People in public health hate H3N2 flu seasons, like the one gripping most of North America right now. So do folks who work in hospitals and in the care facilities that look after the elderly.
To put it flatly, H3N2 is the problem child of seasonal flu.
It causes more deaths than the other influenza A virus, H1N1, as well as flu B viruses. It’s a quirky virus that seems, at every turn, to misbehave and make life miserable for the people who contract it, the scientists trying to keep an eye on it, and the drug companies struggling to produce an effective vaccine against it.
“H3 viruses dwarf the contribution of H1 to overall epidemic burden [of influenza] in terms of hospitalizations, care facility outbreaks, deaths. I think uniformly in public health we dread H3N2 epidemics over and above those due to H1N1,” said flu expert Dr. Danuta Skowronski, an epidemiologist with the British Columbia Center for Disease Control.
Dr. Daniel Jernigan, head of the influenza division at the Centers for Disease Control and Prevention, concurred.
“We just know, over the last several years, when we have an H3 season, it’s unfortunately causing worse disease. But also the vaccine’s effectiveness [targeting it] is not as high as the other components. And so for that reason, even though you’ve been vaccinated, you still can get infected,” Jernigan recently told STAT.
So why is H3N2 such a bad actor? Here are a few reasons why.
H3N2 is especially hard on seniors. As Skowronski noted, whenever H3 viruses dominate in a flu season, there are a lot more outbreaks in long-term care homes and a lot of frail elderly people end up in the hospital, fighting infections that can progress to pneumonia. These are the seasons when flu’s death toll is highest.
Why is that? Is the virus more virulent than the other flu families that infect people? It could be, but that’s not 100 percent clear, said Dr. Ed Belongia, a vaccine researcher and director of the Center for Clinical Epidemiology and Population Health at Wisconsin’s Marshfield Clinic.
There’s long been a theory—and it appears to be gaining ground—that a person’s ability to fight off flu infections is based on their previous experiences with influenza. More specifically, their earliest experiences with flu. It’s thought that the first flu viruses that infect you leave an imprint on your immune system’s memory; if correct, the notion is that you’ll always be able to fight off viruses similar to your first flu foes better than you will other types of flu viruses.
The concept is called original antigenic sin, though the term imprinting is also used.
H3N2 viruses first emerged during the pandemic of 1968—the so-called Hong Kong flu. That means people who are over 50 had their flu immune response set by other viruses, either the H2N2 viruses that circulated from 1957 to 1968, or H1N1 viruses that circulated from 1918 to 1957 and are ancestors of the H1 viruses still circulating today.
Combine with that the fact that people over 50—and especially people in their 70s, 80s, and beyond—are less healthy and have less robust immune systems. They may have health conditions like diabetes, chronic obstructive pulmonary disease, or heart disease. They have a harder time shaking off an illness like the flu.
“People born before 1968 were not imprinted with an H3N2 virus. So they may have increased susceptibility [to it] as well as, by virtue of their age, have greater vulnerability, just through complications. So that could be totally independent of whether the virus itself is more virulent or not,” Belongia said.
H3 is the vaccine’s weak link
It’s increasingly common to hear people complain about the sometimes suboptimal performance of influenza vaccine. And mostly that’s because of the H3N2 component of the vaccine, which protects against either four (both influenza A viruses and both influenza B viruses) or three (the two As and one B) viruses.
“We don’t have a flu vaccine problem so much as we have an H3N2 vaccine problem,” Belongia said.
He and colleagues published a meta-analysis in 2016 that combined data from flu vaccine effectiveness studies done between 2004 and 2015. On average, the H3N2 component of the vaccine protected about 33 percent of the time. The component that protects against H1N1 was nearly twice as effective.
The egg issue
At least part of the reason why the H3N2 component of the vaccine doesn’t work that well is because these viruses don’t grow very well in eggs, the main production method for flu vaccine.
The viruses, which have evolved to infect people, have to adapt to grow in the cells of another species. And with the H3 viruses, scientists have seen that the mutations that arise in that process can occur on critical parts of the virus. The end result: The vaccine trains an immune system to look for viruses that look different than the ones that are actually circulating.
“I think uniformly in public health we dread H3N2 epidemics over and above those due to H1N1.”
DR. DANUTA SKOWRONSKI, FLU EXPERT
Scott Hensley, an associate microbiology professor at the University of Pennsylvania, has conducted some of the research that has shown that egg-induced mutations arise. But he thinks it only goes part of the way to explaining why the H3 vaccine component underperforms.
“There’s something magical about childhood. These first infections you get as a child seem to set up how you will respond immunologically … later in life,” he said, referring back to the imprinting issue.
Still, the H3 part of the vaccine doesn’t just work poorly in older adults. Last year adults aged 18 to 49 got very little protection—13 percent—from the H3 component, according to CDC data.
H3 has attachment problems
In the 2014-2015 flu season, scientists noted an unexpected and inconvenient change in H3N2 viruses. These viruses can no longer be studied using a standard test used in influenza research.
Flu viruses typically bind to blood cells, and scientists take advantage of that phenomenon to test whether antibodies generated against a virus—either by previous infection or vaccination—should protect against future infection. This type of testing is used to determine if the virus targets in flu shots need to be updated.
But H3 viruses no longer bind to blood cells.
“Turkey red blood cells, chicken red blood cells, guinea pig red blood cells—they just don’t bind to these red blood cells very effectively,” Hensley said.
There are other types of tests that can be used, but they’re more labor intensive, which means fewer tests can be run.
H3 is a quick-change artist
All influenza viruses are constantly mutating; it’s how they manage to infect humans repeatedly over a lifetime. But they don’t all do it at the same pace.
And H3N2 evolves at a more rapid rate than H1N1 or influenza B viruses, said Sarah Cobey, a computational biologist at the University of Chicago.
A faster mutation rate affects how often the H3 component of the vaccine needs to be updated. And it is probably having an impact on how well this part of the vaccine works, said Cobey, who is studying what effect these more frequent changes have on the aforementioned imprinting process.
“I think that is important because I think that is exacerbating these original antigenic-sin-like effects,” she said. “We think that ‘sin’ is reducing the effectiveness of the vaccine, independently of these egg adaptations.”
H3 is persistent
For a long time, it was flu dogma that only one influenza A virus could circulate at once. The H1N1 virus that caused the 1918 Spanish flu disappeared when the H2N2 virus that touched off the Asian flu pandemic emerged in 1957. Then in 1968, H3 muscled out H2.
But in 1977, something odd happened. H1N1 reappeared—likely as the result of a laboratory accident. And what was thought to be impossible—two influenza A strains circulating at the same time—was shown to be possible.
When the 2009 pandemic started, flu researchers hoped it would push the reset button. They hoped the new virus—an H1N1 virus that had been circulating in pigs—would drive out both the old H1N1 and H3N2.
The old H1N1 viruses did disappear. But H3N2 viruses didn’t budge. For the time being, we’re stuck with this unpleasant virus.
“The biggest challenge or frustration is that H3 … for whatever reason, is the virus that we see causing the most severe illness in large numbers of people,” said Belongia. “And it’s also the virus for which our vaccine is least effective. And so that’s a double whammy that so far we have not been able to adequately deal with.”