Measles-induced immune amnesia

Measles is no trifling childhood disease. The virus is extremely contagious, and measles infection can have severe complications, such as pneumonia, encephalitis, brain damage, and death. Now, a recent study published in Science suggests that measles can also leave children more vulnerable to other pathogens for as long as two to three years after infection.

Mass measles vaccination is known to be associated with a general reduction in childhood mortality. In every country where it has been introduced, it has been followed by a decrease in the number of childhood deaths, not just from measles, but also from other non-measles infectious diseases.

Why is that? How can a vaccine designed to protect you from measles also protect you from other infectious diseases?

There are two possible explanations to this mystery:
either the vaccine itself has a general beneficial effect, protecting from other diseases besides measles, for example by boosting the immune system in a non-specific way
or it is the measles infection itself that has a general detrimental effect, making a person more vulnerable to other diseases; in that case, the vaccine would protect from other diseases indirectly, by preventing measles infection in the first place.

There is currently not enough scientific evidence to support the first explanation (though it might still be possible). However, two different types of study, epidemiological and immunological, have now gathered evidence supporting the second possibility – that measles infection has long-lasting negative consequences on the immune system, making an individual more susceptible to infection by other pathogens.

1) Epidemiological evidence

At the population level, the number of children deaths from non-measles infectious diseases is linked to the number of measles cases.

In a study published in Science in April, researchers analyzed child mortality records from the US, England, Wales, and Denmark in the decades before and after mass measles vaccination began. They compared the numbers of measles cases to the numbers of non-measles deaths, using a mathematical model to factor in the possibility that measles infection would leave individuals more susceptible to other pathogens.

The results revealed that the number of measles cases strongly correlated to the number of childhood deaths from diseases other than measles when a long-lasting effect of measles on the immune system was taken into account (the biggest killers were pneumonia, diarrheal disease, and meningitis). More precisely, the fluctuations seen in childhood deaths in the populations matched what would be expected if the immunosuppressive effect of measles lasted for about 28 months.

To see if the results were specific to measles or if other factors could explain the fluctuations in childhood mortality rates, the researchers repeated the same analysis, this time using the numbers of pertussis (whooping cough) cases instead of measles. In contrast to the measles findings, they saw no association between the number of pertussis cases and the number of non-pertussis childhood deaths.

To sum up, epidemiological data indicates that measles leaves children more susceptible to infection by other pathogens for about 2 to 3 years.

How can this be explained biologically? What would be the molecular, cellular, immunological mechanisms responsible for this effect?

2) Immunological evidence

In monkeys, measles infection erases parts of the immune system’s memory.

Measles is caused by a virus, which acts like any other virus: it enters the cells of the organism it infects, uses the host cells’ machinery to reproduce, and eventually kills the cells it had infected by making them “explode”. This in turn releases the newly produced virus particles and allows them to go and infect other cells.

Now, it so happens that the measles virus has a thing for immune cells, and especially for the ones that are in charge of remembering past infections and giving you immunity against them (these cells are called memory B and T lymphocytes). These memory cells display on their surface a molecule that the measles virus specifically recognizes, using it as a docking and entry site to the cell.

It is already known that the measles virus kills white blood cells (immune cells) and that measles infection is associated with a state of immunosuppression: the immune system’s ability to fight off pathogens is impaired for a while. However, this was assumed to be transient, lasting from a few weeks to a few months, and it was shown that the numbers of white blood cells circulating in blood quickly came back up to normal levels after recovering from measles.

However, a study performed in monkeys in 2012 adds another twist to the story: its findings suggest that it might not be enough to just look at how many white blood cells there are and assume that all is back to normal because the numbers are back to normal. Rather, one may also need to look at whether the immune cells that are present after measles infection still carry the memory of all the previously encountered pathogens, just like they did before measles.

In their study published in PLoS Pathogens, the researchers looked at the overall numbers of immune cells circulating in blood during and after measles infection, and also investigated the presence of immune memory cells specific for tuberculin (the monkeys had been immunized against tuberculosis three months earlier and had thus acquired immune memory against tuberculin). They found that, although the numbers of immune memory cells circulating in blood indeed bounced back to normal levels about two weeks after measles infection, the monkeys’ immune response to tuberculin was considerably lower after measles infection than what it had been just before. In other words, the monkeys had lost some of their immunity to tuberculosis. The researchers suspect that many of the immune cells replenishing the general pool of memory cells after measles infection are actually specific for measles, and that this may mask the decrease in, or even disappearance of, memory cells specific for other microbes (these cells having been killed by the measles virus during the infection).

The job of immune memory cells is to remember the pathogens that have infected us at some point in our lives (or that we have been immunized against), keeping us ready to mount a quick and very effective immune response against them, should our paths cross again. The kind of “immune amnesia” observed in the monkeys after measles infection suggests that measles may at least dampen that ability for some time, or maybe even erase it, leaving individuals susceptible once again to microbes they had managed to fight off and recover from in the past.

Of course, it remains to be seen whether the measles virus affects immune memory in humans like it does in monkeys. However, such a mechanism would be consistent with the epidemiological findings from the recent Science study: a long-lasting immune amnesia induced by the measles virus would make children more susceptible to other infectious diseases and explain, at least in part, why the introduction of the measles vaccine has been accompanied by a reduction in childhood mortality also from other non-measles diseases.

Further reading:
– the Science epidemiological study and its findings, narrated by its first author Michael Mina in The Conversation: A measles mystery: how could the vaccine prevent deaths from other diseases too?
– the authors of the PLoS Pathogens study, considering the possible mechanisms of measles-induced immunosuppression in an Opinion article in PLoS Pathogens: Measles Immune Suppression: Functional Impairment or Numbers Game?

References

Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality. Mina MJ, Metcalf CJ, de Swart RL, Osterhaus AD, Grenfell BT. Science. 2015 May 8;348(6235):694-9. doi: 10.1126/science.aaa3662
PMID: 25954009

Measles immune suppression: lessons from the macaque model. de Vries RD, McQuaid S, van Amerongen G, Yüksel S, Verburgh RJ, Osterhaus AD, Duprex WP, de Swart RL. PLoS Pathog. 2012;8(8):e1002885. doi: 10.1371/journal.ppat.1002885
PMID: 22952446

ResearchBlogging.orgMina MJ, Metcalf CJ, de Swart RL, Osterhaus AD, & Grenfell BT (2015). Vaccines. Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality. Science (New York, N.Y.), 348 (6235), 694-9 PMID: 25954009

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