Structural similarities reveal why some elderly people were spared in the recent pandemic.
The absence of a sugary viral shield could explain why immune responses to the 1918 influenza virus also work against the 2009 H1N1 (swine flu) pandemic strain.
Researchers have found that the two viruses, although separated in time by nearly a century, are structurally similar in a region that is recognized by the immune system. In seasonal flu viruses, that region — a part of the haemagglutinin protein often used to create flu vaccines — is dotted with sugar molecules; however, the two pandemic flu strains lack this sweet spot. This might explain why seasonal flu vaccines don't protect against swine flu.
The results, published today in Science1 and Science Translational Medicine2, could also explain an unusual feature of swine flu: its tendency to hit the young hardest, rather than the elderly population that is usually most at risk from flu viruses.
Scientists thought that older people might have benefited from exposure to the 1918 flu virus and its immediate descendants. That previous exposure seems to have produced antibodies that cross-react with the 2009 strain. Indeed, earlier this year, researchers identified antibodies from 1918 flu survivors that could target both the 1918 and the 2009 viruses3. But it was unclear exactly how the immune responses to the two viruses overlapped.
The sweet spot
Now, structural biologist Ian Wilson of the Scripps Research Institute in La Jolla, California, and his colleagues have determined the structure of one such antibody that is bound to the haemagglutinin protein from each pandemic virus1. They found that the region bound by the antibody was highly similar in both pandemic viruses — and that it lacked the sugar molecules found in seasonal flu strains.
These sugar molecules can help the seasonal virus to elude capture by the immune system by providing a barrier that prevents antibodies from accessing the protein underneath. And because the sugars are present on human proteins as well, the immune system is less likely to view them as a threat. It is a clever strategy harnessed by many other viruses, including HIV.
In another study, Gary Nabel, a virologist at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and his collaborators traced the evolution of this sugar signature in seasonal and pandemic H1N1 viruses. They found that the sugars began to appear by the 1940s, and by the 1980s, nearly all of the seasonal flu viruses were adorned with the molecules2. But the sugars are all but absent from the pandemic virus.
These data suggest that flu viruses have gone full circle, says Nabel. "When the virus first appeared, it didn't need that shielding because there weren't any human antibodies to it," he says. But when antibodies appeared that targeted that region, there was an advantage for the virus to hide it behind a sugar shield. By the time the 2009 pandemic hit, most of the population no longer made these antibodies, and the shield was no longer needed.
The results suggest that the cycle may now begin anew. Sugars could emerge again in the 2009 pandemic strain, as more of the population is exposed to the virus and begins to produce antibodies against it. Indeed, Nabel and his team have recently found the first evidence of that: four new strains of the 2009 swine flu virus, three from Russia and one from China, have acquired a mutation that would allow a sugar to be attached to the conserved region of the haemagglutinin protein2.
With that in mind, Nabel suggests that future vaccines against the 2009 strain should perhaps be made using viruses that bear sugars on the conserved region of their haemagglutinin protein. Animal studies by his team suggest that such vaccines would work against viruses with or without the sugar molecules.
But he cautions that additional work would need to be done before committing vaccine production to this strategy. "The tricky part is, we don't know that this mutation alone is going to be the thing that's going to give rise to the next-generation virus," he says.
Infectious-disease specialist Jonathan McCullers, of St Jude Children's Research Hospital in Memphis, Tennessee, agrees. Pandemic flu strains often add more sugar molecules the longer they circulate in humans, so it is likely that the 2009 H1N1 strain will shift to a more heavily coated virus over time, he notes.
But McCullers adds that there is a limit to how heavily coated the strain used to make a vaccine should be, because each added sugar obscures another region of the virus from the immune system. Too many sugars could make it difficult to mount an effective immune response to the vaccine, he points out.
Xu, R. et al. Science advance online publication doi:10.1126/science.1186430 (2010).
Wei, C.-J. et al. Science Trans. Med. 2, 24ra21 (2010).
Krause, J. C. et al. J. Virol. 84, 3127-3130 (2010).
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Ledford, H. How 1918 flu antibodies fend off swine flu. Nature (2010). https://doi.org/10.1038/news.2010.148