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17 June 2008 R. John Davenport
The Next Pandemic: Bird flu and the 1918 scourge yield harbingers of threats to come
In 1918, a flu virus swept across the world, killing 50 million or more people. Recently, a bird flu virus swept through domestic bird populations, and occasionally hopped from birds to people. The virus bears resemblance to the 1918 virus, so the bird flu outbreak raised fears of an imminent pandemic. Research over the last few years has provided some clues as to what the next pandemic flu virus might look like and how to prepare.
Influenza, or the flu, is a contagious disease of the respiratory system that is caused by influenza viruses. Influenza typically spreads during the winter--apparently because the virus survives best in cold weather--and each year a slightly different influenza virus triggers disease. Though flu symptoms are unpleasant—fever, aches, cough, runny nose—most people bounce back in a week or so. However, young children and the elderly are especially susceptible to influenza and can develop complications from the illness. According to WHO estimates, as many as 500,000 people die worldwide from influenza.
Epidemiologists track flu strains and, each year, try to predict the flavors of flu virus most like to cause disease. New vaccines are developed each year to combat the likely culprits. Successful flu vaccines can limit the spread of flu, and help protect people at risk for more severe flu, although vaccines don’t protect the elderly as well as it does other ages apparently because elderly immune systems lose their capacity to recognize new infiltrators and its poor response to vaccines.
Nevertheless, flu vaccines aren’t always successful. During winter of 2007-2008, different flu viruses than expected spread around the world and the vaccine that had been developed didn’t protect people as well against those viruses.
That problem highlights the fact that flu viruses are a “moving target,” constantly morphing and changing (through mutations and reassortments). The flu virus genome, for instance, is organized in such a way that gene segments can swap easily between virus strains, so new combinations of genes can arise quickly. Perhaps the biggest fear is that a flu virus will soon emerge that spreads unusually easily, resists current treatments and vaccines, and makes even the healthiest people very sick. Such a virus could trigger the next flu pandemic.
Global Scourges
Three pandemics have emerged over the past 100 years The Spanish Flu swept across the globe in 1918 and 1919, on the heels of World War I. And the 1957 Asian Flu and the 1968 Hong Kong flu also exacted a severe worldwide toll. All three were triggered by new variants of the Type A influenza virus, the type responsible for most human flu epidemics; the bird flu that emerged in the late 1990s and 2000s was a new version of Type A, the so-called H5N1 subtype, that hopped from birds to people. Subtype names refer to two types of proteins that appear on the outside of the virus. The “H” stands for hemagglutinin, a protein that binds a virus to a host cell and helps the virus to be taken up by the cell. In the first step of infection, hemagluttinin binds to sialic acid residues of glycosylated receptor proteins on target cell surfaces. The “N” stands for neuramidase, an enzyme that clips sialic acid and helps new viruses escape from a host cell to infect other cells. The subtypes that caused the Spanish Flu (H1N1) and the Hong Kong Flu (H3N2) are still responsible for annual epidemics of flu in humans. Although the mortality rate of people who contract the H5N1 virus is high (20 times higher death rate of H5N1 infection than that of the 1918 virus infection), the virus does not spread easily between people, and only a few cases of human-to-human transmission have been reported. Typically, someone must have close contact with birds in order to contract the virus.
The fact that the virus doesn't hop easily between humans could have limited its spread. However, if a mutation occurred that turned H5N1 into a different form that does jump easily for person to person, a devastating pandemic could occur.
In order to get clues about how to predict the next pandemic, researchers are scrutinizing the 1918 Spanish Flu virus to understand what made it so deadly. In 2005, researchers in the United States rebuilt the 1918 virus. To construct the virus, they used preserved tissue from U.S. servicemen killed in the pandemic and isolated virus RNA. The team determined the gene sequences of the virus, then used those sequences to rebuild the virus, they reported in Science.
Then the researchers examined how infectious the reconstructed virus was. To infect a human cell, influenza viruses typically need an enzyme from the human cell to snip the hemagluttinin molecule in two. But the researchers found that the 1918 virus didn't need this enzyme. Even without it, the 1918 virus infected cells in culture, replicated itself, and burst the cells open. The finding that the virus didn't need the extra help from host cells suggests that the 1918 version of the virus is especially adept at infecting cells and copying itself.
Next the team infected mice with the 1918 virus. Four days later, the animals bore 39,000 times more virus than did animals infected with a modern-day human influenza virus. The animals also died within days of exposure to the 1918 virus. Moreover, the animals exhibited lung problems, such as inflamed and dead lung tissue, seen in Spanish Flu victims. The team also found that the 1918 virus infected chicken cells, whereas the modern influenza virus did not. Moreover, in a second study published in 2005 in Nature, researchers found that the 1918 polymerase resembles that seen in H5N1. As a result, the team concluded that the Spanish Flu didn’t morph from an existing human virus, but hopped from birds to humans.
However, some researchers have questioned this conclusion. Comparing the sequence of the 1918 flu with other human influenza viruses suggests that the virus evolved for a time in humans or resulted from a shuffling of human viruses, rather than jumping directly from birds, they say. This apparent discrepancy remains to be resolved, but further work should ultimately clarify how the virus originated.
Molecules that Matter
Recent studies are chipping away at the problem. A study published in February 2007 in Nature further defined why the 1918 virus was so deadly.
Hemagluttinin binds influenza virus particles to cells in a host by binding to sialic acid residues on proteins on the cell surface, and urges the cells to take up the virus. In birds and in people, hemagluttinin recognizes different types of sialic acid: in birds, viruses grab to sialic acid connected to a sugar in a particular configuration known as alpha-2,3. In humans, viruses instead grab a variant of this molecule in a so-called alpha-2,6 configuration. The 1918 virus possessed a hemagluttinin variant that prefers alpha-2,6. The researchers knew that two amino acids in the protein determined which molecule hemagluttinin binds to. They constructed the 1918 virus, but tweaked the hemagluttinin so that the two important amino acids were altered to recognize the bird form of sialic acid, alpha-2,3.
To test the viruses, the team infected ferrets. The viruses still replicated in the animals, caused lung damage, and killed the animals. However, with the altered hemagluttinin, animals didn’t readily transmit the virus to nearby uninfected animals. The results suggest that in order for a strain of influenza virus to cause a pandemic, it must acquire the ability to recognize the alpha-2,6 sialic acid, which is the form found on the surface of cells in the human lung. All three pandemic flu strains—Spanish Flu, Asian Flu, and Hong Kong Flu—bore this capacity. H5N1, however, prefers alpha-2,3 sialic acid, perhaps explaining why it does not hop easily from person to person, even though it can be deadly in those it infects.
In addition, another viral protein, called NS1, appears to be crucial for making a flu virus especially pernicious. NS1 appears to squelch host immune responses, making a human body more hospitable to the virus. For instance, NS1 stems the production of interferon, a key immune molecule in fighting off viruses. The 1918 version of the NS1 molecule appears to be better at squashing interferon than does NS1 from milder viruses. New work this year showed that swapping out only four amino acids from the tail end of NS1 was enough to turn an ordinary flu virus into an especially deadly one, at least in animals.
Although researchers don’t fully understand what makes a mild virus deadly, they are starting to get a handle on the possible contributors. And a picture is emerging that only a few genetic changes to an H5N1 virus might be sufficient to turn it into a devastating pandemic-causing virus.
Protection Challenges
Even if researchers can deduce what form the next pandemic flu virus is likely to take, the question remains how to prepare and protect people against the flu. Currently, two types of antiviral drugs can battle flu: adamantanes and neuraminidase inhibitors. Some forms of H5N1 have developed resistance to adamantanes or to neuroaminidase inhibitors, and even in the case of susceptible strains it is unclear whether the drugs help, or when and how much drugs must be administered. That leaves few options in the treatment arsenal, and considerable effort has gone into devising prevention strategies.
Numerous candidate vaccines to protect against H5N1 have undergone testing. Some vaccines based on inactivated viruses have shown promise, but require doses so high that production in quantities sufficient to protect the world’s population is impractical. In addition, many vaccines are produced by growing viruses in chicken eggs. But H5N1 kills chicken cells, so vaccines must be altered so that they do not kill chicken cells, or other production methods must be devised. Some test vaccines have been produced in insect cells; whether these vaccines are effective in humans is unclear, but the production method holds the promise for efficient large-scale manufacture of vaccine. Other vaccines that use in various ways the genetic components of the influenza virus also hold promise, because they can be administered easily in a nasal spray, but safety issues or uncertainties about effectiveness remain in some of these cases.
Some researchers are tackling how to devise vaccines against a deadlier H5N1 virus before it appears. Yang and colleagues identified mutations in hemagluttinin that make it more likely to bind to alpha 2,6 sialic acid, the cell surface component found predominantly in human cells. They then injected into mice the variants most tuned to alpha 2,6. The animals generated antibodies that were tuned for those variants. It isn’t yet clear if the antibodies would provide protection for animals against viruses that contain those variants, but the approach might work as a preemptive strike against the kind of new virus most likely to spur a pandemic.
Whatever the best vaccine-making strategy, recent studies might help scientists better decide which specific strain to use to concoct a vaccine. A research team used the hemagluttinin gene to understand the relationships between 13,000 different influenza virus samples collected from various parts of the world between 2002 and 2007. They wondered whether flu epidemics in a given region were due to new viruses coming in from another region or due to existing viruses in the region that had morphed.
They found that new variants typically appeared first in Southeast Asia, then spread elsewhere in the world, getting to South America last. Moreover, they found that in a particular region, a virus that contributed to an epidemic tended not to be related to strains that had caused previous epidemics in the same region. The findings suggest that flu epidemics anywhere in the world are spurred by viruses that emerge first in Southeast Asia. The team tracked the H3N2 virus, a common contributor to annual flu outbreaks, but the findings might possible apply to the origins of other virus types, including a pandemic type. If that idea holds up, it might help researchers narrow their search for the most promising strategies to fight flu strains that haven’t yet been observed.
As the global outbreak of H5N1 has apparently subsided, the alarm bells of a future pandemic seem to have quieted. Yet, since previous pandemics have occurred every 40 years and since the last one occurred in 1968, a new pandemic seems due. Further work will define what turns an avian influenza virus or a mild human virus into a deadly virus that spreads rapidly through the human population. Bird flu might be the start of that pandemic, or it could arise from another, unknown virus. Hopefully the lessons learned from current studies of H5N1, the 1918 pandemic virus, and other viruses will provide clues to tackle a pandemic, whatever its origins.
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CDC – Influenza
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WHO Influenza
www.who.int/topics/influenza/en/
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