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Archival 1918 Pandemic Flu Samples Give Glimpse Into Viral Genetic Diversity

NEW YORK — The influenza virus behind the 1918 pandemic appears to be the predecessor of the H1N1 strains that now cause seasonal flu, a new study has found.

The 1918 pandemic emerged in the summer of that year, peaked in the autumn, and continued into the winter of 1919. The pandemic led to the deaths of between 50 million and 100 million people across the world. However, it was not until the late 1990s that the causative agent of the 1918 pandemic was determined to be the H1N1 subtype of influenza A, through analyses of preserved tissue samples and remains frozen in permafrost.

Researchers from Germany's Robert Koch Institute have now uncovered additional formalin-fixed lung specimens dating to the time of the pandemic within the collection of the Berlin Museum of Medical History at the Charité and elsewhere, including three samples in which the 1918 influenza virus could be detected and isolated. As they reported in Nature Communications on Tuesday, this enabled them to examine genetic diversity within the pandemic viral genomes and to find that today's seasonal H1N1 is likely a direct descendant of the pandemic strain.

They sequenced those three Charité samples, two originating from Berlin and one from Munich that harbored the 1918 influenza virus, to average depths of 9X, 53X, and 1,944X.

"At the time we started this work, there were only 18 specimens from which sequences were available and only two complete genomes," senior author Sébastien Calvignac-Spencer from RKI said during a press briefing. He added that "any new genome, especially when documenting … new locations and periods, can really add to our knowledge."

He and his colleagues compared the genetic variation both within the new samples and between them and previously analyzed ones from New York and Alaska to find that the strains differed by two to four dozen SNPs. Further phylogenetic analysis of the hemagglutinin gene of these and additional samples placed the new German samples within clusters of North American samples, while two samples from London clustered separately, though with modest support.

These findings indicated there was local transmission as well as transatlantic spread of the 1918 influenza virus, likely in conjunction with human movements at the end of World War I. At the same time, there was no evidence of lineage replacement between the different waves of the pandemic.

But the researchers did home in on changes that arose within the 1918 influenza virus that could have affected its pathogenicity. While the gene encoding the hemagglutinin protein, which is expressed on the viral surface, was largely conserved, the researchers uncovered alterations affecting the viral polymerase. Through in vitro analyses, they found that the Munich sample had a polymerase complex with reduced activity compared to the Alaska sample.

"This may actually be related to adaptive processes, so that the virus is trying to optimize replication during evolution and during the course in the human population," coauthor Thorsten Wolff, also from RKI, added during the briefing.

A molecular clock-based analysis, meanwhile, suggested that seasonal H1N1 is likely a direct descendant of the pandemic strain virus. The researchers noted, though, that due to the paucity of viral samples from the 1920s, they cannot yet say how the pandemic strain changed to transform itself into a seasonal disease.

The researchers have now contacted dozens of other pathology collections across the world to try to uncover additional samples and genomes to reconstruct and analyze, though Calvignac-Spencer noted he has only found one or two new samples so far.

"That's something that is really hard work," he added. "We are actually working hand in hand with a number of other laboratories who are also interested, and we are trying to collectively reach a critical mass so that we could ask more questions with more robustness."