New studies show why elderly weren’t as likely to get swine flu--and warn about future outbreaks

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The elderly are normally the most susceptible to flu viruses, so it was something of a shock to find that they were largely spared in the recent waves of pandemic H1N1 influenza. Experts have speculated that their apparent resistance to the virus may have arisen because they were exposed to a similar virus in the past and developed some antibodies that protected them. Two new studies released Wednesday demonstrate that this is the case, and that the virus they had been exposed to was the one that caused the 1918 ‘Spanish flu’ pandemic that killed millions worldwide.

Both groups studied hemagglutinin (the ‘H’ in H1N1), the spike-shaped protein that sits on the surface of the flu virus. Hemagglutinins are the portion of the virus that binds to host cells, allowing the virus to enter. It is also the portion of the virus that is recognized by antibodies, allowing the immune system to destroy the virus. Hemagglutinin proteins are highly malleable, undergoing frequent mutation of amino acids. As few as three or four mutations are normally enough to prevent an old antibody from recognizing a newly mutated virus--which is why seasonal flu vaccines have to be produced from scratch each year. The hemagglutinin sequence of pandemic H1N1 differs from that of the Spanish flu virus hemagglutin by about 20%, which should be enough to allow it to avoid detection by the immune system.

Virologist Ian A. Wilson of the Scripps Research Institute in La Jolla and his colleagues studied the three-dimensional structure of the two hemagglutinins. They reported Wednesday in the online version of the journal Science that, despite 80 years of mutations, the two proteins had virtually identical amino acid sequences at a crucial binding site known as antigenic site Sa. That allows the two viruses to be recognized by the same antibodies. With colleagues at Vanderbilt, they confirmed this by demonstrating that antibodies against the Spanish flu virus were capable of binding to and neutralizing the swine flu virus.

In a separate study, virologist Dr. Gary J. Nable of the National Institute of Allergy and Infectious Diseases and his colleagues reported in the journal Science Translational Medicine that antibodies produced against the Spanish flu virus protected mice against infection with the swine flu virus and that antibodies against the swine flu virus protected mice from infection by the Spanish flu virus. ‘This is a surprising result,’ Nabel said in a statement. ‘We wouldn’t have expected that cross-reactive antibodies would be generated against viruses separated by so many years.’

To further investigate, Nabel and his colleagues studied other ways in which flu viruses protect themselves from the human immune system. The hemagglutinin spikes of animal flu viruses and those that have newly jumped to humans are bare protein. But, in addition to mutating, flu viruses protect themselves from antibodies by shielding their binding sites with sugar molecules called glycans, effectively hiding the binding sites from antibodies. Pigs and birds don’t have this mechanism because their lifetimes are so short they are not normally exposed to a virus more than once.

In both laboratory and computer modeling experiments, the researchers showed that the swine flu virus and the Spanish flu virus have no glycans covering their binding sites, allowing the viruses easy access to host cells--but also allowing antibodies to readily attack them. In contrast, the vast majority of flu viruses circulating in recent years have one or more glycans shielding such sites. When the team artificially engineered swine flu viruses to have glycans on their surface, the viruses were able to evade the swine flu vaccine. That suggests that the virus could obtain the ability to outwit the current vaccine. The team subsequently discovered that four new isolates of the swine flu virus have acquired this glycan shield. While the new form of the virus has been isolated only a few times and in localized areas, the findings suggest that the virus could develop the ability to trigger a new wave of infection.

-- Thomas H. Maugh II