How will isolation affect long-term immunity?

Every time you kiss another human being intimately for 10 seconds, more than 80m bacteria are transferred from mouth to mouth. If you’re at a party and double dip your tortilla chip into the salsa three times, around 10,000 bacteria will be transferred from your lips to the dip. Say “hi” to your co-workers as you sit down at your office desk and you’ll also be greeted by over 10m bacteria on its surface.

Disturbing as these figures may seem, many scientists believe that exposure to these microbes helps fine-tune our immune systems – the network of cells and molecules that protect us from diseases. In 1989, epidemiologist David Strachan first proposed the “hygiene hypothesis” – the idea that being too clean causes defects in the immune system, leading to a rise in inflammatory diseases, such as asthma and allergies. While Strachan’s theory is debated and hygiene saves countless lives, decades of data support the idea that exposure to microbes helps the immune system develop.

But hang on a minute. For most of the last year, many of us haven’t been kissing strangers, double dipping at parties or sitting down to work in a crowded office. Instead we’ve been locked up at home by ourselves, sanitising our hands every time we go to the shop and holding on to distant memories of restaurants and gyms. So what’s happened to our immune systems in lockdown? What’s going to happen now that the country is opening back up?

Graham Rook, a microbiologist at University College London, proposed an alternative to the hygiene hypothesis in 2003. Rook’s “old friends hypothesis” posits that as humans evolved, our immune systems learned to cope with the microbes around us in the natural world. Rook argues that we need to be exposed to these “old friend” microbes in order for our immune systems to develop properly. (Strachan’s hygiene hypothesis focused on infections, while Rook’s focuses on more harmless micro-organisms.)

“Our immune system is a learning system, just like the brain,” Rook says, explaining that the system has two branches. We are born with an “innate” immune system encoded in our genes, but this is “tuned” by our “adaptive” immune system, which collects data from the microbes around us to determine which are safe and which are dangerous. Without the right data, the immune system starts attacking things it shouldn’t, causing allergies, asthma and autoimmune diseases (when the immune system targets your body’s own tissues).

So first, the good news. By the time you’re an adult, you’ve already encountered a whole host of microbes. Your microbiota – the trillions of microbes living on and in you – is “fairly stable and established,” says Rook. A year of isolation, then, is unlikely to severely damage your immune system’s regulatory mechanisms. But when it comes to children, Rook and other scientists have concerns about the effects of lockdown measures. “A child on the 24th floor of a tower block is simply not meeting the appropriate microbiota,” Rook says, explaining that staying indoors away from the natural world and other people limits the microbes encountered, as does having an unvaried diet (which he fears may be a problem for children going without school meals). “It is worrying.”

Byram W Bridle is an immunologist at the University of Guelph in Canada. Early on during global lockdowns, Bridle wasn’t too concerned for children’s immune development because, after all, kids often get stuck at home for a few weeks when they’re ill or over the summer holidays. “But the issue is now, we are over a year and counting,” Bridle says. “We’re talking about a big chunk of development of the immune system. So it’s hard to imagine that this cannot have a negative impact on our children.”

Like Rook, Bridle worries about a rise in immunological disorders caused by lockdown limiting children’s exposure to the natural world – even before the pandemic, scientists documented that “those who grow up in large urban centres tend to have a much higher incidence of allergies, asthma and autoimmune diseases”. Bridle explains that while the immune system doesn’t fully mature until adolescence, birth to age six is the critical period for its development.

Various studies have posited that problems can arise when infants have limited microbial exposure. It has been shown that children born by caesarean section are exposed to less of their mother’s microbiota than others – they are also statistically more likely to suffer from allergies and inflammatory diseases. One 2014 study from the University of Pennsylvania and Bloomberg School of Public Health found that children who are given repeated courses of antibiotics early in life face a greater risk of obesity (the researchers theorised that the medicine killed off the good bacteria in the children’s guts). Rook says as well as allergies and autoimmune diseases, poor immunoregulation can cause chronic inflammation which can lead to diabetes, obesity, and cardiovascular diseases. “It’s a pretty impressive list.”

Let’s take a moment to press the big “don’t panic” button in our brains. While children’s microbial exposure may have been limited by lockdown, it remains to be seen just how much.

As we have been in and out of lockdown in the UK, many of us haven’t actually been isolated for an entire year. Many children may also have been outside more than usual – one global analysis in the Journal of Forestry Research found that lockdown restrictions correlated with more visits to parks. There has also been a boom in puppy purchases over the past year: studies have shown that children who grow up with dogs have a lower risk of developing autoimmune diseases. Then there’s the fact that microbial exposure isn’t everything: our immune response is also determined by our genes.

Sheena Cruickshank, an immunology professor at the University of Manchester, is more optimistic than Rook and Bridle. “With the best will in the world, how super-duper clean are kids?” she says. Cruickshank notes that research about our immune systems is continually ongoing: “Both of them could be partially right, both of them could be partially wrong,” she says of the hygiene hypothesis and the old friends hypothesis. “It’s something that we’re very much investigating.”

Bridle stresses that while his concerns are based on “sound scientific principles” they do, of course, remain speculation: “We won’t know for sure until we actually see how all this plays out.” It may yet be a few years before we know whether the children of lockdown have higher rates of immunological disorders. “It takes about five years for asthma to really kick in,” says Brett Finlay, co-author of Let Them Eat Dirt: How Microbes Can Make Your Child Healthier. “The data is not there yet, it’s too early, but we’re imploring people to look,” he says. “We’ve really changed the world we live in, and every time we change the world, we change the microbes.”

Immunological disorders are one thing, but what about viral infections? Many of us – adults and children – haven’t so much as sniffled for an entire year: does this mean our immune systems will be ill-equipped to deal with viruses as the world opens up? When it comes to the common cold, Cruickshank says we don’t have too much to worry about. “We don’t really build up a long-term resistance,” she explains – and, “we’ve got an advantage coming out of lockdown now, because we’re going into the warmer seasons and that typically means people are outside more – colds do better in small, enclosed spaces.”

Every time we change our world, we also change our microbes

Between October and November 2020 in Hong Kong, schools reopened after a three-month closure and a large number of common cold outbreaks were reported. Ron Eccles, founder of the Common Cold Centre at Cardiff University, says such outbreaks are to be expected when children crowd together after being apart. Thankfully, however, he says, “There’s very little to indicate that just because you’ve not had a cold for a while the next one you get is going to be more severe.” Yet when it comes to the flu, Bridle has concerns. In January 2021, data from the Royal College of General Practitioners revealed that flu rates had plummeted to a 130-year low – researchers argued that travel bans, social distancing and hand-washing helped stop the spread. While this might sound like good news, Bridle says it puts us on the back foot when it comes to our next flu season.

“We deal with the flu virus on an annual basis because it mutates rapidly,” he explains. “From year to year, we’re actually dealing with fundamentally different variants.” This means flu vaccinations are also constantly changing – every year, scientists base the vaccine on the predominance of variants spreading the year before. “We will potentially be dealing with vaccines that are based on variants that were circulating two years ago instead of one.” Bridle says our immune responses will also be a year out of date.

“Our immune systems and the vaccines that we’re using are going to be targeting a virus that has now been able to accumulate two times the mutations than what we would normally be facing.” Although there is a counter-argument that, with so little flu virus in circulation, it will have had less chance to mutate and therefore using last year’s formulations is an acceptable strategy.

Nevertheless, Bridle says this is most concerning for “the two ends of the spectrum” – the elderly and the very young. Rook also has concerns that limited microbial exposure could affect the elderly. Although there is little evidence that having a less-diverse microbiota means you’re more susceptible to viruses, the kind of isolation induced by lockdown that affects microbial exposure could have knock-on effects in terms of bacterial infections that might otherwise have been less of a problem. One 2012 article in Nature found that the gut microbiota of people in long-term care was less diverse than those out in the community and, in turn, “loss of community-associated microbiota correlated with increased frailty”.

Younger and middle-aged adults aren’t totally off the hook – while they are not at the highest risk for flu complications, there is evidence that both loneliness and stress can weaken the immune system.

So, what on earth should we do? Rook says children should continue to be exposed to the natural environment and “run around in the park as often as possible”. Finlay advises to “think from a microbial exposure point of view” – go outside, hug a dog, and also eat fruit, nuts, legumes, “all the stuff your mum tells you to eat” as nutrition is crucial for a healthy immune system. Cruickshank says the immune system can also be mobilised by moderate exercise. Crucially, don’t be misled into throwing away your disinfectant – lack of hygiene does not lead to better immunological development and it’s important to continue to keep clean in order to ward off harmful pathogens.

Finally, Rook also stresses that it’s imperative to keep up to date with your child’s vaccination schedule. “Not only do vaccines stop you from getting the infection that they are targeting, they also help with the training of the immune system in a nonspecific way,” he says.

Many questions remain. “Our innate and adaptive immune system will develop regardless of whether we are exposed to the microbial world or not. The question is, will they develop appropriately?” Bridle says. Personally, he is concerned. “In some of our children as a result of this excessive isolation, we are likely causing irreparable harm. It’s frustrating as a scientist when you consider this in the context of children being at an extremely low risk from the Sars-CoV-2.”

The data isn’t here yet – it’s too early to see the lasting effects of lockdown. Finlay hopes that scientists will use this opportunity to learn more about microbial exposure. “Here’s, I think, one of the biggest experiments we’ve ever been able to do with humanity – we’ve got the whole globe involved,” he says. “Let’s make use of this opportunity and characterise the microbes over time and follow these things. Let’s see what happens to us because it’s really an experiment that’s happening right now.”