Seasonal Flu May Be Descended From the 1918 Pandemic Strain

A new study has characterized samples of the influenza virus that ravaged the world’s population in 1918, revealing information about the pandemic's spread and also highlighting a link between that viral strain and the seasonal flu that circulates each winter.

One hundred years before the COVID-19 pandemic struck, another pandemic had a far greater impact on the global population. The 1918 influenza pandemic is estimated to have taken between 50‒100 million lives, a gargantuan impact given the global population was then only 1.8 billion people.

A very different pandemic

While researchers have now made great leaps towards understanding SARS-CoV-2, the virus that causes COVID-19, researchers in 1918 were completely in the dark about the nature of the disease sweeping across the world. Most notably, it was only 15 years after the pandemic that the human influenza virus A was even discovered.

While researchers in 1918 had speculated that the pandemic was caused by a virus, it was only once molecular analysis techniques leapt forward at the end of the 20^th century that the exact culprit of the 1918 pandemic was identified in permafrost-preserved bodies and carefully preserved tissue blocks ‒ the guilty party was an influenza A virus of the H1N1 subtype.

A century later, working with preserved samples of the virus has become a difficult task. But new research, published in the journal Nature Communications, has not only brought to light vital epidemiological information on the virus during the 1918 pandemic, but also traced a line between the historical virus strain and modern-day seasonal H1N1 flu, suggesting that the common winter virus may be a direct descendent of the deadly pandemic strain.

A fortunate find

“We were crazy lucky,” said Dr. Sébastien Calvignac-Spencer, a researcher at the Robert Koch Institute in Berlin and co-author of the study. Very few tissue specimens or bodies containing the 1918 pandemic virus are available, but the team found the samples they needed via a short walk to the Charite Hospital’s Medical Museum. In this vast archive, the team found 13 lung specimens dated between 1900 and 1930, 3 of which were found to contain influenza virus genetic material.

Partial genomes were extracted from two specimens, originally from Berlin, and the third sample, from Munich, produced a complete genome. These genomic reads were then compared to the limited library of 1918 samples, none of which had previously been found in continental Europe. These included completed genomes from a patient who died in September 1918 in Camp Upton, New York and another from November 1918 in Brevig Mission, Alaska. Even 100 years later, the fact that the Berlin samples were dated from slightly earlier in the pandemic, in June 1918, made all the difference.

The 1918 pandemic peaked in autumn and winter 1918 and then again in 1919. The Berlin samples therefore allowed the authors to compare the virus before and after it hit its peak transmission. Reconstructing the virus’s genomic story revealed that a combination of local and long-distance dispersal events likely occurred during 1918. Additionally, two key mutations in the virus’s nucleoprotein gene, which is linked to how well the virus can resist the host’s antiviral systems, suggests that the virus had undergone some adaptation during the pandemic to better infect human hosts. Overall, said Dr. Thorsten Wolff, Calvignac-Spencer’s colleague at the Robert Koch Institute, 51 different mutations in nucleotides and 17 changes to amino acids were identified in different virus proteins between the new German virus and the US samples previously sequenced.

Seeking out strains

One feature of SARS-CoV-2 during the COVID-19 pandemic has been the tendency for particular viral strains to be effectively wiped out by successor strains – think of the recent emergence of the omicron variant. But evolutionary analysis of the pre- and post-peak viruses from 1918 suggest that multiple strains of 1918 flu persisted through these stages of the pandemic, rather than one strain becoming dominant.

The team’s final analysis brought the 1918 virus into historical context. They used a technique called molecular clock modeling, which allows the estimation of evolutionary timescales. This analysis, the authors write, “are compatible with the scenario of a pure pandemic origin of seasonal H1N1 viruses.” This is not to say that we should expect next winter’s bout of flu to become an existential threat for humanity. We even had a modern day H1N1 pandemic in 2009 with the spread of swine flu. This variant was previously found to be closely related to 1918 flu, said Wolff. “The 1918 pandemic influenza virus also entered the pig population and was maintained there as classical swine flu, and found a way back, in 2009, into humans.”

While it is impossible to know for certain what the next H1N1 pandemic will be like, Wolff points to the cross-reactivity between current H1N1 vaccine components and the 1918 virus and the regular circulation of H1N1 seasonal flu as reasons why humanity is less naïve to upcoming flu viruses. While the COVID-19 pandemic has showed that pandemics need to be anticipated and guarded against as much as possible, our immune systems are likely ready to avoid another 1918-style flu pandemic.

Reference: Patrono LV, Vrancken B, Budt M et al. Archival influenza virus genomes from Europe reveal genomic variability during the 1918 pandemic. Nat Comms. 2022; 13(2314). doi: 10.1038/s41467-022-29614-9