Scientific Method / Science & Exploration

Useless antibodies made adults more susceptible to swine flu

Otherwise healthy adults may have suffered severely during the 2009 H1N1/S-OIV …

One of the most disturbing aspects of the S-OIV/swine flu/H1N1 pandemic of 2009 is how severely it affected healthy, middle-aged adults instead of the elderly and infirm. Recent work, reported in Nature Medicine, suggests that it is because this population has "an antibody repertoire shaped by seasonal infections," and that these antibodies can recognize, but not fight, the new strain. This preponderance of nonprotective antibodies, combined with respiratory infections, can lead to immune complex mediated disease.

The researchers, based in Tennessee and Argentina, examined lung tissues and aspirates from 75 adults with S-OIV. The patients ranged in age from 17-57 years. Twenty-three of them died, and 15 who survived required intensive care. The scientists compared these samples to some taken from adults with seasonal flu virus and infants with S-OIV. In contrast to the US, infants in Argentina were not routinely vaccinated against seasonal flu until 2010.

Adults with fatal S-OIV had damaged lungs, but not more damaged than those with fatal seasonal flu. The levels of S-OIV RNA did not differ significantly between patients in intensive care and ambulatory cases. And, for the most part, levels of inflammatory and other cytokines were also roughly the same between adults with S-OIV and seasonal flu. But people with severe cases of H1N1 did have lower than normal levels of T lymphocytes, a phenomenon associated with immune-mediated viral respiratory illness.

The S-OIV surface proteins are similar to seasonal flu (17 percent of its hemagluttinin and neuraminidase B cell epitopes), so the researchers looked for what are called cross-reactive but nonprotective antibodies. These antibodies would recognize both seasonal and S-OIV flu viruses, but only neutralize the seasonal versions.

Lo and behold, they were found only in "naïve" (previously unexposed) middle-aged adults. Infants in Argentina had no antibodies, and the elderly had antibodies with much higher avidity (they bind the virus more strongly) because of their exposure to an H1N1 virus that circulated before 1957. Severely ill patients had higher levels of H1N1-specific, low avidity antibodies than mildly ill patients, and severely ill patients had antibodies with lower avidity than mildly ill patients. 

The cell-killing complement system was also activated to a higher degree in the sickest patients, in keeping with the idea that most of the problems were immune mediated. The same mechanism can be used to explain the 1957 H2N2 pandemic; analysis of archived lung sections in Tennessee revealed that samples with viral RNA and a fatal pulmonary infection had activated complement, but those without a pulmonary infection did not.

The authors note that immunity may play other roles in pathogenesis, and that other factors probably contribute to the different degrees to which one virus can affect different people. But they hope that their new finding—that nonprotective antibodies and complement activation can mediate severe illness in otherwise healthy adults during a flu pandemic—can be exploited to generate new therapies.

Nature Medicine, 2010. DOI: 10.1038/nm.22625  (About DOIs).

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