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.
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