is undergoing adaptive changes that enhance innate immune evasion and replication in avian and mammalian hosts. This showcases the importance of monitoring both HA and PB2 in emerging influenza strains to assess their potential for human adaptation.
Our antiviral selection findings provide a mixed but largely reassuring picture regarding the potential for antiviral resistance in circulating H5N1 strains. While the virus continues to evolve in other regions of the proteins that are the main targets for current antivirals, our analysis did not identify positive selection at the primary amino acid sites known to be associated with resistance to the most widely used influenza antivirals.
Future research integrating structural modeling with functional assays will be crucial for validating these computational predictions and improving our understanding of influenza A H5N1 host adaptation mechanisms and potential therapeutics (14).
Limitations
This study has limitations inherent to its computational nature. Our findings on binding affinity and selection are predictive and require empirical validation through in-vitro and in-vivo experiments. Furthermore, while we analyzed two key genes, HA and PB2, viral adaptation is a complex process involving the entire genome.
Nevertheless, the workflow we have established—moving from large-scale phylogenetics to targeted structural biology—is a powerful tool for modern molecular disease surveillance. As sequence data becomes available, this approach can be rapidly deployed to assess new viral variants, providing early warnings and guiding public health responses before a crisis escalates.
None of this tells us how close H5Nx is to becoming a pandemic threat, of course. There may even still be some species barriers that prevents that, although many seem to be falling by the wayside.
But the many flavors of HPAI H5 make up just a small fraction of the viruses, bacteria, fungi, and parasites that have pandemic potential (see 2024 WHO Pathogens Priortization Report).
The question isn't whether HPAI H5 will spark the next pandemic, or when that might happen. Neither are knowable. But we do know that pandemics are inevitable, and appear to be occuring more frequently.
The only question worth asking is: when the next one arrives, will be ready?
Or will we sleepwalk into the next global health crisis as unprepared as we did with the last one.
