Getting sick with measles does not just result in a dangerous infection that causes itchy blisters. It can leave the immune system vulnerable to other infections for some time to come, a new study has found.
Although there had been earlier hints of such "immune amnesia," this study is the first to show how the process might work. The researchers analyzed antibodies to essentially the entire repertoire of viruses that humans face, in drops of blood taken from 77 unvaccinated Dutch children just before and just after they came down with the measles. The children live in a part of the Netherlands where many families forgo vaccination for religious reasons, and the researchers took advantage of an ongoing measles outbreak there to gather samples. All the children recovered and their immune systems functioned normally—but after the infection they were missing many of the antibodies that were present before they fell ill, the study found.
"Measles is much worse and deleterious of a virus than we ever knew," says Stephen Elledge, the senior author on the paper published this week in Science. "Getting the measles virus is like being in [a car] accident—only what's damaged is your immune system," says Elledge, a professor of genetics and medicine at Harvard Medical School and a Howard Hughes Medical Institute investigator at Brigham and Women's Hospital in Boston.
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This immune erasure means that the children have to fight off the same bacteria and viruses they had already conquered. In the U.S., where many children are generally healthy and have access to good health care, a quarter of measles patients end up in the hospital during their infection and deaths are rare, Elledge says. Aftereffects of the disease might lead to antibiotic prescriptions or rehospitalizations.
In the developing world, however, this measles-related immune amnesia probably leads to a lot of avoidable deaths, says Matthew Ferrari, an associate professor of biology at Pennsylvania State University, who was not involved in the research. "Without a doubt, measles is a disease of inequity," he says. "The vast burden of measles mortality is felt in the poorest and least accessible populations."
Ferrari says he had been skeptical of the idea that measles increased long-term vulnerability to other illnesses—until this study. "This is a much, much more convincing argument than we've had in the past," he says.
The measles vaccine is already known to be a good investment for public health authorities and nonprofit organizations, says Ferrari, who works mainly in the developing world: it is cheap, effective, most likely lasts for life—and once vaccinated, a person cannot pass on the virus to someone else. The new study suggests vaccination saves even more money and misery by helping children avoid other infections such as malaria, pneumonia and diarrheal diseases.
The number of severe infections and deaths that could be avoided by measles vaccination remains unclear, Ferrari says, although such a figure could help public officials and organizations understand its true value. Unfortunately, this is a good time to conduct such research, he says, because there are several large outbreaks underway. In the Democratic Republic of Congo, for example, there have been more than 200,000 measles cases and 4,000 reported deaths from the disease this calendar year.
To prevent an even higher death toll, the new research suggests money should be invested in providing extra care for the children recovering from measles, and perhaps revaccinating children against other diseases such as tetanus and polio, if they got those vaccines before falling ill with measles. Michael Mina, the paper's first author, says he is hoping to study whether revaccination makes sense for measles survivors.
The study provides "further strong evidence for the highly immunosuppressive effects of measles infection and the power of measles vaccination to counter it," says Bryan Grenfell, a population biologist at Princeton University who was not involved in this study, but who was Mina's postdoctoral research advisor. In 2015 the two were among the authors on a paper in Scienceshowing with population-level data that measles predisposes people to other infections for years after the initial infection.
Prolonged immune amnesia after a measles infection could explain why there was a "remarkable decline" in childhood deaths from infectious diseases after the introduction of measles vaccination in the U.S., U.K. and Denmark in the 1960s, Grenfell says.
A separate paper, published Thursday in Science Immunology, found that ferrets that had been vaccinated against the flu and then given the measles became less immune to the flu and suffered more severe symptoms when they were infected with the flu again.
Mina and Elledge's new study also showed increases in flu, RSV and adenovirus antibodies in the children after the measles outbreak. These increases clustered among those in the same schools and households, probably suggesting that the children are rebuilding their lost immunity by falling ill, Grenfell says.
In the new study, the researchers used a technology Elledge and his lab developed. Called VirScan, it analyzes antibodies in blood samples. The team got its samples from another co-author, Rik de Swart of the Erasmus University Medical Center Rotterdam in the Netherlands, who had collected before-and-after blood samples (taken seven to 10 weeks apart) from Dutch children, most aged 7 to 11, who had recently been sick with measles. The kids lost anywhere from 11 percent to 73 percent of their antibodies between the two blood tests, the study found, with those who suffered more serious measles infections losing the most.
Elledge, Mina and their collaborators also examined antibodies in the blood of macaque monkeys before and after measles infections, and found the disease tamped down their immune response for at least five months after infection. This dampening suggests the measles virus kills the long-lived plasma cells that inhabit the bone marrow and provide disease memory, Elledge says.
The VirScan technology allows scientists to identify which viruses are recognized by the patient's antibodies, indicating a previous exposure. Then they program bacteriophages—viruses that infect bacteria—to display a certain viral protein, combining them with patient antibodies. Any they stick to indicates a prior exposure.
"You can profile the immune system in a very detailed, high-resolution way" using VirScan, Elledge says.
A similar analysis without VirScan would have cost tens of thousands of dollars more. "With a new innovation, all of a sudden we can take a blood sample and explore hundreds of thousands of antibodies simultaneously for $30," Mina says, and in 0.2 microliters–one drop—of blood.
Measles is one of only a few viruses with the ability to wipe out immune memory, Mina says. HIV can also cause a type of immune amnesia, but it takes much longer and has a different mechanism. The measles virus wreaks its havoc by binding specifically to immune cells, invading them and using them to help it spread throughout the body. This targeting of immune memory cells seems to damage those cells, triggering amnesia, he says.
Mina says he still wants to unravel why undernourished children fare so poorly when they catch the measles. He wants to understand whether the infection itself is worse in these kids, whether the "immune amnesia" makes their recovery much harder, or some combination of the two. Because children in the developing world are exposed to so many more microbes than those in wealthier countries, they may actually build back their immune memory faster and return to normal sooner than more advantaged kids, he says. But he warns that this more rapid relearning period would come with risks: "Children would be more likely to fall ill and possibly die of the infections that they are becoming exposed to as they reacquire their memory."
If enough children are vaccinated against measles and therefore maintain sustained protection against other diseases, that might better protect the whole population from those diseases—a situation known as herd immunity—Mina says. Measles appears to wipe out all types of antibodies. In the U.K. and U.S., children who recovered from measles mostly came down with respiratory infections; and in Central and South America they mostly developed diarrheal diseases and dysentery, Mina says; this suggests they catch whatever diseases are most prevalent in their environment. "In some ways," he says, "measles might just serve [as] an amplifier for the baseline incidence of other infections in the community."