Flu survivors still immune after 90 years

They say that memory declines as age marches on, but that only applies to neurons - the immune system has a very different sort of memory and it stays fresh till the end of life. To this day, people who survived the 1918 flu pandemic carry antibodies that can remember and neutralise the murderous strain.

The 1918 influenza virus was the most devastating infections of recent history and killed anywhere from 20 to 100 million people in the space of two years. Ironically, it seems that the virus killed via the immune system of those infected. It caused immune cells to unleash a torrent of signalling chemicals - cytokines - that recruited other immune cells to the fray. These too started signalling and the resulting "cytokine storm" rages out of control.

This probably explains why the 1918 flu took such a heavy and unexpected toll on the young and healthy. Their strong immune systems would have done them little good against a virus that kills by causing those same systems to overreact. Nonetheless, many children managed to fight off the infection and they are still alive to tell the tale.

Xiaocong Yu from the Vanderbilt University Medical Center and Tshidi Tsibane from the Mount Sinai School of Medicine managed to track down 32 of these lucky survivors. Today, the youngest of the group is 91 and the oldest have seen their first century come and go. During the time of the pandemic, they could all remember one of their family being sick, making it likely that they themselves had been directly exposed to the usually lethal infection. And even though 90 years had passed, every single one of these people was still immune to the virus. To this day, their blood samples can neutralise it.

Molecular memories

Yu and Tsibane took the opportunity to examine the survivors' mighty antibodies. Using blood cells from 7 survivors, the team managed to culture B-cells (a type of white blood cell) that secreted antibodies against the 1918 flu. They purified five of these antibodies, which had a particularly strong affinity for the 1918 strain and to a lesser extent, for a strain from 1930. Against later strains of flu from 1943, 1947, 1977 and 1999, these antibodies provided little defence.

The antibodies recognise a protein on the surface of the virus called haemagglutinin, and while the 1918 and 1930 versions are structurally very similar. But those from the later strains mutated to enough of an extent that antibodies fine-tuned to older viruses no longer worked.

The antibodies weren't just effective in test-tubes or Petri dishes - Yu and Tsibane proved their worth in living animals. They exposed mice to the reconstructed 1918 virus, a treatment that would usually kill them all. A day later, they injected them with the antibodies taken from the human survivors. Sure enough, compared to mice treated with unspecific antibodies, these animals had half the amount of virus in their lungs and lost several times less weight. And best of all, at high doses, all of them survived.  

Lifetime membership

The results indicate that B-cells that respond to infections endure for the lifetime of their host, even if that lifetime spans the best part of a century. The fact that these antibodies reacted strongly to the 1918 flu and not to later generations suggests they were the same defences that were stimulated some 90 years ago. However, Yu and Tsibane say it's likely that infections with related viruses in the intervening years helped to sustain the population of targeted B-cells.

Just as they defended the survivors in 1918 and the mice in this experiment, these antibodies could defend humans in the future, should another similar strain of flu rear its head. And one of the five antibodies may even have a broader remit, for unlike its cousins it also managed to neutralise the 1977 virus. That certainly merits further attention.

The antibody's structure could be broad enough to stick to a variety of different haemagglutinin proteins, or the virus may have effectively gone retro and 'recycled' an older structure that this particular antibody could recognise. Either way, its secrets are worth uncovering, for they could suggest strategies for granting immunity against a wider range of flu strains.

It's worth noting that these experiments were only possible because another group of scientists recreated the 1918 strain of flu in 2005, using samples from a patient buried in Alaskan permafrost to decipher the virus's genome and structure. Resurrecting one of the most infamous viruses in history was a bold and (understandably) controversial move and, even though results like this are very interesting, it remains to be seen if it was a justified one.

Reference: Nature doi: 10.1038/nature.07231