Swine Flu Pandemic Reincarnates 1918 Virus

Researchers have found that the H1N1 swine influenza virus that last year caused the first human pandemic in 4 decades shares an important surface protein with the virus responsible for the 1918 flu, the deadliest in human history. This newfound similarity answers many mysteries about the 2009 pandemic, including why it largely spared the elderly.

A study published 24 March in Science Translational Medicine shows that even though nearly a century separates the widespread circulation of the two viruses in humans, mice given a vaccine against the 1918 strain produced antibodies that "neutralized" the novel 2009 strain. When the team flipped the experiment and used a 2009 pandemic vaccine in mice, the immune response stopped the 1918 virus. "We kind of did a double take," says virologist Gary Nabel, head of the VaccineResearchCenter at the U.S. National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, and the lead researcher on the project. "It was an unexpected finding, but it all makes sense when you look at the data collectively."

Influenza and the human body are like opposing Cold War spies, with the virus repeatedly donning new disguises, and the human immune system racing to foil each incarnation. The surface protein, hemagglutinin (HA), is the virus's main quick-change artist, easily adapting mutations to alter the way it looks to the immune system. Antibodies produced by the immune system, in turn, try to neutralize the various HAs by binding to them, blocking the virus from entering cells. As a rule, influenza viruses change so quickly that a vaccine against a regular "seasonal" strain circulating one year may have little impact against a similar strain a few years later. Yet the HA proteins on the 1918 and 2009 pandemic viruses look remarkably similar in close analyses done in both Nabel's study and a separate one published online this week by Science that includes x-ray crystallographic data. These two reports also clarify the evolution of seasonal strains in the decades between the two pandemics.

The two studies focus on the top part, or the head, of the HA, which is the business end of the protein when it comes to the infection process. Each research group calculated that the amino acids in the head of the two pandemic HAs were only about 80% similar, which is roughly the divergence seen between two seasonal strains. This would suggest that antibodies against the 1918 and 2009 pandemic strains would not cross neutralize. How then to explain the mouse results?

Nabel and colleagues took a closer look at the HA protein. A discrete region of the HA's tip that plays a critical role in binding to cells, they found, has a 95% similarity in amino acid sequence between the old and new pandemic strains. Comparisons between seasonal and the pandemic strains in this region found less than 70% similarity.

In the second study, a team led by structural biologist Ian Wilson of the Scripps Research Institute in San Diego, California, went further, linking the amino acid sequence analysis to the three-dimensional structure. Wilson's group crystallized the 1918 and 2009 pandemic viruses and showed that the HA heads had distinctly similar shapes. "The closest related structure that we have to the current 2009 swine flu is the 1918 structure," says Wilson.

Both the Wilson and the Nabel studies show that the HAs of the two pandemic strains also look markedly different from seasonal viruses when it comes to sugars on their surfaces. All seasonal strains have at least two "glycosylation" sites where sugars attach to the top of their HAs, whereas both the pandemic strains are bald. "The absence of glycosylation at the top of these molecules is making a huge difference in the immune response," says U.S. Centers for Disease Control and Prevention virologist Ruben Donis, who was not involved with the study. Specifically, the antibody that works against the bald 1918 virus stops the bald 2009 incarnation but does nothing to the sugared-up relatives that circulated in between those two pandemics.

The new studies are helping to clarify how influenza viruses have used sugars in their evolution since 1918, says U.S. National Institute of Allergy and Infectious Diseases virologist Jeffrey Taubenberger, a leading investigator of that devastating pandemic. "All the influenza viruses in humans are descendants of the 1918 virus," says Taubenberger, who published mouse experiments 8 March online in Influenza and Other Respiratory Viruses that similarly show how the 1918 virus protects against the 2009 pandemic strain. "Over the last 91 years, we've been in one large 1918 pandemic era."

Mutations in the HA can affect the structure of the protein and the clouds of sugars that surround it. By analyzing the difference in the earliest available seasonal HAs from 1933 to 2009, Nabel's group found that some amino acid mutations restructured the HA head, but after that the bald virus started accumulating new glycosylation sites. Nabel posits that the bald 1918 virus could tolerate only a limited number of amino acid changes that altered its structure. "At a certain point, there's a fitness cost for adopting a new mutation, so the virus says, 'What else can I do?' " says Nabel.

In a perspective he co-authored in Science Translational Medicine about the Nabel study Rino Rappuoli, head of vaccine research at Novartis Vaccines & Diagnostics in Siena, Italy, says elderly people were spared in the recent swine flu pandemic because they were exposed to the 1918 virus or its sugar-free descendants that subsequently circulated for a few decades and developed a lifelong antibody response to the bald viruses. "Evolution does not necessarily bring new things," says Rappuoli. "It sometimes brings things back."

For full coverage, see the 26 March issue of Science.