Mark Naniot remembers 2022 as the summer from hell. As the co-founder of Wild Instincts animal rescue in Wisconsin’s Northwoods, Naniot and his team spent the season sweating in gloves, gowns, smocks, and masks, enduring what felt like endless rounds of disinfection as they moved between the cages of sick and injured animals under their care.

These precautions were necessary due to a trio of infectious diseases occurring frequently in wild animals that summer. COVID-19 was still making life difficult, and a devastating contagion called chronic wasting disease was appearing in deer in the area. Then, there was H5N1 bird flu to contend with. “It’s highly, highly transmissible,” said Naniot, who has been involved in animal rescue for 35 years.

Since it was first discovered in birds in 1996, H5N1 has shown itself to be a Swiss Army Knife of a virus, evolving the necessary tools to break into the cells of a growing list of species. So far, it has infected and killed millions of wild and farmed birds. It’s also been found in at least 26 different kinds of mammals, including, most recently in the United States — cows, cats, and house mice.

The voraciousness of the virus prompted Dr Jeremy Farrar, chief scientist of the World Health Organization, to call it “a global zoonotic animal pandemic.” Along the way, people have been collateral damage. Humans can be infected, but we aren’t the intended targets. That could all change quickly, however.

“Influenza makes mutations, in the sense of making errors copying its genome, at a higher rate than a coronavirus like SARS-CoV-2,” said Dr   Jesse Bloom, a computational biologist who focuses on influenza viruses at the Fred Hutch Cancer Center in Seattle. These errors don’t always work in favour of the virus. Most of the time, viruses with errors won’t work or be fit enough to continue to copy and survive. But every once in a while, a random error can result in a change to the virus that gives it an advantage in its environment, and that version of the virus will continue to spread and grow. If humans happen to be that environment, and H5N1 changes at the right place at the right time, suddenly the animal pandemic could become a major problem for people, too.

Naniot had seen wild birds come into Wild Instinct rescue with H5N1 — bald eagles, hawks, and owls — but nothing had prepared him for the red fox kits. The baby foxes were brought in stumbling and uncoordinated, making him think they might have gotten into some kind of poison. Then the seizures started.

“They would have these severe, severe seizures,” Naniot said. “Screaming very loud, whole-body tremors.” The first seizures lasted for 20 to 30 seconds at a time. “And then it would get longer and longer and longer,” he said. Naniot hadn’t known his young patients could get bird flu. Further research clued him into the fact that foxes had recently joined a growing list of species that could succumb, usually after eating the flesh of infected dead birds. “The severity of the seizures is something I hadn’t seen before,” Naniot said. “It’s a very sad thing to see, the progression of the disease.”

Risks to Human

Though H5N1 is known to have infected nearly 900 people in the past 30 years, these infections have been sporadic and usually self-limiting. The virus can still be deadly, however: More than 50% of people who are known to have been infected with H5N1 have died.

Still, the virus isn’t particularly good at infecting humans. Even when it manages to get into a person and cause symptoms, it rarely gets passed to someone else.

“We call these dead-end infections,” said Dr. Scott Weese, a veterinarian and expert in zoonotic infections at the University of Guelph in Canada.

The way a dead-end infection happens, Weese explains, is that a person is around a large amount of the virus, or their immune system is too weak to resist, and H5N1 gets in. But it is not a virus that’s well-adapted to humans, so it never really builds up in respiratory secretions — the fluid that coats the nose, throat, and lungs — which would give it a way out through coughs, sneezes, or even exhaled breath.

There have been at least three apparent dead-end infections in dairy workers in the US who worked closely with infected milk cows. Two of the workers developed conjunctivitis or eye infections. In one case, the worker reported getting splashed with raw milk in their eyes. A third developed respiratory symptoms after close contact with cows. All were successfully treated with an antiviral medication. None developed severe symptoms or infected others.

Using a strain of H5N1 from the recent cattle outbreak, scientists recently confirmed that this version of the virus is unlikely to be transmitted through the air. In experiments with ferrets, which are considered the gold standard for studying how viruses transmit in people, researchers at the US Centers for Disease Control and Prevention grew a sample of the same H5N1 virus taken from a farmworker with the flu in Texas to experimentally infect six of the animals. Then, three healthy ferrets were placed in the same enclosures with three of the sick animals. These animals could touch, nose, and lick the sick animals, and all of them became ill.

Next, the CDC tested airborne transmission by putting three healthy ferrets into an enclosure where they could breathe the same air as sick animals but couldn’t touch them. Only one of those three animals became ill, suggesting that the virus carried by cattle in the current outbreak is not well adapted to respiratory spread, the CDC wrote in a news release on the study.

So far, that seems to be what’s happening in the real world, too. Though more than 80 dairy herds have tested positive across at least 12 states, the number of human infections has been low, though there’s been little testing to confirm that. A dairy worker’s infection is important because it confirms that humans can be infected with H5N1 after contact with cows.

These early ferret experiments are good news, the CDC noted, because it means the virus would need to change to become an infection spread person-to-person through airborne droplets. The agency said it plans to repeat the tests.

As Covid has shown, all of this could change with the rub of an eye or a small cough. The more opportunity the virus has to spread, the more opportunity it has to change in ways that will help it pry its way into human cells.

“It’s really important to understand everything we know today is a snapshot of today, and these viruses can change very quickly,” said Dr. Rick Bright, an immunologist and former director of the US Biomedical Advanced Research and Development Authority, in an interview with CNN Chief Medical Correspondent Dr. Sanjay Gupta for the Chasing Life podcast.

“They can adapt, and they can spread very easily when they do change,” said Bright, who is now CEO of Bright Global Health.

Dr Erin Sorrell, a virologist and senior scholar at the Johns Hopkins Center for Health Security, says that while humans have been exposed to seasonal strains of the flu, and flu vaccines help build immunity to H1 and H3 flu strains, H5N1 would look pretty different to our bodies.

“Our existing immunity to H3 and H1 is not necessarily going to protect us against exposure to an H5 virus,” she said.

The CDC’s ferret study also had some sobering findings. In contrast to seasonal flu, which makes ferrets sick but doesn’t kill them, H5N1 killed all the ferrets that were infected.

“While the three cases of A(H5N1) in the United States have been mild, there may be serious illnesses among people,” the CDC wrote in its conclusions on the study.

In the more than two dozen human infections with the H5N1 virus worldwide since 2022, with the most recent iteration of the virus, there’s been a wide spectrum of severity. Fourteen illnesses were severe or critical, seven were fatal, six were mild, and eight didn’t have any symptoms at all, according to the CDC.

Dr Seema Lakdawala, a microbiologist and immunologist at Emory University who specializes in the flu, thinks the difference in symptom severity may be due to previous exposure to seasonal viruses. Her experiments in ferrets suggest that our bodies wouldn’t necessarily be defenceless. In her lab, ferrets with previous exposures to seasonal flu strains didn’t get as sick when exposed to new flu viruses compared to those with no prior exposure to seasonal strains. She says she hasn’t tested this with any of the strains involved in the cattle outbreak, however.

So while we probably don’t have any antibodies — the immune system’s front-line soldiers — at the ready to fight off an H5 infection, there are memory cells in our tissues that might recognize parts of a new flu virus and respond.

How much help we might get from past exposures to flu viruses is difficult to predict, however, which is why vaccination would still be important to tune up our immunity.

Plans to Stop the Virus from Spreading

The US has vaccines against H5 viruses in its Strategic National Stockpile, and last month, government officials said 4.8 million doses are being “filled and finished” so they would be ready for use, though there’s no plan to give them to anyone yet.

International Measures

Finland has already ordered 20,000 doses of a different H5 strain — H5N8 — which will be used as soon as they’re available to protect workers who might be vulnerable to the virus, such as scientists and those in direct contact with infected animals on mink farms.

Current Risk Assessment and Precautions

For now, the CDC maintains its assessment that the risk to the general public from H5N1 is low, though people who work with infected animals have a higher risk and should wear protective clothing and take additional precautions to avoid getting sick. The Administration for Strategic Preparedness and Response (ASPR) has made protective equipment available to states for use on farms, and the USDA has made additional funding available to farms to support efforts to safeguard their livestock from disease.

But so far, wearing this equipment is voluntary, and there are concerns that it might be difficult for farm workers to wear the full recommended kit, which includes coveralls, an apron, a mask, eye protection, a head covering, gloves, and boots during the summer, which is again expected to break heat records.

The government has also said it is working on the development of a rapid test for H5N1.

Exposure and Symptom Severity

Dr Rick Bright thinks the severity of symptoms may depend on how much virus a person is exposed to when they are infected. Touching contaminated milk or the body of a dead bird and then rubbing your eyes or nose might deliver a smaller dose of the virus and ultimately result in milder symptoms. Ingesting a large amount of virus — as some animals do when they scavenge for food or as humans in some countries do when consuming dishes made with duck blood — could lead to severe disease.

Characteristics of H5N1

“The virus can infect several internal organs. So it doesn’t just locate, say, in the lungs, as we would think most influenza viruses would,” Bright said. It’s also been found in “the brains and then the spleens, the intestines, and the heart and throughout the body of those animals.”

Dr. Richard Webby, who directs the WHO’s Collaborating Centre on the Ecology of Influenza in Animals and Birds at St. Jude Children’s Research Hospital, agrees.

“It’s at the top of the list in terms of bad guy viruses,” he said, noting that the virus is nerve-loving, or neurotropic. “So it goes to the brain and causes very, very severe disease.”

Monitoring and Future Outlook

So far, the virus hasn’t made the changes that would enable it to become a fully human pathogen, said Dr. Michael Osterholm, who directs the Center for Infectious Disease Research and Policy at the University of Minnesota. It’s unclear whether it ever will.

“I’ve been a student of this virus. And I surely have been amazed at how it’s changed over the last 20-some years, but at the same time, you know, I’m looking for evidence that it is likely to become a virus infecting humans and then transmitted by humans to other humans. And we just haven’t seen that yet,” he added.

Case Study: Wisconsin Animal Rescue

Naniot at the Wisconsin animal rescue said they tried to save about seven infected fox kits in the summer of 2022, but all of them died.

Other rescue organizations in their network had a few foxes infected with H5N1 that survived, but they ultimately went blind.

While all the precautions they took to safely work with the animals were arduous, Naniot said he’s grateful they were effective. They never spread the virus to any of the other animals in the facility — including themselves.

“Unfortunately, it’s kind of like when Covid went through, you know, it first started someplace,” he said.

Naniot says he hasn’t encountered any infected animals since 2022, but he’s watching the news closely in case any cow herds become infected in Wisconsin, knowing that he could easily see H5N1 again.

“It spread kind of like wildfire, and it’s a highly, highly contagious disease.”