An emergency hospital in America during the influenza epidemic. Credit: Otis Historical Archives National Museum of Health & Medicine

The flu epidemic of 1918 was the world’s worst human disaster. At least 50 million died, and it could have been as high a 100 million. It certainly surpassed the great tragedy of World War I where 16 million died.

It is also one of the greatest mysteries in human history.

These questions have never been wholly answered: Where did it come from? Why did it kill so many? Why did healthy adults fall so quickly and not the old and very young?

And always in the background is that big question which can only be solved by answering the first questions: Could it happen again?

The flu didn’t reach Australia until 1919 but when it did it quickly infected about 2 million of the then 5 million population.

At least 12,000 died, the majority of them young men. And this on top of the 60,000 Australians who died in the war.

Now researchers say their studies suggest the types of flu viruses to which people were exposed during childhood may predict how susceptible they are to future strains.

This new knowledge could inform vaccination strategies and arm authorities with pandemic prevention and preparedness.

“Ever since the great flu pandemic of 1918, it has been a mystery where that virus came from and why it was so severe, and in particular, why it killed young adults in the prime of life,” said Michael Worobey, a professor in the Department of Ecology and Evolutionary Biology at the University of Arizona.

“It has been a huge question what the ingredients for that calamity were, and whether we should expect the same thing to happen tomorrow, or whether there was something special about that situation.”

Worobey and his colleagues they found no evidence for either of the prevailing hypotheses for the origin of the 1918 virus: that it jumped directly from birds; or involved the swapping of genes between existing human and swine influenza strains.

Instead, the researchers inferred that the pandemic virus came shortly before 1918 upon the acquisition of genetic material from a bird flu virus by an already circulating human H1 virus, one which likely entered the human population 10 to 15 years prior the outbreak.

“It sounds like a modest little detail, but it may be the missing piece of the puzzle,” Worobey said. “Once you have that clue, many other lines of evidence that have been around since 1918 fall into place.”

Normally in such an epidemic, the weak are the ones to die: infants and the elderly.

But in 1918 those who died were aged 20 to 40, primarily from secondary bacterial infections, especially pneumonia.

The authors suggest that this is likely to be because many young adults born from about 1880 to 1900 were exposed during childhood to a putative H3N8 virus circulating in the population.

This small wedge of the population may have been uniquely susceptible to severe disease in 1918. Most born earlier or later than between 1880 and 1900 would have had better protection against the 1918 H1N1 virus due to childhood exposure to N1 and/or H1-related antigens.

researchers found a remarkable overlap between death rates in various age groups in 1918 and childhood exposure to an H3 influenza virus mismatched in its major antigenic protein to the H1 virus of 1918: age groups with the highest percentage of individuals exhibiting H3 antibodies fared the worst in 1918, and the death-by-age curve closely tracks the peaks and valleys of H3 antibodies in cohorts born before, during and after the 1889 H3 pandemic. Credit: Michael Worobey

The study, “The genesis and pathogenesis of the 1918 pandemic influenza A virus,” was published in the Proceedings of the National Academy of Sciences (PNAS). It was co-authored by Guan-Zhu Han at the UA Department of Ecology and Evolutionary Biology and Andrew Rambaut at the Centre for Infection, Immunity and Evolution at the University of Edinburgh and the National Institutes of Health in Bethesda.

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