Virus World

A third person in the US has tested positive for H5 bird flu in connection to an ongoing outbreak in dairy cattle, the Michigan Department of Health and Human Services said Thursday. This is the second human case reported in the state and the fourth ever in the US. This time, in addition to some of the eye symptoms seen with previous H5N1 cases, the farmworker reported a cough and other respiratory symptoms that are more typical of human influenza infections, the health department said. “This individual had respiratory symptoms, including a cough, congestion, sore throat and watery eyes,” Dr. Nirav Shah, the principal deputy director of the US Centers for Disease Control and Prevention, said at a briefing Thursday. “What the respiratory symptoms tell us, more than anything, is that this virus, like many viruses, can present in more than one way, and for that reason, we should remain alert, not be alarmed,” he added.

Experts said that the addition of respiratory symptoms doesn’t necessarily indicate that the virus has become more dangerous or that it may transmit more easily from person to person. Instead, they say, the person probably developed lung symptoms because of the route of infection, perhaps by breathing in infectious aerosols in the milking parlor instead of rubbing their eyes with contaminated hands. “With the first case in Michigan, eye symptoms occurred after a direct splash of infected milk to the eye. With this case, respiratory symptoms occurred after direct exposure to an infected cow,” Dr. Natasha Bagdasarian, chief medical executive for Michigan, said in a news release. “Neither individual was wearing full personal protective equipment (PPE). This tells us that direct exposure to infected livestock poses a risk to humans, and that PPE is an important toolin preventing spread among individuals who work on dairy and poultry farms. We have not seen signs of sustained human-to-human transmission, and the current health risk to the general public remains low.”....

CDC Statement (May 30, 2024):

https://www.cdc.gov/media/releases/2024/p0530-h5-human-case-michigan.html 

How easy is it to switch from seasonal to pandemic flu vaccine production? Does a bird flu vaccine for cows make sense? The answers are complicated. 

If the H5N1 bird flu virus ever acquires the ability to transmit easily to and among people — keep your fingers crossed that it doesn’t — the world is going to need serious amounts of vaccine. Like, lakes of the stuff. Some manufacturers have been working with H5N1 viruses for years, producing small batches of doses that have undergone preliminary human testing. Some millions of doses — in the low double digits — have even been stockpiled by the U.S. government. But deciding when to start producing H5 vaccine at scale, in the quantities needed to vaccinate the world, is no easy feat. It’s a high-cost, high-risk endeavor. Get it right and you save lives. Hesitate, and lives will be lost. But making the call if the vaccine turns out not to be needed is not a cost-free decision either. There are some obvious questions that come to mind when you start thinking about what might trigger mass production of H5N1 vaccine. Here are a few, and some things to think about to help make sense of a truly complicated situation.

Given the concern about H5N1 in dairy cattle, why not just start making H5N1 vax now, in case we need it?

The global capacity to make flu vaccine is in the range of about 1.2 billion trivalent (three components in one) doses of vaccine a year, according to a market assessment the World Health Organization published in January. Most of the year, that production capacity is in use doing what it was built to do, making seasonal flu vaccine for the Northern and Southern hemisphere flu seasons. In the weeks between those two runs, plant maintenance is typically done. In a flu pandemic, the output of all those production lines would shift to making pandemic vaccine to protect against the new strain of flu that would likely be triggering large waves of illness worldwide. Here’s the thing. The production lines can make seasonal flu vaccine. Or they can make pandemic flu vaccine. They cannot make both at the same time. That’s why deciding to make pandemic flu vaccine at scale is not a no-cost decision. “You can’t just press the button and begin producing pandemic H5 vaccines. You have to stop producing your seasonal vaccine, and all of you out there know how lifesaving that vaccine is,” Mike Ryan, head of the WHO’s health emergencies program, told reporters at a press conference earlier this month. “So, this requires a very careful consideration.” When decisions like these have to be made, it’s not clear how things are going to play out. A new virus might cause a devastating pandemic. Or, as was the case in the 2009 H1N1 pandemic, it might trigger an event that is so mild that politicians will later question whether an emergency response was needed. (In a recent interview, Tom Frieden, who was director of the Centers for Disease Control and Prevention during the H1N1 pandemic, called it “a pimple of a pandemic.”)

In 2009, the world didn’t really have to make a tough decision about whether to stop seasonal flu vaccine production, said Marie-Paule Kieny, who was WHO’s assistant director-general for health systems and innovation at the time. (Kieny has since retired from the global health agency.) That’s because production of the seasonal vaccine for the 2009-2010 Northern Hemisphere winter was almost completed when it became clear the new virus had triggered a pandemic. But another time, a decision might have to be taken to abort the seasonal flu vaccine effort to switch to pandemic vaccine — a decision that would be costly for producers. In most cases, manufacturers only get paid for vaccines they deliver, and if they have to junk a run of seasonal flu vaccine because the client decides it wants pandemic, not seasonal flu vaccine, they have to absorb those costs, said Paula Barbosa, associate director for vaccine policy for the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA). Sure, they’d probably end up selling all the pandemic vaccine doses they could make, as quickly as they could make them. But the costs associated with the abandoned run would eat into those profits. “Individual companies might have specific agreements with certain countries, but overall, what is lost, it’s on the manufacturers,” Barbosa said. There can be opportunity costs as well. At a point during the Covid-19 pandemic, when global vaccine production was operating at full steam, there was a global shortage of glass for vaccine vials. Everything used in vaccine production — the eggs viruses are grown in for most of the traditional flu vaccine manufacturing, the equipment needed to administer vaccines — would likely be in short supply in a serious pandemic. Using any of this stuff to make or administer seasonal vaccine when pandemic vaccine is needed would be a wasted opportunity.

“You have to be totally conscious that, especially when you get to a global scale, it’s syringes, it’s needles, vials. It’s the capacity to fill and finish the vaccine. We don’t have that at global scale and most of it, like the antigen, or much of it is concentrated in better-off countries. So yeah, there is a huge supply chain and logistics challenge if we have a global pandemic,” said Jesse Goodman, who was director of the Food and Drug Administration’s Center for Biologics Evaluation and Research during the 2009 pandemic. Goodman is now director of the Center on Medical Product Access, Safety and Stewardship at Georgetown University. Barbosa pointed out another cost of switching into pandemic vaccine production mode. Big manufacturers, like Sanofi and CSL Seqirus, run their flu vaccine production facilities year round, serving clients in both hemispheres. But some smaller companies that make flu vaccine for local markets make it half the year and produce pediatric vaccines the rest of the time. Switching to pandemic flu vaccine production could mean essential childhood vaccines aren’t available for some period of time, Barbosa said. “We really need a process to altogether take that decision and then for there to be a full understanding of what are the consequences, not only for manufacturers, but for worldwide vaccine production,” she said.

Is there a process? Is it clear how a decision to make H5N1 vaccine will be made?

“Nothing is clear,” said Kieny. After the 2009 pandemic, the WHO held a series of three meetings with industry, regulators, and national authorities to try to figure out whether a framework for making a switch from seasonal to pandemic production could be devised. Industry very much wanted to know they would be issued marching orders. They still do. “Manufacturers themselves cannot be responsible for this decision,” Barbosa said. “Right now there is no formal process to tell all manufacturers to switch from seasonal vaccine production to pandemic production. Industry does need a clear signal to do that switch even fully or partially,” she said. “WHO declaring a pandemic is helpful. But it might not be enough. For instance, if it’s a pandemic, and the pandemic virus causes milder disease … there may not be a need to manufacture a pandemic vaccine at all.” The WHO-led consultations, which were held from 2013 through 2017, did not result in a firm plan for how to do this. It wasn’t clear that anyone wanted to own this decision-making responsibility, Kieny said — “at least until the situation gets really bad.” Gary Grohmann, who used to be the head of immunobiology for Australia’s Therapeutic Goods Administration — its FDA-equivalent — was involved in those meetings. He suggested individual countries will give manufacturers they purchase from directions, based on the best advice available from their public health agencies, and from the WHO. When it perceives there is a need, the latter will make a recommendation that pandemic flu vaccine production begin, Grohmann said.

“That will be only a recommendation. And it would be up to the individual countries to make the decision and then ask their manufacturers … to make their vaccines and to stop production, possibly, of other vaccines,” he said. Major manufacturers, though, sell to multiple clients. What if the country in which the plant is housed wants to start pandemic vaccine production, but another important client wants to proceed with seasonal production, in case the pandemic doesn’t take off? Kieny believes some big national governments may get the ball rolling when they decide it’s time to buy pandemic vaccine. “It depends when the big customers, and especially the U.S., will say, ‘We think that it’s worth putting the money on the table.’ Then everyone will rush and do the same,” she said. “It’s not a question of a switch. It’s a question of a decision. And it’s a financial decision to invest.”

That could be particularly true in the wake of the Covid pandemic, when messenger RNA vaccines made their global debut, especially if a flu pandemic were to happen in the near term. A number of the mRNA manufacturers, Pfizer and Moderna among them, have been working on, but have not yet licensed, seasonal flu vaccines. Without a seasonal product line to disrupt, it would be easier for those players to make pandemic vaccine — should they choose to enter the market. But there would need to be the promise of sales. “For vaccine lines that aren’t used for flu now, the decision isn’t to switch, it’s whether to invest and when to start producing,” Kieny said. Wenqing Zhang, head of the WHO’s global influenza program, said after its 2017 consultation with stakeholders, the WHO revisited the whole question of how pandemic influenza vaccine production would be triggered, eventually coming up with a document called the Pandemic Influenza Vaccine Response-Operational Framework. The document, finalized in 2022, has not been published, she said, because some items in it touch on issues that are up for negotiation in the ongoing efforts to update the International Health Regulations. Zhang said the document, which is not available online, acknowledges that manufacturers would need a signal from the WHO that a pandemic may be underway. But the WHO declaration would be about the risk that the virus poses, she said. Whether the document will be published as is or will require revisions will depend on the outcome of the IHR negotiations. So watch this space.

Flu vaccine manufacturers just took a component out of the seasonal vaccine, the influenza B/Yamagata virus that disappeared during the Covid-19 pandemic. Why not use that space in the seasonal shot to start protecting people against H5N1?

Goodman actually advocates something similar: He’d like to see H5N1 vaccine made in a monovalent shot — in other words, not combined with vaccines targeting seasonal flu viruses — that people could opt to get if they wanted to start protecting themselves against this virus. He proposed it in an article in Clinical Infectious Diseases in 2016. Rather than stockpile vaccine against H5, stockpile immunity in people, he argues. “Even if this particular threat” — the H5N1 outbreak in cows — “doesn’t turn into a pandemic, I do think it should give further impetus to really thinking about doing that,” he told STAT. But the idea of bundling H5N1 vaccine into the seasonal flu shot would cause regulatory challenges. The virus is not very immunogenic, meaning it doesn’t trigger a strong immune response in people. Research done nearly 20 years agoshowed that in order to achieve what would probably be a protective response, the vaccine would need to be given in two massive doses; later research showed two regular sized doses with an adjuvant, a compound that boosts the immune response a vaccine generates, would likely provide protection. Most seasonal flu shots do not contain an adjuvant — the sole exception is a vaccine for seniors sold by Seqirus, which contains the company’s MF-59 adjuvant. Adding an adjuvant to the seasonal shots would change the vaccines enough that new licenses might be needed — a big lift for manufacturers. In addition, studies would be needed to make sure that the H5N1 component did not erode the immune response to the other components of the vaccines. Zhang said that before H5N1 or another potential pandemic vaccine could be used in this way there would need to be more research. There’s no data, she noted, on what happens after repeated vaccination against H5N1. And it’s not clear when would be the best time to give it, because immunity induced by vaccination will wane over time. “All these, I think, are research questions that need to be addressed,” she said.

If vaccinating people is such a tough call to make, why not just vaccinate the cows?

This may turn out to be something that happens, but it’s still very early days. Some makers of animal vaccines are reportedly working on developing H5N1 vaccines for cows. But there are still a lot of questions that need answering before farmers are likely to embrace this approach, said Meghan Davis, a dairy and mixed animal veterinarian who does “One Health” research in Johns Hopkins University’s department of environmental health and engineering and school of medicine. (One Health is a term that refers to the intersection of human and animal health.)

“I think we do not have enough information right now to address the really pragmatic questions that dairy producers are going to have, if they’re going to spend money for this,” Davis told STAT. Farmers will want to know who is going to pay for a vaccine that they may be mainly using to lower the risk that H5N1 will spill over from cows to people. Though animal vaccines can be much less expensive than the human equivalents, the price of the serum itself is not the only cost of an immunization program. If a vaccine has to be administered by a veterinarian, that adds to the cost. If it has to be given more than once, the cost goes up. Will all cows need it, or could you target only lactating cattle? How long will the immunity the vaccine induces last? “Without the answers to those questions, you really can’t think about your cost benefit at all,” she said.

But Davis said farmers may see advantages of vaccination. The impact of H5N1 in cows is still coming into view because farmers have been pretty close-mouthed about what they are experiencing when the virus moves into a herd. However, word is starting to emerge that some of the affected cows do not return to pre-infection milk production levels, that when they recover from the infection some experience a “deficit,” Davis said. “Now you’ve got a cow who’s not going to produce as much as she would have produced at that point in her lactation.” In such cases, farmers may decide to send cows like these to slaughter earlier than otherwise would have been the case, getting fewer years of production out of these animals. If a vaccine prevented infection and protected against a drop in production, that might change the economics of the approach, she said. Another issue related to vaccination of animals against H5N1 relates to international trade. Though the World Organization for Animal Health — the animal equivalent of the World Health Organization — recommends against it, some countries restrict imports of poultry that have been vaccinated against avian influenza strains, because testing can’t easily differentiate between antibodies that are the result of previous infection or vaccination. Davis said this may be less of an issue for dairy cattle, as milk sales are more local and regional than international, but she noted it might be an issue for cheeses.

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....

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...

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.

Available in bioRxiv (May 22, 2024):

https://doi.org/10.1101/2024.05.22.595317 

The infection was detected in a farm worker who had been exposed to cows infected with the H5N1 virus, Michigan health officials said. A second human case of bird flu infection linked to the current H5N1 outbreak in dairy cows has been detected, in a farm worker who had exposure to infected cows, Michigan state health authorities announced on Wednesday. In a statement, health officials said the individual had mild symptoms and has recovered. Evidence to date suggests this is a sporadic infection, with no signs of ongoing spread, the statement said....

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.”