|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
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 www.nih.gov.