Monday, May 18, 2015

A Measles Mystery: How Could The Vaccine Prevent Deaths From Other Diseases Too?

If infectious diseases were a monarchy, measles might be king. Not only does measles reign among the most contagious diseases known to man – likely to infect any non-vaccinated individual who stands in the same room as an infected person – measles has long been known to be one of the great killers of children. Before vaccination, measles was responsible for millions of childhood deaths. Today it remains a cause of great illness and death in low-resource countries, killing over 140,000 children worldwide every year.
Where measles vaccines have been introduced, childhood deaths often plummet by as much as 50%. Measles is deadly, but before the vaccines were introduced in 1963, the virus did not directly cause half of all childhood disease deaths. In other words, where measles vaccines have been introduced, they were associated with reductions in more childhood disease deaths than were actually caused by the measles.
The reason for these major drops in mortality has been a central mystery surrounding the vaccine for decades. My colleagues and I wanted to take a step toward further unraveling this mystery.
We figure, as have others, that there are two ways that the measles vaccine could prevent more deaths than are strictly due to measles virus.
  1. The vaccine itself could have long-lasting non-specific immune-boosting properties that protect the recipient from other diseases.
  2. The measles infection could have long-lasting effects that predispose someone to other diseases.
The first hypothesis has been investigated, but as the World Health Organization (WHO) recently reported, there is insufficient evidence to explain a purely immune-boosting effect from the vaccine.
On the other hand, recently strong evidence was shown to suggest the latter – that measles infections may induce long-term negative effects on the immune system by deleting immune memory cells, and that these effects may be prevented through vaccination.
Measles And ‘Immune Amnesia’
Measles is a virus, and like all viruses, it hijacks the molecular machinery of the human cells it infects. The virus turns infected cells into self-destructing virus-assembly plants.
Hundreds or thousands of viral progeny are produced in a cell before it explodes, freeing the new viruses to do the same thing in neighboring cells. This is how measles moves through the body, layer by layer, damaging cells of multiple major organ systems.

Measles virus particles at different stages of budding. Shmuel Rozenblatt (Shpilke), Israel. Used with permission.
Measles specifically targets the vast assortment of memory immune cells – these are called memory B and T lymphocytes. They are charged with remembering and targeting all previously encountered diseases.
These memory cells are coated with a molecule called SLAM (short for “signaling lymphocyte-activation molecule”), which normally aids the cells in recognizing and destroying known invaders. SLAM also happens to be a molecule to which the measles virus can readily dock and gain entry. Think of SLAM as a lock, and measles carries a matching key. Thus, by binding to SLAM, measles specifically infects memory cells, sending their numbers crashing down.
A recent study in macaque monkeys has shown that when cell levels built up again a few weeks later, after the infection cleared, they didn’t remember the vast array of previously encountered diseases.
Instead the regenerated memory cells were primarily aimed at measles alone. Thus, after having the measles, a person might be left with terrific “immune memory” against measles, but with an “immunologic-amnesia” to the rest of the diseases (or vaccines) he or she had previously encountered.

Measles virus particles at different stages of budding from an acute infected host cell. Shmuel Rozenblatt (Shpilke), Israel. Used with permission.
Assuming these data from macaques represent what happens in humans, then what happens to immune memory?
Does the amnesia eventually wear off and the array of “memories” spontaneously returns, or does the immune memory need to be retrained through new (re-)exposures to disease? And if so, how long might this take? That’s an important question because a person would be at risk of infection from any number of diseases until immune memory returned. And finally, what does this mean in terms of a larger role for measles vaccination?
How Can We Figure Out How Long ‘Immune Amnesia’ Lasts?
My colleagues (Bryan Grenfell and Jessica Metcalfe at Princeton University and Rik de Swart and Ab Osterhaus at Erasumus University in the Netherlands) and I recently took a first stab at answering these important questions using population, or epidemiological, data.
We looked at the number of measles cases that occurred every three months during the decades before and after the introduction of the measles vaccines in children in England, Wales, the US and Denmark. We compared these to the number of children who died from all other (non-measles) infectious diseases in the same periods.
child taking shot  VaccineDiseases
A boy receives a measles vaccination in Atlanta, Georgia in 1962. CDC via Public Health Image Library
During the years before the vaccine was introduced, measles was rampant, infecting nearly all children. So we figured that if immune amnesia occurred because of measles, we would be able to detect it as an increase in deaths from non-measles infections following large natural measles epidemics.
But we didn’t just compare the number of measles cases at a given time to the number of non-measles deaths at that same time. We also assessed how long the potential memory loss effects of measles might last – a point that was critical to the formal analysis and findings.
To do that, we created a mathematical model to explore the association between measles cases and non-measles deaths, but with an added assumption: that the effects of a measles infection (the potential immune-amnesia effects) might carry over into later time points. In other words, we added an assumption that the after effects of the infection (increased risk of other diseases) might be felt for months or even years after the time of the infection itself.
The model allowed us to figure out the (theoretical) prevalence of measles immune amnesia in the populations we studied. This means that we could test how well the possible prevalence of measles immune amnesia correlated with the number of non-measles disease deaths. (See the animation for an annotated explanation of what we did.)
In this animation we show how the mathematical model was used to determine how long the immune effects of measles may last for.
Immune Amnesia May Last For Over Two Years
We found that there were very strong correlations between measles cases and non-measles disease mortality whenever the model was adjusted to assume that the immune effects of measles lasted, on average, 28 months.
This same result, around 28 months of immune amnesia, was found regardless of the country, age group, gender and even the decade, which spanned from the 1940s to 2010 among the various countries.
The association was nearly exactly the same during the decades before and after the measles vaccines were introduced too, showing that the strong associations we noted could not be driven by direct vaccine effects.
We also checked to see if the fluctuations in mortality were due to general improvements in health care. We ran the exact same series of mathematical models substituting the measles data for pertussis (whooping cough), another important vaccine preventable disease that was decreasing over the same time period. In stark contrast to the measles findings, there were no associations between pertussis and non-pertussis childhood deaths.
Ultimately, we found strong evidence that the large reductions in childhood mortality seen following rollout of measles vaccine are likely due to reductions in the number of measles infections (thus avoiding potential measles immune-amnesia effects), and not from potential long-lasting immune-boosting properties of the vaccine itself.
However, our analysis certainly does not rule out other possible non-specific direct immune benefits of the vaccine shot itself, as others have suggested. Rather, it is likely that both mechanisms may work hand in hand.
Measles Is Not A Benign Disease
Once set in place, we hypothesize that immune-amnesia effects cannot be undone without re-exposures and infections over years. Basically, the memory cells need to “relearn” how to recognize and defend against diseases they had known before, and they can only do this through re-exposure to the pathogen or by re-vaccination. This places the child at risk of disease that he or she used to have some protection against, much like the high risk of infection that babies endure (compared to adults) when first acquiring protective immunity through exposures, infections.
Measles isn’t a benign infection. Wellcome Library, London, CC BY
There is a largely held, but incorrect, belief that measles is associated with little severe illness. This is simply not true. The primary infection can have devastating effects, including high fevers, rash, lung infections and encephalitis. And our data suggest that measles infection may have serious immunologic effects, leaving children vulnerable to secondary infections, that brew under the surface, possibly for years. These secondary infections are no less harmful, and would not occur if not for a measles infection, perhaps even two or three years earlier.
Measles vaccination is perhaps the best buy there is towards keeping society free of disease. When vaccine skeptics are weighing the scales of perceived (largely unfounded) risks of measles vaccination versus risks of the infection itself, our findings should add a new set of weights showing that vaccines are the best option for both the child and the population at large.
Indeed, there are regions today not lucky enough to have access to vaccines and where parents are reminded daily of the damage caused by vaccine-preventable diseases long forgotten in much of the world. In these regions, parents often line the hospital walls for an opportunity to get their child vaccinated.
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