Flu Viruses Take One-way Ticket Out Of Asia, Then Travel The World

Seasonal influenza A (H3N2) strains constantly evolve in overlapping epidemics in East and Southeast Asia, which periodically spread to the rest of the world along the pathways shown here. (Credit: Image courtesy of NASA/University of Cambridge)

ScienceDaily (Apr. 17, 2008) — Seasonal influenza strains constantly evolve in overlapping epidemics in Asia and sweep the rest of the world each year, an international research team has found.

These findings suggest that by focusing surveillance efforts on East and Southeast Asia, researchers may be able to extend their forecast of the flu strains most likely to cause epidemics, which may in turn help experts decide which strains should go in the flu vaccine each year.

The study, by a team of researchers from Europe, Australia, Japan and the United States, appears in the 18 April issue of the journal Science.

"The flu virus is constantly mutating, so it's a major challenge for public health as well as a fascinating example of evolution in action. This study advances our knowledge of how new flu strains spread across the globe and how epidemics arise," said Katrina Kelner, Science's deputy managing editor, life sciences.

Colin Russell of the University of Cambridge in the United Kingdom and his colleagues analyzed 13,000 samples of influenza A (H3N2) virus, collected across six continents from 2002 to 2007 by the World Health Organization Global Influenza Surveillance Network. This subtype of influenza is currently the major cause of flu-related illness and death in humans.

The researchers compared physical differences in a surface protein, called hemagglutinin, across the different samples. Hemagglutinin is the primary target of the immune response, and even small changes can allow the virus to evade the immune system and cause disease.

In a subset of the samples, the researchers also compared the sequences of the gene that codes for hemagglutinin.

Together, these analyses allowed the researchers to identify different strains of A (H3N2) as they arrived at new locations around the world over the five-year period. The results revealed that 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. Essentially, once the strains leave East and Southeast Asia they enter an evolutionary graveyard.

"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 of expanding these collaborations in the future," said Derek Smith of the University of Cambridge, who is the corresponding author of the study.

Annual influenza epidemics are thought to result in 3 to 5 million cases of severe illness, and between 250,000 and 500,000 deaths every year, according to the World Health Organization.

A (H3N2) is a subtype of the influenza A virus, and it is one of the three flu viruses included -- in dead or in a weakened state -- in the flu vaccine. The others are the influenza A (H1N1) subtype and the influenza B virus. Each year, the World Health Organization decides which strains within these three categories to include in the next vaccine, based on the recent activity of strains that are currently circulation.

The authors emphasized that the flu vaccine currently works extremely well, protecting about 300 million people from the disease each year, and that people should continue to be vaccinated annually. But, from time to time, a new strain begins infecting people after the vaccine has already been produced.

For decades, researchers haven't known how influenza viruses migrate around the world. According to some of the scenarios that have been proposed, the viruses may migrate between the Northern and Southern hemispheres following the seasons, or they may have come out of the tropics where they were thought to circulate continuously, or they may have come out of China.

The Science study shows instead that each year since 2002, influenza A (H3N2) viruses have migrated out of what the authors call the "East and Southeast Asian circulation network," and from there spread around the world.

Why Asia" For reasons that aren't well-understood, flu epidemics break out during the rainy seasons in the tropics of East and Southeast Asia. On continents at higher latitudes, on the other hand, flu season simply occurs for a few months during the wintertime. Within Asia, different regions experience the rainy season at different times of year.

"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," Smith said.

"Our study is an example of the tremendous synergy between influenza science and public health," he said. "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 basic work on evolution."

"The Global Circulation of Seasonal Influenza A (H3N2) Viruses," by C.A. Russell; T.C. Jones; A, Mosterin; E. Skepner; D.J. Smith at University of Cambridge in Cambridge, UK; T.C. Jones; J.C. de Jong; A.D.M.E. Osterhaus; G.F. Rimmelzwaan; R.A.M. Fouchier; D.J. Smith at Erasmus Medical Centre in Rotterdam, Netherlands; T.C. Jones; A. Mosterin at Universitat Pompeu Fabra in Barcelona, Spain; I.G. Barr; N.J. Cox; R.J. Garten; V. Gregory; I.D. Gust; A.W. Hampson; A.J. Hay; A.C. Hurt; A. Kelso; A.I. Klimov; T. Kageyama; N. Komadina; Y.P. Lin; M. Obuchi; T. Odagiri; M.W. Shaw; M. Tashiro at World Health Organization (WHO) Collaborating Centre for Reference and Research on Influenza in Melbourne, VIC, Australia; N.J. Cox; R.J. Garten; A.I. Kilmov; M.W. Shaw at Centers for Disease Control and Prevention in Atlanta, GA; V. Gregory; A.J. Hay; Y.P. Lin at National Institute for Medical Research in London, UK; T. Kageyama; M. Obuchi; T. Odagiri; M. Tashiro at National Institute for Infectious Diseases in Tokyo, Japan; A.S. Lapedes at Los Alamos National Laboratory in Los Alamos, NM; K. Stohr at Novartis Vaccines and Diagnostics in Boston, MA.

This study was funded by the National Institutes of Health Director's Pioneer Award, the National Institute of Allergy and Infectious Diseases, the NWO Netherlands Influenza Vaccine Research Centre, the Australian Government Department of Health and Aging, and the Medical Research Council.

Adapted from materials provided by American Association for the Advancement of Science.

The great influenza of 1918 started in Kansas a year or two earlier, just before U.S. soldiers were sent overseas to Europe. For some weird reason it was called Spanish Flu; but it is genetically close to the present bird flu that keeps popping up in Asia.

One theory is that the influenza originated in the Arctic among waterfowl who left the virus in our waterways on their migration south every fall. It mutated in hogs which passed it on to humans, who then went away to the military, a spendid setup for disease propagation. Open bay barracks and living in tents during rainy winter weather caused an outbreak. (The death toll among our soldiers before disembarkation to Europe was high, as was the number of deaths on board transport ships. President Woodrow Wilson ordered censorship of that fact). Trench warfare cooked up a really nasty mutated influenza later in France that resulted in a pandemic influenza which killed millions worldwide after everyone went back to their home countries.

Anyway, that’s what I’ve read so far. Anyone have other ideas?

There are some truly bizarre components to the Spanish Flu story.

For example, starting with the Civil War, in which recruits to the Union Army were inoculated for smallpox, through about the first half of World War 2, the same needle would be used for as many as 40 men. This *caused* many other epidemics, exacerbated by the weakened immune systems responding to the primary inoculation. (Senior personnel would fight to get to the front of the line, when the needle was sharpest.)

With what we know today, of the propensity of influenza to swap RNA, this might have resulted in radically increasing the number of virus permutations.

Second, when the Spanish Flu first appeared nine months before the end of hostilities, in the US, it was in a much weaker form. Truly mysteriously, three months before the end of hostilities, the very virulent strain appeared, *simultaneously* in Boston, MA; Sierra Leone, Africa; and in Brest, France.

This presents a fascinating, and extremely menacing possibility. That the influenza sub-strain that ended up in all three places had a mathematically determined evolution, like a clock. So at the same moment, all three sub-strains mutated to the lethal strain. When the “alarm” went off, the pandemic could begin all over the world.

Of course this raises the question of whether H5N1 could perform the same simultaneous mutation. If so, a widely spread weak version of H5N1 could cover the globe, appearing to be a much more benign disease, maybe not even being in the human population yet. And then in several places, simultaneously turn deadly.

Third is the “bad air” theory. The Spanish flu had an extraordinary ability to locate human populations even in very isolated locations, like widely separated Eskimo villages and Pacific islands. The assumption has long been that an animal or human vector *somehow* got through, by so much as a trace of saliva on the back of a postage stamp.

But what if there is a phenomenon of virus transfer through some means not yet known? During many epidemics of the past, the expression “bad air” was looked at with disdain, once a more prominent vector was found.

However, it might not have been the air that was the problem, but the dust in the air. That is, a particular kind of dust whose structure provided a habitat in which the influenza virus could exist, and travel over vast distances. Perhaps the dust of the feces of millions of infected birds.

If you have seen one of the immense Chinese dust storms, that travel all the way to the United States and beyond, it is obvious that dust can travel that far. But can it take passengers? Fungi and bacteria, certainly. But viruses?

At the time, the Spanish flu had no natural immunity in humans, as today there is none to H5N1, only a fraction of the amount of pathogen is needed for infection, as our immune systems have no way of fighting it through partial immunity caused by similar strains.

Inhaling just a tiny bit of bird feces dust that had traveled much of the way around the world. A possibility, perhaps?

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