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Why the flu hit hardest in middle-aged adults last year

Previous influenza infections in childhood may be the culprit, study finds

Oct. 20, 2014
The flu hit hardest in middle-aged adults last year

Only 37 percent of adults aged 18-64 got a flu shot last year, according to the Centers for Disease Control and Prevention.

Photo by Justin Sullivan / Getty Images file

Last year’s flu season was particularly brutal, and a surprising population was hit the hardest: young and middle-aged adults. New research suggests that an immune response unique to this age group may be to blame for last year’s flu toll and points to possible improvements to the annual vaccine.

That poor immune response was shaped by the flu strains that people born before 1985 were exposed to in childhood, according to new work led by researchers at The Wistar Institute that involved investigators from Fred Hutchinson Cancer Research Center and elsewhere.

Normally, influenza takes the highest toll on the very young and very old, who have weaker immune systems than healthy young and middle-aged adults. But in 2013-2014, 60 percent of flu deaths and 61 percent of flu-related hospitalizations in the U.S. were among those aged 18-64, according to the Centers for Disease Control and Prevention.

There are a lot of people in that age range, but those death and disease rates were far larger than normal – in 2012-2013, in contrast, only 18 percent of flu deaths and 35 percent of flu-related hospitalizations occurred in young and middle-aged adults.

“Last year was a very different year,” said Dr. Scott Hensley, a virology researcher at The Wistar Institute who led a study published today in the journal Proceedings of the National Academy of Sciences that examined how the middle-aged respond to the flu. For the first time since the pandemic H1N1 strain emerged in 2009, last year’s U.S. flu season was dominated by H1N1, Hensley said. He wondered whether differences in immune reactions to that strain might have triggered the unusually severe illnesses.

Researchers speculated that reticence toward vaccination among healthy adults may have contributed to the severe flu in this age group – only 37 percent of adults aged 18-64 got a flu shot last year, according to the CDC – but that doesn’t explain the sudden uptick in infections between two years ago and last year, Hensley said, as this age group had low vaccination rates in previous years as well.

Shaped by the past

Instead, Hensley and his team found that many people in their 30s and 40s make antibodies to H1N1 that binds to a part of the virus that has recently mutated. Such antibodies can’t effectively recognize and eliminate today’s H1N1; thus, people who harbor those antibodies may be more likely to get infected with the virus and become sicker from those infections.

The scientists looked at blood samples from 195 healthy volunteers, and found those antibodies in 42 percent of people born between 1965 and 1979. The scientists found no such antibodies, however, in those born between 1985 and 1997.

 “We think that the virus preferentially infected middle-aged people last year not so much because they didn’t get the vaccine … but rather because the virus has evolved in a way that their antibody responses were no longer effective,” Hensley said.

Those antibodies target a part of H1N1 that no longer exists. Hensley believes such antibodies were primed by H1N1 strains circulating in the late 1970s and early 1980s. Those born after 1985 saw a different type of flu.

Although today’s H1N1 is very different from pre-1985 H1N1, young and middle-aged adults’ immune systems were shaped by their childhood exposures. When someone is infected with a virus they’ve seen before, the immune system tends to pump out antibodies created during the first infection. That immune memory normally helps fight off secondary infections faster, but that memory can occasionally backfire if the virus has mutated in the right way to evade those original antibodies – as happened with last year’s flu.

“If [the viruses] change enough, you can get reinfected with them,” said Dr. Jesse Bloom, an evolutionary biologist at Fred Hutch and one of the study authors.

Ferreting out the complexities of human immunity

We need new flu vaccines every year to match the rapidly changing strains, but the H1N1 strain used in vaccines hasn’t changed since 2009, as researchers thought the virus hadn’t changed enough to dampen the vaccine’s protective power.

World Health Organization researchers test different flu strains on ferrets to choose which strains to include in the annual shot. In the laboratory tests to choose last year’s vaccine strains, ferrets infected with H1N1 made antibodies to a different section of the virus, a part that has not changed significantly since 2009.

However, the scientists found that many people born before 1986 did make antibodies to the mutated part of H1N1 when vaccinated. The scientists think this difference is because, unlike most human adults, the animals used to test vaccine strains have never before been infected with the flu.

The flu vaccine selection process as it stands “may not completely capture the complexities of human immunity,” Bloom said.

Through computational analyses, Bloom found that H1N1 mutated in the last two years to evolve away from this older antibody, meaning this virus now looks very different to the immune systems of people in a certain age group.

If someone was first exposed to H1N1 in 2009, Bloom said, this year’s strain will look very similar to that person’s immune system. “But if you’re someone who has an immune system that is already skewed by having been infected with this virus prior to 1985, then the ways that the virus has changed between 2009 and the present make it look different to your immune system,” he said.

The scientists think that recent mutation may be why H1N1 was able to take over the population once again last year, after its four-year dip.

Updating flu vaccine may help

Although this year’s flu vaccine still contains the 2009 H1N1 strain, Hensley thinks the 2014-2015 season won’t necessarily be so harsh for young and middle-aged adults. It’s too soon to tell which strains will prevail in the upcoming flu season, but often a “strong H1N1 year” is followed by a year dominated by the H3N2 strain, Hensley said – and there’s no evidence to suggest that this age group will be uniquely affected by H3N2.

Hensley stresses that those born before 1985 should still get the flu shot, not just because it contains other flu strains such as H3N2, but because not everybody makes those poorly functioning antibodies in response to H1N1. But these new findings strongly suggest that the newly-mutated H1N1 strain should be included in shots going forward, he said. His team is now working on experiments testing whether that new H1N1 strain spurs production of protective antibodies in middle-aged people.

In the meantime, “all age groups should definitely continue to receive the vaccine this year,” Hensley said.

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Dr. Rachel Tompa, a staff writer at Fred Hutchinson Cancer Research Center, joined Fred Hutch in 2009 as an editor working with infectious disease researchers and has since written about topics ranging from nanotechnology to global health. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Reach her at rtompa@fhcrc.org.

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