90 Years Later, 1918 Flu Lives on in Antibodies, Research

Two new studies on the flu were published this week. The first, in the journal Nature, found that some people in their 90s — who were 2 to 10 years old when the pandemic hit — still had antibodies to the virus circulating in their blood. Researchers injected the antibodies into mice, and found that they were powerful enough to protect the mice from a reconstructed version of the virus.

“What this shows is that these [immune] responses can last pretty much the entire human lifetime,” said Christopher Basler, a microbiologist at the Mt. Sinai School of Medicine and a coauthor of the study.

The research sprang from a surprising source — an episode of the now-cancelled TV series “Medical Mysteries.”

In 2006, rehabilitation doctor Eric Altschuler caught an episode of the show in which epidemiologists investigating a mysterious flu outbreak eventually realize that the outbreak is a new version of the 1918 flu strain. In the fictional show, the doctors harvested antibodies from the town’s oldest resident, who was exposed to the virus the first time around, and use them to develop a vaccine.

“I thought, this is so good an idea, why don’t we do this in real life?” said Altschuler. As a rehabilitation doctor, he didn’t have access to the equipment or expertise to do it himself. So he called the National Institutes of Health and staff there was intrigued enough with the idea to pass it on to a team of experts, including Basler, immunologist James Crowe of Vanderbilt University, and others.

Altschuler collected blood samples from 32 New Jersey residents who were toddlers or young children in 1918 and had been closely exposed to someone — perhaps a sibling or parent — who had the disease.

In Crowe’s lab, researchers extracted antibody-producing cells called B cells from the volunteers’ blood. Every B cell produces a specific type of antibody, and Crowe had developed a method of preserving B cells and coaxing them to continue producing antibodies in the lab. However, he had never tried to find B cells from such an old virus.

“When Dr. Basler first chatted with me about doing the 1918 flu rather than new flu[s], I thought it was crazy […] I really thought it couldn’t be done,” he said.

It was like looking for a needle in a haystack — only about one out of every 4.6 million B cells in the blood produced antibodies specific to the 1918 flu. Finding them, Crowe says, “was a combination of art and luck. We’ve developed techniques that are good, yet we feel we were lucky in some ways.”

In order to test whether the antibodies were still effective, researchers at the Centers for Disease Control injected the antibodies into mice, then exposed the mice to a reconstructed version of the 1918 flu strain (CDC scientists reconstructed the virus for research purposes in 2005). The antibodies successfully protected the mice from the disease.

In fact, Crowe says, the antibodies were surprisingly powerful: “These are some of the most potent antibodies ever known,” he says. “It’s kind of counterintuitive, because people think of the elderly as having a weak immune system.”

The research could give scientists insight into how to protect people if a similar flu pandemic were to strike again. In fact, the 1918 flu was a strain of avian flu, like the “bird flu” that set off panic in 2005.

“This is encouraging,” Crowe said, “because it tells us that human beings can make fantastic antibodies to one avian influenza.”

Meanwhile, in the second flu study published this week, researchers suggest that what actually killed most victims of the 1918 flu was not the virus itself, but bacterial pneumonia that took up residence in the victims’ weakened lungs.

David Morens, a researcher at the National Institute of Allergy and Infectious Diseases, and his colleagues examined preserved lung tissue from 58 people killed by the flu. They also reviewed medical records and autopsy reports going back 90 years.

“Conventional wisdom today is that everyone who died then died of viral infection, but that’s just not true — and that was known back then,” said Morens.

Scientists have long wondered what made the 1918 flu so much more deadly than other flu strains. Many think that it provoked an overly-strong, out of proportion immune response. In a 2005 study, researchers injected the reconstructed version of the flu into mice and macaque monkeys. The animals’ immune systems responded violently, inflaming their lungs with blood and fluid — suggesting that the same thing might have happened to people.

But Morens’ research, published online this week in the Journal of Infectious Diseases, suggests that it wasn’t the immune system response itself that killed flu victims, but instead common bacteria that took advantage of the weakened lungs to settle in.

Not all researchers are convinced that bacteria are the key to the virus’s deadliness, though. Michael Katze, who worked on the mice and macaque study, says “it’s hard to argue with the data per se, there’s some bacterial co-infection […] but what we want to know as virologists is ‘why was it so lethal?'” In other words, why was it more likely than other viruses to lead to bacterial co-infection?

Both scientists agree, however, that the research suggests that public health officials planning for the next flu outbreak should consider both viral and bacterial infections. The 1918 flu outbreak occurred before modern antibiotics. It’s unclear whether modern antibiotics would have been able to mitigate it, Morens said, because even modern antibiotics would have had to have been used very quickly to be effective against such severe bacterial pneumonia.

“So then you get into the question of prevention versus cure, whether you use them prophylactically, which ones do you use? You can see it raises a lot of questions and no easy answers — a lot of smart folks need to think about it,” Morens said.