measles virus
This illustration provides a 3D graphical representation of a spherical-shaped, measles virus particle that is studded with glycoprotein tubercles. Those tubercular studs colorized maroon, are known as H-proteins (hemagglutinin), and those colorized gray are referred to as F-proteins (fusion). The F-protein is responsible for fusion of virus and host cell membranes, viral penetration, and hemolysis, and the H-protein is responsible for binding of virus to cells. Both types of proteinaceous studs are embedded in the envelope’s lipid bilayer. [CDC/ Allison M. Maiuri, MPH, CHES. Illustrator: Alissa Eckert]

Two studies of the immune systems of unvaccinated children before and after measles virus (MeV, or MV) infection have shown how the infection can cripple immunity against other viruses and bacteria over the long term. This creates what researchers reporting in Science Immunology, and in Science, refer to as a kind of “immune amnesia” that leaves individuals more vulnerable to future infection by other pathogens. One research team, led by scientists at the Wellcome Trust Sanger Institute, and the University of Amsterdam, describe their studies in the children, and in ferrets, in Science Immunology. They say that their results show for the first time how measles effectively resets the human immune system back to an immature state that can only make a reduced repertoire of antibodies.

“For the first time we see that measles resets the immune system and it becomes more baby-like, limiting how well it can respond to new infections,” commented Colin Russell, PhD, professor of applied evolutionary biology at the University of Amsterdam, and who is senior author of the paper, which is titled, “Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles.” Russell continued, “In some children the effect is so strong it is similar to being given powerful immunosuppressive drugs. Our study has huge implications for vaccination and public health as we show that not only does measles vaccination protect people from measles, but it also protects from other infectious diseases.”

In their report in Science (“Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens,”) investigators at Harvard Medical School, Brigham and Women’s Hospital, and the Harvard T.H. Chan School of Public Health, used an assay called VirScan to track antibody production in the 77 unvaccinated children before and after measles infection. They found that the infection wiped out up to 73% of the childrens’ antibody repertoire. “The threat measles poses to people is much greater than we previously imagined,” said senior author Stephen Elledge, PhD, the Gregor Mendel professor of genetics and of medicine in the Blavatnik Institute at Harvard Medical School and Brigham and Women’s Hospital. “We now understand the mechanism is a prolonged danger due to erasure of the immune memory, demonstrating that the measles vaccine is of even greater benefit than we knew.”

Based on their findings, the scientists have re-emphasized the need for widespread vaccination, not only to prevent measles, but potentially to prevent weakening herd immunity to other kinds of pathogens.

Before the introduction of the measles vaccine, nearly every child experienced measles infection, and this resulted in millions of deaths, Elledge, together with postdoctoral researcher Michael Mina, and colleagues, commented. It’s largely thanks to measles vaccination that the number of cases dropped by 80% between 2000 and 2017, saving an estimated 21.1 million lives, stated Russell, together with first author Velislava Petrova, PhD, and collaborators. However, despite the success of measles vaccination in many countries, the disease does still remain endemic in much of the world, affecting more than 7 million people annually, and causing more than 100,000 deaths,” Elledge et al., continued. And, worryingly, they pointed out, after decades of decline, the number of worldwide cases of measles has increased by nearly 300% since 2018. This is primarily due to a drop in vaccination rates. “… the rise of antivaccination campaigns and nonvaccinating religious communities, together with the limited access to the vaccine in some geographic areas, challenges the maintenance of herd immunity and leaves millions of people unprotected,” the Russell team noted. “Outbreaks in unvaccinated communities led to 110,000 measles deaths globally in 2017, making measles one of the leading causes of infectious disease–associated childhood mortality.”

The two research teams carried out separate investigations to address the hypothesis that measles infection can instigate immune suppression that persists for months or years after the disappearance of any measles symptoms. Previous study results have supported this notion, and there is evidence linking measles to up to 50% of childhood deaths from infectious diseases. “The majority of measles-associated deaths and clinical complications are due to secondary infections that occur as a result of immunosuppression,” Petrova, Russell et al., explained. “A recent cohort study of measles in the United Kingdom showed that ~10–15% of children showed signs of immunosuppression five years after having measles, leading to increased incidence of secondary infections.”

What isn’t well understood is how post-measles immune suppression progresses in humans. In their study reported in Science Immunology, Russell, Petrova, and colleagues sequenced antibodies produced by immune system B cells from 77 unvaccinated children, aged from four to 17 years. The children were all from three Orthodox Protestant schools in the Netherlands, which have low rates of vaccination. None had a history of natural measles infection. The researchers carried out B cell receptor (BCR) sequencing of the childrens’ peripheral blood lymphocytes both before and after they contracted measles infection. The results suggested that their immune systems failed to completely restock the pool of B cells that produce antibodies, and also demonstrated compromised immune memory.

The researchers stated, “… we identified two immunological consequences from measles underlying immunosuppression: (i) incomplete reconstitution of the naïve B cell pool leading to immunological immaturity and (ii) compromised immune memory to previously encountered pathogens due to depletion of previously expanded B memory clones.” In additional, follow-on studies in ferrets, the scientists demonstrated how measles-infected animals that were already vaccinated against the flu became less immune to the flu virus and experienced more severe symptoms when challenged with a secondary flu infection. “Our findings provide a biological explanation for the observed increase in childhood mortality and secondary infections several years after an episode of measles,” they concluded.

“The depleted B memory pools and serological immunity highlights the importance of MeV vaccination not only to protect against measles but also for the maintenance of immunity to a range of other pathogens, which can be compromised after MeV infection … Given the recent record-high cases of measles, this work encourages the closer follow-up of patients with recent episodes of measles, expansion of measles vaccination campaigns, and monitoring of herd immunity to different pathogens in countries experiencing measles outbreaks.”

The measles virus is a paramyxovirus, of the genus Morbillivirus. Thin-section transmission electron micrograph (TEM). [CDC/PHIL]
Reporting in Science, Mina, Elledge, and colleagues used a tool called VirScan to analyze antibody responses in the 77 unvaccinated children before and after measles infection. VirScan is a phage-display immunoprecipitation and sequencing (PhIP-Seq) technology, which tracks antibodies to thousands of viral and microbial antigens in the blood. The researchers’ analyses indicated that the disease wiped out 11–73% of the antibody repertoire across the study individuals two months after measles infection, and this severely compromised their immune memory of various infectious agents, even after recovery from the measles infection. “After severe or mild measles, children lost a median of 40% (range: 11 to 62%) or 33% (range: 12 to 73%), respectively, of their total preexisting pathogen-specific antibody repertoires,” the authors wrote. “In contrast, controls retained ~90% of their repertoires over similar or longer durations.” The researchers also found no antibody depletion in infants who were vaccinated against measles, mumps, and rubella.

In order to confirm their findings in a controlled experimental setting with longer follow-up, the team used VirScan to profile the antibody repertoire in plasma collected from four rhesus macaques, both before and five months after the animals were given a measles virus infection. Again, the results showed that the overall diversity of the antibody repertoire was decreased on average by 26% after measles infection. “Each monkey lost, on average, 40–60% of its preexisting antibody repertoire, and this loss persisted for at least five months after MV infection,” the scientists reported. They noted that although it is possible to rebuild the antibody repertoire through reexposure to the pathogens, this could take months or years and might pose several health risks.

“Comprehensive coverage with MV vaccine would not only help prevent the >120,000 deaths that will be directly attributed to measles this year, but, by preventing MV immune amnesia and thus preserving immunity, MV vaccines could also avert potentially hundreds of thousands of additional deaths attributable to the lasting damage to the immune system,” they concluded. “These findings underscore the crucial need for continued widespread vaccination … The WHO recently reported that between 2000 and 2017, MV vaccines have prevented more than 21 million deaths directly attributable to measles. These findings suggest that the number of deaths averted might be much greater, and they attest to the immense public health value of the measles vaccine.”

 

 

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