How the Measles Virus Induces ‘Immune Amnesia’

In the summer of 1907, a German doctor named Clemens von Pirquet noticed something strange with one of his patients. The five-year-old boy had previously tested positive for tuberculosis. The test involved injecting a tiny bit of TB protein just under the skin. His antibodies recognized it, activating immune cells which formed a little bump at the injection site. This happens to anyone who has ever been infected with TB. But when Pirquet performed the same test on the boy a second time, no bump. Puzzled, he looked through the boy’s medical history. The only thing thing different was that the boy had come down with a case of measles between the two tests.

Curious, Pirquet rummaged through his case file, where he found dozens of other patients who’d previously tested positive for TB only to have their immune response disappear either during or shortly after a bout with measles. His report on this strange phenomenon was the first clue that the measles virus didn’t just cause a high fever and a nasty rash. Something more insidious was going on.

Since then, advances in modern science have helped fit together the puzzle of how the virus simultaneously induces, among its survivors, lifelong protection from measles itself, while crippling victims’ immune systems against other infectious agents, sometimes for years. Now two papers, published today in the journals Science and Science Immunology, drop some of the final pieces of this so-called measles paradox into place.

The new research shows exactly how the measles virus devastates the cells that produce antibodies, damaging the body’s ability to remember the pathogens it’s already been exposed to and inducing a profound “immune amnesia.” With measles surging globally once again, understanding the virus’ long-lasting effects could have sweeping implications for public health.

After the measles vaccine was first introduced in the 1960s, global vaccination campaigns didn’t just slow its spread. It also caused all forms of childhood deaths to plummet by up to 50 percent in resource-poor countries, and up to 90 percent in the most impoverished corners of the world. While obviously a boon for public health, these massive improvements mystified epidemiologists. Measles may be the planet’s most contagious human pathogen, but on its own is not a very lethal disease. Some pointed to the fact that children who tend to get vaccines likely have better health care, and access to clean water and food. Others hypothesized that the measles vaccine must be protecting kids against other kinds of deadly infectious diseases too. But that notion never really sat well with evolutionary biologist Michael Mina.

“Every single day, kids are putting dirt in their mouth and inhaling rhinovirus particles, so how could one vaccine be boosting their immune system so much for years?” he says. “It just didn’t make sense.” In 2015, he published a more plausible explanation for the 50-year-old mystery. He and his collaborators pulled population-level epidemiological data from the US, UK, and Denmark, and compared mortality rates in children between the pre- and post-vaccine eras. They found that for two to three years after measles epidemics spiked, non-measles deaths also increased. They argued that the virus was predisposing children to other infectious diseases. No one had noticed before because in the pre-vaccine era, virtually everyone got measles.

Earlier clues had suggested something like this was going on. As far back as the 1940s, doctors observed that patients with auto-immune-related disorders went into remission following a measles infection. In 2000, scientists discovered that measles preferentially went after cells in the bone marrow responsible for storing immune memories. One study, from 2007, showed just how ravenous its tastes were—in just a few weeks, the measles virus could infect and destroy half a person’s population of these so-called memory B cells. Another, from 2012, proposed that this depletion might lead to a long-term erasure, or immune amnesia. So after an infection a child’s immune system has to start over, rebuilding its protections against pathogens it’s already seen.

Mina’s study provided compelling real-world evidence for the theory of immune amnesia. But critically, it didn’t show a mechanism of how it worked. It wasn’t enough to convince public health officials and policymakers that it was a real thing. That’s when technology and a little bit of luck stepped in.

About a week after Mina published his paper in Science, researchers at Harvard Medical School unveiled a new, powerful way to probe people’s immune systems. At the time, scientists could only fish inside a person’s bloodstream for one antibody at a time, at a cost of about $30 each. The new technique, called VirScan, made it possible to simultaneously scoop up hundreds of thousands of antibodies—to all the pathogens someone’s ever been exposed to—in a single drop of blood. Mina wanted to try it. And he knew just who to talk to about getting the perfect sample.

Years before, one of his collaborators, a Dutch immunopathologist named Rik de Swart, had stumbled upon a scientific goldmine in the Netherlands’ Bible Belt. Fundamentalist Protestant families there are vehemently opposed to vaccines on religious grounds. But they were open to participating in one of de Swart’s studies. As a measles epidemic swept through the tight-knit community in 2013, his team collected blood samples from 90 children ages 4 to 17 who had no clinical signs of measles. They returned again months later, after 77 of them had fallen ill to the virus. This second blood sample collection provided a rare opportunity to examine the effects of the measles virus on the kids’ immune systems.

At the time de Swart had plans to team up with a group of scientists from the Wellcome Sanger Institute and Cambridge University who wanted to sequence the antibody-making genes in memory B cells before and after a measles infection. Using the Dutch samples, they discovered that the virus actually resets the immune system to an immature state, limiting how well it can respond to new infections, as they report today in Science Immunology.

While that work was going on in the UK, Mina connected de Swart with the Harvard team, whom he joined in 2016 for a medical residency. At first, they planned to just run a small test pilot of a few of the Dutch samples through VirScan. But Mina still remembers getting the email with the first results. “It said ‘We see this curious reduction in overall antibodies,’ which fit perfectly with the immune amnesia hypothesis,” he says. “It was a first glimpse. But none of us had any idea the effect would be so massive.”

To make sure what they were seeing was real, they tested the full cohort and added in controls—children who had never been exposed to measles, as well as those who’d received the MMR vaccine, to get a general baseline for antibody fluctuations. The effect was still startling. Two months after measles infection, between 11 and 73 percent of individuals’ antibody repertoires remained wiped out by the virus. On average, kids lost about 20 percent of the antibody diversity they’d had, including protection to all the major childhood diseases—influenzas, pneumonia, and common cold and stomach bugs. They reported these findings today in Science.

Together, the new research makes the immune amnesia hypothesis indisputable, says Roberto Cattaneo, a measles researcher at the Mayo Clinic, who was one of the first to show the virus decimated immune cells and was not involved in either study. “This demonstrates with experimental data hard proof of what we think has been happening,” he says. “If somebody had doubts before, those are all gone.”

But Mina, who started his own epidemiology lab at Harvard earlier this year, says there’s still more work to be done. The biggest outstanding question is just how long the amnesia lasts. His study was performed in healthy kids from a high-income nation with only two time points. No one knows yet what the effect looks like in malnourished populations, where most measles outbreaks actually strike. He’s in the midst of setting up clinical studies in Nigeria and Romania to better understand the disease’s dynamics in different environmental settings. The answers will have important public health implications, including how long after a measles infection children should undergo increased monitoring, or even additional vaccinations. “The effects we’ve found might just be the tip of the iceberg,” says Mina.

That work could be crucial to convincing governments to improve vaccine access in parts of the world where resources are strained. As for Europe and the US, which saw large outbreaks this year in enclaves of vaccine hesitancy, it remains to be seen if today’s scientific revelations prove a useful tool for public health officials and pro-vaccine advocates in the fight against vaccine misinformation. The more complicated immunological picture makes one thing for sure though—measles is more than just skin deep.

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