Bird flu has ripped through the animal kingdom for the past few years now, killing countless birds and crossing into an alarming number of mammals.
Yet people remain largely untouched.
Even though the official tally of human cases in the U.S. is most certainly an undercount, there's still no evidence this strain of H5N1 has spread widely among us. But if the virus gains certain mutations, scientists fear it could trigger another pandemic.
This prospect has propelled research into whether our defenses built up from past flu seasons can offer any protection against H5N1 bird flu.
So far, the findings offer some reassurance. Antibodies and other players in the immune system may buffer the worst consequences of bird flu, at least to some degree.
"There's certainly preexisting immunity," says Florian Krammer, a virologist at Mount Sinai's Icahn School of Medicine who is involved in some of the new studies. "That's very likely not going to protect us as a population from a new pandemic, but it might give us some protection against severe disease."
This protection is based on shared traits between bird flu and types of seasonal flu that have circulated among us. Certain segments of the population, namely older people, may be particularly well-primed because of flu infections during early childhood.
Of course, there are caveats.
"While this is a bit of a silver lining, it doesn't mean we should all feel safe," says Seema Lakdawala, a virologist at Emory University's School of Medicine whose lab is probing this question.
For one thing, the studies can't be done on people. The conclusions are based on animal models and blood tests that measure the immune response. And how this holds up for an individual is expected to vary considerably, depending on their own immune history, underlying health conditions and other factors.
But for now, influenza researchers speculate this may be one reason most people who've caught bird flu over the past year have not fallen severely ill.
Earlier run-ins with flu can pay off
During the last influenza pandemic — the 2009 swine flu outbreak — people under 65 accounted for most of the hospitalizations and deaths.
This was a surprising pattern for influenza, which generally strikes the elderly hardest. Scientists attribute it to the fact that people had dealt with a similar version of flu that had circulated until about 1957.
"They were still getting infected, but they had an advantage," say Alessandro Sette, a researcher at the La Jolla Institute for Immunology. "This is very clear evidence that preexisting immunity against influenza can have a beneficial effect."
So could we hope for a similar phenomenon — this time with H5N1 bird flu?
Research published this month is encouraging.
By analyzing blood samples from close to 160 people, a team at the University of Pennsylvania and the University of Chicago were able to show that people born roughly before 1965 had higher levels of antibodies — proteins that bind to parts of the virus — which cross-react to the current strain of bird flu.
It's almost certain these people were never directly infected with that virus, meaning those antibodies can be traced to past seasonal flu infections.
"They had a much clearer signal of an antibody response" than those born later, says Sarah Cobey, a professor of ecology and evolution at the University of Chicago and senior author on the paper.
"What's driving that appears to be the viruses that people were infected with in childhood," she says.
This is known as "immune imprinting" — when your immune system learns to respond to viruses that are the same or quite similar to the ones that first infected you.
Between 1968 and about 1977, the flu strain going around was more distantly related to H5N1, so people born in those years didn't have the same antibody response. And the picture becomes mixed in the following years because multiple versions of flu were spreading.
Younger individuals, particularly children, could end up being the most susceptible in the event of a pandemic, although the existing bird flu vaccines could boost antibodies in that group significantly, Cobey and her colleagues concluded in their study.
"There's still going to be a lot of individual variation in what this disease could look like," she says. "If I were in my late 60s, I would still not be confident that this is necessarily going to be a mild disease for me."
Flu immunity guards against the 'worst virus' seen in animals
The Centers for Disease Control and Prevention and other researchers have found little to no evidence of past infections with H5N1 bird flu when they analyzed blood samples from the general population.
These tests focus on looking for antibody activity that would directly neutralize the bird flu virus. Other more fine-tuned measures, however, do turn up evidence that we are already familiar with and partly armed to fight this virus.
When battling an infection, the immune system makes antibodies that are targeted all over the virus.
For example, Cobey's study measured antibodies that bind to a particular part of a protein that covers the surface of seasonal flu virus in humans and bird flu. Hemagglutinin, or the HA protein, latches onto the receptors of a cell so that it can gain entry and replicate.
Lakdawala says you can picture the HA as a "lollipop."
The heads can be very different, but those sticks, technically called "stalks," can sometimes be quite similar. That happens to be the case for bird flu and H1N1, which emerged as one of the predominant subtypes of seasonal flu after the 2009 pandemic.
Antibodies directed against the stalks of H1N1 viruses can cross-react with H5N1, likely indicating some protection against severe disease.
Help may also come from antibodies aimed at the other dominant protein on the surface of influenza viruses, called neuraminidase.
In her lab, Lakdawala has recently run experiments on ferrets (a common stand-in for humans when studying respiratory disease) that suggest antibodies against this N1 protein — gained from previous seasonal flu infections — can also reduce severe illness when the animals catch bird flu.
"These animals all survived. They didn't get that sick. Importantly the virus remained restricted to the respiratory tract," says Lakdawala.
She says this was a sharp contrast to previous studies where scientists took lab animals with no immunity to any kind of influenza and infected them with the current strain of bird flu. In that scenario, the infection went systemic, traveling into the bloodstream and brain.
"People had described it as the worst virus they've ever put into an animal," she says. "So this offers a glimmer of hope."
Their results appeared in the journal of Emerging Infectious Diseases last month, alongside another ferret study showing immunity from H1N1 could also limit the spread.
A third piece of the immunity puzzle — what could also explain Lakdawala's findings — are T cells.
Unlike antibodies, these immune cells hunt down the virus once it has broken into a cell and started to replicate.
In a study published last year, Sette and his team tested blood samples collected from volunteers to identify whether their T cells that target fragments of the flu virus could do the same for H5N1 bird flu.
"There was a nearly complete cross-recognition," says Sette.
The reason, he explains, is that proteins inside both of these influenza viruses are quite similar. Those fragments end up decorating the outside of the cell once it's infected, which is how T cells recognize it.
"This is very hopeful, but we do not know how much cross-reactivity is necessary to impact disease severity," he says.
Many unknowns about how deadly a pandemic could be
Researchers caution you can only extrapolate so much about pre-existing immunity from these studies.
It's probably one of many factors that could be at play in the current outbreak including: a person's underlying health, whether they were exposed to a big "dose" of the virus, and the route of exposure.
And whatever mutations the virus gains in the future could change the risk calculus altogether.
There are already concerns a variant of the current strain, known as the D1.1 genotype, might be more lethal, partly because it's linked to several of the severe cases and the only death in the U.S. That variant had circulated widely in wild birds and gained attention recently after being detected in dairy cattle.
Lakdawala says her lab is still analyzing data on the D1.1 variant, but the initial results make her "hopeful" that their findings on pre-existing immunity apply here, as well.
Still, while there are reasons to believe at least some existing protection in the event of a pandemic or spillovers from livestock, scientists stress that bird flu is no joke. The historical record of known H5N1 cases offers a harrowing case fatality rate of about 50% among humans.
That's very likely an overestimate.
Milder cases were probably missed over the years, as appears to be the case during this current outbreak, says Lakdawala. "Because if it were [that high now], we would be capturing so many more of the infections."
But Krammer points out even a much lower fatality rate would be devastating: "You don't need a 50% case fatality rate to have a really bad pandemic, right? If you have 1 or 2%, that could also be very bad already."
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