NEW STUDY HAS IMPORTANT IMPLICATIONS FOR INFLUENZA SURVEILLANCE, VACCINE FORMULATION

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U.S. Department of Health and Human Services 
NATIONAL INSTITUTES OF HEALTH 
NIH News 
National Library of Medicine (NLM)
<http://www.nlm.nih.gov/>

FOR IMMEDIATE RELEASE: Wednesday, October 25, 2006

CONTACT: Kathleen Cravedi, 301-435-3274, <cravedik@xxxxxxxxxxxxxxxx>,
Robert Mehnert, 301-496-6308, <mehnert@xxxxxxxxxxx>


NEW STUDY HAS IMPORTANT IMPLICATIONS FOR INFLUENZA SURVEILLANCE, VACCINE
FORMULATION
Research Provides New Insights into Evolution of Flu Virus

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
<http://www.biology-direct.com/> Oct. 26, 2006, was conducted by
researchers from the National Library of Medicine's National Center for
Biotechnology Information (NCBI) <http://www.ncbi.nlm.nih.gov/> and
Fogarty International Center <http://www.fic.nih.gov/>, 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 Influenza Genome
Sequencing Project <http://www.ncbi.nlm.nih.gov/genomes/FLU/FLU.html>,
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
<http://www3.niaid.nih.gov/>.

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. 

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
<http://www.nlm.nih.gov/> at the National Institutes of Health (NIH).

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.nih.gov>.
  
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This NIH News Release is available online at:
http://www.nih.gov/news/pr/oct2006/nlm-25.htm.

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