Measles wipes out immune system’s memory — 2 studies

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Inoculation with the MMR (measles, mumps, rubella) vaccine did not impair children’s overall immunity. Importantly, it also prevented measles from depleting people’s antibody repertoires and partially obliterating immune memory to most previously encountered pathogens.

The complementary studies came from Harvard and Brigham and Women’s Hospital, and from the Wellcome Sanger Institute, University of Cambridge and the University of Amsterdam.

Consequently, write the authors, “Revaccination following measles could help to mitigate long-term suffering that might stem from immune amnesia and the increased susceptibility to other infections.”

Over the last decade, evidence has mounted that the measles vaccine protects in not one but two ways: Not only does it prevent the well-known acute illness with spots and fever that frequently sends children to the hospital, but it also appears to protect from other infections over the long term.

Some researchers have suggested that the vaccine gives a general boost to the immune system. Others have hypothesized that the vaccine’s extended protective effects stem from preventing measles infection itself. According to this theory, the virus can impair the body’s immune memory, causing so-called immune amnesia. By protecting against measles infection, the vaccine prevents the body from losing or “forgetting” its immune memory and preserves its resistance to other infections.

Past research hinted at the effects of immune amnesia, showing that immune suppression following measles infection could last as long as two to three years. However, many scientists still debate which hypothesis is correct. Among the critical questions are: If immune amnesia is real, how exactly does it happen, and how severe is it?

Now, a study from an international team of researchers led by investigators at Harvard Medical School, Brigham and Womens Hospital and the Harvard TH Chan School of Public Health provides much-needed answers.

The researchers show that the measles virus wipes out 11% to 73% of the different antibodies that protect against viral and bacterial strains a person was previously immune to – anything from influenza to herpesvirus to bacteria that cause pneumonia and skin infections. So, if a person had 100 different antibodies against chicken pox before contracting measles, they might emerge from having measles with only 50, cutting their chicken pox protection in half. That protection could dip even lower if some of the antibodies lost are potent defences known as neutralizing antibodies.

“Imagine that your immunity against pathogens is like carrying around a book of photographs of criminals, and someone punched a bunch of holes in it,” said the study’s first author, Dr Michael Mina, who was a postdoctoral researcher in the laboratory of Stephen Elledge at HMS and Brigham and Women’s at the time of the study and is now an assistant professor of epidemiology at the Harvard Chan School. “It would then be much harder to recognize that criminal if you saw them, especially if the holes are punched over important features for recognition, like the eyes or mouth,” said Mina.

The study is the first to measure the immune damage caused by the virus and underscores the value of preventing measles infection through vaccination, the authors said. “The threat measles poses to people is much greater than we previously imagined,” said senior author Stephen Elledge, the Gregor Mendel professor of genetics and of medicine in the Blavatnik Institute at HMS and Brigham and Women’s. “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.”

The discovery that measles depletes people’s antibody repertoires, partially obliterating immune memory to most previously encountered pathogens, supports the immune amnesia hypothesis.

“This is the best evidence yet that immune amnesia exists and impacts our bona fide long-term immune memory,” added Mina, who first discovered the epidemiological effects of measles on long-term childhood mortality.

The team’s current work was published simultaneously with a paper by a separate team that reached complementary conclusions by measuring changes in B cells caused by the measles virus. An accompanying commentary written by Duane Wesemann, HMS assistant professor of medicine at Brigham and Women’s, contextualizes that study.

Elledge, Mina and colleagues found that those who survive measles gradually regain their previous immunity to other viruses and bacteria as they get re-exposed to them. But because this process may take months to years, people remain vulnerable in the meantime to serious complications of those infections.

In light of this finding, the researchers say that in the aftermath of measles infection, clinicians may want to consider strengthening people’s immunity to other infections by providing a round of booster shots of all previous routine vaccines, such as hepatitis and polio.

One of the most contagious diseases known to humankind, measles killed an average of 2.6m people each year before a vaccine was developed, according to the World Health Organisation. Widespread vaccination has slashed the death toll.

However, lack of access to vaccination and refusal to get vaccinated means measles still infects more than 7m people and kills more than 100,000 each year worldwide, reports the WHO – cases are on the rise, tripling in early 2019. About 20% of people in the US who get infected with measles require hospitalisation, according to the US Centres of Disease Control and Prevention (CDC), and some experience well-known long-term consequences, including brain damage and vision and hearing loss.

Previous epidemiological research into immune amnesia suggests that death rates attributed to measles could be even higher – accounting for as much as 50% of all childhood mortality – if researchers factored in deaths caused by infections resulting from measles’ ravaging effects on immunity.

This new discovery was made possible thanks to VirScan, a tool Elledge and Tomasz Kula, a PhD student in the Elledge Lab, developed in 2015. VirScan detects antiviral and antibacterial antibodies in the blood that result from current or past encounters with viruses and bacteria, giving an overall snapshot of the immune system.

Study co-author Rik de Swart had gathered blood samples from unvaccinated children during a 2013 measles outbreak in the Netherlands. For the new study, Elledge’s group used VirScan to measure antibodies before and two months after infection in 77 children from de Swart’s samples who’d contracted the disease. The researchers also compared the measurements to those of 115 uninfected children and adults.

When Kula examined an initial set of these samples, he found a striking drop in antibodies from other pathogens in the measles-infected children that “clearly suggested a direct effect on the immune system,” the authors said. The effect resembled what Mina had hypothesised could drive measles-induced immune amnesia. “This proved to be the first definitive evidence that measles affects the levels of protective antibodies themselves, providing a mechanism supporting immune amnesia,” said Elledge.

Then, in collaboration with Diane Griffin at Johns Hopkins Bloomberg School of Public Health, the team measured antibodies in four rhesus macaques – monkeys closely related to humans – before and five months after measles infection. This covered a much longer period post-infection than what was available in the Netherlands samples. Similar to the findings in people, the macaques lost an average of 40% to 60% of their pre-existing antibodies to the viruses and bacteria they had been previously exposed to.

Further tests revealed that severe measles infection reduced people’s overall immunity more than mild infection. This could be particularly problematic for certain categories of children and adults, the researchers said.

The authors stress that the effects observed in the current study occurred in previously healthy children. Because measles is known to hit malnourished children much harder, the degree of immune amnesia and its effects could be even more severe in less healthy populations.

“The average kid might emerge from measles with a dent in their immune system and their body will be able to handle that,” said Elledge. “But kids on the edge – such as those with severe measles infection or immune deficiencies or those who are malnourished – will be in serious trouble.”

Inoculation with the MMR (measles, mumps, rubella) vaccine did not impair children’s overall immunity, the researchers found. The results align with decades of research. Ensuring widespread vaccination against measles would not only help prevent the 120,000 deaths that will be directly attributed to measles this year alone, but could also avert potentially hundreds of thousands of additional deaths attributable to the lasting damage to the immune system, the authors said.

“This drives home the importance of understanding and preventing the long-term effects of measles, including stealth effects that have flown under the radar of doctors and parents,” said Mina. “If your child gets the measles and then gets pneumonia two years later, you wouldn’t necessarily tie the two together. The symptoms of measles itself may be only the tip of the iceberg.”

Yumei Leng and Mamie Li of the Elledge Lab are co-authors of the study. Additional authors are affiliated with the University Medical Centre Rotterdam, University of Helsinki, Helsinki University Hospital, University of Colorado School of Medicine, Genentech, Johns Hopkins University School of Medicine and Duke University Medical Centre.
This study was supported by the Value of Vaccination Research Network, Gates Foundation, National Institutes of Health, European Union Seventh Framework Programme, Academy of Finland and PREPARE Europe. Elledge is an investigator of the Howard Hughes Medical Institute.

Abstract
Measles virus is directly responsible for more than 100,000 deaths yearly. Epidemiological studies have associated measles with increased morbidity and mortality for years after infection, but the reasons why are poorly understood. Measles virus infects immune cells, causing acute immune suppression. To identify and quantify long-term effects of measles on the immune system, we used VirScan, an assay that tracks antibodies to thousands of pathogen epitopes in blood. We studied 77 unvaccinated children before and 2 months after natural measles virus infection. Measles caused elimination of 11 to 73% of the antibody repertoire across individuals. Recovery of antibodies was detected after natural reexposure to pathogens. Notably, these immune system effects were not observed in infants vaccinated against MMR (measles, mumps, and rubella), but were confirmed in measles-infected macaques. The reduction in humoral immune memory after measles infection generates potential vulnerability to future infections, underscoring the need for widespread vaccination.

Authors
Michael J Mina, Tomasz Kula, Yumei Leng, Mamie Li, Rory D de Vries, Mikael Knip, Heli Siljander, Marian Rewers, David F Choy, Mark S Wilson, H Benjamin Larman, Ashley N Nelson, Diane E Griffin, Rik L de Swart, Stephen J Elledge

Scientists have shown how measles causes long-term damage to the immune system, leaving people vulnerable to other infections. Researchers from the Wellcome Sanger Institute, University of Cambridge, University of Amsterdam and their collaborators revealed that the measles virus deletes part of the immune system’s memory, removing previously existing immunity to other infections, in both humans and ferrets. Importantly, the team showed for the first time that measles resets the human immune system back to an immature baby-like state with only limited ability to respond to new infections.

The study explains why children often catch other infectious diseases after measles, and highlights the importance of vaccination against measles. The research has great implications for public health, as falling vaccination rates are resulting in rising cases of measles, which could also cause an increase in cases of other dangerous infections such as flu, diphtheria or tuberculosis, even in people who were previously immune.

The measles virus causes coughing, rashes and fever, and can lead to potentially fatal complications including pneumonia and encephalitis – inflammation of the brain. Measles leads to more than 100,000 deaths per year worldwide in unvaccinated communities.

A highly effective measles vaccine was introduced into the UK in the late 1960s and in 2017 measles had been completely eliminated from the UK. However, measles is highly contagious and measles cases are rising again as the UK vaccination rate has dropped below the required level of 95% of the population. This has led to the UK losing its World Health Organisation (WHO) measles elimination status recently.

It is known that measles weakens the immune system, even after the initial infection has cleared, but it has not been known how. During a measles infection, people have fewer white blood cells, which protect the body against disease, and this is seen in the clinic as a low white blood cell count. However, after a few weeks, the patient’s white blood cell count goes back up to previous levels and they have recovered from the measles, yet they are still much more susceptible to other infectious diseases.

To find out what measles does to the immune system, researchers looked at a group of non-vaccinated people in the Netherlands. Blood samples were first taken from healthy volunteers from this community, who were followed-up for repeat sampling after a measles outbreak in 2013.

The researchers sequenced antibody genes from 26 children, before and 40-50 days after their measles infection. The team discovered that specific immune memory cells that had been built up against other diseases, and were present before the measles virus infection, had disappeared from the children’s blood. This would leave them vulnerable against infectious diseases they had previously been immune to.

“This study is a direct demonstration in humans of ‘immunological amnesia’, where the immune system forgets how to respond to infections encountered before. We show that measles directly causes the loss of protection to other infectious diseases,” said Dr Velislava Petrova, lead author from the Wellcome Sanger Institute and Cambridge University.

Researchers then tested this “immunological amnesia” directly in ferrets, showing that infection with a measles-like virus reduced the level of flu antibodies in ferrets that had been previously vaccinated against flu. These ferrets also had worse flu symptoms when infected with flu virus after the measles-like infection.

“We showed that measles-like viruses can delete pre-existing flu immune memory from ferrets. Even after the ferrets had been successfully vaccinated against flu, the measles-like virus reduced levels of flu antibodies resulting in the animals becoming susceptible to flu infection again and experiencing more severe flu-like symptoms. This shows that measles could reverse the effects of vaccination against other infectious diseases,” said Professor Paul Kellam, an author on the paper from Imperial College London, and previously from the Wellcome Sanger Institute.

The researchers also discovered that the measles virus resets the immune system to an immature state that can only make a limited repertoire of antibodies against disease. This means that measles makes it difficult for the immune system to respond to any new infections, increasing the risk of secondary diseases.

“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. 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 also protects from other infectious diseases,” said Professor Colin Russell, senior author from the University of Amsterdam, Netherlands.

The study reveals that it is extremely important that everyone who can be vaccinated, is vaccinated, to prevent the resurgence of measles and other diseases that we have developed immunity to in childhood or for which we vaccinate.

After measles, some children still show signs of immune suppression for up to five years although they appear healthy when their white blood cell counts are measured. This study shows how genetic techniques can reveal new mechanisms of disease that are undetectable using routine clinical tests, and that further research is needed to understand the full effects of measles.

“Measles is highly contagious and its potentially devastating consequences are well known. This study finds that measles also has the potential to weaken our body’s existing immune response to other diseases, leaving us vulnerable to infections. These findings further strengthen the vital role the MMR vaccine plays in public health and protecting us from deadly disease. It is yet another reminder of how important vaccines are as a vital resource in eliminating infectious disease,” said Dr Charlie Weller, head of vaccines at Wellcome.

Abstract
Measles is a disease caused by the highly infectious measles virus (MeV) that results in both viremia and lymphopenia. Lymphocyte counts recover shortly after the disappearance of measles-associated rash, but immunosuppression can persist for months to years after infection, resulting in increased incidence of secondary infections. Animal models and in vitro studies have proposed various immunological factors underlying this prolonged immune impairment, but the precise mechanisms operating in humans are unknown.
Using B cell receptor (BCR) sequencing of human peripheral blood lymphocytes before and after MeV infection, 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. Using a surrogate model of measles in ferrets, we investigated the clinical consequences of morbillivirus infection and demonstrated a depletion of vaccine-acquired immunity to influenza virus, leading to a compromised immune recall response and increased disease severity after secondary influenza virus challenge. Our results show that MeV infection causes changes in naïve and memory B lymphocyte diversity that persist after the resolution of clinical disease and thus contribute to compromised immunity to previous infections or vaccinations. This work highlights the importance of MeV vaccination not only for the control of measles but also for the maintenance of herd immunity to other pathogens, which can be compromised after MeV infection.

Authors
Velislava N Petrova, Bevan Sawatsky, Alvin X Han, Brigitta M Laksono, Lisa Walz, Edyth Parker, Kathrin Pieper, Carl A Anderson, Rory D de Vries, Antonio Lanzavecchi, Paul Kellam, Veronika von Messling,Rik L de Swart, Colin A Russell

Jonathan Ball, a professor of molecular virology at Nottingham University, who was not involved in the work, said in a report in The Guardian: “In our current climate of falling vaccine uptake rates, this serves as a timely reminder of why MMR immunisation is so important – not only to protect against the viruses the vaccine is designed to target, but also to prevent avoidable follow-on complications that can occur after measles infection.”

“This is wonderful science,” said Dr William Schaffner, an infectious disease expert at Vanderbilt University, who was not involved in the research. “These are two wonderfully complementary studies that have provided a basic immunologic understanding of a phenomenon that has been recognized for a long time, mainly that measles infection causes immune suppression.” The New York Times reports the studies arrive at a time of heightened concern about measles, as outbreaks flare up in the US and other developed countries where vaccines had largely eradicated the disease, but where a growing number of parents have begun to refuse vaccination. Some claim religious reasons, and some mistakenly fear a link to autism, based on research that has been discredited as fraudulent.

The study was paid for by the Value of Vaccination Research Network, the Gates Foundation, the National Institutes of Health and several European research organisations.

“These elegant studies provide insights into immunological deficits following measles infections that have intrigued scientists for over 100 years,” said Dr Ian W Lipkin, director of the Centre for Infection and Immunity at Columbia Universitys Mailman School of Public Health.

“This emphasises again what a nasty infection measles is,” Schaffner said. “We know that in and of itself it can lead to ear infections, pneumonia and encephalitis. It remains in the developing world a leading cause of death among children. This makes it clear that measles has detrimental effects beyond measles itself. If we wanted, if we needed even more reason to protect our children with measles vaccine, here’s some more information you ought to think about.”

Harvard University material Science abstract Science commentary Wellcome Sanger Institute material Science Immunology abstract The Guardian report The New York Times report

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