Scientists announced Monday that they may have solved one of history's biggest biomedical mysteries—why the deadly 1918 "Spanish flu" pandemic, which killed perhaps 50 million people worldwide, largely targeted healthy young adults. (Related: "How Flu Viruses Attack.")

The explanation turns out to be surprisingly simple: People born after 1889 were not exposed as kids to the kind of flu that struck in 1918, leaving them uniquely vulnerable. Older people, meanwhile, had been exposed to flu strains more closely related to the 1918 flu, offering some immunity.

Simply put, the Spanish flu owed its ferocity to a switch in dominant influenza varieties that had occurred a generation earlier. (Related: "1918 Flu That Killed 50 Million Originated in China.")

"All a matter of timing," says virologist Vincent Racaniello of Columbia University in New York, who was not part of the study.

Researchers involved in the study looked at the evolutionary history of the components of the 1918 flu, which was built of genes from human and avian flu strains. They unraveled the history of dominant flu strains stretching back to 1830.

The evolutionary biologists found that a worldwide 1889 outbreak of the so-called Russian flu, the H3N8 flu virus, left a generation of children that had not been exposed to anything resembling the Spanish flu, which was an H1N1 strain. (The H and N in the flu designation stand for proteins called hemagglutinin and neuraminidase, respectively).

The spread of a more closely related H1 flu variety after 1900 provided partial immunity to children born after that time. That closed the window of vulnerability.

"You have the most deadly flu pandemic in history essentially leaving the elderly, its most frequent victims, completely alone," says biologist Michael Worobey of the University of Arizona in Tucson, who led the Proceedings of the National Academy of Sciences report.

Instead, people aged 18 to 29 died in droves during the outbreak, which killed about 1 in 200 of victims.

Experts have suggested that such a window of vulnerability partly explained the 1918 pandemic, Racaniello notes. But the new study provides computational evidence that the 1918 flu's precursor originated around 1907, he says, and explains how the window of vulnerability opened and closed for the disease.

The new finding may help public health officials deal with future pandemics, amid current worries about deadly avian flu strains jumping to humans.

It may also alter how we vaccinate against future flu outbreaks, keying vaccines not to current seasonal flavor, but instead to strains that people didn't gain immunity to as children. (Related: "Influenza—A Killer Cold?")

Flu Fluctuations

Seasonal flu strains typically enjoy decades of dominance in the human population. These periods are often capped by outbreaks of new flu varieties, such as the 2009 H1N1 flu pandemic that led to the current reign of this strain of flu, which killed perhaps 284,000 people worldwide, according to the U.S. Centers for Disease Control and Prevention.

"The seasonal drift is normal and is the reason why we have yearly vaccines produced to protect against these seasonal changes," says immunologist Michael Gale, Jr., of the University of Washington in Seattle.

The key to the team's reconstruction was the realization that flu genes evolve at different speeds in birds, pigs, and people, Worobey says (it's faster in chickens, for example). Once the evolution of flu strains is reset with timing tuned to each carrier species, "the picture came clear," he says.

Rather than a sudden movement of avian flu genes in 1918 explaining the Spanish flu, the study suggests that many of them moved into seasonal flu after 1900. A change in the kind of hemagglutinin used by an already-existent flu strain likely led to the pandemic around 1918.

Universal Vaccine

The overall message of the study is a hopeful one, say the researchers, because the bacterial pneumonia secondary to the 1918 flu that killed most of its victims is treatable with modern antibiotics.

"If there was something particularly deadly about the 1918 strain, then you are out of luck when something like it happens again," Worobey says. "But if this is just the effect of lack of exposure, then we can be more confident of treatment."

If that's the case, the makers of future flu vaccines may want to tune their ingredients to people's ages, aiming to arm them against flu strains they likely missed exposure to during childhood, the prime age for getting the flu.

"It really offers a lot of support for a 'universal' flu vaccine that aims to prevent all varieties of flu," Worobey says. Such a vaccine would be aimed at all strains of flu viruses, not just the current dominant seasonal ones.