Travel itinerary of flu mapped

Source: University of Cambridge

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 - including scientists from Melbourne's WHO Collaborating Centre for Reference and Research on Influenza - 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 today's edition of Science.

Annual influenza epidemics are thought to infect five to 15 per cent of the world population each year, cause three to five million cases of severe illness, and between 250,000 and 500,000 deaths, according to the WHO. The flu vaccine protects the 300 million people vaccinated each year.

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 analysed 13,000 samples of influenza A (H3N2) virus, collected worldwide by the WHO 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," Derek Smith of the University of Cambridge said.

"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."

The authors emphasised 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," Smith said.

"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."

A fundamental component of the study is the integration of quantitative analyses of genetic and 'antigenic' data 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.

Another fundamental component of this work is its thoroughly collaborative and global nature. Many authors on this paper are scientists in the surveillance network, which comprises over 100 labs in 80 countries around the world, including the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne.

Influenza virus evolves continuously at such pace that the scientists in charge of its surveillance are essentially "tracking its evolution in real time," Smith said.

"Because flu evolves so quickly, flu science and public health necessarily go hand in hand," he said.

"The [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."