Nearly a century after the 1918 influenza pandemic claimed 50 million lives, survivors continue to produce powerful antibodies against the virus, researchers have found.

The 1918 flu pandemic filled military barracks with victims. Credit: U.S. Naval Historical Center

These antibodies have now been isolated from their nonagenarian hosts and could be exploited to defend against future outbreaks. In work published this week in Nature1, researchers report that five of the antibodies were able to rescue mice that had been infected with the 1918 flu virus.

Antibodies attach themselves to viral proteins and, ideally, neutralize the virus. But antibodies vary widely in the specific proteins or regions within a protein that they bind. Researchers can take advantage of this to learn more about weaknesses in the virus: the regions targeted by an antibody could also make a good target for a vaccine or drug.

Despite this, no one had yet characterized the antibodies in survivors of the 1918 pandemic. Eric Altschuler, now a doctor of physical medicine and rehabilitation at the University of Medicine and Dentistry of New Jersey, was inspired to do so after watching a television show one night while on call as a medical resident. (“It was a slow night,” he says.) The show was a short-lived series called 'Medical Investigation', and featured fictional scientists who track down the causes of mysterious disease clusters.

In the episode he watched that night, scientists respond to an outbreak of a lethal virus that curiously spares an elderly butler who had survived the 1918 flu pandemic. The investigators realize the culprit is a flu virus similar to the 1918 strain, and give an ailing heroine a transfusion of blood from the butler just in time to save her life. "It’s TV," says Altschuler, "so everything worked out in about an hour." His own efforts to replicate the programme’s result in mice – admittedly with considerably more detailed analysis along the way – would take about four years.

Long-life antibodies

With little immunological training of his own, Altschuler recruited a research team including microbiologist Christopher Basler of Mount Sinai School of Medicine in New York, who had worked on the reconstruction of the 1918 flu virus, and immunologist James Crowe of Vanderbilt University in Nashville, Tennessee. The team gathered blood samples from 32 people aged 91 to 101 years.

Many of the participants remembered having a sick relative during the pandemic. “It was a horrible time and unfortunately many people can recall that,” says Altschuler. “We met people who had multiple relatives die on the same day.”

The researchers found that 94% of the participants produced antibodies that neutralized the 1918 virus. In contrast, only one out of ten people born after the pandemic produced such antibodies.

Scientists had expected the influenza antibodies to be long-lived. “But it’s never been demonstrated in this capacity,” says Michael Gale, an immunologist at the University of Washington in Seattle who was not affiliated with the study. “This is a true demonstration that neutralizing antibodies can persist for many decades.”

The researchers went on to infect mice with the reconstructed 1918 flu virus and then treated them with the antibodies. Like the heroine from the television show, mice that received the antibodies survived the infection. Those that did not invariably succumbed.

Altschuler's team also isolated antibody-producing cells, generating five cell cultures that each produced a single type of antibody and could be grown in the lab. When they studied the sequence of the genes that encoded these antibodies, the scientists found they had accumulated many mutations - suggesting that the cells had made further adaptations to similar viruses after 1918, says Gale.

The results suggest that the antibodies could be used therapeutically should an outbreak of a similar virus occur. What’s more, one of the antibodies reacted not only with the 1918 flu strain, but with several other strains as well. "It’s probably binding to something that’s really important for the flu virus – possibly so important that the virus can’t change it to avoid immunity," says immunologist Patrick Wilson of the University of Chicago. "As a target for drug development, that would be ideal."