Measles: The race to understand 'immune amnesia'

Scientists have known for years that measles can alter the immune system – but the latest evidence suggests it's less of a mild tweaking, and more of a total reset.

It was late at night on 15 November 2019, on the Samoan island of Upolu – a tiny jade-green splodge in the Pacific Ocean, somewhere between Hawaii and New Zealand. Government officials were rushing to attend a meeting in the sleepy harbourside capital to discuss an urgent public health issue. By the end of the evening they had declared a state of emergency, with immediate effect. 

Three months earlier, a member of the public had developed a characteristic red-brown blotchy rash after arriving on a flight from New Zealand, where there was an ongoing measles epidemic. They were swiftly diagnosed as a "suspected" case, but no further action was taken.

By 2 October, another seven measles cases had materialised. Schools – ideal environments for the virus to spread among its preferred victims – continued as normal, with the small concession that prize-giving ceremonies were banned. Even then, some ignored this. Just over a month later, the outbreak had spiralled to alarming proportions – with 716 people infected, out of a total population of around 197,000. 

But with the new state of emergency in place, the country radically stepped up its efforts to halt the spread. Schools and businesses closed. Workers abandoned their offices. Residents were advised to stay in their homes. In a sinister echo of the red crosses marked on doors during medieval plague outbreaks, red flags popped up outside the homes of unvaccinated families across the country, draped on bushes, tied to columns and hung from trees. This allowed doctors to go house to house, administering compulsory vaccinations to those who needed them. Otherwise, Samoa became a ghost island – with empty roads and cancelled flights.

Eventually infections slowed, and the state of emergency ended on 28 December 2019. In all, 5,667 people were infected – including 8% of the population under 15 years old. Of those, 81 died, including three children from the same family.

The epidemic was over – but the virus hadn't necessarily taken its last victim. 

Enter "immune amnesia", a mysterious phenomenon that's been with us for millennia, though it was only discovered in 2012. Essentially, when you're infected with measles, your immune system abruptly forgets every pathogen it's ever encountered before – every cold, every bout of flu, every exposure to bacteria or viruses in the environment, every vaccination. The loss is near-total and permanent. Once the measles infection is over, current evidence suggests that your body has to re-learn what's good and what's bad almost from scratch.  

"In a way, infection of the measles virus basically sets the immune system to default mode," says Mansour Haeryfar, a professor of immunology at Western University, Canada, "as if it has never encountered any microbes in the past".

How does it work? How long does it last? And could it be driving other epidemics?

A master contagion

Measles is an ancient respiratory virus, transmitted via aerosols and droplets, that's thought to have first made the leap from cattle to humans around 2,500 years ago – possibly taking advantage of the crammed cities that were springing up across the globe.

For millennia, measles had free rein to plague the world's children – particularly in the first few years of life – infecting nearly everyone before their 15th birthday. In 1967, the year before the vaccine was introduced in the UK, there were 460,407 suspected cases. When European colonists first made it across the Atlantic, the virus is thought to have been one of the new imports – along with others such as smallpox and typhoid – that wiped out 90% of the indigenous population of the Americas within a century.

Scientists have known for decades that even after they recover, children who have been infected with measles are significantly more likely to fall ill and die from other causes. In fact, a study from 1995 found that vaccinating against the virus reduces the overall likelihood of death by between 30% and 86% in the years afterwards.

However, exactly why measles was such a potent driver of childhood illnesses wasn't clear.

Then in 2002, a group of Japanese scientists discovered that the receptor the measles virus binds to – a kind of molecular lock that allows it to enter the body – isn't in the lungs, as you would expect for a respiratory virus. Instead, it's on cells from the immune system.

"It was really quite a surprise if you compare it to what we knew at that time from the textbooks of how measles virus would enter our host," says Rik de Swart, an associate professor of Viroscience at Erasmus University Medical Center in the Netherlands. 

A decade later, an international team of researchers – including Swart – decided to take a closer look. They tagged measles with a green fluorescent protein, infected macaque monkeys with it – and tracked where the green viral particles ended up.

"[We saw that] it infects many cells systemically," says Swart. "So, this virus causes a viremia, which means that then there's virus in the blood – actually, white blood cells become infected and bring the virus to all the lymphoid tissues, which are your lymph nodes and your spleen, your thymus [a gland in the chest that's part of the immune system]," he says, explaining that this confirmed that measles is an infection of the immune system.

An outbreak of measles in the Netherlands in 2013 provided an opportunity to test this theory. It started among an Orthodox Protestant community, who refused vaccination on religious grounds, and eventually infected 2,600 people. Years later, scientists investigated blood samples taken from patients – and confirmed that they contained memory T cells infected with measles.   

A bewildering paradox

But this was not the end of the story. The team mostly found the receptor measles binds to on a specific kind of immune cell, the memory T cell. Their job is to remain in the body for decades after an infection, quietly looking out for the specific pathogen each one was trained to target. So, measles actively infects the only cells that can remember what the body has encountered before.

What happens next is still baffling scientists to this day – so much so that it's been called the "measles paradox".

"Measles suppresses the immune system, and activates it at the same time," says Swart. Though measles deletes immune memories, there is one exception to these losses. Oddly, the only virus you'll definitely be able to recognise after falling sick with measles is measles itself.

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Measles infections generate a powerful immune response against the virus, leading to lifelong immunity in the vast majority of people. And though no one yet knows why, this may be what causes immune amnesia in the first place.

First measles infects memory cells, then somehow the immune system learns how to identify the virus itself. Once it's started producing immune cells specific to measles, they travel around the body, hunting down infected memory cells  So you end up with cells that can identify measles systematically killing off cells that can identify other viruses. The virus leads us to destroy our own immune memories.  

Eventually, measles ends up replacing all your normal immune memory cells with ones that can identify it, and nothing else. This means you're only immune to measles – while all other pathogens are forgotten. It's a counter-intuitive strategy, especially from the virus' perspective, since it won't be able to sneak into the body again without being recognised.

(Unfortunately there's no evidence this immune reset can be beneficial for those who have malfunctioning immune systems, such as people with autoimmune disorders – and even if it was, Swart points out that measles-based treatments would only work in those who had never encountered measles or the vaccine before.)

"Another virus that uses a similar strategy is HIV," says Swart. "It infects cells of the immune system and as a consequence, breaks it [the immune system] down and makes it less competent. But the big difference there is that HIV does this slowly but persistently, chronically, so that decay goes on over a really long periods of time."

In fact, though HIV damages the immune system, the amnesia generated by measles is unique among human infections. In other animals, viruses such as canine distemper in dogs and dolphin morbillivirus (DMV) in dolphins also suppress the immune system, and might have a similar mechanism, says Swart.

A two-year gap

Since the discovery of immune amnesia, the pieces have started to fit together.

Once the immune system has lost its memory cells, it has to painstakingly re-learn everything it once knew. One population-level study from 2015 suggests that this process of recovery can take up to three years – which intriguingly, is around the time it takes infants to acquire immunity to everyday pathogens in the first place.

"Children develop a lot of colds and gastrointestinal diseases and need quite a bit of time to develop their immune system," says Swart. "So this is sort of in the same order of magnitude in terms of duration."

In the meantime, children are at risk from a broad range of pathogens their bodies would once have been able to recognise. "Probably all those infections need to be experienced, again, to really repair all the damage there," says Swart. "And every infection has another risk of disease development."

It's not surprising, then, that measles doesn't just increase the risk of illness, but also death. In fact, childhood mortality from other viruses is strongly linked to the incidence of measles. The 2015 study showed that when childhood mortality in the UK, US, or Denmark goes up, this is usually because measles has become more prevalent.

The findings explain why vaccinating children against measles has the unexpected, beneficial side-effect of reducing deaths among children, way beyond the numbers who were ever at risk of dying from measles itself.

A surprising impact

All this means that measles can have a profound impact on a population's health, even years after an outbreak has disappeared.

Take Samoa. It's thought that the 2019 outbreak of measles on the island stems from a traumatic and exceptionally rare incident years before, when two nurses mixed a batch of the measles, mumps and rubella (MMR) vaccine incorrectly, and two children died. (The nurses were subsequently jailed.) This led to a widespread fear of vaccines, and as a result, just 30% of the country's population had been fully immunised as of 2018.

By the time measles – one of the most contagious viruses on the planet, with an R number of 12-18 (meaning each infected person infects that number of others, on average) – arrived, it found near-perfect conditions for its spread. 

And though the authorities did manage to get the measles epidemic under control, its impact may have lingered on. Just under a year after measles vanished from the island, another arrived – on the 27 November 2020, Samoa recorded its first case of Covid-19.

As it happens, Covid-19 was never given the opportunity to take off on the island – a comprehensive programme of vaccination and lockdowns prevented its spread. However, modelling suggests that had it been able to, the population would have been at significantly higher risk as a result of the measles outbreak. According to these calculations, the islands' legacy of immune amnesia could have increased the total number of cases by 8% and deaths by more than 2%.  

Meanwhile, other modelling work has found that measles outbreaks occurring after Covid-19 vaccine rollouts could wipe out herd immunity to the coronavirus and lead to a resurgence of cases.   

"Maybe you underwent an infection with measles virus that you thought, okay, that's irrelevant, regarding my protection to Covid-19," says Miguel Muñoz, a professor of statistics at the University of Grenada who led the study. "Maybe it's not, because if you get infected with measles, then your coverage is going to disappear. You're not safe anymore."

All this makes measles decidedly unappealing, if it weren't already. It also raises an important question – should people who have been infected with the virus get re-vaccinated?

According to Swart, this is currently not standard practice – though it wouldn’t be a bad idea. "In some cases that might be required. But on a programmatic basis, that is not being done now, as far as I'm aware," he says. Unfortunately, in practical terms, Swart points out that re-vaccinating people would only be useful to a minority.  

"So it would only apply to people that have been fully vaccinated, but just not to measles," says Swart. "…that is such a small subgroup, that that's not really substantial enough, I think, to develop a programme like this on an individual basis."

So, while the jury is still out on re-vaccinating, one simple-yet-powerful thing people can do to protect their precious immune memories – painstakingly gathered over decades, until they're a kind of record of our interactions with the world – is to get vaccinated against measles. If you count immunity that's acquired naturally, it's really hundreds of inoculations for the price of one.

* This article was originally published on 16 November 2021. It was updated on 14 February 2024 to include the latest outbreak figures in the US and Europe.

Zaria Gorvett is a senior journalist for BBC Future and tweets @ZariaGorvett

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