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The mystery of why some vaccines are doubly beneficial
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Woman receiving vaccination (Credit: Getty Images)
Vaccines have been providing a kind of hidden, unintended protection for over a century. Now scientists are racing to find out how it works.

Peter Aaby shakes his head, as though he still can’t believe it. “That was the start of it really – something very strange happened,” he says.

Today Aaby is speaking with me via Skype from his native Denmark. But he has spent the best part of the last four decades in Guinea-Bissau – a small, impoverished West African country with a troubled colonial past and recent history of repeated coups d'état. He moved there in 1978 to set up a charity, the Bandim Health Project.

At the time, there was no national programme of measles vaccinations, so after a particularly devastating outbreak, the team decided to focus their efforts on providing them for children in the local area.

It was around a year after the vaccinations began that they made an extraordinary discovery: those who had been vaccinated against measles were 50% less likely to die than those who hadn’t. “It was stunning,” says Aaby – but not for the reasons you might at first think.

The thing is, measles was never killing anywhere near half of Guinea Bissau’s children. Based on the proportion who were dying of the disease originally, the vaccine should have been far less beneficial than it was. The numbers didn’t add up. “We were asking ourselves ‘How can this happen?’,” says Aaby.

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In the large-scale trials that followed, it emerged that the vaccination was reducing the chances of children dying by a third (other studies led to significantly higher estimates) – while only 4% of this decline was explained by the fact that it was preventing them from catching measles. This is the power of a mysterious phenomenon Aaby has called “non-specific effects”.

Happy accidents

For more than a century, certain vaccines have been providing us with a kind of clandestine bonus protection – one that goes far beyond what was ever intended.

Evidence from trials in the impoverished African country of Guinea-Bissau showed vaccines often conferred protection against other diseases (Credit: Getty Images)

Evidence from trials in the impoverished African country of Guinea-Bissau showed vaccines often conferred protection against other diseases (Credit: Getty Images)

Not only can these mysterious effects protect us in childhood, they can also reduce our risk of dying at every stage of our lives. Research in Guinea-Bissau found that people with scars from the smallpox vaccine were up to 80% more likely to still be alive around three years after the study began, while in Denmark, scientists discovered that those who had the tuberculosis vaccine in childhood were 42% less likely to die of natural causes until they were 45 years old. It’s also true in dogs: an experiment in South Africa found that dogs that had been vaccinated against rabies had much higher survival rates, beyond what would be expected from their immunity to rabies alone.

Other happy accidents include protecting us from pathogens which are entirely unrelated to their target, reducing the severity of allergies, fighting certain cancers, and helping to prevent Alzheimer’s disease. The tuberculosis vaccine is currently being trialled for its ability to guard against Covid-19, though the microorganisms behind the two diseases are entirely different – one is caused by a bacterium, the other by a virus. And the two are separated by 3.4 billion years of evolution.     

Despite decades of research, these surreptitious effects still haven’t given up their secrets. But until we understand them, scientists are reluctant to use them to their advantage – so the race is on to find out what’s going on.

The benefits of the BCG

Though the existence of “non-specific effects” wasn’t well-established until Aaby’s work in the 1980s, scientists have suspected for far longer that something weird happens when we’re vaccinated.

Take tuberculosis – one of humanity’s oldest foes.

The turning point came when French bacteriologists Albert Calmette and Camille Guérin invented the BCG vaccine

We’ve been living with this sausage-shaped bacterial villain for at least 40,000 years, and for the vast majority of our history, it was a death sentence. It’s been found in a third of all ancient Egyptian mummies and we may have given it to Neanderthals. Even since the beginning of the 20th Century, it has snatched away the lives of tens of millions of people, including the visionary author George Orwell, political figure Eleanor Roosevelt, and the Bohemian novelist Franz Kafka.

The turning point came when French bacteriologists Albert Calmette and Camille Guérin invented the BCG vaccine, which was made by gradually altering the version of the bacteria found in cows, since many farm animals carry their own strains. It was first administered to a child in 1921, and by the 1950s, it was clear that this was a game-changer; the vaccination is thought to be 70-80% effective in preventing the most severe forms of the disease.

Even this early on, scientists noticed that the BCG was associated with a dramatic drop in the number of children dying in their first few months of life. This was always jarring – it was unlikely to be because of the vaccine preventing serious cases of tuberculosis, because the disease usually takes a while to develop. “It decreased by nearly 70%,” says Mihai Netea, an immunologist at Radboud University in the Netherlands. “So right from the beginning, the beneficial effects were actually quite substantial.”

Tuberculosis has been responsible for the deaths of tens of millions of people (Credit: Getty Images)

Tuberculosis has been responsible for the deaths of tens of millions of people (Credit: Getty Images)

Since then, it’s become clear that the BCG is not only linked to lower mortality, but provides protection from a broad range of infections unrelated to tuberculosis, such as the flu, septicaemia and herpes.

Immune training

One possible explanation for the ability of certain vaccines to protect us from microorganisms other than the ones they’re supposed to target is that they share antigens – molecules used by the immune system to identify foreign invaders. For example, the BCG vaccine might introduce the body to a particular protein which is also found in another bacteria or virus. But when you consider the enormous diversity of other infections that this particular vaccine can prevent, it seems unlikely that they would all happen to have the same antigens.

Another idea is that vaccines are inadvertently providing the immune system with a more general kind of training. Recent studies have uncovered tantalising evidence to support this, including the discovery that a group of young adults who were given the BCG and then exposed to pathogens other than tuberculosis had a different kind of immune response to those who hadn’t been vaccinated.

Our immune cells are constantly scouring the body for mutated tissues to destroy

The real surprise is that this suggests these strange beneficial effects aren’t down to the adaptive immune system – the kind vaccines are engineered to trigger, involving cells which learn to hunt down specific pathogens – but the innate immune system. This is unusual, because this more primitive, general defence isn’t thought to be able to evolve and adapt in the same way.   

“The BCG vaccine is reprogramming the DNA of the immune system,” says Aaby. “So this means that you have created immunity against tuberculosis specifically, but you have also trained the immune system.”

This might explain why the vaccine can also protect people from certain cancers and dementia, since the immune system plays an important role in the development of both. Our immune cells are constantly scouring the body for mutated tissues to destroy, and cancer is significantly more common in people on immunosuppressant drugs. Meanwhile, lingering inflammation has long thought to be the involved in Alzheimer’s Disease, which has links to immune conditions, such as Crohn’s disease.

Surprisingly, the BCG is now a standard treatment for non-invasive bladder cancer, and one of the most successful therapies of its kind. Bladder cancer patients who have been treated with the vaccine are less susceptible to Alzheimer’s, and now it’s in clinical trials to see if it reduces the incidence of plaques – abnormal clumps of protein linked to the disease – in healthy people. 

Aaby explains that while one dose of a vaccine is good, the more doses you have, the stronger these unexplained beneficial effects tend to be. “Somehow the immune system reacts positively to being boosted,” he says. 

The BCG jab, which many of us get in the first few months of life, essentially upgrades the human immune system (Credit: Getty Images)

The BCG jab, which many of us get in the first few months of life, essentially upgrades the human immune system (Credit: Getty Images)

In fact, it’s not just vaccines which seem to be able to do this – those who have been naturally infected by pathogens like measles, and lived, have better long-term survival prospects than those who were never infected. It’s not entirely clear why this is, but again, it’s thought to be down to the immune training the body receives, which helps it to fight off other diseases. 

Bizarrely, though these hidden benefits are already thought to be saving millions of lives every year, Aaby believes their potential is not being maximised. “I would rather say the opposite,” he says. For one, they’re not currently taken into account when designing vaccination programmes. This is problematic, because not all vaccines are equally capable of generating them.

Girls vs boys

An example is the measles vaccine. When Aaby and his team introduced a new type to Guinea-Bissau in the 1990s, they were horrified to discover that it doubled the mortality rate of girls – though not boys. Years later, they realised why.

Though non-specific effects are associated with a wide variety of vaccines, from whooping cough to polio, smallpox, yellow fever and the flu, they work best in those containing living viruses. These “live” vaccines are made by taking pathogens that are still able to make copies of themselves and weakening them so they’re not as harmful. “Inactivated vaccines”, on the other hand, involve bacteria or viruses which have been “killed” with heat or chemicals – and are therefore unable to reproduce.

Because live vaccines carry hidden benefits and inactivated ones do not, the order in which they are given matters.

Somehow immunology has been blind to sex – Peter Aaby

There’s now mounting evidence that if children are given an inactivated vaccine after having a live one, it cancels out some of the benefits it would have provided.

Before the new measles vaccine was introduced in Guinea-Bissau, it was normal to receive a dose of the inactivated diphtheria, pertussis and tetanus (DTP) vaccine, followed by the live measles vaccine at nine months. But the new vaccine was given at four months, meaning DTP was given last. (Other inactivated vaccines might also mess up the beneficial effect if they're given out of sequence, such as polio.)

Though scientists are now aware of the vital significance of the order in which vaccines are given, Aaby says this is still not routinely taken into account, so many children could be missing out on their hidden benefits.

It’s not clear why the sequence of the vaccines only mattered in girls, partly because there has been very little research into how male and female immune systems are different. “Somehow immunology has been blind to sex,” says Aaby. “If you read research about mortality in low income countries, there is no such thing as boys and girls – there are children. So we perceive that they have to be the same, and they are definitely not the same.”

Even though smallpox has been eradicated in the wild, treatment with its vaccine could still bring other health benefits (Credit: Getty Images)

Even though smallpox has been eradicated in the wild, treatment with its vaccine could still bring other health benefits (Credit: Getty Images)

Research has repeatedly shown that women have stronger immune systems than men – they’re less likely to become seriously ill from infections, less susceptible to cancer, and significantly more prone to overreactions such as autoimmune diseases and allergies. Women also tend to mount more powerful immune responses to vaccinations.

“The female immune system has to be very different for the obvious reason that they have to be able to become pregnant and not reject the foetus. Therefore you have to have an immune system which has a more intricate feedback mechanism. And that is true from birth,” says Aaby.

If the unintended bonus effects of vaccines – and how best to benefit from them – were taken into account when planning vaccination programmes, it’s been estimated that a further 1.1 million deaths could be prevented each year. Equally, the consequences of ignoring them could be catastrophic.

The eradication paradox

In 1980, the World Health Assembly announced that smallpox had been eradicated, after a long and determined campaign to vaccinate the world’s children against it. But no sooner had the virus been driven to extinction, than something else disappeared too – the vaccinations. In the UK, children born after 1971 won’t have had this vaccination, and this might have serious implications for their health.

“In both Guinea-Bissau and in Denmark the smallpox vaccine was associated with a very strong beneficial effect. But when we removed the vaccine there was not a single study into what that meant,” says Aaby.

Afghanistan is one of the few places where polio has not yet been eradicated (Credit: Getty Images)

Afghanistan is one of the few places where polio has not yet been eradicated (Credit: Getty Images)

Right now, the world is on the cusp of another victory. Polio has been driven from almost every corner of the globe and Africa was officially declared free of the virus earlier this month, after it was eradicated from Nigeria. It is now only found in small pockets of Afghanistan and Pakistan.

This has led to concern about what might come next. Like with the smallpox vaccine, the polio vaccine is accompanied by a major dose of non-specific effects. For example, in 2004 it was partly credited with reducing child mortality by around 67% in Guinea-Bissau – despite the fact that polio had already been almost completely eradicated there at the time.     

“It might be that when we eradicate the disease, we stop the live vaccine. And we think we are doing something good, but we are actually increasing mortality,” says Aaby.

While the anti-vaccine movement has been falsely stirring up suspicion against vaccines for decades, it seems that ironically, the only secret vaccines have been hiding is that they’re better for us than anyone ever imagined.

Perhaps it’s time we realise their full potential before it’s too late.

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