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Curing our Influenza Amnesia, May 17, 2012

Our brains are not the only places where we can store memories. Each time a new pathogen invades our bodies, our immune cells have an opportunity to recognize it by some feature, usually some distinctive cleft or spike of a protein on its surface. After our bodies defeat the infection, some immune cells are tasked with keeping the memory of that feature alive for years. If that same pathogen returns for a second attack, our bodies can launch a far faster counterattack.

We can tutor our immune systems with vaccines. Depending on the disease they protect against, vaccines may contain dead viruses, protein fragments, or some other substance derived from a pathogen. Our bodies then make antibodies against those substances, and some immune cells continue making those antibodies for years. For many diseases, our memories can endure like etchings in stone. Once children get shots for polio, they’re usually protected for the rest of their lives.

Unfortunately, the same can’t be said for the flu virus. When it comes to influenza, it’s as if we have short-term amnesia.

Every fall, doctors offices and pharmacies get a fresh load of influenza vaccines. Time and again, studies have demonstrated that flu vaccines are effective--but usually only for a single flu season. When the next flu season arrives, the viruses have changed, and we have little protection from the year before. We have to teach our immune systems yet another lesson.

This cycle of failure is due to the fact that flu viruses are masters of evolution. Each time they replicate in our cells, they have a high probability of mutating. Natural selection allows many of these mutations to accumulate in viruses, enabling them to escape our immune systems and replicate even faster.
Flu viruses evolve quickly for another reason: They can have a viral version of sex. When two different flu viruses invade a cell at the same time, the cell creates many copies of both sets of genes. The genes can get mixed up as they’re packaged in new viruses, and the result is hybrid flu.
As a consequence of all of this flux, the dominant flu strain that arrives at the start of a new flu season may be different enough that the previous year’s vaccine offers much less protection.

Every few decades, this cycle of flu evolution is punctuated by a dramatic change. All human flu viruses get their start as viruses that infect birds. From time to time, a bird flu strain gets into humans and adapts to our biology. A new bird flu strain can be particularly devastating, because human immune systems have never seen anything like it. The most devastating of these debuts was the arrival of H1N1 in 1918. An estimated 50 million people died in that great pandemic.

Influenza’s evolutionary malleability has created a nightmare for vaccine developers. In a regular year, they’ve had to guess in advance which strain will end up being the dominant player in the next flu season, and then tailor vaccines for it. If a new flu strain sweeps into humans, as happened in 2009, they have to create a new vaccine from scratch. The development of a vaccine against 2009 H1N1 was alarmingly slow. We were lucky that it was a relatively mild strain. We may not be so lucky next time.

For decades, vaccine developers have dreamed of a vaccine that would protect people again every strain of influenza for life. In 1993, scientists at Osaka University in Japan offered the first reason to hope that this might actually be possible. They infected mice with a strain of virus called H2N2. Flu virus names refer to the two kinds of protein knobs that stud their surface. The one that really matters to us is H, which stands for hemagglutinin. It’s a protein that the virus uses to latch onto the cell and then to slip inside it. There are sixteen different of hemagglutinins in birds, and three of them have ended up in human flu viruses.

The mice produced antibodies against the H2N2 flu, which the Japanese scientists isolated from their blood. They then added the antibodies to dishes of H2N2 viruses and host cells. When the antibodies grabbed onto the H2N2 viruses, the viruses could attach to the cells but could no longer invade them.
Then the scientists tried out the antibodies on other kinds of flu. To their surprise, the antibodies also blocked viruses with H1 hemagglutinin proteins.
Of course, two types of hemagglutinin are a far cry from the full range of sixteen known in nature. But the success of the Japanese researchers inspired other researchers to try to developing antibodies effective against more of hemagglutinins.

For fifteen years they made very little progress. But recently scientists have made some exciting advances. One of the most exciting results, published last August, came from a team of scientists from Switzerland and England. They took blood from volunteers who had just received flu shots. The vaccines switched the antibody-producing cells in their bodies, known as B cells. In the first few days after a vaccination, B cells produce lots of different antibodies before settling on just a few. The scientists isolated these exuberant B cells from the blood of the volunteers and harvested their antibodies. From that harvest, the scientists discovered one remarkable antibody, which they dubbed FI6. It was effective against eleven out of sixteen types of hemagglutinins.
To see why these antibodies were so broadly effective, the scientists looked at how the antibodies attacked the viruses. Traditional flu vaccines teach our immune systems to recognize the “head” of the hemagglutinin protein. That’s the part of the hemagglutinin protein that latches onto a host cell.

FI6 does something different, the scientists found. It grabs onto the “stem” of the hemagglutinin protein. The stem is what actually opens up a passageway in the host cell so that the virus can enter it.

It seems that traditional flu vaccines fail because the hemagglutinin head can evolve into different shapes, In its new forms, it can escape the immune system, but still be able to grab onto host cells. The stem, on the other hand, can’t work if it’s tinkered with too much. So the stem on one type of flu virus is a lot like the stem on any other. And an antibody against one stem may work against many others.

FI6 is not, on its own, a universal flu vaccine. But in the April issue of Current Opinions in Virology, Damian Ekiert and Ian Wilson of the Scripps Research Institute argue that it could lead to one. The first step on that path would be a search for more antibodies like FI6. There may be other ones that attack the stem of all sixteen hemagglutinin proteins.

Next would come the design of vaccines that could stimulate B cells to make these antibodies. Such a vaccine might contain “headless” versions of hemagglutinin proteins that would focus the immune system’s learning on the stem--and the stem alone.

A universal flu vaccine would probably not be a panacea. It would reduce the chances of getting influenza during a pandemic, but not eliminate them. But even that would be a tremendous achievement in the history of medicine. By curing our influenza amnesia, it would take another global pandemic off the table.

Copyright 2012 Carl Zimmer
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