Despite viruses' reputation as constant shape-shifters, the recent pandemic flu (influenza A H1N1, 2009) bears an uncanny resemblance to the 1918 flu, new research has found. Two new studies, published online March 24 in Science and Science Translational Medicine, describe a small, but crucial structure that the two flu viruses share—and how that similarity might help prevent future outbreaks.

"Although the swine flu has a very different genetic composition and makeup within the inside, on the outside, this particular protein, which is called the hemagglutinin, looks very similar between the 1918 influenza virus and the swine flu," Ian Wilson, of the Department of Molecular Biology at The Scripps Research Institute in La Jolla, Calif. and co-author of the Science paper, explained in a podcast interview with Science.

These hemagglutinin look like tiny spikes on the virus's surface and are responsible for infecting other cells, but when an immune system learns to recognize a certain spike pattern on a particular virus strain, it will start an attack and usually prevent infection. Most circulating seasonal flu viruses have developed sugars on their surface that hide their hemagglutinin signatures, thereby helping them better evade the immune system's recognition.

Researchers in both of the new studies found that the 1918 flu (also an H1N1 strain) and the 2009 flu had so-called "bald head" hemagglutinin that weren't covered by sugars, but were instead nearly identical and easily recognized by an immune system that had been exposed to either. In fact, in the Science Translational Medicine study led by Chih-Jen Wei, of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health, a team of researchers vaccinated groups of mice against either the 1918 strain or 2009 strain and then exposed each vaccinated mouse to the other virus. It turned out that exposure to either conferred protection against both, the researchers concluded.

"This was a surprising result," Gary Nabel, also of NIAID and a coauthor on the Wei study, said in a prepared statement. "We wouldn't have expected that cross-reactive antibodies would be generated against viruses separated by so many years."

This physical similarity would better explain why the 2009 pandemic flu proved to be more infectious—and deadly—to people under the age of 65. Those who were born in the early 20th century likely came into contact with either the pandemic strains of the 1918 virus or later seasonally circulating versions of it, and thus their immune systems recognized the 2009 H1N1 strain.

Many scientists consider the appearance of an H1N1 pandemic good luck in a sense. As Wilson pointed out in the podcast interview with Science, "There are 16 different possible types of H. You can have H1 to H16…. In the last century we've only actually had three of these H numbers (the H1N1, the H2N2, the H3N2)." And the appearance of an as-yet uncirculated variation, such as H16, as a human pandemic would likely prove more infectious because no previous group—or "herd"—immunity would exist.

The reason H1N1 was able to return to the human population as a pandemic flu—even after it had been circulating several decades ago—has a lot to do with the pattern of virus evolution in animals, explained a team of researchers for Novartis Vaccines and Diagnostics led by Rino Rappuoli in an essay that accompanied the two Science studies. Animals such as pigs and birds, which harbor many diseases that have been known to jump to humans, put little evolutionary pressure on viruses to change because the animals themselves have relatively short lives. Thus each individual animal is unlikely to develop immunity to many viruses—unlike humans, who carry immunity for decades, forcing viruses to mutate in order to continue being infectious. "Birds and pigs harbor an archive of well-preserved antigenic types," the Novartis researchers wrote, which means that as overall human immunity to a strain still circulating in animals decreases, it is more likely to reemerge in humans.

"The pandemic teaches us that a main driver of influenza evolution is not to find new solutions but to reuse the same solutions as herd immunity wanes," Rappuoli and his colleagues noted. "This, in principle, is good news for vaccine development, because vaccination against viruses present in the animal reservoirs could prevent some future pandemics."

In the meantime, the 2009 H1N1 pandemic virus is likely to become resistant to the vaccine developed and distributed for this flu by the very difference Wei et al. observed in other strains: by developing sugar coating on the previously bare hemagglutinin sites, and thus becoming a circulating seasonal flu strain.

But the new findings also offer hope that researchers might be able to detect other structural similarities across various viruses. Wilson and his colleagues are currently investigating this, he explained in the Science podcast. And if they find any, "that would lead us along the road to a more universal vaccine," he noted.

Image of pandemic H1N1 [left] and seasonal H1N1, with the same red hemagglutinin (red) circled in pink—the hemagglutinin on the right is partially hidden by the sugar layer common in seasonal influenza strains, courtesy of Jeffrey Boyington/Gary Nabel