Small shot,
big impact
Some vaccines seem to provide us with a host of extra
benefits. Michael Brooks sees the cornerstone of
modern medicine in a new light
H
AVE a look at your left shoulder: if you
are past your mid-twenties it almost
certainly bears a circular scar. Do you
remember how it got there? You queued up in
the school hall, perhaps, or outside the nurse’s
office, watching your friends rubbing their
arms as they walked away, relieved at having
survived their BCG jab.
The Bacille Calmette-Guérin vaccination
was given to protect you from tuberculosis.
What we are only just realising is that, in
common with several other vaccines, it may
have done far more than that.
There is growing evidence that vaccines
have a wider-ranging influence on the
immune system than we thought. In Africa,
for instance, studies have shown that measles
vaccine cuts deaths from all other infections
combined by a third, mainly by protecting
against pneumonia, sepsis and diarrhoea.
Even in the West, where it is far less common
for children to die from infectious illnesses,
there are still surprising benefits: some
vaccines seem to reduce our susceptibility to
eczema and asthma. Exactly what causes these
“non-specific effects”, as they are termed, is a
mystery. But some scientists are arguing that,
despite the uncertainties, it is time to start
harnessing them more effectively.
The World Health Organization, which is
the main provider of vaccines in developing
countries, has asked a group of vaccine experts
to get to the bottom of it. “This could have
huge implications for global healthcare,”
says Christine Benn, a senior researcher at
the Statens Serum Institute in Denmark and
a member of the WHO committee.
“Vaccines have been a fantastic success,
but we can probably do much better by
taking non-specific effects into account. An
examination of these issues is long overdue.”
Considering vaccines have been used since
the 1800s and are the central plank of our
public health system, it may seem hard to
believe that such profound effects could have
gone ignored all this time. In fact, an early
20th century Swedish physician called Carl
Näslund did notice something was up after
the BCG vaccine was introduced in his country.
Vaccinated children had a much higher chance
of reaching their first birthday – even though
TB normally kills older children.
In the 1940s and 50s, trials in the US and UK
suggested that BCG-vaccinated children had a
25 per cent lower death rate from diseases other
than TB. But no one took much notice until
30 years ago, when a Danish anthropologist
called Peter Aaby began working in the West
African state of Guinea-Bissau. In 1979 he
witnessed a severe measles outbreak that
killed 1 in 4 infants affected. Aaby arranged for
measles vaccination to be introduced, but was
surprised to see that even after the epidemic
abated, immunised children were more likely
to survive childhood. Aaby began digging, and
discovered studies from elsewhere in Africa,
as well as Bangladesh and Haiti, that also
suggested measles vaccine gives a wider kind
of protection. “We are collecting more and
more data consistent with non-specific
effects being very important,” says Aaby.
What could the explanation be? Several >
17 August 2013 | NewScientist | 39
”If past infections can alter the immune
system, it is not a major leap to suggest
that vaccines might also do so”
lines of evidence suggest that our immune
systems can be affected by many factors,
including past encounters with microbes.
Those microbes can be in the environment or
a vaccine syringe. “If infections can alter the
immunological milieu, it is not a major leap
to suggest that vaccines might also do so,” said
Andrew Pollard, head of the Oxford Vaccine
Centre at the University of Oxford, in an
editorial about Aaby’s work last year.
According to the old view of vaccines,
they work by priming what is known as our
adaptive immune system. This consists of
various defence cells circulating in the blood,
which make antibodies and other molecules
that recognise and latch on to specific foreign
proteins on bacteria, viruses or other germs.
It is this lock-and-key specificity that is
responsible for our immune memory. On our
first encounter with the measles virus, say, the
immune cells that make potent antibodies to
it reproduce, giving rise to successive
generations of daughter cells that make
progressively more powerful antibodies.
The end product is highly proficient measles-
killing machines that linger in our bodies for
years. That’s why, if we re-encounter the virus,
it is defeated so quickly we don’t even notice.
But that may not be the whole story.
Another, evolutionarily older, branch of our
defences known as the innate immune system
might also be playing a role. These cells are
programmed to react to anything unfamiliar
or untoward, such as the chemicals released
when tissues are damaged, attacking any
molecules or microorganisms that might
pose a threat. Last year, surprising evidence
emerged that BCG stimulates the innate
immune system as well as the adaptive one.
In people who received the shot, certain
kinds of innate immune cells responded more
strongly to bacterial and fungal pathogens
completely unrelated to the TB bug. This is the
first indication that the innate immune
system reacts to vaccines, and the researchers
suggested it could explain some of the general
SPL
immune-boosting effects of BCG. “It’s quite
preliminary data, but it’s very important,”
says Nigel Curtis, head of infectious diseases at
the Royal Children’s Hospital in Melbourne,
Australia, who studies BCG.
40 | NewScientist | 17 August 2013
The discovery may be only one part of the
explanation for BCG’s mysterious powers,
though. For starters, it emerged recently that
even memory cells of the adaptive immune
system can target unrelated microbes, if there
is sufficient cross-reactivity with a germ we
have previously vanquished.
Tipping the balance
But the theory that probably has most
evidence behind it concerns two competing
arms of the adaptive immune system, known
as type 1 and type 2 helper T-cells. Broadly,
type 1 cells promote immune reactions against
bacteria and viruses, while type 2 cells are
geared towards fighting off parasitic worms
in the gut. Both BCG and the measles vaccine
seem to tip the balance to type 1, according to
studies of the antibodies released into the
bloodstream after vaccination.
Whatever the explanation is, we might be
able to maximise the benefits, either by
designing new vaccines or augmenting the
effects of existing ones. But the WHO
committee has another line of inquiry: there
are suggestions that one vaccine could have
harmful non-specific effects. The vaccine
under suspicion is DTP, which prevents
diphtheria, tetanus and pertussis, otherwise
known as whooping cough.
It was Aaby, again, who first drew attention
to this. These days, he works as a vaccine
researcher for the Danish Statens Serum
Our immune cells can see off TB
bacteria (yellow) , especially
when primed by a vaccine
Institute, but he is still based mainly in
Guinea-Bissau. For several months in 2001 and
2002, health centres in the capital city, Bissau,
ran out of DTP, and some infants never got
their shot. Aaby noted that, among children
who had been admitted to hospital for some
reason, those who had had the shot were over
twice as likely to die during their hospital stay.
Further studies showed that the effect was
particularly pronounced for girls.
What no one knows is why DTP might have
such an effect. One possible explanation is
that the pertussis component is made from
killed whooping cough bacteria. There are
other ways to make vaccines, including using
live but weakened bacteria or viruses, with
both BCG and the measles shot being this type.
Killed vaccines, on the other hand, seem to tip
the type 1/type 2 balance away from the
bacteria and virus-fighting type 1 arm. Animal
studies show that, for unknown reasons,
females have a naturally stronger type 2 bias,
which could explain the sex difference in
mortality seen in Guinea-Bissau.
No one is suggesting we stop giving the DTP
vaccine. Its protection from diptheria, tetanus
and whooping cough is hugely beneficial –
especially in the West. “Mortality from
infectious diseases is incredibly low in wealthy
countries in 2013,” Pollard says. “Any non-
specific effects are likely to be trivial and
unmeasurable.”
However, Aaby thinks that, in developing
countries, there might be cleverer ways to
schedule the vaccinations that increase their
overall benefit. That’s because BCG and
measles seem to be such strong immune
boosters they may be able to undo the
immune-weakening effect of DTP. So Aaby is
planning to test giving DTP and BCG
simultaneously, in the hope it leads to an even
more positive effect on the immune system
overall. Another possibility is to shorten the
period of time during which a child’s last shot
is DTP, by giving the measles vaccine earlier in
life. “I’m in no doubt we could reduce
mortality in low-income countries,” Aaby says.
But the case for change is not yet strong
enough to convince everyone. Most of Aaby’s
studies are what are known as “observational”.
That means they count the number of deaths
in children who ended up getting different
vaccines by chance. These kinds of studies can
lead to bias in the results. “Randomised
controlled trials are the only way you can
answer this question,” Pollard says.
“Aaby has written some papers, and some
are more interesting and credible than others,”
says Paul Fine of the London School of Hygiene

Olivier Asselin/gavi/reuters
and Tropical Medicine, who is also on
the WHO committee. “But we’re not in a
position where they should influence
[vaccination] schedules.”
Benn is not so sure. While observational
studies can be biased, any bias would tend to
be towards showing DTP in a more favourable
light, she says. That’s because one reason for
missing out on a vaccination is that you are
already sick. So unvaccinated children are
more likely to have higher death rates.
In addition, it is hard to get the go-ahead for
randomised trials of vaccination schedules
that are different to the WHO-recommended
one. “Where randomised trials are just not
possible, observational studies should
definitely be taken into account,” she says.
“We may be able to save several million
more lives each year just by making better use
of current vaccines,” says Frank Shann of
Melbourne’s Royal Children’s Hospital, who
has worked on child health in the developing
world for more than 30 years.
It is not just in poor countries that vaccine
programmes may need to be reconsidered.
Many developed countries are phasing out
routine BCG vaccination as TB rates have
receded. In the UK, for instance, BCG is now
A vaccine designed
to protect against TB
does more than we
bargained for
given only in certain inner city areas with large
immigrant populations, who could have been
infected in their home country.
Hygiene hypothesis
That might have affected more than our
ability to fight off infectious diseases. Several
studies have suggested BCG reduces eczema
and asthma by 25 per cent, and reduces food
allergies by 35 per cent. “That’s not a small
effect,” Curtis points out.
The latest thinking is that allergies are
caused by an imbalance in type 1 and 2 helper
T-cells, with type 2 becoming too dominant.
Allergies may be on the rise in the West
because we no longer meet enough germs in
childhood to strengthen the type 1 arm,
according to the “hygiene hypothesis”. If BCG
does push the balance back to type 1, that
could be why it reduces allergies.
Again, though, these studies were not
purpose-built: they were done by looking back
at data collected for other purposes and most
were fairly small. Curtis is about to begin a
proper trial looking at this issue in Melbourne,
which will give the BCG shot to 1400 newborn
children who wouldn’t normally have got it.
While the primary aim is to see if BCG reduces
allergic disease, a subset of 200 children will
regularly have blood samples taken to see how
the vaccine has affected their response to
infectious diseases too. “That’s a really
interesting question,” Pollard says.
There is no doubt that BCG has effects on
the immune system that are wider than just
defending against TB. It even stimulates an
immune reaction against bladder cancer and
is now a standard treatment for this disease,
delivered directly into the bladder.
Despite the implications of his work, Aaby
has had no end of trouble getting people to
listen. That’s probably because, even though
most of the non-specific effects are beneficial,
the DTP effects are potentially harmful. And
people are wary of triggering another vaccine
scare, like the one over the measles, mumps
and rubella vaccine. “Our observations are
clearly inconvenient,” says Aaby.
That’s a fair analysis, Pollard thinks. “The
last thing to do is induce a loss of confidence
in immunisation,” he says. “What if children
in poor countries die as a result?”
But Benn reckons it is important to be open
about the unknowns. “People are scared of
causing vaccination rates to drop overnight,
but I think we could do with a more balanced
discussion than there is now,” she says.
Aaby is no troublemaker: he is a respected
researcher leading networks of scientists.
Support for non-specific effects of vaccines
comes from dozens of studies involving many
thousands of children. And vaccine researcher
Richard Moxon at the University of Oxford has
called Aaby’s work “an important body of
meticulously compiled data” that merits
“serious consideration”.
This is certainly a field with many
unknowns: not only whether the non-specific
effects are real and if so, why they occur, but
also which other vaccines may cause them.
And can we design new vaccines to maximise
the benefits? While the mechanisms are not
yet understood, says Calman MacLennan,
a researcher for Novartis, they are under
investigation and any findings would certainly
inform the design of future vaccines.
The questions cannot be answered soon
enough for Curtis. “There’s enough data out
there to suggest there is an effect, and I think
that needs investigating properly,” he says.
“If this is real, it’s too important to ignore.” n
Michael Brooks is a writer and New Scientist
consultant based in Sussex, UK
Links to the research in this article can be found in the
online version at newscientist.com/article/dn24027
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