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Influenza viruses that infect mainly children circulate more slowly worldwide than those that infect mainly adults. The difference may be explained by an increasingly important factor in the spread of infectious diseases: modern air travel.
Researchers at Fred Hutchinson Cancer Research Center and Cambridge University developed a mathematical model that looks at RNA mutations to track how different flu viruses move around the world. The study, published today in the journal Nature, is the first large-scale attempt to track H1N1 and influenza B viruses rather than the more frequently studied – and it turns out, faster-traveling – H3N2 flu virus.
“There is this interesting interaction between how the viruses behave and how we behave,” said Dr. Trevor Bedford, a Fred Hutch virologist who, with Dr. Colin Russell of Cambridge, led the study. “Because they evolve slightly differently, they end up infecting people of different ages. Because of how people travel – adults get on planes more – you end up with these very large-scale differences in how these viruses move around the world.”
The researchers also found that, unlike H3N2 strains, which burn quickly through a region and then die out, distinct B strains can persist independently in different regions, suggesting that there may be benefits to exploring region-specific vaccines for influenza B. They also observed that, in addition to China and Southeast Asia, India plays a role in seeding new strains of H3N2. The finding could expand where flu vaccine developers look for new strains to arise.
Around the world with H3N2
Influenza viruses are primarily classified as type A or B. Type A viruses are divided into subtypes based on two proteins – hemagglutinin (H) and neuraminidase (N) – on the surface of the virus, and then further classified into strains. H1N1 and H3N2 are the current subtypes of influenza A viruses circulating in people. Influenza B viruses also show seasonal circulation throughout the world.
As an RNA-based virus, influenza changes rapidly, quickly outfoxing our immune response, which is why we need a flu shot every year instead of one, lifelong vaccination. Each flu season, several types of flu viruses circulate, and scientists working on vaccine development select three or four of the most prominent flu strains – one each out of the hundreds of strains of influenza A subtypes H1N1 and H3N2 and one or two out of hundreds of influenza B strains – to create that year’s vaccine.
Because H3N2 usually dominates in terms of frequency and severity of infection, its global circulation dynamics have been well studied. In 2008, research by Russell and others showed that new strains of H3N2 arose in East and Southeast Asia – an area that includes China, Malaysia, western Indonesia, Korea and Japan – then showed up in Europe and North America six to nine months later, before continuing to South America, where they died out. In other words, the flu virus circulating in Europe and the Americas did not directly descend from the previous year’s strain but was “re-seeded” with variants from Asia each year.
Going into the study, Bedford and Russell had hypothesized that H1N1 and B would circulate similarly to H3N2. But that is not what they found.
To test their hypothesis, the researchers compared the global circulation patterns of H3N2, H1N1 and influenza B viruses, using genetic sequences collected as part of the World Health Organization Global Influenza Surveillance and Response System and from public databases sampled between 2000 and 2012. The sequences were processed by five WHO Influenza Collaborating Centers in Atlanta, Bejing, London, Melbourne and Tokyo. This was all part of a massive effort by WHO to predict which flu strains would dominate and should be included in the annual vaccine, but it also resulted in a treasure of data. The sequences comprised “the most geographically and temporally comprehensive seasonal influenza virus datasets assembled to date,” the study noted.
“Usually when people think about looking at genetic sequences, they’re looking for function – for mutations that do things,” said Bedford. “Here, we’re using mutations as this marker that will let us track a particular strain as it spreads around the world.”
Bedford and Russell used the data to make a phylogenetic tree, or genetic history, for each virus. What surprised the scientists was that global circulation patterns for H1N1 and influenza B differed substantially from H3N2. While H3N2 burned through regions quickly, with new strains seeded from East and Southeast Asia arriving the next season, distinct strains of H1N1 and, especially, B viruses persisted independently in different regions for several years.
For reasons that are not entirely understood, H3N2 changes more rapidly than H1N1 and B, allowing it to elude the body’s immune system sentries and infect both adults and children. Because H1N1 and B evolve more slowly, people’s immunity works more effectively, resulting in initial childhood infections but fewer adult ones. These viruses show younger average ages of infection, with more children than adults making up the susceptible pool.
“For H3N2, these sparks land and they cause an intense epidemic in the wintertime, and it seems to burn itself out,” Bedford said. “Whereas H1 and B cause less intense epidemics. Because they haven’t evolved as rapidly, they don’t burn out the susceptible population as much.”
The differences in age of infection onset may explain differences in global flu circulation, as children travel long distances less frequently than adults, the researchers wrote. Such an explanation could apply to a variety of human viruses, they noted.
It is not the first time that plane travel has been associated with flu spread. Researchers reported a delayed flu season following the flight ban in the U.S. after the Sept. 11, 2001, terrorist attack and subsequent decline in air travel.
Look to India
The phylogenetic tree for H3N2 showed most viruses originating from East and Southeast Asia, as previous studies have reported, but also from India. The scientists noted that India may have long played a role in seeding seasonal flu epidemics, but countrywide influenza surveillance only began there in 2004 and large-scale sequence data did not appear prior to this study. The finding might help virologists predict which strains of flu virus to include in annual flu vaccines.
“This was the first study to look in detail at India, and we find that India is also a source of H3N2 variants,” Bedford said. “This won’t tell us which strain to pick, but it tells us where to look for novel variants. Very obviously, this says that we need to be focusing more of our surveillance efforts on India.”
The study addressed the origin of seasonal flu viruses, not the far rarer pandemic flus such as the 1918 pandemic that killed at least 50 million people worldwide. Pandemics are sparked by the mixing of human flu viruses and ones carried by birds or pigs that adapt enough to be transmitted from human to human.
Mary Engel is a former staff writer at Fred Hutchinson Cancer Research Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.
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