Has COVID-19 weakened our immunity?

0:18Hello, welcome to the Naked Scientist podcast, the show that brings you the biggest breakthrough and talks to the major movers and shakers in the worlds of science, technology and medicine. I'm Chris Smith and today we're examining the impact of Covid on our immunity.

0:41You've probably heard of Omicron but how about Nimbus or Stratus? These are the latest Covid strains that are spreading around the world and thankfully for most people now they'll just amount to a heavy cold at worst and last a few days. Or will they? Are these coronaviruses doing more to our immune systems than meets the eye? That's what we're going to explore this week because anecdotally and officially we're seeing more frequent infections and also some more unusual and more severe infections that are occurring at greater rates for the time of year than we would do normally. Is it, as some argue, because measures like lockdowns deprived us of contact with these bugs and therefore the opportunity to reinforce our existing immunity, this, so the argument goes, will amount to an immunity debt that we're now repaying by catching things symptomatically again?

1:33Or have our immune systems been altered by infections with these new coronavirus variants? Before we consider both possibilities, let's hear about the patterns of diseases that we're seeing from the UK Health Security Agency's Colin Brown. So we typically have a winter season of seasonal viruses that come along in a crop together. So respiratory syncytial virus, which we've just got a new vaccine implemented for, influenza, where we have the seasonal vaccines, and then a variety of other seasonal viruses. And we're now largely back to the kind of winter season pattern that we saw before, but not completely.

2:13And there are other bacterial infections, mycoplasma, which is a big bacterial cause of pneumonia that sees peaks every number of years. And with group A streptococcus, which causes scarlet fever, but can also cause invasive group A streptococcus, a very severe cause of sepsis and mortality in particularly the children and the elderly. And then with some novel infections, there was a hepatitis that was seen among children because of adenovirus and a virus associated with adenovirus that was a novel thing that we hadn't particularly seen before, all of which happened in the years after COVID-19, some of which happened unseasonally.

2:54For example, the group A streptococcus, the scarlet fever, normally we get a spring peak, but that was brought back in winter 2022 into a much earlier phase that then coincided with that respiratory virus season. And it was the co-infections that we saw that in particular caused lots of severe pneumonia and unusual presentations in children in particularly. We also saw globally changes and resurgences in RSV and in influenza following the COVID-19 period. We're largely back to sort of seasonal kind of norms, but particularly those viruses and bacteria that have cyclical peaks every three to four years.

3:37It's by no means certain and that we're out of the altered pattern that we saw on the back of COVID-19. What have been the impacts then of disrupting the cycle of those normal seasonal things that crop up at this time of year by having those various manoeuvres to keep the pandemic under control? What's been the impact on the population, do you think? We're exposed day to day to all number of viruses and bacteria and fungi. And there clearly is a certain extent to which that constant exposure, as any parent of young children at nursery school knows, that leads to low level infections of things that otherwise, had we not been exposed to them on a more routine basis, might cause more severe disease.

4:25If we, for example, look at the group A streptococcus surge, because that was really quite significant. We had rates not seen since the 1950s of scarlet fever in winter 2022, 2023. Almost certainly because children in particular had not had that routine mixing and exposure for a number of kind of months and indeed years. that that altered dynamic of exposure and probably low-level infection meant that there was suddenly a group of people that were exposed to a bacteria that in a small number of cases causes a very severe and unfortunate endpoint of either severe infection, hospitalization, or indeed death.

5:09That small number of people that occurs every year was greatly amplified by the lack of that constant sort of exposure, that meant that there was a whole cohort of people that were probably more likely to get exposed than of severe outcomes. Colin Brown at the UK Health Security Agency. So the COVID-19 pandemic has clearly altered the dynamics of circulating infections. But what's the mechanism? Has SARS-CoV-2 affected the way the immune system works? Or is it simply the case, as some scientists suggest, that this is a side effect of social distancing, school closures, lockdowns and other measures like mask wearing.

5:49Avoiding COVID meant reduced exposure to other diseases which potentially robbed us of an opportunity to build or top up existing immunity to what's going around. And in the aftermath as measures are relaxed since their remains are now much bigger pool of susceptible people both to catch and pass on infections we end up with more cases overall. The concept is sometimes called immunity debt and I asked Michael Marks, a professor of medicine at the London School of Hygiene and Tropical Medicine, to explain it to us, as well as reviewing the evidence that Covid might reprogram our immunity. People think there are two main ways this might have happened.

6:28One is that because we weren't interacting with other people, because we were locked down, we were not having other infections that we might normally have. We weren't having flu or the cold. And although those things are unpleasant, they also teach your immune system how to respond to them. So if you have three or four years where your immune system isn't exposed, then now where we're all mixing again together, perhaps you are in some way slightly more susceptible than you were before the lockdown. The second hypothesis is that COVID itself as an infection does something to your immune system, which means that you are more susceptible.

7:12It's that you've had COVID and that's changed the way your immune system responds to infections long after the COVID has gone. Is there a precedent for viruses reprogramming our immunity in this way or is that something special and specific with COVID? So I think it is a thing that we know can occur with other viruses and I guess there are two broad categories. so there are obviously chronic viral infections such as HIV which have a profound effect on the immune system but that isn't really what we're talking about here what we're talking about here is an acute respiratory infection where you'll probably only have the infection for three to 15 days and can that have an effect that lasts after and there are some examples of that so it's definitely true that for a period of time after you've had measles you are more susceptible to other infections.

8:07In measles, that change to your immune system. It is, relatively speaking, prolonged, but it's still transient. We're not talking one year, two years after the exposure, really. And what's the evidence that COVID might be inducing some kind of immune amnesic state like that? It is clear that people who have COVID, as with, in fact, many viral infections, have changes in their immune system and that they can last for some period of time after the infection has gone. That doesn't necessarily really show that those changes in the immune system are the driver of your increased susceptibility to other infections and we certainly don't see evidence that I'm aware of six or 12 months later the vast majority of people who've had COVID have changes that are long lasting in their immune system that we would think cause you to be more susceptible to other infections.

9:09So I think we see what we see in many viral infections. There is some transient change in your immune system in and around the time that you have the infection that might slightly alter your propensity for other infections, but this doesn't appear to be lasting six months, one year, two years after the infection in the vast vast majority of people. And returning to the first hypothesis you outlined which is that lockdowns and other manoeuvres that we put in place to try to stop the spread of the pandemic in some way robbed us of an opportunity to expose ourselves via the natural course of things to things and update our immunity that way.

9:49Is there evidence that lockdowns did do that as in they deprived us of the normal pattern of infection? So we know for sure that the normal patterns of infections was significantly disrupted by lockdown. For example, there was almost no flu in the UK during what should have been flu season because people were not interacting in the same way. And so if you imagine that in a year, let's say 10 % of the population should get flu, And those 10 % of the people, the next year, they will have some protection because they had flu the year before. And we had this lockdown for a sort of prolonged period.

10:33So in the first year, there might be 10 % of people who should have got flu who didn't get it. And then the next year, a different 10 % of people who should have got flu but didn't get it. And then you come out of lockdown and what you now have is far more people who are susceptible to flu in the next year or two years than there would normally be. There is quite good evidence that this could explain a large proportion of why we have seen spikes in some infections afterwards. We are essentially catching up on the cases that we would normally have expected to be spread out over, say, three or four years.

11:09But instead, we're seeing them in one or two years. Does this also account for some of the more exotic or unusual presentations we've seen? A few years ago, we had a rash of young babies getting very severe adenovirus infections that cause liver problems. Could it be that the same pattern and disruption to the circulation accounts for those sorts of manifestations as well? Because people are catching lots of things all at once and they may be having unforeseen effects. So I think that's definitely possible. adenovirus is transmitted in a way that makes that plausible and it might not even be that they are having unforeseen effects it's just that they are occurring at an uncommon frequency and so we become more aware of it so this adenovirus is associated with liver problems in a subset of very small children and if you only have one case of that a year you might not notice that but if rather than having one case a year for five years, you have five cases all in one year, that becomes very apparent.

12:14People's attention is drawn to it because you have this unusual pattern. Michael Marks at the London School of Hygiene and Tropical Medicine on what might account for the apparent immunity debt that we're seeing post-pandemic.

12:37for UK businesses. Find out how Spitfire can empower your company at spitfire.co.uk. Music in the programme is sponsored by Epidemic Sound, perfect music for audio and video productions. You're listening to the Naked Scientist podcast with me, Chris Smith, and today we're exploring whether COVID, or the policies that were used to control it, have had an impact on our immunity. Now one aspect we haven't mentioned yet is long COVID. This is almost certainly an umbrella term that describes a range of different post-viral syndromes with possibly different mechanisms but this may well also include longer-term changes to the immune system.

13:21Natalie McDermott is a paediatric infectious diseases consultant. She had a particularly severe run-in with COVID herself which has left her with some significant health problems but it's also fired up her interest in how the disease has affected us all, and she's currently involved in research to look at some of the long-term effects of the infection. I asked her what her view is on the idea of an immunity dead, and also to remind us what happened to her personally. I contracted COVID in March of 2020, and then again two months later in May of 2020. And the second time, I noticed I wasn't able to walk as far as I could.

13:58I had neuropathic pain in my feet, and I had issues with fatigue and concentration. Things then progressed from there and about two, three months after that, my walking became worse and it affected my bladder and my bowel. And I would say neurologically, things progressed for about 18 months and there's been a slight improvement recently, but I still really struggle with walking long distances. And in the last year and a half or so, I've also developed a variety of autoimmune diseases. I certainly think that COVID caused my neurological issues because the initial neuropathic pain that I had in my feet started during that second COVID infection.

14:42In terms of the autoimmune disease, that's always a bit difficult. I'm a woman in my 40s, so I'm sort of the right age to develop autoimmune diseases. However, there is no family history of autoimmune disease in my family. So elements like that lead me to think that it's likely it was COVID, but I couldn't say that for definite. Michael Marks, as we've just been hearing, is leaning towards the fact that we disrupted the circulation of normal infections. And that meant that there's a catch-up process going on. We're catching things that we spent time not catching in the previous years, and we're catching more things more quickly.

15:19That might have a knock-on effect and be causing new syndromes. So is it COVID or is it just people catching stuff in a different way than they would have done previously or is it both? I haven't necessarily been won over by the immunity debt kind of conversation yet. I think part of the problem is I haven't seen any robust publications yet that have factored in the confounding factors in that. So I guess where I sit is I look at how long were for instance our children in lockdown and not at school. That was actually really quite a limited period. But many of these children were at the time teenagers, so they would already have had a significant amount of exposure during their primary years to a lot of these infections.

16:05And we know that teenagers have a fairly robust immune system and are quite good at dealing with viruses and often have milder infections when it comes to viruses. So I'm not entirely convinced by the immunity debt situation. I also think that we have to look at what happened during the pandemic, where we had an increase to some degree, although it was already increasing in vaccine hesitancy, and vaccine uptake post-pandemic has possibly been at its all-time worst in certain regions of the world. Some of the viruses and bacteria we're talking about often follow a fairly cyclical pattern anyway so we did have certainly a significant rise in group a streptococcal infections in around 2022 in children and quite severe infections as well um i think from my understanding that that's actually persisted to some degree it hasn't actually fallen but that doesn't make sense if we're talking about immune debt because if we had a big wave a couple of years ago then realistically a lot of those children should have been exposed and developed a degree of immunity to it but instead we've seen persistently raised levels.

17:13RSV we're starting to see increases again which is that due to immune debt? Is it due to an older population who have had COVID who may have an immune system that is not functioning as optimally? And I think the other conclusion I kind of come to is we've actually got a generation of children now who've started school recently in the last year or two who have never received a COVID vaccination. And I just think there's a little bit of a risk in saying that we have an immune debt from what happened during the pandemic in that we say, oh, we should just be exposing our children to infection. But arguably, we shouldn't be exposing our children to infection.

17:54We should be vaccinating our children. The goal isn't to build up immunity to pathogens through active infection on a repeated basis. the goal is to try and prevent our children getting the infection in the first place through vaccination so I remain undecided about whether there's an immune debt or whether it's the overall just what we're seeing now or whether there is the overall impact of COVID having possibly affected our immune systems as well and certainly for people with long COVID or the severe impacts of COVID there is some data particularly from Akiko Iwasaki at Yale that suggests that our memory T cells are no longer, the populations of them are no longer as good and they don't seem to last or live as long as they used to.

18:40And so whether actually there is an element of COVID has caused an impact, at least in the immediate aftermath of a COVID infection, whether that is sustained in the long term, I guess might vary from person to person, but has it caused a damage to our immune system that makes us more susceptible to other infections or more severe versions of other infections. Would your view then be perhaps everyone's got an element of long COVID and it's a continuum and some people have a very severe manifestation, some have a legacy, some think they have no legacy but if you were to delve hard enough you might find there are still some footprints left behind in the aftermath.

19:19I think we need to remember that the SARS-CoV-2 virus is a highly inflammatory virus and there also seems to be the ability of our body to some degree to misrecognise the spike protein or recognise the spike protein but then somehow misrecognise that within our own bodies and potentially attack our own bodies. So yes I think that there is a lasting effect of Covid likely in most people but many people may not have symptoms of it. I think we see that in the rates of cardiovascular disease that we are seeing in younger people, people who we wouldn't necessarily have anticipated seeing it in, is that just because genetically we have a predisposed population or is it because actually almost everyone in this country, bar some of our very young population, have probably had COVID at some point and it has caused some form of endothelitis or some kind of inflammatory process in the vascular system that is then ultimately predisposing people to earlier cardiovascular disease such as heart attacks and strokes and so on we know that there are links to those autoimmune diseases which suggests that covid certainly has the ability to stimulate our immune system to perhaps misrecognize cells within our own body and attack them resulting in autoimmune disease and then i think there's just been a surge in in various infections as well so those three things put together suggests to me that that there is an element of COVID within that.

20:52Now, there are many confounding factors in that and we can't separate that perhaps from do we have a genetically predestined population. My thinking is that COVID certainly has done something to our bodies, at least in the acute phase after infection, that is meaning our bodies respond differently to infections and possibly also we are set up to be more predisposed to inflammatory conditions and autoimmune conditions. Natalie McDermott, paediatric infectious diseases consultant there. Well so far we've heard that rates of infections have changed in the aftermath of COVID-19 and we've heard that one reason might be that measures taken to control the pandemic itself might have affected our exposure to other diseases which has in turn disrupted the circulation and hence the rates of those infections as well.

21:41We've also heard arguments that the pattern might not entirely fit and that perhaps everyone who's been infected might therefore have seen their immune response altered in some way in the aftermath. So what does Claire Bryant, Professor of Innate Immunity at the University of Cambridge, think? It's been very interesting looking at what's happening to people and their susceptibility to different infections, really since the pandemic, since we've all been released from lockdown. And it was really clear in the first sort of year or two that there's a very high burden of diseases like RSV and flu that was going through the roof.

22:12And I thought that's just because everybody's been locked up. But since you asked me to talk on the program, I went away and did a bit of reading. And I'm going, well, you know what? We're like 2026. It's been a while now. And people are still going down with lots of infectious diseases, probably in a way that you wouldn't expect. And certainly this is hitting people's radar in the hospitals. So that's making me wonder, you know, are we looking at something where there's a genuine immune difference? So has the virus actually affected our immune system? We know, for example, that HIV does that because people get very immunosuppressed.

22:45And we now know that things like Epstein-Barr virus, EBV, and some of the herpes viruses, they can remain latent and then come back. So you can get potentially multiple sclerosis, may have a EBV cause, which is driving an autoimmune complex. And herpes viruses can remain latent and then reactivate. In fact, COVID is doing this a lot, so that people who get shingles, for example, you know, the virus is sort of being reactivated because of some kind of immunosuppression that people have. And when you've got the COVID virus, then that makes sense. But at other times, it's kind of weird. So I'm starting to think now, well, is there something to the concept that perhaps COVID is actually having long term effects on the immune system?

23:23As an immunologist, can you think of a mechanism by which that would occur, though? What would have to have physically changed in the immune makeup to make us more susceptible to more things more often for more time, like people are anecdotally saying they're experiencing? The pandemic showed us that certain people, like older people or people that had genetic defects in their immune system, particularly around a cytokine called interferon gamma, which is really antiviral. We know that people who had defects in those pathways clearly were more susceptible to COVID and actually more susceptible to viruses per se.

24:01But the potential for a sort of non-selective immune deficit. So there's some evidence to suggest that maybe natural killer cells or CD8 killer cells, the T cells, these are, so they're a type of immune cell, comes along and takes out other cells which are infected with virus. There's some evidence emerging suggesting that the virus has had some kind of long-standing effect on these cells such that there's not as many of them or they've been depleted in some way. And this then means that when another virus comes along, you're not as well armed to come and fight these infections. We're kind of inventing this as we go along.

24:37It's all a bit on the hoof. We are 2026 nearly, the sixth year of the pandemic. Wouldn't this have been manifest sooner? Why now? And why does it keep happening? Well, I think there's two factors to that. So I think to begin with, we definitely thought it was an immune debt. And how do you disentangle that? How do you disentangle an immune debt from a potential effect on the immune system? And that's really hard. And I think that's only now starting to emerge because we're seeing people getting repeated infections. If you have an immune debt, you might expect, I would have expected there to be a burst.

25:08You have a couple of years of where you get really nasty infections. And then as soon as everything's circulating as per normal, whatever normal is, then you would expect to see levels of infectious disease spikes to drop back to what we were seeing pre-pandemic. But the fact that this is not happening and that we're seeing repeated instances of people getting more nasty infections, and to a degree some unexpected infections does lean towards the possibility that people are having some kind of immune deficit whereby they're not able to fight infections as well as they were before and so maybe COVID has led to this kind of change in an immune system that has some kind of memory component to it and T cells are kind of an obvious candidate or depleting B cells is another potential way which would change the antibody level so this data would emerge because of course other thing is there are so many people who've had COVID, most of the world have had COVID and as we watch this we will understand it more.

26:03Yeah I'm beginning to lean towards the possibility that a change in the immune system is indeed possible. Would we not expect to see though a stark difference between people who did and people who didn't get vaccinated? Well I think one thing that the vaccines did they showed that we could really protect people against severe disease. People didn't die from COVID having got the vaccines. But the other thing we realised, it was very clear that you still got COVID even if you were vaccinated. So because of that, you didn't die from the severe infection, but you still had the infection. So the potential then for other things to happen, I think, cannot be ruled out.

26:40And this is one of the things that, you know, we would love to be able to find one, a pan COVID vaccine that stops us ever getting COVID again, but also one that stops you getting infected and stops you transmitting the infection. and we're not there yet. So it's really difficult to understand exactly what's going on, but I don't think the vaccine would necessarily stop this happening. Do you know what it is about coronaviruses that can do this though? Is there something special about the virus? Could any virus do this if we got enough people infected? And are we noticing this because it's a mass effect where billions of people have had the same infection and they're getting the same sorts of symptoms?

27:17Or is it something special about that group of viruses that cause COVID-19? That's an interesting question. I think that for sure with so many people have had it that even a minor phenotype, you know, increase in susceptibility to infection, which might normally be lost in the noise, is apparent because we've got so many people who got infected. We know that other viruses can do this. You know, measles is absolutely brilliant at changing the immune system. Coronaviruses and other species can have complicated immune effects. So, you know, I'm a veterinary surgeon and there's a very nasty coronavirus in cats that they get it and then they get an immune disease afterwards that you can't control.

27:52And it's one of the things I was scared about during the pandemic. What happens if it's like this horrible coronavirus in cats and we vaccinate people and then they get worse immune disease? You know, that would have been a nightmare. We didn't see that, fortunately. So as an immunologist, what would you like to see that would convince you one way or the other what we're dealing with? There's two cohorts of people that are really interesting to study now post-pandemic. So one is obviously the people who've got long COVID and the horrible inflammatory disease that that's leaning to in the different manifestations and that seems to be a probably a hyper response to the disease and that's why people have got these inflammatory syndromes which are awful but then also there's the people who are getting the repeat infections and so understanding the people who are getting repeat infections and looking at their immune cells and what they're doing is the kind of work that's being done and that will help us then really understand what's going on it will come out because we have these massive populations to study you know, and this work is ongoing.

28:44So we will know it will come. Immunologist Claire Bryant at Queen's College, Cambridge there. So for now, the jury remains out. We don't know why we're seeing higher rates of circulating diseases in the aftermath of the pandemic. It's certainly true that the control measures we implemented did alter the way that many seasonal infections circulate. And we did indeed rob ourselves of opportunity to catch them for a few years. But is that enough to explain everything we're seeing? Is everyone a bit affected by some sort of long COVID, as Natalie McDermott was wondering? Or are all of our immune systems operating in a reprogrammed state, like Claire Bryant speculates?