The H7N9 bird flu virus, which has sickened and killed several hundred people in China for the past four winters, had seemed over the past couple of years to be diminishing as a threat.

But a resurgent wave of activity this winter has produced more than a third of all infections recorded since the first human case was hospitalized in February 2013. And with this large burst of cases, H7N9 has overtaken another bird flu, H5N1, which has been causing sporadic human infections at least a decade longer than H7N9.

Changes in the virus are also worrying, said Dr. Daniel Jernigan, director of the Centers for Disease Control and Prevention’s influenza branch. Jernigan noted Tom Price, the new health and human services secretary, has been briefed on the situation.

“We’re concerned about the uncertainties here and the number of changes that are happening at this point. We are monitoring this closely,” Jernigan told STAT.

To date, all of the infections have been contracted in China, although a few cases involved tourists from elsewhere who were infected there.

Overall, 460 of the 1,258 H7N9 cases have been recorded in the latest wave of cases. About a third of people who have been diagnosed with H7N9 have died from their infections — though experts note undetected mild cases are probably occurring, which would lower that case fatality rate.

“The situation is not particularly reassuring at the moment in the field,” said Professor Malik Peiris, a virologist in the school of public health at the University of Hong Kong. Peiris, a veteran bird flu researcher, called H7N9 “the most significant pandemic threat currently.”

A CDC risk assessment concurs, placing H7N9 at the top of the list of pandemic threats from among a dozen bird and animal flu viruses.

The way in which the virus has evolved undermines the usefulness of a 12 million-dose emergency stockpile of H7N9 vaccine made for the United States several years ago. That vaccine is now less effective at targeting the strains of the virus that are circulating.

Influenza experts who advise the World Health Organization are meeting this week in Geneva to make recommendations on the flu viruses that should be in next winter’s seasonal flu vaccine for the Northern Hemisphere. They are also likely to recommend that the H7N9 vaccine seed strain — the virus used as a target for companies that make vaccine stockpiles — should be changed due to this evolution.

While the vaccine in the emergency stockpile would likely still offer some protection, “we think that there could be a better vaccine match,” acknowledged Todd Davis, principal investigator on the CDC team that studies flu viruses that infect other mammals and birds.

Another genetic change is also amplifying the sense of anxiety about this virus. The genetic sequences of about a dozen H7N9 viruses from the southern Chinese province of Guangdong have mutated in a way that makes them more dangerous for chickens — and perhaps people.

Like all bird flu viruses, H7N9 originated in wild aquatic birds such as ducks. These viruses occasionally make their way into domestic poultry flocks, as H7N9 did. And from there, the viruses can trigger sporadic human infections — generally among people who work in poultry production or who sell or buy live chickens at Asia’s popular so-called wet markets.

Most bird flu viruses don’t kill poultry. They are of low pathogenicity — better known in the flu world as low path viruses. But viruses that carry an H5 or an H7 hemagglutinin protein on their outer shell can be deadly to chickens. The ones that do are called highly pathogenic or high path viruses.

H7N9 has, until now, been a low path virus. But it has long been known that low path H5 and H7 viruses can evolve to become highly pathogenic if they are allowed to circulate among poultry for too long.

The genetic sequences from Guangdong, recently posted in a flu virus database, suggest that has happened there.

While the designations high path and low path relate specifically to how bird flu viruses behave in chickens, it is known that high path viruses, when they infect people, can cause more disseminated disease than human flu viruses, involving organs other than the lungs, Davis said.

Flu experts find these changes unsettling.

“It certainly introduces uncertainty into the mix,” Jernigan said. “Where we kind of thought things were under control and going away, they’ve increased. We thought we had a low path [virus] and it’s now become high path. And so we do want to make sure that all mitigations that can be done will get done.”

In the early days of the H7N9 outbreak, authorities in China enacted strict rules to try to bring spread under control. Markets were ordered to institute clean days, when no chickens could be stored in or brought in. The idea was to stop the virus from circulating among the birds in the markets.

But in parts of the country, enforcement of containment efforts has become more lax as human cases declined in 2015 and 2016, Peiris said.

News that the virus may be evolving to high path status may actually have a beneficial effect, he noted. “Because this would now mean that the agriculture sector would take this much more seriously. Although I must say that the horse is now bolted from the barn and I doubt exactly what can be done to contain it at this stage.”

To date H7N9 has restricted itself to China, though experts fear that may soon change with word that the virus has been found in provinces bordering Vietnam. “I think now Vietnam is under very severe risk,” said Peiris.

There have also been reports that some of the viruses may no longer be susceptible to oseltamivir — sold as Tamiflu — and other flu drugs of the same class. There are few drugs that treat influenza, and if H7N9 became resistant to these drugs, it would be a highly unwelcome development. But the CDC’s Davis said so far it appears that the cases of resistance have involved hospitalized people who were taking the drugs for protracted periods.

Resistance can evolve during treatment, but resistance among viruses that haven’t yet been exposed to the drug would be more alarming, he and Jernigan said.

Scientists at the CDC would like to test virus samples from China to ensure that the flu drugs are still effective. But a disease diplomacy problem is getting in the way of that work.

While China has been reporting cases and sharing the genetic sequences of viruses, it has not shared actual virus samples with the United States since the early days of the H7N9 outbreak, Jernigan said.

Thanks to developments in synthetic biology, genetic sequences can be used to make sample viruses that can tell scientists a lot about how a virus behaves. Still, viral samples would be useful. “Synthetic biology is amazing. But it still takes time,” said Davis.

Jernigan said scientists at the China CDC collaborate openly with their international colleagues. But a green light to share viruses would need to come from other parts of the government. He said efforts are underway to try to open those doors.