Virus World

The avian influenza virus that has been infecting dairy cows and spreading alarm in the United States was expected to reach Germany this week. But that’s actually good news. A shipment of samples of the H5N1 virus from Cornell University virologist Diego Diel is destined for the Federal Research Institute for Animal Health in Riems, which has one of the rare high-security labs worldwide that are equipped to handle such dangerous pathogens in cattle and other large animals. There, veterinarian Martin Beer will use the samples to infect dairy cows, in search of a fuller picture of the threat the virus poses, to both cattle and people, than researchers have been able to glean from spotty data collected in the field. Six weeks into the outbreak that has spread to farms in nine U.S. states, the flow of data from those locations remains limited as public health officials sort out authorities and some farms resist oversight. “It’s incredibly difficult to get the right sample sets off the infected farms,” says Richard Webby, an avian influenza researcher at St. Jude Children’s Research Hospital. “It’s clearly a barrier to understanding what’s going on. … That’s why these experimental infections of cows are really going to be super informative.”

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.

Preprint in bioRxiv (May 01, 2024):

https://doi.org/10.1101/2024.05.01.591751 

Testing conducted by the FDA on pasteurized commercially purchased milk has found genetic evidence of the H5N1 bird flu virus, the agency confirmed Tuesday. But the testing, done by polymerase chain reaction, or PCR, cannot distinguish between live virus or fragments of viruses that could have been killed by the pasteurization process. The agency said it has been trying to see if it could grow virus from milk found to contain evidence of H5N1, which is the gold standard test to see if there is viable virus in a product. The lengthy statement the agency released does not explicitly say FDA laboratories were unable to find live virus in the milk samples, but it does state that its belief that commercial, pasteurized milk is safe to consume has not been altered by these findings. “To date, we have seen nothing that would change our assessment that the commercial milk supply is safe,” the statement said.

The document was long on assurances but short on details of what has been undertaken or found. It does not specify how many commercial samples were taken or in how many markets, nor does it indicate what percentage of the samples were PCR-positive for H5N1. The statement did not indicate if the testing suggested the amounts of viral genetic material in the milk were low or high. Furthermore, the statement did not reveal if the milk products were purchased in parts of the country where outbreaks have occurred, or in areas where cows haven’t been seen to have been infected. The FDA did say it is testing milk from infected animals, in the processing system, and from store shelves with the goal of producing a “large representative national sample” of the milk supply. Beyond assessing the safety of the supply, such a sample could enable the agency to construct a more robust picture of H5N1’s spread among dairy cows nationally. The agency emphasized that testing of commercially available milk is ongoing, and this includes efforts to discern any potential differences between different dairy products, such as cream and whole milk....

The bird flu virus spreading through dairy cattle in the United States may be expanding its reach via milking equipment, the people doing the milking, or both, U.S. Department of Agriculture (USDA) representatives reported today at an international, virtual meeting held to update the situation. The avian virus may not be spreading directly from cows breathing on cows, as some researchers have speculated, according to USDA scientists who took part in the meeting, organized jointly by the World Organisation for Animal Health and the United Nations’s Food and Agricultural Organization. “We haven’t seen any true indication that the cows are actively shedding virus and exposing it directly to other animals,” said USDA’s Mark Lyons, who directs ruminant health for the agency and presented some of its data. The finding might also point to ways to protect humans. So far one worker at a dairy farm with infected cattle was found to have the virus, but no other human cases have been confirmed.

USDA researchers tested milk, nasal swabs, and blood from cows at affected dairies and only found clear signals of the virus in the milk. “Right now, we don’t have evidence that the virus is actively replicating within the body of the cow other than the udder,” Suelee Robbe Austerman of USDA’s National Veterinary Services Laboratory told the gathering. The virus might be transmitted from cow to cow in milk droplets on dairy workers’ clothing or gloves, or in the suction cups attached to the udders for milking, Lyons said. (In a 30 March interview with Sciencenone, Thijs Kuiken, a leading avian influenza researcher at Erasmus Medical Center, had suggested the milking machines might be responsible because the components may not always be disinfected between cows.)

The influenza virus causing the outbreak, an H5N1 subtype that is known as clade 2.3.4.4b, has devastated wild birds and poultry around the world for more than 2 years, and researchers at first thought migratory birds were responsible for spreading it to all of the affected dairy farms. But USDA scientists now think the movement of cattle, which are frequently transported from the southern parts of the country to the Midwest and north in the spring, may also have played an important role. And they floated the possibility, without naming specific herds or locations, that all affected cows may trace back to a single farm. Since first revealing the infection of dairy cows with this bird flu virus on 25 March, USDA has confirmed it has spread to cattle in six states. And the agency has used the virus’ genetics to track its movements. The virus found on U.S. farms has a specific genetic signature, which led USDA to name it 3.13. “It’s not a common [strain], but it’s very much a descendant of the viruses that have been dominating the flyways in the Pacific and the central flyways in the United States,” Robbe Austerman said.

The USDA scientists reported that the agency’s analysis of the different viruses from the cows indicates they likely came from one source. Cows from infected farms in Texas appear to have moved the virus to farms in Idaho, Michigan, and Ohio. “The cow viruses so far have all been similar enough that it would be consistent with a single spillover event or a couple of very closely related spillover events,” Robbe Austerman said. “So far we don’t have any evidence that this is being introduced multiple times into the cows.” The virus in cows could spread to poultry, which has that industry on edge. USDA tightly regulates avian influenza virus strains that are deadly to poultry, requiring culling of entire flocks if one bird tests positive for this H5N1 or one of its relatives; to date, commercial and backyard poultry farms have had to cull 85 million birds because of this virus. But USDA is not calling for any such drastic measures with cow herds. In response to questions from Sciencenone, Ashley Peterson, who handles regulatory affairs for the National Chicken Council, said “out of an abundance of caution, we believe it is prudent to restrict the movement of cows from positive herds.” Although some researchers agree USDA should stop the transport of dairy cows, the agency has so far declined to take that disruptive action. “We heavily rely on the producers who have been isolating the animals within the dairy herds,” Lyons said. USDA also says it has no evidence of beef cattle becoming infected. USDA and the Food and Drug Administration have stressed that pasteurization kills viruses, so there is “no concern” about the safety of commercial milk. They do recommend people not consume raw milk or products made from it.

Sources tell Science none some dairy farms that were later shown to be infected first noticed dead cats as early as mid-February. The animals, which often drink spilled milk on farms, “were the canary in the mine,” one said. The cows’ milk was also unusually thick. Those signs, coupled with the discovery of dead birds on the farms, led to the testing of cow milk for the bird flu virus and the 25 March USDA announcement. Oddly, the dead birds on infected farms were not waterfowl, the migratory birds that typically spread the avian flu viruses to poultry, but “peridomestic” species such as grackles, blackbirds, and pigeons. One farm had the virus detected in poultry before it was found in its cows, and although Robbe Austerman said she hesitated to call it the “ancestral strain,” she noted that “all of the detection so far in cattle are clustered around that.” Further studies should clarify how the virus wound up in cows, which sometimes become infected with flu viruses but have never before been shown to have one that causes high mortality in birds. One possibility is that birds infected cows by shedding their droppings in the cows’ feed or water. But bird flu viruses in the past have also spread for many kilometers in the wind, moving from one poultry farm to another. So the current H5N1 strain could have moved from waterfowl to poultry to cattle—or directly from poultry to cattle and then even to the peridomestic birds. “This could be a multifactorial presentation that we’re seeing,” Lyons said. “Lots of questions still to be answered.”

The Idaho State Department of Agriculture announced that HPAI, known as highly pathogenic avian influenza, or bird flu, has been found in dairy cattle in Idaho.  This now brings the number of affected states to four, adding more evidence the virus may be spreading cow to cow. The cows were recently brought into the Cassia County dairy from another state that had found HPAI in dairy cattle, according to the ISDA. The USDA Animal and Plant Health Inspection Service (APHIS) announced that an investigation into mysterious illnesses in dairy cows in three states—Kansas, New Mexico, and Texas—was due to HPAI and that wild birds are the source of the virus.

Symptoms of HPAI in cattle include: 

• Drop in milk production 
• Loss of appetite 
• Changes in manure consistency 
• Thickened or colostrum-like milk 
• Low-grade fever 

At this stage, there is no concern about the safety of the commercial milk supply or that this circumstance poses a risk to consumer health. The pasteurization process of heating milk to a high temperature ensures milk and dairy products can be consumed safely. 

The ISDA encourages all dairy producers to closely monitor their herd and contact their local veterinarian immediately if cattle appear to show symptoms. HPAI is a mandatory reportable disease, and any Idaho veterinarians who suspect cases of HPAI in livestock should immediately report it to ISDA at 208-332-8540 or complete the HPAI Livestock Screen at agri.idaho.gov/main/animals/hpai/.  

APHIS (USDA) update on the dairy cattle bird flu outbreaks (March 29, 2024):

https://www.aphis.usda.gov/news/agency-announcements/usda-fda-cdc-share-update-hpai-detections-dairy-cattle 

An outbreak of H5N1 highly pathogenic influenza A virus (HPIAV) has been detected in dairy cows in the United States. Influenza A virus (IAV) is a negative-sense, single-stranded, RNA virus that has not previously been associated with widespread infection in cattle. As such, cattle are an extremely under-studied domestic IAV host species. IAV receptors on host cells are sialic acids (SAs) that are bound to galactose in either an α2,3 or α2,6 linkage. Human IAVs preferentially bind SA-α2,6 (human receptor), whereas avian IAVs have a preference for α2,3 (avian receptor). The avian receptor can further be divided into two receptors: IAVs isolated from chickens generally bind more tightly to SA-α2,3-Gal-β1,4 (chicken receptor), whereas IAVs isolated from duck to SA-α2,3-Gal-β1,3 (duck receptor).

We found all receptors were expressed, to a different degree, in the mammary gland, respiratory tract, and cerebrum of beef and/or dairy cattle. The duck and human IAV receptors were widely expressed in the bovine mammary gland, whereas the chicken receptor dominated the respiratory tract. In general, only a low expression of IAV receptors was observed in the neurons of the cerebrum. These results provide a mechanistic rationale for the high levels of H5N1 virus reported in infected bovine milk and show cattle have the potential to act as a mixing vessel for novel IAV generation.

Preprint in bioRxiv (May 3, 2024):

https://doi.org/10.1101/2024.05.03.592326 

We report highly pathogenic avian influenza A(H5N1) virus in dairy cattle and cats in Kansas and Texas, United States, which reflects the continued spread of clade 2.3.4.4b viruses that entered the country in late 2021. Infected cattle experienced nonspecific illness, reduced feed intake and rumination, and an abrupt drop in milk production, but fatal systemic influenza infection developed in domestic cats fed raw (unpasteurized) colostrum and milk from affected cows. Cow-to-cow transmission appears to have occurred because infections were observed in cattle on Michigan, Idaho, and Ohio farms where avian influenza virus–infected cows were transported. Although the US Food and Drug Administration has indicated the commercial milk supply remains safe, the detection of influenza virus in unpasteurized bovine milk is a concern because of potential cross-species transmission. Continued surveillance of highly pathogenic avian influenza viruses in domestic production animals is needed to prevent cross-species and mammal-to-mammal transmission.

Published in Emerging Infectious Diseases (April 20, 2024)

https://doi.org/10.3201/eid3007.240508 

Experts warn that lax regulations could also see the virus spread to US pig farms, with serious consequences for human health. Fears are growing that the H5N1 outbreak among cattle in the United States could have been caused by contaminated animal feed.  In contrast to Britain and Europe, American farmers are still allowed to feed cattle and other farm animals ground-up waste from other animals including birds. Dairy cows across six US states – and at least one farm worker – have become infected with the highly pathogenic virus, which has already killed millions of animals across the globe since 2021. The farm worker, who is thought to have been exposed via infected cattle in Texas, is only the second recorded human H5N1 case in the US. Since February, the US has investigated and discounted a further 8,000 possible exposures, according to Dr Joshua Mott, WHO senior advisor on influenza.  The development is of concern because it allows the virus, which has killed millions of birds and wild mammals around the world, more opportunities to mutate...

This is a technical summary of an analysis of the genomic sequences of viruses associated with an outbreak of highly pathogenic avian influenza (HPAI) A(H5N1) viruses in Texas. This analysis supports the conclusion that the overall risk to the general public associated with the ongoing HPAI A(H5N1) outbreak has not changed and remains low at this time. The genome of the virus identified from the patient in Texas is publicly posted in GISAID and has been submitted to GenBank.

April 2, 2024 – CDC has sequenced the influenza virus genome identified in a specimen collected from the patient in Texas who was confirmed to be infected with highly pathogenic avian influenza A(H5N1) [“HPAI A(H5N1)”] virus and compared these with HPAI A(H5N1) sequences from cattle, wild birds and poultry. The virus sequences are HA clade 2.3.4.4b HPAI A(H5N1) with each individual gene segment closely related to viruses detected in dairy cattle available from USDA testing in Texas. While minor changes were identified in the virus sequence from the patient specimen compared to the viral sequences from cattle, both cattle and human sequences maintain primarily avian genetic characteristics and for the most part lack changes that would make them better adapted to infect mammals.

The genome for the human isolate had one change (PB2 E627K) that is known to be associated with viral adaptation to mammalian hosts, and which has been detected before in people and other mammals infected with HPAI A(H5N1) virus and other avian influenza subtypes (e.g., H7N9), but with no evidence of onward spread among people. Viruses can undergo changes in a host as they replicate after infection. Further, there are no markers known to be associated with influenza antiviral resistance found in the virus sequences from the patient’s specimen and the virus is very closely related to two existing HPAI A(H5N1) candidate vaccine viruses that are already available to manufacturers, and which could be used to make vaccine if needed. Overall, the genetic analysis of HPAI A(H5N1) viruses in Texas supports CDC’s conclusion that the human health risk currently remains low. More details are available in this technical summary below...