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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 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 -- in what has become one of the largest and longest avian flu outbreaks 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 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 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 .

Only one person in the U.S. has become infected with H5N1 during this outbreak -- . CDC maintains a 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, . 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.

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