What Didn’t Kill Them Could Make You Stronger

Hoping to ward off the flu bug, these boys wear bags of camphor around their necks during the influenza epidemic of 1918.
Hoping to ward off the flu bug, these boys wear bags of camphor around their necks during the influenza epidemic of 1918.

The influenza pandemic of 1918 killed nearly 50 million people worldwide, including many healthy young adults. With fears of another flu pandemic stoked by “bird flu” in Asia in recent years, researchers have wanted to study history’s most lethal flu and the immune response to it.

But how do you go about obtaining samples from something that happened 90 years ago? First you mine Mother Nature’s deep-freeze for the virus. Then you find a hardy group of elderly survivors for antibodies.

In 2005 researchers from the Mount Sinai School of Medicine and the Armed Forces Institute of Pathology resurrected the 1918 virus from the bodies of people killed in the outbreak. The bodies, and the virus, had been preserved in the permanently frozen soil of Alaska.

The investigators approached Dr. James E. Crowe Jr., professor of pediatrics and director of the Vanderbilt Program in Vaccine Sciences, whose lab had developed methods of making antibodies, about trying to make antibodies to the 1918 flu.

Crowe was skeptical but agreed to try. Researchers collected blood samples from 32 survivors, and not a minute too soon. They ranged in age from 91 to 101. All of them reacted to the 1918 virus—suggesting they still possessed antibodies to the virus.

Crowe’s team isolated exceedingly rare B cells—the immune cells that produce antibodies—from eight of those samples and grew them in culture. Seven of those samples produced antibodies to a 1918 virus protein, suggesting that their immune systems were waiting on standby for a long-awaited second outbreak.

“The B cells have been waiting for at least 60 years—if not 90 years—for that flu to come around again,” says Crowe, who is also the Ingram Professor of Cancer Research and professor of microbiology and immunology. “That’s amazing … because it’s the longest memory anyone’s ever demonstrated.”

Crowe’s team then fused cells showing the highest levels of activity against the virus with “immortal” cells to create a cell line that secretes monoclonal (or identical) antibodies to the 1918 flu. The antibodies reacted strongly to the 1918 virus and cross-reacted with proteins from the related 1930 swine flu—but not to more modern flu strains.

To test if these antibodies still work against 1918 flu in a living animal, Crowe’s collaborators at the Centers for Disease Control and Prevention infected mice with the 1918 flu and then administered the antibodies at varying doses. Mice receiving the lowest dose of 1918 antibody—and those receiving a nonreactive “control” antibody—died. All mice given the highest doses of 1918 antibodies survived.

Although aging typically causes immunity to weaken, “these are some of the most potent antibodies ever isolated against a virus,” Crowe says. “They’re the best antibodies I’ve ever seen.”

The findings suggest that B cells responding to a viral infection—and the antibody-based immunity that results—may last a lifetime, even nine or more decades after exposure.

These are some of the most potent antibodies ever isolated against a virus.

~Dr. James Crowe Jr.

In addition to revealing the surprisingly long-lasting immunity to such viruses, these antibodies could be effective treatments to have on hand if another virus similar to the 1918 flu breaks out in the future. And the technology theoretically could be used to develop antibodies against other viruses, like HIV.

Most important, says Crowe, “the lessons we are learning about the 1918 flu tell us a lot about what may happen during a future pandemic.”

The study—led by Crowe, Christopher Basler of the Mount Sinai School of Medicine, and Dr. Eric Altschuler of the University of Medicine and Dentistry of New Jersey—is published in the Aug. 17 edition of the online journal Nature.

Researchers at the Scripps Research Institute in La Jolla, Calif., also contributed to the study. The work was supported by grants from the National Institutes of Health. 

Find out more: www.nature.com/nature

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