Dr. Anne Schuchat
When the 2009 H1N1 flu strain began to emerge last April, U.S. public health authorities quickly had to revise some of their expectations on what proved to be the start of a flu pandemic.
“We had been practicing for a pandemic,” Dr. Anne Schuchat, director of the National Center for Immunization and Respiratory Diseases  at the Centers for Disease Control and Prevention in Atlanta, told an audience at AAAS on 30 November. Federal health officials had been preparing diagnostic tests and working with state health departments and overseas partners on surveillance efforts to stay on top of any new flu developments.
“In our minds, we were thinking something’s going to happen, but it probably is going to be really far away and it’s going to be very lethal,” Schuchat said. Specialists were worrying about the emergence of a new flu strain with virulence comparable to the 1918 strain or the more recent H5N1 bird flu strain that arose in Asia. “What we had was completely different,” Schuchat said.
Some of the first cases appeared close to home among children in Southern California and were quite mild, while at about the same time more severe cases and resulting deaths were being reported in Mexico.
“We immediately had to move away from pre-conceived ideas and take things slowly and carefully,” Schuchat said.
2009 H1N1 flu, which quickly went global, infected millions of Americans in the spring and summer when influenza virus normally doesn’t circulate. While some U.S. communities were hard hit by the new flu strain in the spring and summer, Schuchat and her colleagues were concerned that the virus might come back even more strongly in the fall, a pattern seen in the 1918 pandemic that killed tens of millions worldwide.
“We’ve just had disease all over the country,” Schuchat said, “As much disease as seen during some typical flu season in the fall.” As children returned to school in August and September, a second wave of infections began, with an unusual number of deaths among children (more than 210 from 2009 H1N1 so far, three times the number during a typical flu season).
In addition to disproportionately affecting young people, the virus has been less prevalent among the elderly, usually a high-risk group during flu outbreaks. It also seems to have carved out an ecological niche that has prevented the usual seasonal flu strain from causing much disease this fall.
Schuchat spoke at the final installment of the “Science & Society: Global Challenges” series, co-sponsored by AAAS, Georgetown University and the American Chemical Society. Schuchat, who is also an assistant surgeon general in the U.S. Public Health Service, was joined by Jeffrey Taubenberger, an influenza specialist at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. Richard Harris, a science reporter for National Public Radio, moderated the salon-style event.
The second wave of 2009 H1N1 flu infection appears to have crested for now, and some experts predict the outbreak will result in far fewer deaths than past pandemics. But they warn that flu is unpredictable and the H1NI pandemic could surge again this winter.
“This is the most complicated flu season any of us have ever experienced,” Schuchat said. Public health authorities are used to doing flu vaccinations in the fall in anticipation of flu outbreaks in the spring, she said. Instead, there were an estimated 22 million cases and nearly 4,000 deaths from 2009 H1N1 flu by mid-October, and vaccine manufacturers were unable to produce large amounts of vaccine against the new strain as rapidly as hoped.
Compared with seasonal influenza strains, the new pandemic virus grows slowly in eggs, the traditional culture medium for flu vaccines, and the tight supplies led to long lines at immunization sites and complaints from the public and politicians. There are now at least 80 million doses of vaccine available. Citing the early problems with vaccine production, Health and Human Services Secretary Kathleen Sebelius recently ordered a review of federal policies for development and production of countermeasures against a variety of public health threats.
The problems with vaccine production highlighted the need for new technologies. “We were working to squeeze every last bit of efficiency and dependability out of a safe but outdated technology,” Sebelius said as she announced the policy review. “It was like an old car we had tuned up but still didn’t accelerate like we needed it to.”
The federal government has been funding research that could eventually provide new vaccine production capabilities. There have been promising results growing vaccine in cell culture rather than chicken eggs. Schuchat cautioned, however, that a virus could grow slowly in cells just as it does in eggs. Researchers also are looking at other vaccine methods that are more chemical than biological, including use of expressed proteins, viral DNA segments or peptides to invoke an immune response in the body.
The effort to develop better vaccines and treatments for influenza depends, ultimately, on a better understanding of the flu virus itself and its behavior in the body. Taubenberger said that despite the advances of modern genomics, there remain many unanswered questions.
The basic structure of the flu virus is quite simple. Unlike most other viruses, its genome is not a single piece of nucleic acid but eight segments of RNA, each piece containing one or more genes that encode for 10 or 11 proteins in all. Those include hemagglutinin (H) and neuraminidase (N), the two large glycoproteins on the outside of the viral particles. There are 16 H and 9 N subtypes known, with only a few of them commonly found in humans. Flu strains are identified by the subtypes of H and N on their surface, such as “H1N1” or “H5N1.”
Because of the separate RNA segments, if one animal is infected with two different strains of flu at the same time, there can be a mixing of genes to create a new, hybrid reassortant virus that didn’t exist before. That mechanism can help explain how new pandemic viruses emerge, Taubenberger said, and jump from one species to another (including humans).
Correlating the genetic sequence of a flu virus on paper with how the virus actually behaves in the real world remains a challenge. “It’s still something that we’re really not able to do,” Taubenberger said. Although the flu virus is one of the most intensively studied viruses around, he said, “We still don’t know exactly how the virus replicates, even though it only makes 10 proteins compared to the 30,000 genes that you have. We still don’t actually know what they all do.”
Despite the seeming simplicity of the virus and the wealth of genetic sequencing information now available, researchers don’t know why the virus behaves so differently from host to host. For example, the H5N1 bird flu virus causes 100% mortality in chickens, Taubenberger said, while ducks do not get sick even though the virus is able to replicate in their bodies. Each organism’s so-called host factors play a crucial role in the susceptibility to a particular flu strain.
Ultimately, scientists would love to develop a universal flu vaccine that could be used in any year against whatever flu strains are circulating. But Taubenberger said that, given the variability of the flu virus, the pursuit of a universal vaccine is a daunting undertaking. The flu virus mutates at such a rapid rate, he said, that scientists can use genetic sequencing to date a sample of human influenza virus to a specific year.
“Trying to keep up with that evolution is what makes flu vaccinology so challenging,” Taubenberger said. The flu strains are so different in their genetic sequences from one subtype to another, he said, that it is difficult to identify protein products that are conserved from one strain to another. Finding those identical proteins is at the heart of any effort to develop a universal vaccine.
Researchers have been looking at proteins that are much more conserved than hemagglutinin, for example. Taubenberger said there have been some promising results with one of the matrix proteins that helps bind the envelope of the virus to its core. That work is “not ready for prime time,” he said, but the approach is an encouraging avenue for further study.