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Swine flu: The predictable pandemic?

29 April 2009 by Debora MacKenzie

newscientist.com

THE swine flu virus has been a serious pandemic threat for years, New Scientist can reveal - but research into its potential has been neglected compared with other kinds of flu.  As New Scientist went to press, cases were being reported far from the original outbreak in Mexico. The clusters of milder infections in the US suggest the virus is spreading readily among people. The US Centers for Disease Control and Prevention (CDC) says this strain is so different from existing human flu viruses that most people have no immunity to it. There are no existing vaccines.  All this means the virus could go pandemic. Or it might not: if the virus spreads less readily than is feared, it might not be able to maintain itself in the human population and could fizzle out (see "What makes flu go global?").  We could have seen this coming, though. This type of virus emerged in the US in 1998 and has since become endemic on hog farms across North America. Equipped with a suite of pig, bird and human genes, it was also evolving rapidly.  Flu infects many animals, including waterfowl, pigs and humans. Birds and people rarely catch flu viruses adapted to another host, but they can pass flu to pigs, which also have their own strains.If a pig catches two kinds of flu at once it can act as a mixing vessel, and hybrids can emerge with genes from both viruses.  This is what happened in the US in 1998. Until then, American pigs had regular winter flu, much like people, caused by a mutated virus from the great human pandemic of 1918, which killed pigs as well as at least 50 million people worldwide. This virus was a member of the H1N1 family - with H and N being the virus's surface proteins haemagglutinin and neuraminidase.

Over decades, H1N1 evolved in pigs into a mild, purely swine flu, and became genetically fairly stable. In 1976, there was an outbreak of swine H1N1 in people at a military camp in New Jersey, with one death. The virus did not spread efficiently, though, and soon fizzled out.  But in 1998, says Richard Webby of St Jude's Children's Research Hospital in Memphis, Tennessee, swine H1N1 hybridised with human and bird viruses, resulting in "triple reassortants" that surfaced in Minnesota, Iowa and Texas. The viruses initially had human surface proteins and swine internal proteins, with the exception of three genes that make RNA polymerase, the crucial enzyme the virus uses to replicate in its host. Two were from bird flu and one from human flu. Researchers believe that the bird polymerase allows the virus to replicate faster than those with the human or swine versions, making it more virulent.  By 1999, these viruses comprised the dominant flu strain in North American pigs and, unlike the swine virus they replaced, they were actively evolving. There are many versions with different pig or human surface proteins, including one, like the Mexican flu spreading now, with H1 and N1 from the original swine virus.  All these viruses still contained the same "cassette" of internal genes, including the avian and human polymerase genes, reports Amy Vincent of the US Department of Agriculture (USDA) in Ames, Iowa (Advances in Virus Research, vol 72, p 127). "They are why the swine versions of this virus easily outcompete those that don't have them," says Webby.  But the viruses have been actively switching surface proteins to evade the pigs' immunity. There are now so many kinds of pig flu that it is no longer seasonal. One in five US pig producers actually makes their own vaccines, says Vincent, as the vaccine industry cannot keep up with the changes.

This rapid evolution posed the "potential for pandemic influenza emergence in North America", Vincent said last year. Webby, too, warned in 2004 that pigs in the US are "an increasingly important reservoir of viruses with human pandemic potential". One in five US pig workers has been found to have antibodies to swine flu, showing they have been infected, but most people have no immunity to these viruses.  Our immune response to flu, which makes the difference between mild and potentially lethal disease, is mainly due to the H surface protein. The Mexican virus carries the swine version, so the antibodies we carry to human H1N1 viruses will not recognise it.  That's why the CDC warned last year that swine H1N1 would "represent a pandemic threat" if it started circulating in humans.

The avian polymerase genes are especially worrying, as similar genes are what make H5N1 bird flu lethal in mammals and what made the 1918 human pandemic virus so lethal in people. "We can't yet tell what impact they will have on pathogenicity in humans," says Webby.  It appears the threat has now resulted in the Mexican flu. "The triple reassortant in pigs seems to be the precursor," Robert Webster, also at St Jude's, told New Scientist.  While researchers focused on livestock problems could see the threat developing, it is not one that medical researchers focused on human flu viruses seemed to have been aware of. "It was confusing when we looked up the gene sequences in the database," says Wendy Barclay of Imperial College London, who has been studying swine flu from the recent US cases. "The polymerase gene sequences are bird and human, yet they were reported in viruses from pigs."

So where did the Mexican virus originate? The Veratect Corporation based in Kirkland, Washington, monitors world press and government reports to provide early disease warnings for clients, including the CDC. Their first inkling of the disease was a 2 April report of a surge in respiratory disease in a town called La Gloria, east of Mexico City, which resulted in the deaths of three young children. Only on 16 April - after Easter week, when millions of Mexicans travel to visit relatives - did reports surface elsewhere in the country.  Local reports in La Gloria blamed pig farms in nearby Perote owned by Granjas Carroll, a subsidiary of US hog giant Smithfield Foods. The farms produce nearly a million pigs a year.  Smithfield Foods, in a statement, insists there are "no clinical signs or symptoms" of swine flu in its pigs or workers in Mexico. That is unsurprising, as the company says it "routinely administers influenza virus vaccination to swine herds and conducts monthly tests for the presence of swine influenza." The company would not tell New Scientist any more about recent tests. USDA researchers say that while vaccination keeps pigs from getting sick, it does not block infection or shedding of the virus.  All the evidence suggests that swine flu was a disaster waiting to happen. But it got little research attention, perhaps because it caused mild infections in people which didn't spread. Now one swine flu virus has stopped being so well-behaved.

What makes flu go global?

A "pandemic" is an epidemic that goes global, so technically there is a flu pandemic every year. But the term is usually reserved for bad outbreaks that follow large changes in the virus.  The influenza virus constantly evolves, and pandemics happen every few decades when the flu virus gets new surface proteins that people have little immunity to, generally because they come from an animal strain. The lack of immunity means the virus affects more people more severely.  That's why H5N1 bird flu is so dangerous. Its H5 surface protein is totally new to humans, and the virus has killed more than half of the people it infected. It or another bird flu that can infect humans, such as a virus from the H7 or H9 families, only needs to become readily contagious to go pandemic.  H1N1 has received less attention partly because an H1N1 strain already circulates in humans. The problem is the Mexican strain carries different versions of H1. Still, that alone is not enough to make this virus pandemic.  It must also transmit efficiently in people. Every victim must infect more than one other person for the virus to spread. The new strain could do this, as it is packing an altogether faster engine than previous H1N1 strains. It has an avian gene that has powered it to dominance in pigs, though no one knows for certain if this will make it dangerous in people.