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.
-
The vaccine itself could have long-lasting non-specific
immune-boosting properties that protect the recipient from other
diseases.
-
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.
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.
