#17,419
As we watch avian H5N1 spread globally, and increasingly spill over into mammals (see Chile: SERNSPESCA Reports > 4,300 Marine Animal Deaths), the overriding question is whether (and how) the virus could mutate enough to pose a genuine pandemic threat.
While the media loves their `Bird Flu Just 4 Mutations Away' stories, no one really knows exactly what combination genetic changes it would take for H5N1 to begin spreading efficiently in humans.
Granted, there are some `mammalian adaptations' we know to look for (e.g. E627K, D701N, Q591K, etc.) but there may be many others we are simply not aware of. Meaning there are likely multiple `solutions' available to the virus, depending on the evolutionary path it takes (see graphic above).
While H5N1 might get there via a combination of host adaptations and antigenic drift, influenza's super power is its ability reassort - to create a hybrid virus - out of two or more existing viruses. This is how most pandemic viruses are thought to emerge (see 3 min. NIAID Video: How Influenza Pandemics Occur).
Reassortment can involve multiple gene segments, and can result in new genotypes, or occasionally new subtypes. We've seen reports of literally dozens of new H5N1 genotypes emerging the past two years, some of which appear to be more virulent, and potentially more transmissible, than others.
All of which brings us to a preprint, published today, from researchers at the Public Health Agency of Canada, The Canadian Food Inspection Agency, and several other Canadian research entities, that finds this growing diversity among H5N1 viruses has already yielded at least one variant that appears to be both transmissible and lethal in ferrets.
Due to its length, I've only posted the link, abstract, and a couple of excerpts from the main body of the report. You'll want to follow the link to read it in its entirety.
I'll return with a postscript after the break.
Transmission of lethal H5N1 clade 2.3.4.4b avian influenza in ferrets
Darwyn Kobasa, Bryce Warner, Tamiru Alkie, Robert Vendramelli, and 10 more
This is a preprint; it has not been peer reviewed by a journal.
https://doi.org/10.21203/rs.3.rs-2842567/v1
This work is licensed under a CC BY 4.0 License
Abstract
Highly pathogenic avian influenza viruses of the H5N1 subtype are highly lethal in many avian species. Since 2014, viruses of the genetically distinct clade 2.3.4.4 have been circulating in Eurasia, Africa and briefly in North America, killing millions of wild and domestic birds. In December, 2021 clade 2.3.4.4b H5N1 viruses were first isolated from poultry and wild birds in Canada. Further spread of H5N1 viruses has since led to infection in many terrestrial and aquatic mammalian species.Some of the H5N1 viruses isolated from mammals have acquired adaptations previously shown to increase viral replication in mammals as well as novel patterns of reassortment of internal gene segments with North American (NA) lineage influenza A viruses (IAVs). While there have been few human cases of infection with clade 2.3.4.4b viruses reported to date, the potential for spillover, particularly of viruses harboring mammalian adaptation signatures remains a critical concern.Here we show that multiple naturally circulating reassortant H5N1 viruses can replicate in primary human airway epithelial cells and cause lethal disease in multiple mammalian species.One isolate, A/Red Tailed Hawk/ON/FAV-0473-4/2022, efficiently transmitted by direct contact between ferrets, resulting in lethal outcomes. Historically, H5 subtype viruses do not transmit effectively between mammals, and recent studies of currently circulating H5N1 viruses showed mild infection outcome in ferrets without detectable transmission.While known specific mutations within the Eurasian lineage H5Nx viruses have allowed for increased viral fitness in mammals, reassortment of H5N1 viruses with NA lineage avian IAVs may be unpredictably (unexpectedly) contributing to further enhancements in virulence and transmissibility in mammals, with potential increased risk to humans.Our research has determined that certain, as yet uncharacterized, genetic signatures may be important determinants of mammalian adaptation and pathogenicity of these viruses. Ongoing surveillance of circulating HPAI A(H5N1) viruses across species, including humans, should be a top priority so as to promptly identify viruses that may have pandemic or outbreak potential in mammals.
(SNIP)We isolated five distinct HPAI H5N1 viruses from infected wild animals in Canada, three from avian species and two from red foxes. Genetic characterization revealed they consisted of Eurasian Gs/Gd lineage HPAI H5N1 with some containing unique combinations of North American and Eurasian avian virus genes as well as lysine (K) or valine (V) residues at position 627 of PB2, a known adaptation for virulence in mammals 6,7.Four viruses tested in BALB/c mice, deer mice, and ferrets as models of mammalian infection exhibited differential virulence. In addition to lethal disease following direct inoculation, infection of ferrets resulted in efficient contact (horizontal) transmission leading to lethal disease with one virus isolate with additional evidence of infection due to airborne transmission.
These results highlight the possibility for HPAI H5N1 viruses to acquire adaptations through sustained transmission chains in mammalian populations, with potential for further long-term mammalian adaptation.
(SNIP)Consistently in two independent ferret experiments, RT.Hawk/ON/22 showed efficient direct contact transmission. This led to death in three of those contact animals, and two others likely would have required euthanasia if the second experiment had been extended past day 8.To the best of our knowledge, the high degree of transmission seen is unique among H5N1 viruses in the ferret model and suggests that RT.Hawk/ON/22 may have certain adaptations that allow for a higher degree of replication, pathogenicity, and transmission. We also detected probable airborne transmission in our second experiment.(SNIP)
Conclusion
The contact and potential airborne transmission of RT.Hawk/ON/22 in the ferret model suggests potential for this virus to infect and transmit between mammals including humans. Furthermore, as RT.Hawk/ON/22 can readily infect human airway cells of the upper respiratory tract, and since there have been a small number of humans cases of H5N1 infection during the current outbreak, there is a need for awareness of the potential for spillover, particularly in highly exposed populations.
Because there is little to no H5-specific population-wide immunity, if an H5N1 isolate capable of sustained transmission made a species jump into humans, this would likely represent a destructive infection in immunologically naïve population. Current work is underway to identify key residues in viral proteins that confer the ability to replicate to high levels and transmit by both contact and airborne routes.
Outbreak and pandemic preparedness will rely on continuous surveillance of viruses that are circulating in wild and domestic animal populations, and continuous research will help to identify those with potential for spillover into mammals and humans. Furthermore, the development of H5-specific vaccines, and evaluation of efficacy of antivirals, should be an area of active research and development
While none of this means that H5N1 is ready for prime time, the enhanced ability of RT.Hawk/ON/22 to infect ferrets, to readily transmit (via the airborne route) to other ferrets - and to infect and replicate in human upper airway cells - suggests it is getting closer.
Whether it can fully adapt to humans is unknown (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?), but we can't assume it won't.
Remarkably, this study only tested 5 isolates collected from 1 country (Canada) and still found a viral `overachiever' among them. That suggests there may be others in the wild developing similar abilities around the world.
Although most will be lacking in some important trait, and will likely fade into obscurity, it only takes one to succeed to propel the world into a new crisis.
Which is why we need to be preparing for the next pandemic now, while there is still time.
