#17,946
While we've been watching HPAI H5 for more than two decades, the biggest - and as yet, unanswered - question is: what it would take to change H5Nx from primarily an avian disease to a pandemic threat?
Some are comforted by the fact that after > 20 years, millions of rolls of the genetic dice, and roughly 1,000 confirmed human infections (combined H5N1,H5N8,H5N6), the virus has failed to get a foothold in humans.
But over the past 3 years we've seen HPAI H5 make huge gains both in terms of susceptible (avian and mammalian) hosts, and geographic expansion. Tens of thousands of marine mammals have died from the virus, along with (largely uncounted) numbers of terrestrial mammals.
As we discussed yesterday, in Pacific and Atlantic Sea Lion Mortality Caused by HPAI A(H5N1) in South America, while unproven, some scientists believe limited mammal-to-mammal transmission may be happening.
While there are limited opportunities for infected marine mammals to spread the virus to humans, we've known for years that pigs are somewhat susceptible to HPAI H5 infection (see 2018's Sci. Rpts.: Evidence Of H5N1 Exposure In Domestic Pigs - Nigeria), raising concerns they could become `mixing vessels' for the next pandemic virus.
The additional reports of transmission events to and potentially between mammals, e.g. mink, sea lion, seals, foxes and other carnivores as well as seroepidemiological evidence of transmission to wild boar and domestic pigs, associated with evolutionary processes including mammalian adaptation are of concern and need to be closely followed up.And last May, in Netherlands: Zoonoses Experts Council (DB-Z) Risk Assessment & Warning of Swine As `Mixing Vessels' For Avian Flu, we looked at similar concerns that avian H5Nx could increase its pandemic threat by spreading (and evolving) in farmed swine.
While we've seen scattered reports of H5N1 in swine (see here, here, and here), between extremely limited testing, and the fact that H5N1 tends to be asymptomatic (or mildly symptomatic) in pigs, it is probably more common than we realize.
Complicating matters, H5N1 is not a single virus, it encompasses a large (and growing) array of similar viruses, which have evolved into numerous clades and subclades, and literally scores of genotypes. Those (and other small) genetic variations can produce vastly different characteristics (see Differences In Virulence Between Closely Related H5N1 Strains).
In other words, if you randomly selected a handful of wild H5N1 viruses, you'd find some were more pathogenic, more transmissible, or better adapted to mammals than others.
In their December 2023 EFSA Avian flu report for Europe, European authorities reported eleven different genotypes, seven of which were new in the previous 3 months. This constant creation and swapping out of genotypes continues - with great variety - around the world.
All of which brings us to a new study, published yesterday in the CDC's EID Journal, which looks at the pathogenesis and transmissibility of 4 North American H5N1 viruses (2 with known mammalian adaptations) in swine.
Due to its length and technical nature, I've only posted the abstract and some excerpts. The takeaway is that swine were susceptible to all 4 viruses, but only those with a known mammalian adaptation (PB2 E627K), replicated efficiently in the nasal cavity, and was transmissible.
Follow the link to read the report in its entirety. I'll have a postscript after the break.
Divergent Pathogenesis and Transmission of Highly Pathogenic Avian Influenza A(H5N1) in Swine
Bailey Arruda, Amy L. Vincent Baker, Alexandra Buckley, Tavis K. Anderson, Mia Torchetti, Nichole Hines Bergeson, Mary Lea Killian, and Kristina Lantz
Abstract
Highly pathogenic avian influenza (HPAI) viruses have potential to cross species barriers and cause pandemics. Since 2022, HPAI A(H5N1) belonging to the goose/Guangdong 2.3.4.4b hemagglutinin phylogenetic clade have infected poultry, wild birds, and mammals across North America. Continued circulation in birds and infection of multiple mammalian species with strains possessing adaptation mutations increase the risk for infection and subsequent reassortment with influenza A viruses endemic in swine. We assessed the susceptibility of swine to avian and mammalian HPAI H5N1 clade 2.3.4.4b strains using a pathogenesis and transmission model.All strains replicated in the lung of pigs and caused lesions consistent with influenza A infection. However, viral replication in the nasal cavity and transmission was only observed with mammalian isolates. Mammalian adaptation and reassortment may increase the risk for incursion and transmission of HPAI viruses in feral, backyard, or commercial swine.
(SNIP)
If an avian IAV strain, such as H5Nx 2.3.4.4b, successfully infected domestic swine, pig-to-pig transmission, reassortment with endemic swine IAV, or acquisition of adaptive mutations that might enable an avian-to-mammalian switch could potentially occur (1). Continued circulation in the wild bird population and peridomestic wild mammal infections elevate the risk for exposure of swine because of the current outbreak’s wide distribution in states with large pig populations.
To address concerns over susceptibility of swine to HPAI H5N1 clade 2.3.4.4b virus detected in the United States and to elucidate potential molecular mutations associated with H5N1 replication and transmission in swine, we conducted a study with 4 strains representing 3 different genotypes in a pig pathogenesis and transmission model. This information is key to building awareness and detection capabilities in the swine sector, as well as to informing risk assessments and early warning systems to safeguard human health.
(SNIP)
DISCUSSION
We conducted a pathogenesis and transmission study to understand the susceptibility of swine to 3 genotypes of HPAI H5N1 belonging to the goose/Guangdong 2.3.4.4b HA phylogenetic clade detected within the United States. Our data demonstrated that pigs are susceptible to infection. All 4 HPAI isolates that were evaluated replicated in the lungs of pigs. In comparison to an H1N1 swine-adapted virus, the qRT-PCR Ct values in BALF of the 4 HPAI strains were lower (≈3–8 Ct), except for the A/bald eagle/FL/22 (genotype B1.1) 5 dpi group (Appendix 1 Table 3) (24).Replication in the nasal cavity and transmission occurred only in the A/raccoon/WA/22 (genotype B2.1) and A/redfox/MI/22 (genotype B3.2) groups containing the mammalian adaptation mutation E627K in the PB2 gene.
(SNIP)
Interspecies spillovers commonly result in dead-end infections because the virus likely requires multiple transmission events to acquire the necessary adaptive mutations (40). The probability of a virus acquiring a complete set of adaptive mutations in a single immunocompetent host with onward transmission is extremely low (34). However, continued circulation of HPAI strains that have already adapted within various mammalian species makes that possibility more likely (1,34).On-farm transmission among pigs in Indonesia of an HPAI H5N1 and identification of a purified clone with the ability to recognize α2,6 sialic acid receptors were reported (3). More recently, serologic evidence of infection of domestic pigs with clade 2.3.4.4b was reported (41). In addition, because reassortment occurred with the past 4 influenza pandemics, the propensity for reassortment in swine may increase the risk for H5N1 adaptation toward humans, particularly with the maintenance of 2009 pandemic H1N1 human seasonal virus genes in pigs (42). Although infrequent, incursion of LPAI into commercial swine herds in North America occurs periodically, yet the sources of incursion often remain unknown (43–45). Increased viral fitness characterized by transmission of LPAI strains after reassortment with swine-adapted IAV in pigs was demonstrated both in commercial swine herds and experimentally (43,46).
The genetic attributes that resulted in the continued circulation of the HPAI H5N1 2.3.4.4b lineage are not well understood. Repeated spillover and spillback events resulted in genotypically and phenotypically diverse reassortant viruses, some of which caused neurologic disease in mammals, a manifestation not observed in pigs (47). However, detection of NP antigen in endothelial cells of pigs infected with A/bald eagle/FL/22 suggests this strain might spread systemically.
The risk for reassortment of the HPAI H5N1 2.3.4.4b lineage with endemic swine IAV is a consideration on the basis of the susceptibility to this lineage demonstrated in our study, the prevalence of IAV infection and comorbidities in swine herds, and animal husbandry practices (48,49). However, the risk for incursion is likely lower in confinement operations with industry standard biosecurity than for backyard or feral pigs.
Birdproofing feed and facilities, avoiding the use of untreated water, and restricting peridomestic scavenger mammals from premises are measures to increase biosecurity against HPAI H5N1 clade 2.3.4.4b virus incursion into swine herds.
While swine - due to their susceptibility to influenza, huge numbers, and general lack of surveillance - are a legitimate concern, they aren't the only species where H5N1 might hit the genetic jackpot. Mink and fur farms have been hit hard by avian flu, and have produced worrisome mammalian adaptions as well.
Last summer, in PNAS: Mink Farming Poses Risks for Future Viral Pandemics, we looked at an excellent opinion piece penned by two well known virologists from the UK (Professor Wendy Barclay & Tom Peacock) on why fur farms - and mink farms in particular - are high risk venues for flu.
But H5N1 is just one of many novel flu viruses with zoonotic potential circulating in the wild. And all of them - to one degree or another - are going through similar evolutionary paths.
