Tracking the bird flu, experts see a familiar threat — and a virus whose course is hard to predict

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.

“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.

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.”