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Outwitting Influenza

Researchers are plotting strategies against the next major flu outbreak using clues from the 1918 virus.

When the H1N1 virus swelled into a pandemic last year, it seemed to defy the rules: Not only was it completely resistant to the seasonal flu vaccine, but it also seemed least dangerous to people over 65 years old–the very population that’s usually most susceptible to influenza. Now, two new studies that take a look at the structure of the swine flu virus begin to explain why. And in the near future, they could also help inform vaccine development.

Shape shifter: Seasonal viruses typically have outer envelopes studded with sugar-attachment sites (blue) that help deflect immune attacks. But the pandemic influenza virus shown here–a composite of both 1918 and 2009 viruses–has three antibody binding sites (red) that lack sugars.

The research, published today in Science Express and Science Translational Medicine, offers both a structural and chemical close-up of the 2009 H1N1 virus. In fact, both studies examine hemagglutinin, a protein found on the surface of virus particles that activates the human immune system’s protective response. The results reveal remarkable similarities between both pandemic-causing swine flu and 1918 Spanish flu viruses, two fast-spreading troublemakers separated by more than 90 years.

Influenza has a well-earned reputation for speedy evolution–hemagglutinin mutations allow the virus to effectively evade the human immune response and reinfect the same population every year. But despite the near-century-long gap between the 1918 and the 2009 viruses, they have surprisingly similar hemagglutinin structures. In research led by Ian Wilson, a structural immunologist at the Scripps Research Institute in La Jolla, CA, x-ray crystallography shows that the two viruses share a near-identical binding site for the flu-fighting immune proteins called antibodies. Together with colleagues at Vanderbilt University, Wilson shows that an antibody isolated from someone who survived the 1918 pandemic was equally effective at attacking and neutralizing the 2009 virus.

“We looked at the site the antibodies respond to in the 1918 virus, and that site was completely conserved in the novel H1N1,” Wilson says. “There are similarities between the 1918 influenza virus and the recent swine flu, at least at the level at which our immune system recognizes these different viruses.”

The structural similarities explain why the 2009 H1N1 virus was having a reverse age-group effect. “We all realized we weren’t seeing the mortality rates that we’d expect to see in elderly people, and now we know why. These viruses share a characteristic in their most important protein,” says flu specialist Greg Poland, director of the Mayo Clinic’s Vaccine Research Group, in Rochester, MN, who was not involved with the research.

The second study, led by virologist Gary Nabel of the National Institute of Allergy and Infectious Diseases, also found striking similarities between the two pandemic viruses as well as one shared difference from the seasonal flu viruses that have been circulating for the last few decades. When Nabel and colleagues found that immunizing mice against the 1918 flu also protected them from the new 2009 virus–a result explained by Wilson’s research–they, too, took a hard look at the viruses’ structure.

Typically, one of the ways the influenza virus fends off antibody attacks is by using sugars called glycans as a shield, covering the hemagglutinin rather “like an umbrella,” Nabel says. He and his colleagues found that both the 1918 and the 2009 H1N1 viruses lack glycans at the tip of their hemagglutinin proteins.

Viruses use these glycans mainly to hide from the human immune system; such measures are unnecessary in pigs and birds, which have shorter lifespans and tend not to be infected more than once. But in humans, adding sugars allows the virus to mutate and attack the same person multiple times. “Because humans live longer than one or two flu seasons, there’s more pressure on the virus to evolve mechanisms to escape antibody response, and one way to do that is by acquiring glycans,” says Richard Webby, who specializes in flu virology and ecology at St. Jude’s Research Hospital in Memphis, TN.

In the two pandemic viruses, the lack of glycans indicates a very recent jump from animals–so recent that they hadn’t yet had time to evolve. That worries Nabel. He is concerned that as the 2009 virus morphs, attaching sugars to better evade detection, it will become a more dangerous flu. When he and his collaborators forced the virus to evolve in the laboratory, attaching glycans to the sites where none currently exist, they found that the resulting viruses were resistant to the current H1N1 vaccine.

“That’s a great concern, because it says that it’s very likely this 2009 virus isn’t going to stop dead in its tracks. It’s going to find ways to outwit the human immune system,” Nabel says. In fact, he points out, it already has. Four strains of H1N1 have now been found in Russia and China that indicate the addition of glycans has already occurred, just as the researchers predicted.

But predicting evolution also means that it’s possible to vaccinate against it. When the researchers immunized mice against their lab-evolved strain of H1N1, the mice generated an effective immune response. “So we actually have a way of trying to anticipate what the virus might do, and developing vaccines that would be effective against the change,” Nabel says.

“We change the vaccine every year because these viruses drift so frequently. And yet, an important element of this particular virus was conserved for 90 years,” says the Mayo Clinic’s Greg Poland. “Now you have a marker to try and understand viral evolution and how that plays out in terms of the human experience with that virus.”

Nabel and others believe it could also inform vaccination protocol. If the cause of H1N1’s virulence was due to a lapse in our “herd” immunity, with too much time elapsed since the last time it circulated, the researchers propose that it might be worth considering regular vaccinations with prior pandemic strains–using history to predict viral evolution and inform vaccine development.

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