The exact likelihood of an H5N1 pandemic moving into humans is still unknown, pointed out Derek Smith, a professor of infectious disease informatics at the University of Cambridge in the U.K. From a scientific perspective, he noted, "one expects that's a low probability, but it's a really high-impact thing to prepare against—it's like preparing against terrorism."
Despite all of the concern about H5N1, scientists are also keeping an eye out for other emerging varieties. With 16 known forms of influenza hemagglutinin (the "H" in the strain name), nine known varieties of neuraminidase enzyme (the "N" in the name), and different subtypes within each type, the potential for new enzymatic combinations—and recombinations—is great.
Even H1N1 is not yet in the clear. Since the 2009 outbreak in humans, H1N1 has become much more prevalent in pig populations, and, currently, "we are seeing quite large numbers of re-assortments," Malik Peiris, of the University of Hong Kong, said at ESWI. And a swine-origin triple re-assortment of the H3N2 strain had recently infected two children in the U.S., the Centers for Disease Control and Prevention in Atlanta reported earlier this month.
But the basic dynamics of how these diseases spread are still being worked out. "We don’t know enough about how they transmit from human to human—whether re-assortments in pigs makes it more likely or less likely" to spread among humans, Smith said.
In addition to shifts in virulence and method of spread, slight mutations in the virus can also lead to major changes in how easily it can be treated. A single-point mutation, for example, can render it resistant to commonly used antiviral medications, such as Tamiflu.
The body enigmatic
One of the most disconcerting things about influenza pandemics, as opposed to the seasonal flu, is their tendency to sicken—and often kill—the young and seemingly healthy. Underlying risk factors, such as heart disease and neurological conditions, have been linked to higher fatality rates. But as Maria Van Kerkhove, of the Imperial College London's (I.C.L.) School of Public Health, found in a survey of global data following the H1N1 pandemic, no chronic conditions were reported among some 40 percent of people who were hospitalized for the flu and then died.
There is a "massive difference in the way people respond" to the same strain of influenza, noted Peter Openshaw, director of the Center for Respiratory Infection at I.C.L. He and his colleagues are studying samples from hundreds of people, many of whom became severely ill from the H1N1 pandemic strain, to look for clues as to why one apparently healthy 40-year-old might wind up in intensive care whereas another will fight the virus off just fine at home. But because too little is known about these varied reactions, the team is looking everywhere: in human and viral genetics, for traces of bacterial infections, and elsewhere for hints about what might release the "cytokine storm" that kills some people, now seemingly at random, Openshaw said.
The 2009 outbreak of H1N1 caught most people off guard—not in the least, those charged with tracking new flu strains and outbreaks. Especially after the 2003 emergence of SARS in Asia, most pandemic plans were centered on a Southeast Asian or Asian emergence for the next flu epidemic.
Modeling had predicted that a Southeast Asia–based strain would take some two to four months to spread extensively and arrive in Europe and North America about one to three months after that. That delay would give Western countries three to seven months to develop comprehensive treatment and vaccination plans.
When the flu emerged in Mexico, instead, North America endured the peak of the epidemic without a vaccine.
An outbreak's point of origin can also play a large role in determining how quickly a pandemic is detected. Regions such as Africa and some places in Southeast Asia are still lagging in surveillance capabilities, noted Maria Zambon, of the U.K. Health Protection Agency.
To the advantage of epidemiologists and the public, "the severity of a virus will determine how quickly we detect it," Neil Ferguson, a professor of mathematical biology of infectious diseases at I.C.L., said on Tuesday. The 2009 H1N1 virus had already been circulating in Mexico for some months before the full scope of its potential came to light. "We detected the 2009 virus as late as we did just because it was as mild as it was," he noted. And lingering immunity in the older population further reduced its spread. But if the next virus is more virulent and more rapidly transmitted, "we will detect it earlier," he said.
Subsequent analysis of the spread of the 2009 pandemic showed that it matched up with commercial air traffic from Mexico—spreading more rapidly into the U.S. and Spain, which are strongly socially connected to the Latin American country. If an outbreak were to begin in Asia, however, South America is "a great place to be," because there is very little direct air traffic from Asia to the region, Smith noted on Monday. So by the time the pandemic would arrive in force, a vaccine would likely already be available.
Asia is still at the focus of pandemic watchfulness, especially for hints of H5N1 spread. The virus is relatively common among migratory birds, which it usually does not sicken. As Osterhaus noted, "dead birds don't fly," so the well ones that still carry the disease are free to travel, infecting other flocks—and domestic poultry as well. It can also be spread via human activity, with exports of birds, feathers and other related products.
A recent study of the H5N1 virus in Laos found that some 0.6 percent of ducks sampled showed traces of the infection. And in places like Laos, where local poultry markets facilitate the movement of fowl around the country, the spread of the infection is of great concern to local and foreign health officials. The country has seen a documented outbreak of H5N1 every year since 2006.
Surveillance of the virus has been ramping up throughout Southeast Asia. In Bangladesh, for example, backyard farms predominate, putting fowl in close contact with both humans and migratory birds, so spread to the dense human population is of particular concern. "Bangladesh is in the front line now," explained Syed Ahmed, of the University of Southern Denmark.
Preparing for the unpredictable
With the virus mutating in the dark, hidden cells in billions of birds, pigs and other animals, tracking their changes might seem impossible. "If we're going to [create] the best interventions that we can, we need to understand how they circulate around the world," Smith said of flu viruses. Surveillance of animal populations worldwide has improved vastly in the past decade, boosting the chance that scientists will spot new potentially dangerous mutations early.