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nfluenza viruses are among the most unpredictable disease actors around. These constantly changing germs regularly humiliate anyone who is rash enough to forecast the potential severity of an upcoming flu season or how well — or poorly — the vaccine might work this year.

“I wouldn’t,” Dr. Kanta Subbarao, director of the World Health Organization’s influenza collaborating center in Australia, said with a laugh when asked what she would project the Northern Hemisphere might be facing, flu-wise, in the coming months. “I’ve been in this business too long to fall into the trap of trying to predict.”

That said, flu experts are a bit worried right now. There are some signals they think may foretell that we’re facing a nasty flu season. But they hand-to-heart don’t know whether the constellation of things that is worrying them will lead to clogged doctors offices.

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STAT talked to Subbarao and other flu experts about the coming flu season. Beyond the basics — there will be a wave or two of flu activity sometime between now and next spring, and the people caught up in the wave will curse the virus — we cannot tell you what’s going to happen. But we can explain why experts are on edge.

Here are three things they’ve been watching.

The Southern Hemisphere had a nasty flu season

In the flu world, scientists in one hemisphere keep a close eye on the other to try to figure out what might be headed their way.

And during their 2017 winter, parts of the Southern Hemisphere, including Australia, had a pretty nasty flu season. Hong Kong and some other places in the tropics have also experienced a surprising amount of flu of late.

The illness has been caused mainly by H3N2 viruses, which trigger the worst outbreaks of the two influenza A viruses and two types of influenza B viruses that circulate among people. Flu seasons in which H3N2 viruses dominate are typically miserable, with lots of hospitalizations and more deaths.

“At this point the data look like it was a big season. Started earlier than usual, lasted a bit longer. … And all segments of the population were affected, including people who were vaccinated,” Subbarao said of the Australian winter outbreak.

The severity of the flu in at least some parts of the Southern Hemisphere has created concern a similar assault is heading toward the Northern Hemisphere.

But there’s a complicating factor: Last winter North America had a pretty active flu season, caused mainly by H3N2 viruses. So did countries in the Southern Hemisphere follow us? Or are we about to follow them?

“That’s the million-dollar question,’’ Sabbarao said.

People who were infected by the virus last year are less likely to fall prey to it again this winter. So the amount of illness experienced in North America last year could blunt the impact of this season, if another H3N2 onslaught is headed our way, suggested Jacqueline Katz, deputy director of the influenza division at the Centers for Disease Control and Prevention.

“I’ve been in this business too long to fall into the trap of trying to predict.”

Dr. Kanta Subbarao, World Health Organization

But we could be facing a season in which H1N1 viruses — which tend to cause less severe outbreaks — dominate. Or we could have what’s known as a mixed season, with all the flu viruses that infect people taking a substantial share of the pie.

There have been few mixed flu seasons in recent years, noted Dr. Daniel Jernigan, director of the CDC’s influenza division, who added — perhaps hopefully — “It could be if that trend follows that maybe we’ll have an H1N1 year.”

What’s the likelihood we would suffer through back-to-back H3N2 seasons? Dr. Danuta Skowronski, a flu expert with British Columbia’s Center for Disease Control, said that does happen on occasion. And the second or third wave of H3N2 can actually be worse than the season or seasons that proceeded it.

“The bottom line is you should never say never with influenza,” Skowronski said.

The flu vaccine is probably not an optimal match

Late last month leading flu experts from around the world — Katz and Subbarao among them — met at the World Health Organization for a twice-annual ritual. They selected the viruses that should be covered by the winter 2018 Southern Hemisphere flu vaccine, using recent viral surveillance data from flu laboratories around the globe.

It takes months to make and distribute flu vaccine, which is updated regularly in an effort to keep pace with the ever-changing viruses. The strain selection meeting for the Northern Hemisphere vaccine takes place every year in late February.

Rather than recommend a flu shot with the same composition as the ones clinics, pharmacies, and doctors’ offices in the Northern Hemisphere are injecting right now, the experts decided to update two of the target viruses. Interpretation: The Northern Hemisphere shot is already a bit out of date.

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That happens more often than experts would like. Sometimes the differences between the viruses in the shot and the circulating viruses are significant; in those years, lots of people who got vaccinated get sick anyway, and there are lots of headlines about flu shot “mismatches.”

The H3N2 component of the vaccine was one of the ones that was updated. In light of the damage that family of viruses does, that’s not a terrific sign. But Katz said the update was “incremental” rather than a big switch, so perhaps that component of the vaccine won’t be way off target.

It’s worth remembering, however, that the H3N2 component we’re getting now was in the winter 2017 Southern Hemisphere flu shot. And as Subbarao noted, some of the people who got sick in Australia had been vaccinated. If the H3N2 viruses that circulated in Australia head to North America, that component of the vaccine will offer some protection “but it won’t be optimal,” she said.

Last winter’s flu shot contained the identical H3N2 component, and even then it only provided moderate protection, Skowronski noted. Studies in the U.S. and Canada estimated the H3N2 component of the vaccine reduced infection risk by 34 percent and 37 percent, respectively. Given that these viruses have continued to evolve away from that target, Skowronski warned the H3N2 component would not be expected to perform better this year.

“Don’t consider yourself invincible if you received the vaccine,” she cautioned. “Because there are signals to be concerned about in terms of the possible [H3N2] protection this season.”

She suggested people who are at high risk of getting really sick if they catch the flu might consider asking their doctor in advance for a prescription for an antiviral drug like Tamiflu that they could fill quickly if they need it.

That only really matters, however, if there is a lot of H3N2 activity this year.

The repeat vaccination problem

In recent years, Skowronski and others have been noticing a surprising phenomenon. Some winters people who were vaccinated two seasons (or more) in a row seem to be more apt to contract the flu than people who were only vaccinated in the season under study.

The still-emerging theory suggests that when people are revaccinated with the same target virus or viruses, their immune system doesn’t generate as many antibodies as when it is presented with a new target. Then if the viruses they encounter are different from the viruses in the vaccine, the fact they generated fewer antibodies puts them at higher risk of infection. (You can read more about this issue here.)

This year’s Northern Hemisphere flu shot contains the exact same H3N2 component as last year’s. And as the updating of the Southern Hemisphere vaccine signals, the H3 viruses have mutated. So the repeat vaccination effect may be a factor this winter, Skowronski suggested, adding that public health authorities should be on the lookout.

“There should be systems in place to assess that at the earliest possible opportunity,” she said.

Again, though, that only matters if there’s a lot of H3N2 activity this season.

“It will be an interesting year from many perspectives,” Skowronski predicted.

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