Normally, our body is well equipped to deal with influenza; our immune system can ward off infections, causing no more than a few days of discomfort. However, once every few decades, a new strain of rapidly spreading influenza emerges. New research suggests that should such a pandemic occur, we may be able to predict our chances of survival based on the year we were born in and the flu we were exposed to as children.

[3-D model of flu virus in yellow blue and red]Share on Pinterest
A 3-D print of an influenza virus shows how its surface (yellow) is covered with proteins called hemagglutinin (blue) and neuraminidase (red) that enable the virus to enter and infect human cells.
Image credit: National Institutes of Health

The 1918 flu pandemic killed over 20 million people, more than twice the number of people killed in the First World War. In the United States, the estimated death toll was 675,000, according to the Centers for Disease Control and Prevention (CDC).

More recently, H5N1 and H7N9 have caused the highest number of flu-related illness and death worldwide, the CDC report. In May 2013, the World Health Organization (WHO) reported 131 human cases of H7N9 influenza, of which 24 resulted in death.

The Asian H5N1 was first diagnosed in the Americas in Canada in January 2014. Although human cases are very rare, when they have occurred, about 60 percent of them ended in death.

Both of these viruses have caused severe respiratory problems, such as pneumonia and respiratory failure.

Until now, scientists thought that the virus you were exposed to as a child was irrelevant in predicting immunity to viruses that are transmitted from animals to humans.

New research – published in the journal Science – suggests that, on the contrary, the kind of flu virus we are exposed to as children predicts what avian-origin flu virus we will be protected from later in life.

Researchers from the University of Arizona in Tucson, in collaboration with the University of California-Los Angeles, examined two types of “bird flu” viruses, H5N1 and H7N9. Both of these strands have caused severe illness and death in humans, and they have the potential of spreading very quickly from animals to humans and among human hosts.

When someone gets a flu virus for the first time, the body produces antibodies that target hemagglutinin.

Hemagglutinin is the reason why a flu virus can spread so quickly. It is a protein that sticks out from the surface of the virus, targeting, attacking, and clumping together red cells. The name “hemagglutinin” refers to this protein’s ability to agglutinate red blood cells.

Virus types differ according to the type of hemagglutinin they have. There are only two main types of hemagglutinin and each of the 18 known types of influenza A virus falls into one of these two types.

One type of influenza virus includes human H1 and H2 viruses, as well as the avian H5 virus, and the other includes human H3 and avian H7.

Michael Worobey, the head of the Department of Ecology and Evolutionary Biology at the University of Arizona and senior author of the study, explains their results with the help of an analogy.

Say the two types of hemagglutinin are like two different flavors of a lollipop, he suggests.

“In this analogy, let’s say you were first exposed to a human ‘orange lollipop’ flu as a kid. If later in life you encounter another subtype of flu virus, one from a bird and one that your immune system has never seen before but whose proteins also are of a similar ‘orange’ flavor, your chances of dying are quite low because of cross-protection. But if you were first infected with a virus from the ‘blue lollipop’ group as a kid, that won’t protect you against this novel, ‘orange’ strain.”

Michael Worobey

This so-called immunological imprinting seems to depend exclusively on the very first exposure to a flu virus and is quite difficult to reverse.

This study explains why some age groups have been more prone to severe or fatal complications from an infection with new flu viruses. For instance, the Asian H5N1 virus has caused the higher mortality rates in people aged 10-19 years old and young adults.

“All sorts of possibilities have been put forth, and here my colleagues from UCLA and I present a strong result showing that whatever other minor factors are at play, there is one really major one, and that is – surprise, surprise – we’re not a completely blank slate when it comes to how susceptible we are to these emerging flu viruses,” says Worobey.

“Even if we’ve never been exposed to H5 or H7 viruses, we have some kick-ass protection against one or the other,” he adds.

Knowing this information might help us predict which of the 18 subtypes of influenza will cause the next pandemic, as well as which age groups it will hit the hardest. It also sheds light on why some groups of people were affected harder than others during past pandemics.

Following the lollipop analogy, people born before the late 1960s were exposed to the “blue” virus as kids. Researchers found that these older individuals are resistant to H5N1, which shares a “blue” hemagglutinin, but instead often die from “orange” H7N9. Conversely, those born after the late 1960s are resistant to the “orange” virus but are severely affected by “blue” H5N1.

Worobey and team show that there is a 75 percent chance of protection against severe illness from a “matched” virus they were exposed to as children, and an 80 percent protection rate against death.

In the future, Worobey and collaborators hope to find ways to modify the immunological imprinting with a vaccine.

A vaccine could help us prevent the rare but serious instances of a flu epidemic.

“Even a comparatively weak, mild pandemic flu event like the 2009 H1N1 (swine flu) outbreak is a trillion-dollar affair,” says Worobey. “A major pandemic like the one we saw in 1918 has the potential to kill large numbers of people and shut down the world’s economy.”

The recent findings are both “good news” and “bad news,” Worobey says.

“It’s good news in the sense that we can now see the factor that really explains a big part of the story: your first infection sets you up for either success or failure in a huge way, even against ‘novel’ flu strains. The bad news is the very same imprinting that provides such great protection may be difficult to alter with vaccines: a good universal vaccine should provide protection where you lack it most, but the epidemiological data suggest we may be locked into strong protection against just half of the family tree of flu strains.”

Michael Worobey

Read about the recently identified protein that allows flu virus to replicate in cells.