Zoonotic Bird Flu News from 7 Feb till 8 Feb 2023

Tracking the bird flu, experts see a familiar threat — and a virus whose course is hard to predict [STAT, 8 Feb 2023]

By Helen Branswell

Veteran influenza epidemiologist Keiji Fukuda remembers vividly when he first became fearful that a virulent bird flu virus, H5N1, might be on the verge of triggering a devastating pandemic. The virus, seemingly out of nowhere, did something bird flu viruses were thought not to be able to do. It infected 18 people, killing six of them.

That happened in 1997, in Hong Kong.

A quarter century later, H5N1 has returned to the headlines, with an outbreak at a Spanish mink farm — reported in mid-January — triggering the latest round of fears that the virus might be inching closer to acquiring the ability to easily transmit among humans.

The mink outbreak is concerning, there is no doubt about that. Minks are closely related to ferrets, the animals most often used as a proxy for people when scientists study the characteristics of flu viruses.

But it’s important to remember that we’ve been somewhere like this before with this virus. Not precisely this spot — H5N1 has a much larger geographic footprint now and it’s been found to infect many more species of mammals. But there have been periods, some spanning years, when H5N1 was wreaking havoc, doing things that until that point had been thought to be out of reach for bird flu viruses, raising global concerns a pandemic might be right around the corner. And then, unexpectedly, it quieted down for a while.

So while scientists who have been studying it for a couple of decades have a very healthy respect for H5N1, a number with whom STAT spoke are hedging their bets about the path H5 may be on.

“I still think that this thing is as unpredictable as it has ever been,” said Ron Fouchier, a virologist at Erasmus Medical Center in Rotterdam who moved into the field of influenza research, at Erasmus, because of the 1997 H5N1 outbreak. Scientists there, along with a colleague from Hong Kong, were the first to report that the virus was a bird flu virus.

“Trying to predict what H5N1 will do in the human population absolutely requires a great deal of scientific humility,” cautioned Michael Osterholm, director of the University of Minnesota’s Center for Infectious Disease Research and Policy.

“I will never, ever, take H5N1 for granted,” he said.“I just don’t know what it’s going to do.”

Fukuda, who in 1997 was an influenza scientist with the Centers for Disease Control and Prevention, was sent to Hong Kong by the agency to help in the investigation of that first outbreak.

“Everything was really new and the sense of things back then was that we were deeply, deeply afraid that this was the beginning of the next pandemic, of a really severe pandemic,” said Fukuda, who later went to the World Health Organization, where he served for a time as an assistant director-general. He retired from Hong Kong University at the end of 2021.

How does he feel about the latest act in the multi-act play that is H5N1’s evolution, the spread into wild birds and poultry flocks throughout the Americas, and the lengthening list of mammalian species seen to have been infected with the virus? What does he think it portends?

Fukuda gives the auditory equivalent of a shrug. “Anyone who tries to predict anything about influenza is a bit foolish and hasn’t been in the field very long,” he said.

“I definitely have no idea what H5 is going to do, in 20 years whether we would have a similar discussion ‘Oh is it ever going to do anything?’ or if we’d be having a discussion saying ‘Oh, my God, couldn’t imagine that it was going to do that! That was really horrible,’” Fukuda said. “I think both of those discussions are plausible.”

STAT asked a number of experts, all of whom have been studying or following H5N1 for years, how they assess the current situation and how they’d describe their individual level of concern.

None of them ever stopped worrying about H5N1. None of them like what they’re seeing now. But most of them struggled to answer when asked if they are more worried now than earlier.

Like in 2004, when a cluster of cases in a Vietnamese family raised the specter of limited person-to-person spread. Or 2005, when what was by then a poultry virus moved back into wild birds, which spread it to North Africa, Turkey and Europe. Or in the mid-to-late teens, when Egypt recorded more than 250 human cases in unsettling succession, 93 of them fatal.

Since the 1997 outbreak, about 870 confirmed human cases have been detected. Just over half of those people died from the infection.

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“I grapple with this a little bit myself,” said Richard Webby, an influenza virologist who heads the WHO Collaborating Center for Studies on the Ecology of Influenza in Animals at St. Jude Children’s Hospital in Memphis. “The way I look at the current situation, I don’t think the virus itself is necessarily any more worrying than what we’ve been seeing for the past 20-plus years.

But what worries me right now is that this is a change in the epidemiology and the ecology of the disease. So we’re absolutely seeing more chances of people coming in contact with this virus.”

Fouchier agreed.

“For me, that risk hasn’t changed. In ’97 there was a pandemic threat. And that pandemic threat has continued to exist, and we cannot really quantify the threat because we still don’t really understand what it takes,” said Fouchier, who in 2011 showed that with some mutations, H5N1 viruses could gain the capacity to transmit easily among ferrets.

Yoshihiro Kawaoka, a virologist at the University of Wisconsin-Madison, did similar work and got the same result. Both scientists had to fight to publish their studies, because of concerns the so-called gain of function work could provide a dangerous how-to guide for bad actors.

(The debate this work sparked continues to this day, and it constrains — with good reason, critics say — the research that can be done to delve into what is keeping H5 from becoming a human flu virus.)

Malik Peiris, a professor of virology at Hong Kong University, does not view the mink farm outbreak in Spain as H5N1’s third act. “I mean to me it’s just one big act,” he said.

The outbreak, which occurred in October, saw H5N1 viruses move about a large mink farm in Galicia, in the northwest of Spain, sickening and killing a number of the animals. Eventually all the remaining minks — there were nearly 52,000 animals before the outbreak began — were euthanized.

It is not clear how the virus entered the farm. But it seems possible, perhaps even probable, that at some point H5N1 spread from mink to mink. “Our findings also indicate that an onward transmission of the virus to other minks may have taken place in the affected farm,” the scientists who reported the event wrote in the journal Eurosurveillance. “This is suggested by the increasing number of infected animals identified after the confirmation of the disease and the progression of the infection from the initially affected area to the entire holding.”

The mere idea of mink-to-mink transmission gives flu researchers pause. If a virus can transmit from one mammal to another, what’s to stop it from transmitting between other mammalian species — like ours?

The U.S. Department of Agriculture alone reports 110 reports of mammalian infections with H5N1 in 2022-2023 — multiple types of bears, foxes, skunks, possums, racoons, even seals.

It’s hard, though, to assess the significance of these infections in mammals. For starters, the virus has long had the capacity to infect mammals. Tigers and snow leopards in a zoo in Thailand died in late 2003 after being fed poultry infected with H5. Over the years infections in domestic cats and dogs, stone martens, and civet cats have been detected.

“We have been there. But we also shouldn’t be lulled into complacency when there are new facts,” said Kanta Subbarao, director of the WHO’s Collaborating Centre for Reference and Research on Influenza in Melbourne, Australia. Subbarao, who in 1997 was at the CDC, was the lead author on the first scientific publication characterizing the H5N1 virus.

Related: Experimental flu vaccine, developed using mRNA, seen as potential game changer
She said it’s not clear if the virus is entrenched in some animal populations — which she said would “escalate our problems quite significantly” — or if there is just so much virus in wild bird populations at this point that carnivores are becoming infected because they happen upon and eat infected birds.

Even with the mink farm, one cannot say with certainty whether there was ongoing transmission or if the infected animals all had a common exposure, such as contaminated food — they were fed poultry byproducts — or contact with wild birds that could have moved about the netted cages the animals were housed in. Dead and sick birds infected with H5N1 were reported in the region in the weeks leading up to the outbreak.

Webby doesn’t like the sheer geographic spread of the virus and the increasing reports of spillover events — instances when the bird virus infects mammals — though he noted the viruses don’t appear to have changed in significant ways.

“If we look at the virus and the sequence of it, there’s nothing that suggests to us that it’s become more infectious. But of course we don’t know everything about that,” he said. “The virus may be the same, but there’s just a whole lot more of it out there.”

“So absolutely worried from this new development in the ecology, epidemiology,” Webby said. “But luckily nothing that’s associated with that from the virologic side that has me running for the hills yet.”

One thing that does mitigate some of the concern is the fact that in recent years, there have been few human infections with H5N1. Whereas at points in the first two decades of this century it wasn’t uncommon to have 20 or 30 cases a year, reports of human cases are rare these days, and often involve such mild disease it is not clear if the person who tested positive was infected or simply had viruses in their nostrils. A man in Colorado who was culling infected poultry last spring. Two poultry workers in Spain in November. A British man who had infected ducks in 2021. A recent H5 infection in a young girl reported from Ecuador is a rare severe case.

One school of thought is that the decline in human cases is due to genetic changes in the virus that took place a while back.

For years, the internal genes of H5N1 were unchanging. Their origin was another bird flu virus, H9N2. Many, even most, of the human infections with bird flu viruses were caused by viruses that had that combination of internal genes from H9N2, Fouchier said. The current version of H5N1, known by the unwieldy name 2.3.4.4b, acquired other internal genes through reassortment, a gene-swapping process that can occur when multiple viruses infect a single host. “If you like, the engine under the bonnet is different,” Peiris said.

Fouchier worries primarily at the moment about the virus’ impact on biodiversity. Some species of wild birds are being decimated by the virus. But he also believes countries should be dusting off their pandemic influenza plans.

“There will be a new pandemic for sure. Whether it is this one, I don’t know. But I think that the current situation is enough that countries actually [should] review their pandemic preparedness plans again,” Fouchier said.

None of the scientists quoted here would disagree. But Fukuda, and one of his former colleagues from the CDC, Tim Uyeki, think at this point the world would be better off focusing on spillover threats plural than one single type of bird flu.

“I think it’s a major problem for the agricultural industry. And certainly there is a public health threat, but right now, it’s probably low,” said Uyeki, the chief medical officer of CDC’s flu division. Uyeki joined the CDC the year after the 1997 outbreak, but was involved in the investigations of many of the outbreaks that happened from 2003 onward.

“This is not the only virus that we should be concerned about for pandemic preparedness,” he stressed. “There are many other avian influenza A viruses circulating in birds and poultry that have sporadically transmitted to people and have caused a wide range of illness, including severe lower respiratory tract infection and fatal outcomes. And for that matter, if we even step back further and take a really big picture perspective… wherever you go in the world if you sample pigs, you will find swine influenza viruses.”

Fukuda said it would be short-sighted to focus solely on H5 bird flu, suggesting the world needs to invest more in being ready to detect and mitigate outbreaks caused by the array of animal viruses that could jump from animals to people and start transmitting among us. He worries that the Covid-19 experience, rather than strengthening our response capacity, has eroded political support for this type of work. And Osterholm worries about what the Covid pandemic has done to public support for public health.

“If we did have another pandemic right now I think it would be very difficult to get the public to do anything to try to limit or control transmission. That is to me a big setback,” he said.

Fukuda concurred. “What has become clear to me over time is that the big challenge is not the viruses. That’s not what gives me a pit in my stomach,” he said. “The real challenge is whether people, whether governments, whether policymakers have the ability to actually address the challenge in the way that needs to be done. And I don’t see so much which encourages me, to be blunt. That’s what gives me a pit in my stomach.”

Be warned: the next deadly pandemic is not inevitable, but all the elements are in place [The Guardian, 8 Feb 2023]

By George Monbiot

If you wanted to kill as many people as possible, deniably and with no criminal consequences, what would you do? You’d do well to start with a bird flu. Bird flus are responsible for all the known flu pandemics: the great influenza that started more than a century ago, “Asian flu”, “Hong Kong flu” and “Russian flu”, which killed tens of millions between them. They also cause many of the annual outbreaks that slaughter hundreds of thousands of people.

Once you have found a suitable variant, two further components are required to weaponise it.

The first is an amplifier. The best amplifier is a giant shed or factory in which thousands of birds are packed. These birds should be genetically homogenous, so that your viral strain can travel freely between them. Intensive poultry farms would serve very well. Before long, a low-pathogenic strain should mutate in these circumstances into a highly pathogenic variety.

To ensure maximum transmission, you should move some of the birds around, faster than the flu’s incubation period. You might carry them across borders. Some would be shifted to free-range or hobby farms, to enhance the possibility of infecting wild birds.

But it’s difficult for a flu virus to travel directly from birds to humans, so another component is required: a mixing vessel. This is a species that can simultaneously harbour the newly pathogenic bird virus and a flu variety already adapted to humans. Then the viruses, conveniently brought together, can exchange genetic material – a process known as “reassortment”.

Pigs are reasonable mixing vessels. They might have played this role in some previous outbreaks and pandemics. But there’s a much better candidate: mink. Mink readily harbour human and avian flu viruses. As predators, they can easily acquire avian flu from the meat they eat. The distribution of sialic acid receptors – a key determinant of infection – in their respiratory tracts is similar to that of humans. Human flu strains can pass between them through aerosol transmission.

Mink also possess, to a remarkable degree, what scientists call “zoonotic potential”: in other words, they can be infected by, and infect, many different species. During the first phases of Covid-19, they proved to be highly effective intermediaries, partly because the virus seemingly evolves faster in mink than in humans. They appear to have generated at least two new variants that spread to humans, one in Spain and one in Italy. Mink are the only known species that both received Covid-19 from humans and passed it back to them.

To enhance their mixing ability, you would cram hundreds or thousands of the tiny cages housing them together, so that this usually solitary animal is forced into contact with others.

You would reduce genetic diversity by breeding only those with a particular fur type. In other words, you would do what mink farms do today. Then you would sit back and wait.

The next pandemic might not have been seeded by a murderous psychopath, but, unless we are lucky, the effect could be the same. H5N1 was a fairly harmless bird flu until a highly pathogenic variant was hatched in a Chinese goose farm in 1996. It is deadly to humans. On the rare occasions when people have contracted this variant, it has proved fatal more often than not: of 868 infected up to October last year, 457 have died. Though it has been devastating to both poultry flocks and wild birds, however, its transmissibility from birds to most mammals, and from person to person, is thankfully extremely low.

But mink farming offers the mixing vessel it needs. In 2021, a paper in the journal Emerging Microbes & Infections reported that about a third of the mink the researchers tested harboured both bird flu and human flu antibodies. It warned that this joint infection could generate novel viruses “with high human infectivity”. The public health threat “should not be ignored”, as it had “pandemic potential”. Needless to say, it was ignored.

A few days ago, the journal Eurosurveillance revealed the first known case of large-scale mammal-to-mammal transmission of the H5N1 flu virus. It happened, to no gasps of surprise, on a mink farm; in Galicia, northern Spain. While the mink were fed with poultry products, a practice scientists have long warned against, it seems that the likely cause of infection was contact with a sick wild bird that might have fallen against the bars of a cage, and was dragged through and eaten. Once inside its mixing vessel, the virus mutated to become transmissible to the other mink, then spread rapidly in this farm of more than 50,000 animals from cage to cage.

This epidemic was contained before it left the farm. All the mink were killed, and we might narrowly have missed a pandemic potentially more deadly than Covid-19. But farming mink for their fur, a cruel and pointless practice, continues in Europe, North America and China. There’s a high chance that the next pandemic, whatever it may be, will emerge in one of these places.

Because of both the abominable cruelty suffered by the animals and the grave threat it presents to human life, we need a global treaty to ban mink farming.

The H5N1 virus, having acquired its deadly mutations on a poultry farm, is now raging through wild bird populations with horrific consequences. It is killing so many that, in conjunction with other threats, it could drive some species towards extinction. In particular, it is shattering colonies of seabirds. As they reproduce late and slowly, they’re especially vulnerable to extinction. Wild birds could easily introduce the virus to another mink farm.

Bird flu is a huge problem now – but we’re just one mutation away from it getting much worse

This threat is bookended by grotesque cruelty: the poultry, mink and pig farms whose horrors we have somehow normalised and accepted. If you treated dogs or cats in the same way as we treat these animals, you would be sent to prison. But do it to farmed species on a large enough scale and you are treated with the special respect accorded to a “captain of industry”.

Governments will sweep the dust from your path. Newspapers will write panegyrics of the kind once accorded to emperors.

So who is the homicidal maniac in this story? It’s a scarcely examined abstraction we call “the economy”, a monster to whom anything and everything must be sacrificed without question or resistance: farmed animals, wild ones, even, unless we are fortunate, human beings in their millions. We will prevent the pandemics of the future only when we value life ahead of money.

Here's Why Experts Are Concerned About Bird Flu [Medpage Today, 8 Feb 2023]

by Kristina Fiore

— Mink paper sets off alarms about potential for viral recombination

What appears to be mammal-to-mammal transmission of highly pathogenic avian influenza (HPAI) A(H5N1) on a mink farm in Spain has caught the attention of infectious disease epidemiologists around the world.

A paper published in Eurosurveillance last monthopens in a new tab or window detailed an H5N1 outbreak among farmed minks in the Galicia region of Spain in October 2022.

Montserrat Agüero, of Spain's agricultural ministry, and colleagues suspected that transmission occurred between the animals based on "the increasing number of infected animals identified after the confirmation of the disease, and the progression of the infection from the initially affected area to the entire holding."

While none of the farm workers were infected, experts said these are the conditions that can ignite a deadly H5N1 pandemic in humans.

That paper has "sent up a yellow caution light" in the infectious disease public health community, said William Schaffner, MD, of Vanderbilt University Medical Center in Nashville, Tennessee, who is also a spokesperson for the Infectious Diseases Society of America.

"There was no evidence of infection among any of the mink caretakers, who had very sustained, close contact with those animals, so everybody took a deep breath," Schaffner said. "But nonetheless, everybody [in the infectious disease public health community] is a little bit anxious, and they are watching this."

There have been increasing global reports of other types of mammals picking up H5N1 -- including bears, foxes, skunks, and raccoonsopens in a new tab or window -- in what has become one of the largest and longest avian flu outbreaksopens in a new tab or window in history. Fortunately, there has so far been no evidence of mammal-to-mammal transmission in those populations.

But the mink example shows that's possible: It allows for the type of recombination of influenza viruses that could lead to a pandemic, Schaffner said.

On farms across the U.S., concern has mostly been about pigs being co-infected with human and avian influenza viruses, he noted.

"If the pig is simultaneously infected with human flu and bird flu, those viruses can exchange genetic material, and that would provide an opportunity for a bird flu virus, which hardly ever infects humans, to pick up the genetic capacity to readily spread among humans," he said.

Indeed, in the mink, Agüero and colleagues noted a novel mutation in the PB2 gene (T271A), which they say could have public health implications. That amino acid influences acquisition of another mutation that confers human receptor recognition, they wrote.

While this change could have arisen de novo in minks, they said, the "data available are not sufficient to exclude the possibility of an unobserved circulation of avian viruses bearing this substitution in the avian population."

Indeed, a December report from the U.K. Health Security Agencyopens in a new tab or window said the risk to human health of avian influenza currently stands at Level 3 out of 5: "Evidence of viral genomic changes that provide an advantage for mammalian infection."

Schaffner said global surveillance systems are homed in on detecting a "pandemic" influenza in its early stages. Such was the case for the most recent example of pandemic influenza, the 2009 H1N1 "swine flu" pandemic, he added.

The World Health Organization's Global Influenza Surveillance and Response System monitors influenza viruses globally, and the CDC serves as a "Collaborating Center" in this network. The U.S. Department of Agriculture's Animal and Plant Health Inspection Serviceopens in a new tab or window also surveils animals for the virus, including both farmed and wild birds.

Should a pandemic occur, H5N1 vaccines are available, Schaffner said, as the U.S. has built a stockpile of bird flu vaccines. If a new strain pops up, vaccine makers would have to modify the vaccine to attempt a better match, and ramp up manufacturing of new vaccines, he said.

However, mRNA vaccine technology could cut down that timeline, he added.

So far, this has been the deadliest avian flu outbreak on record, with almost 50 million wild and domestic birds killed or culled in the U.S. and another 50 million killed or culled in Europeopens in a new tab or window.

Only one person in the U.S. has become infected with H5N1 during this outbreak -- a patient in Colorado in April 2022opens in a new tab or window. CDC maintains a bird flu trackeropens in a new tab or window that reports data for wild birds, poultry, and humans.

The first time HPAI H5N1 was detected in North America was in 2014, and it caused widespread poultry outbreaks and deaths of wild birds in the U.S. and Canada before it disappeared in 2016, according to the CDCopens in a new tab or window. It first emerged in southern China and led to large poultry outbreaks in Hong Kong in 1997. It was controlled, but not eradicated, and re-emerged in 2003, spreading widely among birds throughout Asia and then later in Africa, Europe, and the Middle East.

Globally, there have been more than 860 human infections since 2003, with a substantial mortality rate of about 53%, the CDC reported.

While the risk to humans currently remains low -- the only impact at the moment appears to be higher egg prices, which are also driven by inflation overall -- Schaffner warned an influenza pandemic is something the U.S. should always be ready for.

"There will be another pandemic," he said. "I hope we've learned lessons from having gone through COVID, so that we can do better the next time around."

Correction: An earlier version of this story incorrectly reported New Mexico as the state in which one person was infected with H5N1.

Peru: Over five hundred sea lions, 55,000 pelicans, gulls and penguins die due to bird flu [WION, 8 Feb 2023]

By Manas Joshi

STORY HIGHLIGHTS
It is rare that bird flu jumps over into mammals -- and rarer still that humans catch the potentially deadly virus.

Peru on Tuesday (February 7) said that H5N1 bird flu virus has caused the death of 585 sea lions and 55,000 wild birds in recent weeks. This has been mentioned in the country's latest report on the disease's impact.

Following the discovery of 55,000 dead birds in eight protected coastal areas, rangers found the bird flu that killed them had also claimed 585 sea lions in seven protected marine areas, the Sernanp natural areas protection agency said.

The agency further said that the dead birds include pelicans, various types of gulls and penguins.

Presence of H5N1 in dead sea lions, confirmed by laboratory tests has led authorities to announce a "biological vigilance protocol."

For its part, Peru's National Forest and Wildlife Service (SERFOR) urged people and their pets to avoid contact with sea lions and sea birds on the beach.

The authorities in Peru culled 37,000 birds on a chicken farm over bird flu in December.

Killing infected birds is part of the usual protocol to control avian influenza outbreaks.

In November, the country declared a 180-day health alert after finding three cases of highly contagious H5N1 in pelicans.

According to the SENASA agricultural health agency, the disease is transmitted by migratory birds from North America.

Since late 2021 Europe has been gripped by its worst-ever outbreak of bird flu, while North and South America are also experiencing severe outbreaks.

It is rare that bird flu jumps over into mammals -- and rarer still that humans catch the potentially deadly virus.

Nearly 600 sea lions die due to bird flu outbreak in Peru [Hindustan Times, 8 Feb 2023]

In November, the country declared a 180-day health alert after finding three cases of highly contagious H5N1 in pelicans. According to the SENASA agricultural health agency, the disease is transmitted by migratory birds from North America.

Peru said Tuesday that 585 sea lions and 55,000 wild birds have died of the H5N1 bird flu virus in recent weeks, the latest report on the disease's impacts.

Following the discovery of 55,000 dead birds in eight protected coastal areas, rangers found the bird flu that killed them had also claimed 585 sea lions in seven protected marine areas, the Sernanp natural areas protection agency said.

The dead birds included pelicans, various types of gulls, and penguins, the Sernanp said in a statement.

Laboratory tests also confirmed the presence of H5N1 in the dead sea lions, prompting the authorities to announce a "biological vigilance protocol."

For its part, Peru's National Forest and Wildlife Service (SERFOR) urged people and their pets to avoid contact with sea lions and sea birds on the beach.

In December, Peruvian authorities culled 37,000 birds on a chicken farm over bird flu, following previous outbreaks that affected wildlife.

Killing infected birds is part of the usual protocol to control avian influenza outbreaks.

In November, the country declared a 180-day health alert after finding three cases of highly contagious H5N1 in pelicans.

According to the SENASA agricultural health agency, the disease is transmitted by migratory birds from North America.

Since late 2021 Europe has been gripped by its worst-ever outbreak of bird flu, while North and South America are also experiencing severe outbreaks.

It is rare that bird flu jumps over into mammals -- and rarer still that humans catch the potentially deadly virus.

But the virus has recently been found in foxes and otters in Britain, a cat in France, and grizzly bears in Montana. All the mammals were suspected to have eaten infected birds.

Peru reports hundreds of sea lion deaths due to bird flu [Phys.org, 8 Feb 2023]

Peru said Tuesday that 585 sea lions and 55,000 wild birds have died of the H5N1 bird flu virus in recent weeks, the latest report on the disease's impacts.

Following the discovery of 55,000 dead birds in eight protected coastal areas, rangers found the bird flu that killed them had also claimed 585 sea lions in seven protected marine areas, the Sernanp natural areas protection agency said.

The dead birds included pelicans, various types of gulls, and penguins, the Sernanp said in a statement.

Laboratory tests also confirmed the presence of H5N1 in the dead sea lions, prompting the authorities to announce a "biological vigilance protocol."

For its part, Peru's National Forest and Wildlife Service (SERFOR) urged people and their pets to avoid contact with sea lions and sea birds on the beach.

In December, Peruvian authorities culled 37,000 birds on a chicken farm over bird flu, following previous outbreaks that affected wildlife.

Killing infected birds is part of the usual protocol to control avian influenza outbreaks.

In November, the country declared a 180-day health alert after finding three cases of highly contagious H5N1 in pelicans.

According to the SENASA agricultural health agency, the disease is transmitted by migratory birds from North America.

Since late 2021 Europe has been gripped by its worst-ever outbreak of bird flu, while North and South America are also experiencing severe outbreaks.

It is rare that bird flu jumps over into mammals—and rarer still that humans catch the potentially deadly virus.

But the virus has recently been found in foxes and otters in Britain, a cat in France, and grizzly bears in Montana. All the mammals were suspected to have eaten infected birds.

Study characterizes mutations in neuraminidase of human-like H5N1 influenza viruses [News-Medical.Net, 7 Feb 2023]

By Dr. Sanchari Sinha Dutta

A study published in PLOS PATHOGENS describes the prevalence and functions of mutations in neuraminidase enzyme of avian H5N1 influenza viruses that are preferentially selected in human H5N1 influenza viruses.

Background
Influenza A viruses are negative-sense RNA viruses that infect a wide-range of species, including birds and humans. The classification of these viruses depends on the variations in surface glycoproteins hemagglutinin and neuraminidase.

Some strains of zoonotic influenza viruses are capable of infecting and replicating in humans, causing mild to fatal diseases. Most human influenza viruses carry genetic sequences from avian influenza viruses that encode hemagglutinin, neuraminidase, and polymerase basic-1.

Genetic mutations in these viral proteins are responsible for bird-to-human transmission of avian influenza viruses.

In the current study, scientists have characterized the mutations in viral neuraminidase that facilitate zoonotic transmission of influenza viruses. They have analyzed all neuraminidase sequences of H5N1 influenza viruses of human- and bird-origin from Eurasia and Africa to identify the causative mutations.

Furthermore, they have characterized the functions of identified mutations by infecting chickens, mice, and ferrets with several recombinant viruses carrying these mutations.

Important observations
The analysis of neuraminidase genetic sequences identified A46D, L204M, S319F, and S430G mutations that act synergistically to improve H5N1 viral fitness and adaptability in humans. The scientists determined the functions of these mutations in both in vitroand in vivo (chickens, mice, and ferrets) setups.

The analysis of neuraminidase activity revealed that human-like H5N1 viruses have significantly lower activity compared to bird-like H5N1 viruses. Such reduced activity might be needed to maintain an optimal receptor binding/destroying balance. Moreover, low activity might be required for the selection and adaptation of avian influenza viruses in humans.

Specifically, it was observed in the study that the reduced neuraminidase activity of human H5N1 viruses is due to potential conformational changes in the enzyme, as well as due to a low amount of enzyme incorporation into viral particles.

Regarding the incorporation of neuraminidase into viral particles, the study found that the level of RNA replication and transcription of human-like neuraminidase is lower than that of bird-like neuraminidase. The findings of co-transfection experiments revealed that the abundance of bird-like neuraminidase favors its selection over homologous human-like neuraminidase. This explains the relatively lower incorporation of human-like neuraminidase into viral particles.

Regarding receptor binding activity of neuraminidase, the study found that the S430G mutation is primarily responsible for increasing the binding affinity of human-like neuraminidase for human-like receptors.

The head domain of neuraminidase has sialidase activity, which helps cleave sialic acid (SA) to release progeny viral particles in the respiratory tract for systemic viral transmission. The analysis of human-type 2,6-SA receptors and bird-type 2,3-SA receptors revealed that mutated human-like neuraminidase removes 2,3-SA during viral entry, leading to a reduction in bird-type receptors. This might reduce the adherence of hemagglutinin of progeny viral particles to 2,3-SA during viral release.

As speculated by the scientists, the abundance of 2,6-SA during viral release might act as the main driver for the adaptation of hemagglutinin and neuraminidase of avian influenza viruses to human-type receptors.

The findings of the mutational analysis revealed that all identified mutations in human-like neuraminidase act synergistically to increase viral replication in the human airway epithelium.

These mutations also conferred moderate virulence and longer survival of H5N1 avian influenza virus in mice and ferrets, while not affecting the high virulence of the virus in chickens.

Study significance
The study identifies four mutations in neuraminidase of human-like H5N1 influenza viruses that act synergistically to increase viral replication and induce moderate virulence in mammals, while maintaining high virulence in birds.

Collectively, these mutations reduce neuraminidase activity, expression, and incorporation in viral particles and increase the binding affinity of H5N1 viruses to human-like receptors.
As mentioned by the scientists, these findings are vital to understand the genetic changes that improve the fitness of avian influenza viruses in humans. The scientists highlight the requirement of continuous genomic surveillance to monitor avian virus replication in mammals.

This is particularly needed for the early detection of emerging viruses that have the potential to induce a pandemic condition.

Journal reference:
• Scheibner D. (2023). Phenotypic effects of mutations observed in the neuraminidase of human origin H5N1 influenza A viruses. PLOS PATHOGENS. doi: https://doi.org/10.1371/journal.ppat.1011135 https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011135

Could bird flu in mink signal threat of a human pandemic? [DW (English), 7 Feb 2023]

By Jeannette Cwienk

A bird flu outbreak on a Spanish mink farm has alarmed scientists. The virus may be spreading for the first time from mammal to mammal — and could become a danger for humans.

It started in October 2022, when several dead mink were discovered on a farm in Galicia in northwestern Spain. Veterinarians initially blamed the coronavirus. But tests revealed that the highly pathogenic avian flu virus H5N1 was the culprit.

To stop the spread of the dangerous pathogen, more than 50,000 mink on the farm were killed.

While farm workers themselves were not infected, the case remains a cause of concern for scientists.

Mink farm outbreak 'incredibly concerning'
The spread of the virus from birds to other species is nothing new. The pathogen that causes bird flu, or avian influenza, has been found in raccoons, foxes and seals, though these remain isolated cases.

While there have been some cases of H5N1 infecting humans, the World Health Organization has said there's no evidence of human-to-human transmission so far.

When the disease has spread to humans and other mammals, it has been via direct contact with excrement from infected birds or their carcasses, according to Timm Harder, an avian influenza expert at the Friedrich Loeffler Institute's diagnostic virology department in Germany.

But the mink outbreak appears to be a rare case where mammals are transmitting the disease to each other rather than through direct contact with an infected bird. This is something "new," said Harder.

Part of the problem is that mink are intensively farmed. They're kept in high numbers in confined spaces, which means infection spreads rapidly in the highly susceptible mammals, said Harder.

Harder added that researchers have identified several pathogen mutations in the mink, one of which allows "the virus to better reproduce in mammals."

Scientists are worried that the virus, which has led to the deaths of tens of millions of birds globally, could spread to more mink farms and become "more transmissible."

"This is incredibly concerning," said Tom Peacock, a virologist at Imperial College London, in an interview with the scientific journal, Science. "This is a clear mechanism for a H5 pandemic to start."

Could avian influenza trigger a human pandemic?
Of the 868 known cases of H5N1 infection in humans worldwide between January 2003 and November 2022, 457 were fatal, according to the WHO.

However, because there has been no sustained human-to-human transmission, the risk of human infection from avian flu is low, said the WHO.

Some highly pathogenic avian influenza viruses have an increased potential to cause new zoonotic diseases — which are transmissible from animals to humans and vice versa.

While Timm Harder said there are "numerous hurdles for a more extensive adaptation to humans," he added the mutations seen in the virus that infected mink must be further studied and evaluated.

How a harmless virus became dangerous
Waterfowl have long played host to influenza viruses, but these early strains were low in pathogenicity, said Wolfgang Fiedler, an ornithologist at the Max Planck Institute of Animal Behavior. The viruses weren't too contagious or damaging.

But when these viruses that were harmless to wild birds spread to factory poultry farms — where thousands of animals were crammed tight — the disease spread rapidly and the virus could mutate, Fiedler explained.

The result was the highly contagious virus strains H5N1 and H5N8, which likely originated on poultry farms in East Asia, according to the Scientific Task Force on Avian Influenza and Wild Birds established by the UN.

Farmed ducks likely become infected from wild birds. Ducks are "kept together with pigs, for example," which aided the mutation process, noted Fiedler. Such animal husbandry methods "make a virus like this insanely happy."

In fact, outbreaks of these highly pathogenic strains are typically associated with "intensive domestic poultry production and associated trade and marketing systems ... via contaminated poultry, poultry products and inanimate objects," according to the UN's bird flu task force.

The highly contagious H5N1 and H5N8 virus strains were in turn transmitted to wild birds via infected farmed birds, explained virologist Timm Harder. The viruses could then be transmitted over great distances during bird migrations.

How much damage has the bird flu outbreak caused?
The ongoing avian flu outbreak is considered the largest observed in Europe to date, according to the European Food Safety Authority, an EU agency.

Between October 2021 and September 2022, 50 million farm birds had to be culled in 37 countries.

More than 3,800 highly pathogenic bird flu cases were counted in wild birds. Experts believe the number of unreported cases is probably much higher.

"Now the virus is also circulating in wild birds during the summer months," confirmed Harder, noting that the animals breed closely in large colonies in the warmer months, providing ideal conditions for the spread of the virus.

The avian influenza wave also reached South America for the first time in the fall. Peru, Venezuela, Ecuador and Colombia were among the countries affected. In Honduras, more than 240 dead pelicans were found in one week alone.

Harder said he is concerned that the virus could spread from South America to Antarctica and endanger penguin populations. Apart from Antarctica, only Australia has escaped the virus.

Despite the acute outbreak among birds, Harder sees one ray of hope in that the broad spread of the virus could promote immunity in wild birds. Antibodies have already been found in live animals.

This article was adapted from German by Stuart Braun.

Bird flu is spreading among mammals. How worried should we be? [Sydney Morning Herald, 7 Feb 2023]

By Sydney Morning Herald

In Spain, bird flu appears to have spread from mink to mink for the first time. This is a troubling situation that warrants close attention.

“These are exactly the kind of situations we’re really worried about,” Associate Professor Paul Horwood tells me. Dr Michelle Wille says she and “many of my colleagues globally are very concerned”.

In today’s Examine: what’s happened, and why it matters.

What is bird flu? Why should we worry?
Virus risk is a numbers game. Human viruses tend to come from animals. Animals have been around for a lot longer than humans, so they have many more viruses than we do. The closer we get to animals – by farming and land-clearing – the more we risk a new virus jumping into humans and causing a pandemic.

There are well over 100 known subtype combinations of influenza A; only two subtypes of influenza A and influenza B circulate in humans. Most of the others circulate in waterfowl.

Since the discovery of this particular lineage of H5N1 in 1996, scientists have focused on it as one of the viruses that could plausibly cause a pandemic – for two reasons.

First, H5N1 is endemic in poultry in several countries, including Bangladesh, China and Indonesia. Second, it is extremely lethal in humans.

Influenza viruses bind to certain sialic acid-containing receptors on the surface of cells, using them to get inside and take over. These receptors come in multiple varieties; human influenza viruses bind to alpha-2,6 receptors, while the viruses that infect birds prefer alpha-2,3.

This difference is important. Humans also have alpha-2,3 receptors, but they tend to be deep in the lung rather than in our upper airways. That makes it very hard for H5N1 to get a purchase, giving us good protection from the virus. The tradeoff is when it does take hold, that infection is deep in our body, often leading to severe disease. This explains why bird flu infections in humans are extremely rare but often lethal: the World Health Organisation has tracked 868 cases and 457 deaths since 2003.

Put those two factors together – lots of virus in birds, high lethality in humans – and you have a pandemic risk that worries a lot of scientists and governments.

So what’s changed? Why are minks important?
Since H5N1 was first spotted in 1996, we’ve seen several huge outbreaks in birds. We’re in the middle of a very large one right now, driven by a new viral lineage that appears to be highly transmissible. And we’re seeing more infections of mammals – raccoons, foxes, seals – than we’ve seen previously.

“With high levels of transmission we are seeing unprecedented numbers of dead birds and outbreaks,” says Michelle Wille, a bird flu researcher at the Doherty Institute and the University of Sydney.

In October, a team of scientists arrived at a mink farm in Carral, a small municipality on Spain’s northern coast, to investigate an unexplained viral outbreak. The farm housed more than 51,000 mink in wire cages. Swabs soon revealed the virus was H5N1.

The mink were immediately culled. But the Spanish team’s study, published in January, raises troubling issues.

After H5N1 was first detected at the farm, more and more mink fell sick. The cases at first clustered in several hotspots before spreading across the farm. This suggests the virus wasn’t being spread from birds to mink, but from mink to mink.

“We’ve never seen mammal to mammal transmission, ever. It has never happened,” says Wille. “Now it’s no longer just a hypothetical. Now we’ve actually seen it happen”

This is important for several reasons.

First, mink are mammals. Humans also happen to be mammals.

Second, the mink upper respiratory tract is very similar to that of humans. Humans passed COVID-19 to farmed mink in 2020, leading to huge outbreaks and, eventually, the transmission of COVID-19 back from mink to human.

Third, mink-to-mink transmission may allow the virus to pick up mutations which allow it to better spread in mammals, including humans.

“You’re basically selecting for those kinds of mutations for mammalian adaptation,” says Paul Horwood, a tropical disease researcher at James Cook University who authored a 2021 study warning of H5N1’s pandemic risk. “That becomes more and more refined the more hosts the virus spreads between.”

Indeed, the virus isolated from the mink in Spain had an uncommon mutation that allows it to more-easily infect mammal cells.

And it does not need to take many more steps before it is a danger to humans. Lab evidence suggests as few as five specific amino acid changes are all H5N1 needs to spread effectively in humans. Wild viruses with two of these mutations have been spotted. “It’s not really a big stretch for it to happen,” says Horwood.

Is this an imminent pandemic threat?
“No,” says Professor Ricardo Soares Magalhães, director of the Queensland Alliance for One Health Sciences at the University of Queensland, “the situation is indeed concerning, but not a matter for alarm.”

The Spanish researchers tested all the people who worked with the mink but did not turn up any evidence of H5N1, suggesting the virus has not picked up a mutation that enables easy spread to humans.

And CSIRO bird flu expert Dr Frank Wong points out there’s no evidence the virus has a new mutation that allows it to spread easily in mammals. The mink, which are jammed together in small cages, may be a special case. “The risk of onward, mammal-to-mammal transmission has not really changed,” he says. “It’s still a bird-adapted virus.”

Nor is the situation analogous to COVID-19. That virus was (unfortunately) unexpected by health authorities; scientists have tracked H5N1 for years and have prepared vaccines and antivirals.

But this should be a major warning shot. Our efforts need to concentrate on making sure this virus does not get a chance to pick up any more mammal-adapted mutations.

“We need to make sure we starve the virus of mammal cells to infect,” says Magalhães.

That means close surveillance of farmed animals and wild birds. We should aggressively start vaccinating animals at risk − a strategy that was highly effective during the earlier H7N9 influenza outbreak. And given this scare, and the COVID-19 transmission, it may be time to stop farming mink altogether. Mink fur is used in clothing and furniture; doing without fur coats seems a small price to pay to cut our pandemic risk.

CORRECTION
An earlier version of this story stated there were 27 subtypes of influenza. This is incorrect. There are well over 100 known subtype combinations of influenza A.

Bird flu cases spill over to mammals in Oregon, across the U.S. [OregonLive, 7 Feb 2023]

By Gosia Wozniacka

Oregon wildlife officials said they have diagnosed a handful of wild mammals with highly pathogenic avian flu – but they do not consider it an outbreak.

The disease, commonly known as bird flu, is usually associated with wild birds and backyard flocks. It has killed thousands of birds throughout the state in recent months and led to the death and euthanization of millions of chickens and other domestic birds across the U.S.

The U.S. Agriculture Department has recorded avian flu infections in 110 mammals across the country since May 2022, including six skunks and one raccoon in Oregon. The disease has not affected the state’s wildlife populations, said state wildlife veterinarian Colin Gillin.

In other parts of the U.S., foxes, coyotes, bobcats, fishers, possums, bears and even seals and dolphins also were found to carry the disease.

Health officials say it’s rare for bird flu to spill over to mammals and the risk to humans is very low, though several hundred people across the world have tested positive for the disease in past years.

Typically, the wild mammals diagnosed are scavengers who likely ate a very sick or recently dead bird that carried bird flu, said Gillin. The animals also might have contracted the disease by congregating in areas contaminated with the virus, which can survive in feces or mud for several days.

Transmission of bird flu from mammal to mammal has not been observed so far in Oregon or elsewhere, Gillin said, except on mink farms where the animals are packed in cages nose to nose, with little ventilation. In the wild, he added, most animals don’t congregate in large groups and are usually outside in the open air.

Human infections with bird flu have most often occurred after close or lengthy contact with infected birds or places that the birds touched, according to the Centers for Disease Control and Prevention. While more than 800 cases have been recorded world-wide since 2003, fewer than 10 cases have been reported since 2021. The U.S. recorded its first case of avian influenza in humans last April.

Owners of backyard flocks should be especially cautious about letting their birds go outside if nearby properties have ponds where wild birds could land, Gillin said. They also should watch for wild animals who might be sick or dead, he said.

In one recent case in Columbia County, investigators with the Oregon Department of Agriculture who responded to a backyard flock sick with bird flu found six skunks dead nearby, department spokeswoman Andrea Cantu-Schomus said.

Approximately 20 birds in a noncommercial flock had to be euthanized, she said. The skunks were sent to the Oregon Department of Fish and Wildlife and tested positive for bird flu.

It’s unclear whether the dead skunks had contracted bird flu by eating contaminated backyard birds or wild birds or by being present in an environment contaminated by the virus, Gillin said.

Deadlier strains of bird flu have been on the rise in recent years. Highly pathogenic avian influenza has devastated wild birds and the poultry industry across the globe. The virus is now endemic in Europe and Asia.

And avian flu cases will likely increase soon in Oregon and elsewhere, Gillin said, as wild birds start to migrate from their southern wintering grounds up north as part of their annual migrations. As more wild birds and backyard flocks get sick, more mammals might also be diagnosed.

Could bird flu in mink signal threat of a human pandemic? [DW (English), 7 Feb 2023]

By Jeannette Cwienk

A bird flu outbreak on a Spanish mink farm has alarmed scientists. The virus may be spreading for the first time from mammal to mammal — and could become a danger for humans.

It started in October 2022, when several dead mink were discovered on a farm in Galicia in northwestern Spain. Veterinarians initially blamed the coronavirus. But tests revealed that the highly pathogenic avian flu virus H5N1 was the culprit.

To stop the spread of the dangerous pathogen, more than 50,000 mink on the farm were killed.

While farm workers themselves were not infected, the case remains a cause of concern for scientists.

Mink farm outbreak 'incredibly concerning'
The spread of the virus from birds to other species is nothing new. The pathogen that causes bird flu, or avian influenza, has been found in raccoons, foxes and seals, though these remain isolated cases.

While there have been some cases of H5N1 infecting humans, the World Health Organization has said there's no evidence of human-to-human transmission so far.

When the disease has spread to humans and other mammals, it has been via direct contact with excrement from infected birds or their carcasses, according to Timm Harder, an avian influenza expert at the Friedrich Loeffler Institute's diagnostic virology department in Germany.
But the mink outbreak appears to be a rare case where mammals are transmitting the disease to each other rather than through direct contact with an infected bird. This is something "new," said Harder.

Part of the problem is that mink are intensively farmed. They're kept in high numbers in confined spaces, which means infection spreads rapidly in the highly susceptible mammals, said Harder.

Harder added that researchers have identified several pathogen mutations in the mink, one of which allows "the virus to better reproduce in mammals."

Scientists are worried that the virus, which has led to the deaths of tens of millions of birds globally, could spread to more mink farms and become "more transmissible."

"This is incredibly concerning," said Tom Peacock, a virologist at Imperial College London, in an interview with the scientific journal, Science. "This is a clear mechanism for a H5 pandemic to start."

Could avian influenza trigger a human pandemic?
Of the 868 known cases of H5N1 infection in humans worldwide between January 2003 and November 2022, 457 were fatal, according to the WHO.

However, because there has been no sustained human-to-human transmission, the risk of human infection from avian flu is low, said the WHO.

Some highly pathogenic avian influenza viruses have an increased potential to cause new zoonotic diseases — which are transmissible from animals to humans and vice versa.

While Timm Harder said there are "numerous hurdles for a more extensive adaptation to humans," he added the mutations seen in the virus that infected mink must be further studied and evaluated.

How a harmless virus became dangerous
Waterfowl have long played host to influenza viruses, but these early strains were low in pathogenicity, said Wolfgang Fiedler, an ornithologist at the Max Planck Institute of Animal Behavior. The viruses weren't too contagious or damaging.

But when these viruses that were harmless to wild birds spread to factory poultry farms — where thousands of animals were crammed tight — the disease spread rapidly and the virus could mutate, Fiedler explained.

The result was the highly contagious virus strains H5N1 and H5N8, which likely originated on poultry farms in East Asia, according to the Scientific Task Force on Avian Influenza and Wild Birds established by the UN.

Farmed ducks likely become infected from wild birds. Ducks are "kept together with pigs, for example," which aided the mutation process, noted Fiedler. Such animal husbandry methods "make a virus like this insanely happy."

In fact, outbreaks of these highly pathogenic strains are typically associated with "intensive domestic poultry production and associated trade and marketing systems ... via contaminated poultry, poultry products and inanimate objects," according to the UN's bird flu task force.

The highly contagious H5N1 and H5N8 virus strains were in turn transmitted to wild birds via infected farmed birds, explained virologist Timm Harder. The viruses could then be transmitted over great distances during bird migrations.

How much damage has the bird flu outbreak caused?
The ongoing avian flu outbreak is considered the largest observed in Europe to date, according to the European Food Safety Authority, an EU agency.

Between October 2021 and September 2022, 50 million farm birds had to be culled in 37 countries.

More than 3,800 highly pathogenic bird flu cases were counted in wild birds. Experts believe the number of unreported cases is probably much higher.

Until recently, bird flu mainly occurred in fall and winter.

"Now the virus is also circulating in wild birds during the summer months," confirmed Harder, noting that the animals breed closely in large colonies in the warmer months, providing ideal conditions for the spread of the virus.

The avian influenza wave also reached South America for the first time in the fall. Peru, Venezuela, Ecuador and Colombia were among the countries affected. In Honduras, more than 240 dead pelicans were found in one week alone.

Harder said he is concerned that the virus could spread from South America to Antarctica and endanger penguin populations. Apart from Antarctica, only Australia has escaped the virus.

Despite the acute outbreak among birds, Harder sees one ray of hope in that the broad spread of the virus could promote immunity in wild birds. Antibodies have already been found in live animals.

This article was adapted from German by Stuart Braun.

Study characterizes mutations in neuraminidase of human-like H5N1 influenza viruses [News-Medical.Net, 7 Feb 2023]

By Dr. Sanchari Sinha Dutta,

A study published in PLOS PATHOGENS describes the prevalence and functions of mutations in neuraminidase enzyme of avian H5N1 influenza viruses that are preferentially selected in human H5N1 influenza viruses.

Background
Influenza A viruses are negative-sense RNA viruses that infect a wide-range of species, including birds and humans. The classification of these viruses depends on the variations in surface glycoproteins hemagglutinin and neuraminidase.

Some strains of zoonotic influenza viruses are capable of infecting and replicating in humans, causing mild to fatal diseases. Most human influenza viruses carry genetic sequences from avian influenza viruses that encode hemagglutinin, neuraminidase, and polymerase basic-1.

Genetic mutations in these viral proteins are responsible for bird-to-human transmission of avian influenza viruses.

In the current study, scientists have characterized the mutations in viral neuraminidase that facilitate zoonotic transmission of influenza viruses. They have analyzed all neuraminidase sequences of H5N1 influenza viruses of human- and bird-origin from Eurasia and Africa to identify the causative mutations.

Furthermore, they have characterized the functions of identified mutations by infecting chickens, mice, and ferrets with several recombinant viruses carrying these mutations.
Important observations

The analysis of neuraminidase genetic sequences identified A46D, L204M, S319F, and S430G mutations that act synergistically to improve H5N1 viral fitness and adaptability in humans. The scientists determined the functions of these mutations in both in vitroand in vivo (chickens, mice, and ferrets) setups.

The analysis of neuraminidase activity revealed that human-like H5N1 viruses have significantly lower activity compared to bird-like H5N1 viruses. Such reduced activity might be needed to maintain an optimal receptor binding/destroying balance. Moreover, low activity might be required for the selection and adaptation of avian influenza viruses in humans.

Specifically, it was observed in the study that the reduced neuraminidase activity of human H5N1 viruses is due to potential conformational changes in the enzyme, as well as due to a low amount of enzyme incorporation into viral particles.

Regarding the incorporation of neuraminidase into viral particles, the study found that the level of RNA replication and transcription of human-like neuraminidase is lower than that of bird-like neuraminidase. The findings of co-transfection experiments revealed that the abundance of bird-like neuraminidase favors its selection over homologous human-like neuraminidase. This explains the relatively lower incorporation of human-like neuraminidase into viral particles.

Regarding receptor binding activity of neuraminidase, the study found that the S430G mutation is primarily responsible for increasing the binding affinity of human-like neuraminidase for human-like receptors.

The head domain of neuraminidase has sialidase activity, which helps cleave sialic acid (SA) to release progeny viral particles in the respiratory tract for systemic viral transmission. The analysis of human-type 2,6-SA receptors and bird-type 2,3-SA receptors revealed that mutated human-like neuraminidase removes 2,3-SA during viral entry, leading to a reduction in bird-type receptors. This might reduce the adherence of hemagglutinin of progeny viral particles to 2,3-SA during viral release.

As speculated by the scientists, the abundance of 2,6-SA during viral release might act as the main driver for the adaptation of hemagglutinin and neuraminidase of avian influenza viruses to human-type receptors.

The findings of the mutational analysis revealed that all identified mutations in human-like neuraminidase act synergistically to increase viral replication in the human airway epithelium.

These mutations also conferred moderate virulence and longer survival of H5N1 avian influenza virus in mice and ferrets, while not affecting the high virulence of the virus in chickens.

Study significance
The study identifies four mutations in neuraminidase of human-like H5N1 influenza viruses that act synergistically to increase viral replication and induce moderate virulence in mammals, while maintaining high virulence in birds.

Collectively, these mutations reduce neuraminidase activity, expression, and incorporation in viral particles and increase the binding affinity of H5N1 viruses to human-like receptors.
As mentioned by the scientists, these findings are vital to understand the genetic changes that improve the fitness of avian influenza viruses in humans. The scientists highlight the requirement of continuous genomic surveillance to monitor avian virus replication in mammals. This is particularly needed for the early detection of emerging viruses that have the potential to induce a pandemic condition.

Journal reference:
•　Scheibner D. (2023). Phenotypic effects of mutations observed in the neuraminidase of human origin H5N1 influenza A viruses. PLOS PATHOGENS. doi: https://doi.org/10.1371/journal.ppat.1011135 https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011135