Science Stays Alert, Part II: Past Pandemics and Future Vaccines

A hundred years ago, migrating wild birds may have been the main threat for influenza outbreaks among humans. Today, we are our own biggest risk. "With air travel, it takes one passenger getting on an airplane and landing 10 hours later in the United States to be able to transmit a virus quickly," says Gary Nabel, a doctor and research scientist at the National Institute of Allergy and Infectious Diseases (NIAID).

A Seattle street car conductor refuses passengers to board without a mask during the 1918 flu pandemic. National Archives

A Seattle street car conductor refuses passengers to board without a mask during the 1918 flu pandemic.

National Archives

Nearly 6.5 billion humans live on Earth. Our species' ballooning population is fueled by our unique ability to create agriculture and domesticate animals. These animals outnumber us more than tenfold, and they can harbor viruses like flu. "With our success as a species has come a vulnerability to infectious agents," says Nabel. Our success has also brought about a technology that helps prevent viral infection: vaccines. Looking at the history of our species in terms of our vulnerability to infections is helping researchers like Nabel develop new vaccines to address the emerging H5N1 avian flu.

Chasing 1918

Creating effective pandemic influenza vaccines takes awareness of how viruses jump between hosts and change over time. "Unfortunately, we don't actually understand at a molecular level what allows a virus to be transmissible," says Jeffery Taubenberger, an influenza research scientist at NIAID. To dig deeper, Taubenberger and his colleagues are studying a viral killer that nearly every human on the planet harbored in 1918 and 1919: the so-called Spanish flu. Understanding the parallels and differences between the current avian flu and the 1918 virus can answer some key questions. Already, the 1918 virus, which was an H1N1 influenza subtype, is informing researchers about transmissibility as well as practical ways to address H5N1.

"The 1918 virus clearly had figured out how to fully adapt to humans," Taubenberger says. "It was able to go from person to person very efficiently over just a couple of months." World War I was winding down, and the mobility of soldiers on foot and by ship aided its rapid spread. The 1918 virus was fatal to only a fraction of those infected--about 2.5 percent. But its victims totaled 50 million, enough to cause a visible ditch in the ever-climbing line graph of life expectancy. Within a couple of years, the pandemic virus mutated, immunity spread, and the flu became ordinary influenza.

In 1918, viruses were not yet identified as agents for disease, so they were not archived for future medical study. To study the virus, Taubenberger and his team literally had to resurrect 1918 from the dead. They cobbled together its complete sequence of RNA segments from formaldehyde-fixed lung tissue of U.S. and British victims. They also extracted pieces of its RNA from lung tissue of an exhumed, permafrost-frozen Inuit woman who had died in northern Alaska. Taubenberger's collaborators reassembled the virus's nucleotide sequence from cloned genes and created an infectious virus, which now resides in several high-biosecurity laboratories.

After studying the complete 1918 virus sequence, Taubenberger and other researchers hypothesized that the 1918 virus was also avian in origin. "We think this was an entirely novel virus in which all of its genes were new to humans in or around 1918," he says. Its novelty contributed to its incredible virulence. The 1918 virus produced a similar course of disease as seen in the 291 people who have contracted H5N1 as of April 11, 2007. "Their lungs actually filled with blood," Taubenberger says of the 1918 victims. "They, in a sense, drowned in this infection."

Some of 1918's surface protein structures also appear similar to those in the current avian flu. One of these structures, the receptor-binding pocket on the H, or hemagglutinin protein, is sparking the interest of virologists and vaccine developers. It is literally a groove in which a structure on a host cell fits, allowing the virus to fuse to its victims. Though H5N1 and 1918 have similarly shaped receptor-binding pockets, H5N1 seems to have less success using this groove to attach to human hosts than did 1918. Whereas 1918 was both highly virulent and highly transmissible among humans, H5N1--so far--is only highly virulent.

Future Vaccines

The Vaccine Research Center at NIAID, which Gary Nabel directs, runs one of the two dozen projects worldwide working to develop prototype vaccines for H5N1. Many of these prototypes have been tested in people, and their protective abilities are finally starting to show promise. Developing vaccines for influenza, even those for low pathogenic viruses (your yearly flu shots), is especially tricky. Replicating flu viruses undergo such rapid antigenic drift and reassortment that they constantly evolve, escaping the retaliations of our immune system. The flu shot must be reformulated yearly to keep pace with viral evolution.

Yearly flu vaccines are made by growing whole viruses and administering a weakened or neutralized version to promote immune-fighting antibodies in a person's body. But since millions--even billions--of people may need an avian influenza vaccine in a short period of time, Nabel's lab is working on more efficient ways to produce a vaccine. One trick may be to target the receptor-binding pocket alone, without having to harvest weakened or neutralized viruses. His lab is also using new approaches to immunization, like making vaccines with flu virus genes rather than inactivated virus or proteins.

Nabel's lab has used these techniques to develop a prototype vaccine against the 1918 virus. So far, it is effective in mice. "It's not proof," says Nabel, "but it's certainly a strong lead that if we generate those same kinds of neutralizing antibodies against the avian influenza, or what the avian influenza would evolve to in humans, that we'd have a good chance of protecting against it."

The world's population has quadrupled since 1918, and our mobility is unprecedented. A new virus with capabilities as lethal as the Spanish flue--even if it afflicted just 1 percent of individuals on Earth--would be a horrendous toll on human life. Will the virus evolve those qualities? Will it mutate so quickly that vaccines will be useless against it? Will H5N1 be our next pandemic at all? Nabel and his colleagues don't know the answer to these questions. "I think that we can be somewhat reassured by the fact that it hasn't happened yet," says Nabel. "But at the same time, I think it would be foolish not to take this seriously, and not to be prepared."