New study has important implications for flu surveillance

Vaccine formulation research shines light on virus's evolution

Researchers are reporting results of a study that substantially alters the existing understanding of how the influenza virus evolves and that could have important implications for monitoring changes to the virus and predicting which strains should be used for flu vaccine. The study, which will be published in the online journal Biology Direct Oct. 26, 2006, was conducted by researchers from the National Library of Medicine's National Center for Biotechnology Information (NCBI) and Fogarty International Center, both part of the National Institutes of Health.

In an effort to better understand how seasonal influenza evolves into new strains, the researchers analyzed the genomic sequences of a large and representative collection of the two most common flu strains (called H3N2 and H1N1) from the 1995-2005 flu seasons in New York state and New Zealand. The sequence data was obtained from the Genome Sequencing Project , which recently generated over 1,000 fully sequenced influenza genomes from clinical isolates; the project is funded and managed by the National Institute of Allergy and Infectious Diseases.

The analysis revealed a picture of flu evolution that was surprisingly different from the prevailing conception of how the virus changes. Evolution of influenza A virus is commonly viewed as a typical Darwinian process. In this mode of evolution, the virus' main surface protein, hemagglutinin (HA), is thought to continually change to evade human immune response, resulting in new dominant strains that eliminate all competitors in a series of rapid successions. Unexpectedly, however, the study found that the periods of intense Darwinian selection accounted for only a relatively small portion of H3N2 flu evolution during the ten-year period examined.

The study found that much of the time the H3N2 virus seemed to be "in stasis"; that is, the HA gene showed no significant excess of mutations in the antigenic regions (those recognized by the immune system). During these stasis periods, none of the co-circulating strains is significantly more fit than others, apparently because multiple mutations are required to substantially improve the virus' ability to evade the immune system. As a result, an increased variety of strains accumulates. Ultimately, however, one of the variants will come within one mutation of achieving higher fitness and becoming dominant. Once the crucial last mutation does occur, virus evolution shifts from stasis to a brief interval of rapid Darwinian evolution, where the new dominant virus rapidly sweeps through the human population and eliminates most other variants.

Based on their results, the researchers conclude that "the common view of the evolution of influenza virus as a rapid, positive selection-driven process is, at best, incomplete." Because the periods of stasis allow the proliferation of many small groups of related viruses, any of which could become the next dominant virus strain, the authors suggest that sequencing much larger numbers of representative isolates could be helpful in augmenting current surveillance methods.

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The study, titled "Long Intervals of Stasis Punctuated by Bursts of Positive Selection in the Seasonal Evolution of Influenza A Virus," is authored by Yuri Wolf, PhD, NCBI; Cecile Viboud, PhD, Fogarty International Center; Edward Holmes, PhD, Fogarty International Center and Pennsylvania State University; Eugene Koonin, PhD, NCBI; and David Lipman, MD, NCBI.

Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing molecular and genomic data, and disseminates biomedical information - all for the better understanding of processes affecting human health and disease. NCBI is a division of the National Library of Medicine at the National Institutes of Health (NIH).

Located in Bethesda, Maryland, the National Library of Medicine is the world's largest library of the health sciences. For more information, visit the Web site at http://www.nlm.nih.gov/. The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nlm.nih.gov/.


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