An avian flu pandemic in people? Here's what it might look like.

As far as public health authorities know, the avian flu outbreak in dairy cattle has so far spread to just three farm workers in the United States. All had mostly mild symptoms.

But that doesn't guarantee that the virus, called H5N1, will remain benign if it begins to spread between people. Accumulated evidence from the animal world and data from other parts of the globe, in fact, suggest the opposite.

Some dairy cows never recovered from the H5N1 virus and died or were slaughtered from it. The infected terns appeared disoriented and unable to fly. The baby elephant seals had difficulty breathing and developed tremors after contracting the virus. Infected cats went blind and walked in circles; two-thirds of them died.

“I definitely don't think there's room for complacency here,” said Anice Lowen, a virologist at Emory University.

“H5N1 is a highly pathogenic type of influenza virus and we must have a high degree of concern in case it spreads to humans,” he said.

In ferrets experimentally inoculated with the virus through the eyes — the presumed route of infection in U.S. farm workers — the virus spread rapidly to the airways, lungs, stomach and brain, according to a report released Wednesday.

Other studies have found similar patterns in mice fed contaminated milk. The findings suggest that entry through the eyes or digestive system may ultimately not make the virus any less of a threat.

H5N1 has been shown to be promiscuous and rapidly acquire new hosts: wild birds and poultry, mice and bears, cats and sea lions. Since its discovery in 1996 in Hong Kong, it has infected nearly 900 people.

An earlier version of the virus circulating in Asia killed about half of those infected.

Of the 15 people known to have been affected by the version now circulating in cattle, one in China has died and another has been hospitalized. Two patients in Chile and Ecuador had severe symptoms. Four Americans – one last year and the three infected in the latest outbreak – fared better.

Crucially, no form of the avian influenza virus appears to have spread efficiently from person to person. That's no guarantee that H5N1 won't acquire that ability, said Yoshihiro Kawaoka, a virologist and avian flu expert at the University of Wisconsin-Madison.

“I think the virus is clearly changing its properties, because we have never seen outbreaks in cows,” Dr. Kawaoka said. Conjunctivitis, also known as pink eye and the primary symptom in two of three farm workers, is not typical of H5N1 infection. The appearance of the virus in mammary glands – in cattle and also in non-lactating mice – was also unexpected.

The concern now is that as H5N1 continues to infect mammals and evolve, it could pick up the mutations needed to spread efficiently between people, sparking another pandemic.

The incubation period for influenza is two to four days, and a human-to-human version could spread long before cases are detected, said Erin Sorrell, a virologist and senior scholar at the Johns Hopkins Center for Health Security.

“If it gets to the general public, it's too late,” he said. “We missed the train.”

The flu is generally more severe in older adults and children under 5 years old. (A swine flu epidemic in 2009 was not as devastating as feared, but it killed nearly 1,300 children.) exposed and for how long, as well as the route of entry, their genetic background and general health.

Infected people generally have fever and respiratory symptoms; some cases progress rapidly to pneumonia or death. If the bird flu virus were to adapt to people, the world would need billions of doses of vaccines and antivirals to avoid these outcomes.

The federal stockpile contains four types of flu antivirals, but the drugs must be taken within 48 hours of symptoms appearing to be effective. A recent review found too little evidence to evaluate the effectiveness of three of four drugs, including the commonly used oseltamivir, sold as Tamiflu.

Some new versions of H5N1 have mutations that make the virus resistant to oseltamivir and the other two drugs, but such changes, fortunately, have not been widely transmitted to animal populations. No mutations were observed against the fourth drug, baloxavir.

But according to David Boucher, director of infectious diseases at the federal Strategic Preparedness and Response Administration, there are only a few hundred thousand doses of that drug in the stockpile.

Vaccines represent the best solution to stem a pandemic, but it is likely that sufficient doses will not be available for at least many months. Even if global seasonal flu vaccine production were entirely shifted to H5N1 vaccines, the number of doses produced would be sufficient for fewer than two billion people, assuming two doses are needed for each person.

In the United States, the national stockpile contains hundreds of thousands of vaccine doses that could be distributed to at-risk people, including children. Companies that contract with the government could produce more than 100 million doses in the first 130 days, Dr. Boucher said.

Officials recently announced they had taken steps to prepare 4.8 million doses that could be bottled without interrupting production of the seasonal flu vaccine.

But most of these plans will only help if the virus cooperates.

Since its first appearance, H5N1 has branched into many forms, and scientists have created a library of 40 so-called candidate vaccine viruses to match them. Having them ready saves crucial time, because creating a new candidate can take three months, said Todd Davis, a virologist at the Centers for Disease Control and Prevention.

So far, he said, the virus has changed only minimally, especially the part of the virus that binds to human cells, called hemagglutinin, or HA.

If the virus were to spread between people, it would first have to change significantly, some experts noted. “If this virus transmits to humans, you can bet that the HA will change, because right now the HA from this virus doesn't bind very effectively to human cells,” said Scott Hensley, an immunologist at the University of Pennsylvania .

Traditional flu vaccines are made by growing candidate viruses in eggs or mammalian cells, both of which are fraught with potential problems: The virus may not grow quickly enough or it may mutate too much as it grows.

In 2009, the candidate virus grew well in eggs, but evolved a poor match to the wild H1N1 virus, introducing long delays in distribution to the public. “By the time vaccine supplies were produced and distributed, the initial wave of the pandemic had already subsided,” Dr. Hensley said.

CSL Sequiris, a leading manufacturer of seasonal influenza vaccines, has a cellular H5N1 vaccine already approved by the Food and Drug Administration.

In the event of a pandemic, once CSL receives a vaccine virus candidate that matches the circulating virus, it could provide 150 million doses to Americans within six months, said Marc Lacey, the company's executive director. (The company also has contracts with 19 other countries.)

But 150 million doses would protect only about one in five Americans. Federal officials are also exploring mRNA avian flu vaccines, which could be produced very quickly, as the Covid pandemic has illustrated, to protect both cows and people. Dr. Hensley's team is testing an mRNA vaccine in cows.

Officials have hesitated to distribute cow vaccines because of trade concerns, experts said: Some countries ban the import of products from vaccinated birds and animals.

But immunizing cows would limit the risk to farm workers and other cows and limit opportunities for the virus to continue to spread and evolve, experts said.

So far, federal officials have also been reluctant to vaccinate farm workers, saying the risk is still low.

The real danger, said Emory's Dr. Lowen, is that a farm worker becomes infected with both the H5N1 virus and a seasonal flu virus. Influenza viruses are adept at gene swapping, so a coinfection would give the H5N1 virus the opportunity to acquire genes that allow it to spread between people as efficiently as seasonal flu.

This possibility highlights the importance of vaccinating agricultural workers, Dr. Lowen said: “Anything we can do to limit seasonal infection in people occupationally exposed to H5N1 could really reduce the risk.”

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