From Spanish to swine - how H1N1 kicked off a 91-year pandemic era

The swine flu pandemic (S-OIV) currently sweeping the world is the result of an influenza H1N1 virus that made the leap from pigs to humans. But this jump is just the latest leg of a journey that has taken over 90 years and shows no signs of finishing.

Today's pandemic is a fourth-generation descendant of the 1918 flu virus that infected around a third of the world's population. This original virus is an incredible survivor and one that has spawned a huge legacy of daughter viruses. By importing and exporting its genes, it has contributed to several new strains that have been responsible for at least three further pandemics, including the current one.

In an editorial in the New England Journal of Medicine, David Morens says, "We are living in a pandemic era that began around 1918." This is one of two papers that narrate the incredible story of the 1918 virus and its descendants - a thrilling tale of survival, adaptation, extinction and resurrection.

All influenza A viruses contain 8 different genetic segments that they can freely exchange with one another. Morens beautifully compares each virus to a squad of eight players, rather than a single entity. For the viral team to be successful, its eight-person genetic team has to work together. Their individual skills become more or less useful with time and the team will often swap its members for fresh faces that add something new to the mix. In technical terms, they "reassort".

To do that, viruses need to infect the same cell and they find communal ground in the internal passages of birds, pigs and humans. Animal bodies are essentially viral networking events where different squads can meet and exchange players.

In 1918, one such squad of players went on an infamous world tour. H1N1 influenza viruses had been around for a long time, but the story of the current "pandemic era" really begins in that year. While H1N1 was busy killing humans in our millions, pig farmers at the Cedar Rapids Swine Show in Iowa also noticed something unusual. Even though H1N1 had never been described in pigs before, their herds were suffering from an unusual respiratory illness, whose symptoms were very similar to those afflicting the world's humans. Swine flu had landed.

Over the next decade or so, scientists confirmed that the human and pig infections had the same cause. Robert Shope, a veterinarian, even went on to show that antibodies from infected humans could neutralise the virus in pigs. To this date, it's unclear how these early steps in H1N1 occurred. Morens and colleagues suggest that in 1918, the human virus jumped into pigs and seeded future populations in this new host. In another paper, Shanta Zimmer and Donald Burke favour a history where both human and swine viruses emerged simultaneously from a bird source.

From that point on, the human and swine versions of 1918 took diverging evolutionary courses that crossed each other at key points. The human version is still around today, carrying the same squad of genes as its 1918 forebears. It has certainly changed, by through the gradual build-up of mutations rather than the wholesale swapping of any individual gene.

This wasn't a continuous run though - for two decades, H1N1 was essentially extinct in humans. It vanished in 1957, to be replaced by a new strain, H2N2, that combined five genes  from H1N1 itself and three from a strain of bird flu. No one is sure why the original virus disappeared, but it was probably seen off by a combination of existing immunity, and a bust of cross-immunity to the newly emerged H2N2 strain.

For the next 20 years, H1N1's descendants were busy. H2N2 caused a pandemic in 1957, killing a few million people. This strain swapped two of its genes with another bird flu strain to produce H3N2, a grandchild of H1N1 that went pandemic in 1968, killing around a million people. All the while, the cause of all this bother - the original H1N1 strain - was nowhere to be seen.

Swine-based strains of H1N1 crossed over into humans on the odd occasion, but failed to establish a new foothold. The closest they came was in January 1976, when soldiers at Fort Dix Army base in New Jersey were hit with an outbreak epidemic  of swine origin, that led to 230 cases. Within the tightly-knit barracks, the virus spread quickly but it failed to ignite a broader epidemic among civilians, partly thanks to a mass vaccination programme.

Then, in November of 1977, the H1N1 strain made its triumphant return, infecting humans in the former Soviet Union, Hong Kong and China. This resurrected virus appeared to be most closely related to a 1950 strain, which has led some scientists to speculate that it was accidentally released from a laboratory.

It is possible that the Fort Dix outbreak stimulated a burst of research on old frozen strains, which could have unintentionally resurrected the previously extinct virus. If that's the case, Zimmer and Burke describe it as a "'self-fulfilling prophecy' epidemic".  Since its resurrection, H1N1 has circulated among humans as seasonal flu and for the first time, it was one of two influenza A viruses to be doing the rounds. Its dancing partner is its grandchild - H3N2.

While all of this was happening, H1N1 swine flu viruses were evolving too. In 1998, it reassorted with two other viruses - the human H3N2 strain and an avian H1N1 strain. This new "triple-reassortant" made the odd jump into humans but it was only by swapping out two of its genetic players that it truly became a problem. It retained six of its genes, but brought in two from a Eurasian lineage of swine-based H1N1. It is this final viral team (S-OIV) that is currently doing the global rounds.

So the current virus has a long and storied history linking it back to the 1918 H1N1 strain, and one that involves at least four different reassortments between bird, swine and human viruses. The original 1918 virus went extinct for a brief window of time, but not before lending its genes towards several generations of pandemic strains and not without being resurrected through potentially accidental means.  As Morens said, the 1918 virus and its progeny have been engaged in an elaborate 90-year dance with our immune systems, with both partners "remaining linked and in step, even as each strives to take the lead".

How we fare in the current dance will depend on the characteristics of the new virus, including how well it transmits from person to person, and how skilful it is at causing disease. And I'll be back to discuss those issues on Thursday...

Embiggenise the image.

Reference:Morens, D., Taubenberger, J., & Fauci, A. (2009). The Persistent Legacy of the 1918 Influenza Virus New England Journal of Medicine DOI: 10.1056/NEJMp0904819Zimmer, S., & Burke, D. (2009). Historical Perspective -- Emergence of Influenza A (H1N1) Viruses New England Journal of Medicine DOI: 10.1056/NEJMra0904322

More on flu:

• Origins of the swine flu pandemic
• Swine flu gains sentience, begins social networking
• Flu survivors still immune after 90 years
• New flu viruses emerge in tropical Asia before going on one-way world tour
• Round peg, square hole - why our bird flu drugs are a fluke