Just over a dozen years ago, a bird flu virus known as H5N1 was charting a destructive course through Asia, North Africa, and the Middle East, ravaging poultry in apocalyptic numbers and killing 6 in 10 humans known to have contracted it.
The overall human death toll was low — in the hundreds — but scientists and government officials feared that the virus could ignite a human pandemic reminiscent of the catastrophic 1918 Spanish flu. Emergency plans were drafted, experimental H5N1 vaccines were created and tested, antiviral drugs were stockpiled.
And then … nothing happened.
The virus continued to kill chickens and to occasionally infect and sometimes kill people. But as the years passed, the number of human H5N1 cases subsided. There has not been a single H5N1 human infection detected since February 2017.
This is the good news. The bad news is that the situation could change in an instant.
“We don’t know how the story’s going to end,” warned Nancy Cox, who retired from the Centers for Disease Control and Prevention in late 2014 after leading its influenza operations for more than two decades.
It’s not just H5N1 that has dissipated. The virus’s nearly-as-scary cousin, H7N9, emerged in China in 2013 and sickened more than 1,500 people in China over five years, killing roughly 40 percent of them.
But after an extraordinary surge of cases — 766 — in early 2017, there were a mere three infections recorded in 2018. So far in 2019 there have been none.
Although there are ways to make sense of H7N9’s decline, no one knows precisely why H5N1 has faded from view.
“There are things that occur with influenza that don’t quite add up completely,” Cox admitted.
Scientists do know the H5N1 viruses have mutated in ways that may be important to their ability to interact with people. Several years ago, these viruses effectively splintered, with some dumping their N1 neuraminidase — a gene that produces a key protein found on the surface of flu viruses — and replacing it with another. The process is called reassortment, and, in this case, it resulted in the emergence of a lot of new pairings over a fairly short period of time.
The most common and most dangerous viruses to emerge — for birds at least — have been H5N6 and H5N8 viruses. Both are highly pathogenic, meaning they kill domestic poultry.
“The H5N1 virus has not gone away. It’s just changed into different versions of itself,” explained influenza expert Malik Peiris, a professor of virology at the University of Hong Kong.
“We don’t know how the story’s going to end.”
Nancy Cox, led the CDC's influenza operations for more than two decades
Peiris suggested it might be a mistake to see the evolution of the virus as nothing but a positive development.
“It is good news, the fact that overall the H5N1 problems have reduced,” he said. “But you know, you can look at it the other way around. So now we have two high pathogenic [H5] viruses kicking around.”
H5N6 viruses have infected about two dozen people since first being spotted in 2014; roughly half of those cases have been fatal. To date, no human infections with H5N8 have been detected.
“I think the dominant viruses now are probably less infectious for humans than the dominant viruses five years ago,” said Richard Webby, who heads the World Health Organization’s Collaborating Centre for Studies on the Ecology of Influenza in Animals and Birds, located at St. Jude Children’s Research Hospital.
He also noted that, while bird flu may no longer be in the headlines, it very much still remains a concern for influenza experts.
“We still certainly worry about it. Today it doesn’t do very well. But two or three mutations later, we don’t know,” Webby said.
That uncertainty is amplified by a biological quirk of the H5 viruses. They are able to infect a wide variety of birds — not just domestic poultry but ducks and migratory birds such as some types of geese. The wild birds have moved the viruses over vast swaths of the globe and continue to contribute to their evolution. Just days ago a crow die-off in eastern India was attributed to H5N1.
That host diversity phenomenon also complicates control efforts, said Peiris, who noted H5 poultry vaccines have not been as effective as those developed to combat H7N9. “Poultry vaccines are much less effective in ducks and these viruses tend to reassort and change much more rapidly in ducks as well,” he said.
H7N9, on the other hand, has been pretty much exclusively plagued poultry to date. And there, poultry vaccines can likely be credited, or at least credited in part, for the sharp decline in human infections, experts said.
In 2017, after failing for several years to contain geographic spread of the virus, China instituted a policy of vaccinating chickens. It helped significantly slow spread of the virus.
China had an added incentive to take action. While H7N9 viruses had been low pathogenicity viruses — they weren’t killing chickens — in the first few years of the outbreak, by 2017 the viruses were evolving to become highly pathogenic.
“Many people are surprised at how effective it has been,” said Peiris of the H7N9 vaccination effort. In fact, he noted that its apparent success has led some people to question whether Chinese authorities are underreporting cases. He doesn’t believe that to be the case.
If H7N9 doesn’t adapt to be able to infect wild birds — a development that cannot be ruled out — the prospects for its control with poultry vaccines seem good. Said Webby: “With the biology of the current H7s, I’m a little more optimistic that control is a possibility.”
But whither H5N1? Its earlier aggressive spread among poultry flocks and across countries took everyone by surprise, and even years later, no one wants to underestimate this virus.
At its twice-a-year gathering of influenza experts to determine which flu viruses manufacturers should be ready to develop vaccines for, the WHO still devotes time for discussion about which H5 viruses pose the greatest threat. And an H5N1 virus is in fifth spot in a CDC risk assessment ranking of flu viruses with pandemic potential. (The first two spots are held by H7N9 viruses.)
This refusal to write off a seemingly passé threat reflects a truism of influenza science. You cannot say a flu virus can’t do X or will never do Y. You can only say: It hasn’t done X or Y yet.