#18,036
As we have discussed repeatedly over the years, the superpower of influenza viruses is its ability to reinvent itself via reassortment; the swapping of genetic material between two influenza viruses co-infecting a single host.
Since HPAI H5N1 arrived in North America in late 2021, it has reassorted repeatedly with other avian viruses which are native to this part of the world. As a result, instead of having one H5N1 virus to contend with, we have scores of genotypes circulating in the wild.
Each genotype can have different capabilities, with some being more pathogenic in birds, while others may be more transmissible to mammals. Each genotype, however, is on its own, distinct evolutionary path.
Some will thrive, while others may fail. And every once in a while, one comes along that does something completely unexpected.
Up until six weeks ago, cattle were thought unlikely hosts for influenza A infection. While cattle had been experimentally infected with H5N1 more than 15 years ago and a few studies had hinted at prior influenza outbreaks in cattle (see A Brief History Of Influenza A In Cattle/Ruminants), no one expected to see a multi-state outbreak of H5N1 in cattle.
But the emergence of a new genotype - B3.13 - changed all that. Demonstrating that HPAI H5 still has a few tricks to show us.
According to the following report, this virus likely spilled over into cattle in late 2023, and circulated for 4 months before it was detected in March of this year.
During that time, it spilled back into wild birds, poultry, cats, other peridomestic mammals, and at least 1 human.
Today we've a detailed preprint from U.S. Government researchers and from several Universities that describes the emergence, spread, and potential threat from this new genotype. Due to its length I've only posted some excerpts, so follow the link to read it in its entirety.
I'll have a brief postscript after the break.
Emergence and interstate spread of highly pathogenic avian influenza A(H5N1) in dairy cattleThao-Quyen Nguyen, Carl Hutter, Alexey Markin, Megan N Thomas, Kristina Lantz, Mary Lea Killian, Garrett M Janzen, Sriram Vijendran, Sanket Wagle, Blake Inderski, Drew R Magstadt, Ganwu Li, Diego G Diel, Elisha Anne Frye, Kiril M Dimitrov, Amy K Swinford, Alexis C Thompson, Kevin R Snevik, David L Suarez, Erica Spackman, Steven M Lakin, Sara C Ahola, Kammy R Johnson, Amy L Baker, Suelee Robbe-Austerman,Mia Kim Torchetti, Tavis K Anderson
doi: https://doi.org/10.1101/2024.05.01.591751
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Abstract
Highly pathogenic avian influenza (HPAI) viruses cross species barriers and have the potential to cause pandemics. In North America, HPAI A(H5N1) viruses related to the goose/Guangdong 2.3.4.4b hemagglutinin phylogenetic clade have infected wild birds, poultry, and mammals.Our genomic analysis and epidemiological investigation showed that a reassortment event in wild bird populations preceded a single wild bird-to-cattle transmission episode. The movement of asymptomatic cattle has likely played a role in the spread of HPAI within the United States dairy herd.Some molecular markers in virus populations were detected at low frequency that may lead to changes in transmission efficiency and phenotype after evolution in dairy cattle. Continued transmission of H5N1 HPAI within dairy cattle increases the risk for infection and subsequent spread of the virus to human populations.
(SNIP)
Our Bayesian discrete state analysis (Fig. 3) that quantified the movement of HPAIV between six different host categories (poultry, wild bird, cattle, wild mammal, domestic cat, and 20 humans) demonstrated sufficient evidence to support the proposition of HPAI in cattle resulted in infections in other hosts.
We cannot exclude the possibility that this genotype is circulating in unsampled locations and hosts as the existing analysis suggests that data are missing and undersurveillance may obscure transmission inferred using phylogenetic methods (31).
The gap in data is highlighted by the human infection with genotype B3.13 HPAIV where the HA gene sequence was not nested within cattle HA gene 25 sequences. This could indicate that HPAIV in unsampled cows were the source of infection or within-host evolution resulted in divergence sufficient to result in a different phylogenetic grouping.
It is most likely, however, that asymptomatic transmission and undersurveillance in epidemiologically important populations drove this pattern. Our analysis of transmission chains within the cattle B3.13 clade using a phylogenomic approach suggested unsampled transmission in late 2023 and early 2024 (Fig. S8), and the 30 TMRCA indicates there may have been 4 months of circulation prior to confirmation by USDA. However, given the decline in milk production in highly monitored dairy herds, it is unlikely that the spillover occurred significantly outside of the described TMRCA ranges.
Discussion
The potential for HPAI H5N1 to become endemic in cattle will shape the zoonotic risk of the B3.13 genotype. There may be low levels of immunity against H5N1 viruses (36-39) and the immunological landscape in the human population affects disease severity (40). Genetically similar viruses do have the potential to cross the species barrier as there has already been a clade 2.3.4.4b B3.13 virus infection in a person with conjunctivitis in March of 2024.
The existing prepandemic candidate vaccine viruses (CVV) do retain cross-reactivity with currently circulating clade 2.3.4.4b HPAI H5N1 (41). These CVVs are coordinated and shared among the WHO Global Influenza Surveillance and Response Network for use by academic, government, and industry partners for research and development (42).
However, recent viruses collected in the US had reduced reactivity with the A/Astrakhan/3212/2020 candidate vaccine virus and 15 based on these data and other genetic and epidemiologic measures, a new CVV for the clade 2.3.4.4b viruses was proposed (41).
The HPAI H5N1 genotype B3.13 viruses circulating in cattle represent a potential zoonotic threat based on the evidence we present for transmission in a mammalian host. Based upon current information, it appears that once infected, a cow may shed virus for 2-3 weeks.
We detected some amino acid mutations at sites associated with mammalian adaptation that had already become fixed in the virus population that likely reflect the ~4 months of evolution and limited local circulation in dairy cattle.
Notably, important low frequency sequence variants within cattle were also detected, even within the limited time following the first spillover. If these low-frequency variants become dominant, they may have phenotypes that increase the probability of interspecies transmission.
Further studies are needed to understand the pathobiology and evolution of the virus in dairy cattle. In addition, there is the potential for multiple animal species to be colocated on agricultural premises, each species may be infected with endemic IAV strains, and an IAV coinfection with HPAI could result in reassortment and the emergence of new strains that increase zoonotic risk (43, 44).
Monitoring of cattle for HPAI will inform epidemiological risk and provide an early warning 30 for whether this interspecies transmission event and dissemination of the viruses throughout the US dairy cattle herd represents a future threat to human health.
Even if cattle don't turn out to be the right jumping off point for HPAI to spill over into humans, it is another important - and unexpected - stepping stone for the virus.
From cattle, the virus could easily continue to take a more circuitous route, passing through dogs and cats, or other peridomestic mammals, where it can pick up additional mammalian adaptations.
Obviously, the growing diversity of HPAI H5 viruses doesn't guarantee we'll see a more humanized virus, but it certainly increases the chances.
