Outbreaks of the most common type of influenza virus, A (H3N2), are seeded by viruses that originate in East and Southeast Asia and migrate around the world, new research has found. This discovery may help to further improve flu vaccines and make the evolution of the virus more predictable.
Scientists at the University of Cambridge, in collaboration with scientists from the World Health Organisation (WHO) Global Influenza Surveillance Network, found that each year since 2002 influenza A (H3N2) viruses have migrated out of what the authors call the "East and Southeast Asian circulation network" (which includes tropical, subtropical, and temperate countries) and spread throughout the world. Their findings are reported in the current edition of Science.
Annual influenza epidemics are thought to infect 5-15% of the world population each year, cause 3 to 5 million cases of severe illness, and between 250,000 and 500,000 deaths, according to the World Health Organization. The flu vaccine protects the 300 million people vaccinated each year.
Because the flu virus evolves so quickly, there are a number of challenges involved in making the vaccine. In order to create an effective vaccine, each year in February and September a WHO committee meets to select the strains of flu to use in the influenza virus vaccine. These scientists (many of whom are co-authors on this study) decide which strains pose the greatest threat for the next flu season.
One of the serious challenges to creating flu vaccines is that the global migration pattern of influenza viruses has been a mystery. Several competing hypotheses have emerged including migration between the Northern and Southern hemispheres following the seasons, migration out of the tropics where influenza viruses were thought to circulate continuously, and migration out of China.
Colin Russell of the University of Cambridge and his colleagues analyzed 13,000 samples of influenza A (H3N2) virus, collected worldwide by the World Health Organization Global Influenza Surveillance Network between 2002 and 2007.
The analyses allowed the researchers to identify different strains of A (H3N2), the subtype of seasonal flu that causes the most disease, as they arrived at new locations around the world over the five-year period. The results revealed that new strains emerge in East and Southeast Asia and then about six to nine months later reach Europe and North America. Several months later still, the strains arrive in South America. Once viruses leave East and Southeast Asia they rarely return and thus regions outside of East and Southeast Asia are essentially the evolutionary graveyards of influenza viruses.
For reasons that aren't well-understood, flu epidemics typically occur during the winter months in the temperate regions of the northern and southern hemisphere and in tropical countries, flu epidemics often coincide with the rainy season. Because there is variation in the timing of the rainy season in different parts of East and Southeast Asia, combined with the wintertime epidemics in the temperate parts of the region, the overlap in the timing of epidemics gives the opportunity for influenza viruses to circulate year round in East and Southeast Asia. The authors find that this year-round circulation allows East and Southeast Asia to serve as the source of influenza A (H3N2) viruses for epidemics in the rest of the world.
"Flu epidemics appear to be driven by seasonal factors such as winter, or rainy seasons. So there can be cities that are only 700 miles away from each other, such as Bangkok and Kuala Lumpur, which have epidemics six months apart. There is a lot of variability like this in East and Southeast Asia, so lots of opportunity for an epidemic in one country to seed an epidemic to another nearby country, like a baton passed by runners in a relay race," said Derek Smith of the University of Cambridge, who is the corresponding author of the study.
The authors emphasized that the flu vaccine works very well, and protects the 300 million people vaccinated each year. But, from time to time, a new strain emerges after the vaccine strain selection has already been made.
"The ultimate goal of our collaboration is to increase our ability to predict the evolution of influenza viruses. This study is one step along that path and in particular highlights the importance of ongoing collaborations and surveillance in East and Southeast Asia, and expanding these collaborations in the future," said Smith.
A fundamental component of the study is the integration of quantitative analyses of genetic and 'antigenic' data (data that can be used to infer the similarity of viruses from the perspective of the immune system) on the strains of flu. Combining these two types of data provides a comprehensive picture of virus evolution. The key innovation that enabled the quantitative analysis of the antigenic data is a computational technique called antigenic cartography, map-making that shows differences between viruses.
Antigenic cartography is a method developed by researchers at Erasmus Medical Center, Los Alamos National Laboratory and the University of Cambridge. Given measurements for multiple viruses, antigenic cartography can be used to create a map in which the distance between viruses in the map reflects their antigenic similarity and can be used to compare thousands of viruses at a time. From these antigenic maps it is then possible to trace the evolution of the viruses.
"By applying an innovative strategy to map differences in seasonal influenza strains worldwide, Smith and his colleagues have offered important insights into patterns of influenza virus spread that could greatly improve surveillance and vaccine strain selection," said Elias A. Zerhouni, M.D., director of the U.S. National Institutes of Health. "This research, which was partially funded by our Pioneer Award programme, shows the value of supporting exceptionally creative approaches to major challenges in biomedical and behavioural research."
Another fundamental component of this work is its thoroughly collaborative and global nature. Many authors on this paper are scientists in WHO's Global Influenza Surveillance Network, which comprises over 100 labs in 80 countries around the world. Influenza virus evolves continuously at such pace that the scientists in charge of its surveillance are essentially "tracking its evolution in real time," said Smith.
"Because flu evolves so quickly, flu science and public health necessarily go hand in hand," said Smith. "The World Health Organization's Global Influenza Surveillance Network tracks the evolution of influenza viruses for the primary purpose of influenza vaccine strain selection, but this also enables the Network to improve strain selection through evolutionary studies as witnessed by this highly collaborative and thoroughly international study."
For additional information please contact:
Genevieve Maul, Office of Communications, University of Cambridge
Tel: +44 (0) 1223 332 300
Mob: +44 (0) 7774 017 464
Notes for editors:
1. The article 'The global circulation of seasonal influenza A(H3N2) viruses' is published in the 18 April 2008 edition of Science.
2. Images are available upon request.
3. The co-authors of this paper include scientists from the Centers for Disease Control and Prevention in Atlanta, USA, the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne, Australia, the National Institutes for Infectious Disease in Tokyo, Japan, the National Institute for Medical Research in London, UK, Universitat Pompeu Fabra in Barcelona, Spain, Los Alamos National Laboratories, Los Alamos, USA, Novartis Vaccines and Diagnostics in Boston, USA, and Erasmus Medical Center in Rotterdam, the Netherlands.
3. For additional statistical information from the World Health Organization, please visit: http://www.
4. Additional information regarding the Pioneer Award programme can be found at: http://nihroadmap.