Preprint: Emergence and Interstate Spread of HPAI A(H5N1) in Dairy Cattle - New Preprint 5/22 Spillover & Interspecies Transmission

[Michael Coston]

Preprint: Emergence and Interstate Spread of HPAI A(H5N1) in Dairy Cattle

#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 cattle

Thao-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.​

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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.

https://afludiary.blogspot.com/2024/05/preprint-emergence-and-interstate.html
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[Michael Coston]

Preprint: Spillover of HPAI H5N1 Virus to Dairy Cattle Led to Efficient Intra - and Interspecies Transmission




USDA - 9 States Reporting 58 Infected Herds

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The above map is thought to under-represent the spread, and prevalence of HPAI H5N1 in dairy cattle, as many farmers, and some states, have been reluctant to aggressively test and report cases. Nor does this map indicate how many other animals (cats, raccoons, skunks, etc.) may have been infected by exposure to cattle or cattle products.

Similarly, we've seen a reluctance to actively test and report symptomatic human infections, which suggests the number of spillovers into humans may be higher than reported as well.​

This newfound ability to infect, and efficiently spread between cattle has been attributed to a reassortment event - likely occurring sometime last year in an unknown host - where a novel genotype (B3.13) was generated, and began spreading in birds.




Nearly every `great leap forward' by HPAI H5 over the past 20+ years has been preceded by either a reassortment event - or the emergence of a new clade (see EID Journal: HPAI H5N8 In Migratory Birds - Qinghai Lake, 2016).

With so much diversity among H5 viruses circulating in the wild, these events are becoming more frequent.​

Genotype B3.13 is the most recent reassortant to raise concerns, but it is unlikely to be the last. While evolution is rarely linear, B3.13 may become a stepping stone to H5's next `big evolutionary leap'.

Only time will tell.​

Today we've a preprint from researchers at Cornell, Texas A&M, and the USDA which attempts to document and quantify just how big of a leap H5N1 has made as it has spread through American cattle. And as they say in their wrap-up, it is unprecedented.

Given its size (43 page-PDF), and technical nature, I've only posted some excerpts. Follow the link to read the preprint in its entirety.​

I'll return with a brief postscript after the break.

From birds to mammals: spillover of highly pathogenic avian influenza H5N1 virus to dairy cattle led to efficient intra- and interspecies transmission
Leonardo C Caserta, Elisha A. Frye, Salman L. Butt, Melissa A Laverack, Mohammed Nooruzzaman, Lina M. Covalenda, Alexis Thompson, Melanie Prarat Koscielny, Brittany Cronk, Ashley Johnson, Katie Kleinhenz, Erin E Edwards, Gabriel Gomez, Gavin R. Hitchener, Mathias Martins, Darrell R. Kapczynski, David L. Suarez, Ellen Ruth Alexander Morris, Terry Hensley, John S. Beeby, Manigandan Lejeune, Amy Swinford, Francois Elvinger, Kiril M Dimitrov,Diego G. Diel
doi: https://doi.org/10.1101/2024.05.22.595317

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Abstract

Infections with the highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b virus have resulted in the death of millions of domestic birds and thousands of wild birds in the U.S. since January, 2022. Throughout this outbreak, spillovers of the virus to mammals have been frequently documented.​

Here, we report the detection of HPAI H5N1 virus in dairy cattle herds across several states in the U.S. The affected cows displayed clinical signs encompassing decreased feed intake, altered fecal consistency, respiratory distress, and decreased milk production with abnormal milk. Infectious virus and RNA were consistently detected in milk collected from affected cows. Viral staining in tissues revealed a distinct tropism of the virus for the epithelial cells lining the alveoli of the mammary gland in cows.​

Analysis of whole genome sequences obtained from dairy cows, birds, domestic cats, and a racoon from affected farms indicated multidirectional interspecies transmissions.​

Epidemiologic and genomic data revealed efficient cow-to-cow transmission after healthy cows from an affected farm were transported to a premise in a different state. These results demonstrate the transmission of HPAI H5N1 clade 2.3.4.4b virus at a non-traditional interface and to a new and highly relevant livestock species, underscoring the ability of the virus to cross species barriers.​

(SNIP)

Figure 6. Model of spillover and spread of HPAI H5N1 genotype B3.13 into dairy cattle. A reassortment event in an unknown host species led to the emergence of H5N1 genotype B3.13 which circulated in wild birds and mammals before infecting dairy cattle. Following spillover of H5N1 into dairy cattle, the virus was able to establish infection and efficiently transmit from cow-to-cow (intraspecies transmission) and from cow to other species, including wild (great tailed grackles) and peridomestic birds (pigeons) and mammals (cats and raccoons) (interspecies transmission). Spread of the virus between farms occurred by the movement of cattle between farms, and likely by movement wild birds and fomites including personnel, shared farm equipment and trucks (feed, milk and/or animal trucks).​

(SNIP)​

The ability of HPAI H5N1 clade 2.3.4.4b to cross species barriers has been evident and spillover into mammalian species has been reported throughout the current global outbreak 23,43. Prior to the detection in cattle, however, most mammalian species were considered dead-end hosts,given that virus tropism for the central nervous system commonly resulted in fatal encephalitis 44,45.

Our epidemiological investigation combined with genome sequence - and geographical dispersal analysis provides evidence of efficient intra- and inter-species transmission of HPAI H5N1 genotype B3.13. Soon after apparently healthy lactating cattle were moved from Farm 1 to Farm 3, resident animals in Farm 3 developed clinical signs compatible with HPAI H5N1 providing evidence to suggest that non-clinical animals can spread the virus.​

Analysis of the genetic relationship between the viruses detected in Farms 1 and 3, combined with phylogeographical modeling indicate that the viruses infecting cattle in these farms are closely related, supporting the direct epidemiological link and indicating long-range viral dispersal and efficient cattle-to-cattle transmission.​

The results from the phylogenomic and phylogeographical analyses in both sites of Farm 2 and on Farms 5, 6 and 7 also indicate regional long-range farm-to-farm spread of the virus.In these cases, fomites such as shared farm equipment, vehicles, or personnel may have played a role in virus spread.​

The dispersal of virus between Farms 5, 7 and 9 could have been vectored by wild birds; as suggested by the fact that blackbirds found dead near Farm 7 were infected with a virus closely related to the virus circulating in cattle in these farms. Alternatively, the birds at these premises could have been infected with virus shed by cattle.​

Our phylogenomic analysis in affected cats (Farms 1, 2, 4, and 5) and the raccoon (Farm 8) combined with epidemiological information revealing the practice of feeding raw milk to cats in these farms indicate cattle-to-cat and cattle398 to-raccoon transmission. These observations indicate that complex pathways underlie the introduction and spread of HPAI H5N1 in dairy farms (Fig. 6), highlighting the need for efficient biosecurity practices and surveillance efforts in affected and non-affected farms.​

The spillover of HPAI H5N1 into dairy cattle and evidence for efficient mammal-to mammal transmission are unprecedented.​

This newly acquired viral property is concerning as it can lead to adaptation of the virus which may further enhance virus infectivity and transmissibility in other species, including humans. Therefore, it is imperative that robust and continuous surveillance and research efforts be established to monitor the circulation, spread, and adaptation of the HPAI H5N1 virus in this new host species.​

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While there are no guarantees that H5N1 (regardless of genotype) will spark the next pandemic - or if it happened, how bad it would be - the evidence before us is increasingly hard to ignore.

• The H5N1 virus of today is a far cry from the HPAI H5 virus of even 4 years ago, having now spread across 90% of the globe, conquering both North and South America.

• During this time H5N1 has diversified into more than 100 distinct genotypes, with some displaying a predilection for spilling over into a wide range of mammals.

• While the known cases in the U.S. have been mild (so far), this virus has a history of producing severe, and often fatal illness. In recent years it has also become more neurotropic, further increasing the threat (see Cell: The Neuropathogenesis of HPAI H5Nx Viruses in Mammalian Species Including Humans).

Given the unpredictability of influenza - and the plethora of other threats out there - I might not bet good money on H5N1 sparking the next pandemic.


But I wouldn't bet against it, either.



https://afludiary.blogspot.com/2024/05/preprint-spillover-of-hpai-h5n1-virus.html
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