In 1918, as one global devastation in the shape of World War I came to an end, people around the world found themselves facing another deadly enemy, pandemic flu. The virus killed more than 50 million people, three times the number that fell in the Great War, and did this so much faster than any other illness in recorded history.

But why was that particular pandemic so deadly? Where did the virus come from and why was it so severe? These questions have dogged scientists ever since. Now, a new study led by the University of Arizona (UA) may have solved the mystery.

Michael Worobey, a professor in UA College of Science’s Department of Ecology and Evolutionary Biology, and colleagues describe their findings in the Proceedings of the National Academy of Sciences.

They hope the study not only offers some new clues about the deadliness of the 1918 pandemic, but will also help improve strategies for vaccination and pandemic prevention, as Prof. Worobey explains:

“If our model is correct, then current medical interventions, especially antibiotics and vaccines, against several pneumonia-causing bacteria, could be expected to dramatically reduce mortality, if we were faced today with a similar set of pandemic ingredients.”

One of the questions that has been particularly vexing is why the 1918 pandemic human influenza A virus killed so many young adults in the prime of life, he says, adding: “It has been a huge question whether there was something special about that situation, and whether we should expect the same thing to happen tomorrow.”

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Researchers reconstructed the origins of the 1918 pandemic virus, the classic swine flu and the postpandemic seasonal H1N1 flu virus lineage that circulated between 1918 and 1957, to find out why the 1918 pandemic was so deadly.

Usually, the human influenza A virus is deadlier to infants and the elderly. But the 1918 strain killed many people in their 20s and 30s, who mainly died from secondary bacterial infections, especially pneumonia.

For their investigation, the researchers developed an unprecedentedly accurate “molecular clock,” a technique that looks at the rate at which mutations build up in given stretches of DNA over time.

Evolutionary biologists use molecular clocks to reconstruct family trees, follow lineage splitting and find common ancestors of different strains of viruses and other organisms.

Prof. Worobey and his team used their molecular clock to reconstruct the origins of the 1918 pandemic virus, the classic swine flu and the postpandemic seasonal H1N1 flu virus lineage that circulated between 1918 and 1957.

They found that a human H1 virus that had been circulating among humans since around 1900 picked up genetic material from a bird flu virus just before 1918 and this became the deadly pandemic strain.

Exposure to previous strains of flu virus does offer some protection to new strains. This is because the immune system reacts to proteins on the surface of the virus and makes antibodies that are summoned the next time a similar virus tries to infect the body.

But the further away the new strain is genetically from the ones the body has previously been exposed to, the more different the surface proteins, the less effective the antibodies and the more likely that infection will take hold.

This is what the authors suggest happened to the young adults in the 1918 pandemic. In their childhood around 1880 to 1900, they were exposed to a supposed H3N8 virus that was circulating in the population. This virus had surface proteins that were very different from those of the H1N1 pandemic strain. Their immune system would have made antibodies, but they would have been ineffective against the H1N1 virus.

But people born either before or after those decades would have been exposed to a virus much more like the 1918 one and their immune systems were thus better equipped to fight it.

Prof. Worobey notes:

We believe that the mismatch between antibodies trained to H3 virus protein and the H1 protein of the 1918 virus may have resulted in the heightened mortality in the age group that happened to be in their late 20s during the pandemic.”

He says their finding may also help explain differences in patterns of mortality between seasonal flu and the deadly H5N1 and H7N9 bird flu viruses.

The authors suggest perhaps immunization strategies that mimic the often impressive protection that early childhood exposure provides could dramatically reduce deaths from seasonal and new flu strains.

In February 2014, Prof. Worobey and colleagues began challenging conventional wisdom about flu outbreaks, when in the journal Nature, they reported the most comprehensive analysis to date of the evolutionary relationships of flu virus across different host species over time.

Among other things, they challenged the view that wild birds are the major reservoir for the bird flu virus. Instead of spilling over from wild birds to domestic birds, they say the more likely scenario is the other way around – that new strains jump from domestic to wild birds.