David Stokes 0:15
Hello and welcome to another episode of Doctor family podcast. On today’s episode we’ll be exploring the role of the immune system both in fighting the new COVID-19 virus, as well as the damage that the immune system itself does to the body as part of the disease. Today, I’m very lucky to be joined by Dr. Babak Javid, an infectious disease consultant and associate professor in experimental Medicine at the University of California San Francisco. Before starting Dr Javid wants to make it absolutely clear that as COVID is such a new virus, anything that anyone tells you is likely to change within a short space of time.

Babak Javid 0:56
But I should I should couch that these are my personal opinions. of my understanding of the literature, and not meant to be any definitive, gold plated truth. I don’t think that exists at the moment in this very rapidly evolving situation at any rate, and certainly, some of my opinions and thoughts have evolved over the last few months. And I’m sure I’ll continue to do.

David Stokes 1:20
So I think recently, we’ve been learning more about the immunity to the COVID virus. We’re also aware that a lot of the pathology that’s caused the damage caused to the to the body by the COVID virus is mediated by the response that the body has to the virus itself. I was just wondering if we could perhaps touch a little bit on obviously, a lot of the people who might be listening won’t necessarily know very much about the way that the immune system fights infection. You’ve got both an antibody response, which is the thing that people probably hear about an awful lot and then there are the immune cells, the white cells, the T cells, that will actively fight against an infection and particularly one that lives within the cells like a virus. So I didn’t know if you could perhaps talk about some of the thinking that has is going on around the immunity to this new virus.

Babak Javid 2:11
And I think I think this is a really important question. And it’s generally true for most infectious diseases, that immune responses to the pathogen, the disease causing entity, whether that’s a virus, in this case, SARS CoV2 or bacteria is, is necessary to protect ourselves from the infection. And you know, that’s why we say we’re immune to an infection or we become immune after having recovered. But often the pathology of the disease driven by the infection is also due to collateral response, you know, sort of friendly fire damage from the immune system in its attempt to kill the pathogen in this case in trying to kill the virus. It could have been over exuberant immune response that actually results in the disease in the pathology. So just to sort of go from basic principles, there are many different types of immune response. There’s some type of immune response, that happens immediately after you get infected. Those are, for example, the most common white blood cells that we have neutrophils and various other white blood cells in the lung, for example, they called macrophages that gobble up foreign bodies, including viruses and bacteria that might enter the lungs. And it could well be that some people can overcome an infection with SARS CoV2 to just with those elements of the immune response, and that’s important because you’d never know they’d been infected in the first place. It doesn’t leave a sort of signature. But if you establish an infection, then there are two types of immune response that come into play which are called adaptive immunity, and that’s because they get stronger over time and over repeated exposures, and the Two main items that are, as you said, the antibody response and antibodies are protein molecules that can recognise a very specific antigen it is called and in this case, it would be, for example, the surface of the virus, in particular, and in and they might, for example, recognise this viral surface, and then allow other elements of the immune response to destroy the virus, and more effectively.

So that’s why antibody mediated immunity is thought to be important. And one of the terms that people might have read about in news articles is neutralising antibody responses because you can have antibodies that bind the virus, but don’t destroy it or don’t prevent it from causing an infection. And they actually may even be harmful in some cases and we’ll come to that. Or it might be that they can destroy the virus and those are neutralising antibody responses especially in vaccine development. It’s important to measure the neutralising antibody responses. Secondly, you can have Actual different white blood cells called lymphocytes, T lymphocytes in particular, that can recognise a virus infected cells and destroy them. And that’s called cell mediated immunity often. And usually you you know, both of these arms work in collaboration with each other, they work together the T cell response often makes the antibody response more specific and more effective, especially over time. And antibodies can allow the immune system to recognise the virus more effectively and destroy it through cell mediated immunity. So the to work in concert, and that’s what makes an effective immune response and no one says that it’s, you know, one or the other. It’s either one or the other and not at all of the other one, and so on. Usually, we need both to be healthy and most the vast majority people do have both. We do know from because some people don’t have one or the other especially not having antibodies. As you know, it’s rare but not vanishingly rare. We do know that people without antibodies have been infected by SARS CoV2 And actually they get a mild disease. And this in itself is also informative, because it does suggest that the immune response is in part responsible for the disease in severe cases. So I think that again, that’s exactly right. And another clue about why the disease is mediated by the immune response is that we know that people with covid become severely unwell after 10 to 15 days, which is exactly when that adaptive immune response kicks in. And then at that point, we know that that’s when people become unwell. And that, again, is very strongly suggestive of this the immune response that’s causing the disease. And finally, one other piece of evidence that the immune response is partly responsible for the disease is that the drug dexamethasone that was discovered in randomised controlled trials. In

was an Oxford collaboration with lots of other hospitals, NHS hospitals in the UK, next to methods and suppresses the immune response in particular, from lymphocytes. So the fact that that was effective in severe disease only, but actually made things worse in mild disease is against strongly suggestive that severe diseases, again due to an immune response. Now, once you get infected if you if you’re able to recover your adaptive immune responses, now primed and can act even more quickly, it doesn’t take 15 days anymore, but only take two or three days to kick in. And that’s how usually immunity to an infection works. And for some infections like measles, you only need to be infected once to have lifelong immunity, but for the majority of infections, immunity doesn’t last forever. It gets weaker over time and we know that other coronaviruses that cause the common Call, one can get reinfected multiple times over a lifetime. You know, every few years or so.

David Stokes 8:06
I was going to ask a little bit about that, because clearly we know that the common cold is something that people get multiple times. I wasn’t sure in this case, whether it was thought that this is people could be reinfected because the virus itself is adapting, changing, mutating to evade the immune system, or whether there is a short term memory of the immune system so that it sees it as if it’s in it the first time.

Babak Javid 8:32
So that’s a great question And again, in the infectious diseases both happen for influenza, we know that actually the immune response that you develop is very good, and is long lasting, so you’re unlikely to get infected by the same strain, at least for many, many years. But the influenza virus mutates very rapidly. And that’s why we need an annual flu jab because the strain That’s circulating this year is subtly different from last year’s strain, and the immune response no longer is able to protect you against that new strain as effectively. But with coronaviruses coronaviruses are also RNA viruses, just like flu, and normally RNA viruses mutates quite rapidly. But Coronavirus does actually have a very, very large RNA genome. And because of that, they’ve actually had to reduce their mutation rate because otherwise, the mutations would destroy the virus very rapidly over time. So they’ve evolved to have a lower mutation rate than influenza. And certainly, over, you know, a few years coronaviruses in general, don’t seem to mutate in general enough that the immune system wouldn’t recognise it. Obviously, it can’t say that for indefinitely and it’s mostly because of a waning immune response. We know that from classic studies done in the common cold unit in the UK in the 70s, were actually people were given the common cold and then given it again, months later. And we know therefore how long immunity to a common cold lasts.

David Stokes 10:15
That’s fascinating. I don’t think I probably realised that myself the fact that the immune system was forgetting this, because I’ve also heard in the literature, a lot of people who have had the COVID virus and then have been retested for their antibody levels relatively rapidly. For the sounds of things.

Babak Javid 10:32
This has been a big news story in the last few days, actually. So I think there’s a there’s truth and sort of an panic related with the story is sort of unwarranted panic. So it’s certainly true that the immune response wanes over time. Actually, that’s true for any infection including measles, because otherwise, we get infected so many times over our lifetime of blood would be congealed to mud with antibodies. If the The amount of antibodies in our blood didn’t go down over time because we’d never, we’d only have antibodies in the blood and there’d be no room for blood cells. So it’s absolutely important that antibody levels reduce over time, but the cells that drive that antibody response are still existing the memory cells and they can rapidly deploy more antibody if they get reexpose. The question becomes can they do that efficiently and in you know, in sufficient numbers to protect you against a subsequent infection over long periods of time, and we know that for the common cold coronavirus, that we’re tested with the human challenge in 70s. After about eight months, the immune response is sufficiently diminished that you can get reinfected but you don’t become ill. So you actually get a viral infection. Which you can test by culturing the virus, but that person didn’t become ill they had no symptoms at all. And I suspect from what we’re learning about the immune response to covid, that people with severe covid are going to have long lasting neutralising antibody immunity because they make more antibodies and takes longer for them to diminish from mild or asymptomatic disease, you are going to get more rapidly waning immunity and you might get reinfected but not even know it or get very mild disease, at least over a period of let’s say, six months to a year. That’s, that’s my suspicion. We don’t know that for sure. The problem is you might still be able to infect other people in that case, if you’re if you’re not able to completely contain the virus. The other issue is that he cell immune responses last longer than antibody responses. So it could be that although the antibody responses have diminished a lot, your T cell responses are sturdy enough to protect you from overload. periods of time. And given the fact that really over, you know, the last six months. In reality, we’ve probably had 100 million or more people infected with COVID. And we’ve only seen one or two very convincing reinfections. That suggests to me that immunity last at least for six months in general.

David Stokes 13:21
Now, that’s that’s some some good news for people, I’m sure. When we’re talking about the reinfection, I suppose the worry I had was more along the lines of if this is a disease, which is mediated or caused the symptoms generally caused by the immune systems response, someone who’s had a severe case of COVID-19 if they became reinfected, would that is it likely that their immune system would respond again in an appropriately forceful way?

Babak Javid 13:53
That’s a great question as well. And we don’t know is the honest answer. So this is does happen with some infections. So the classic infection that happens, this happens, a human infection this happens with is called Dengue fever. So Dengue fever is caused by four related viruses. And we know that if you get infected with that a virus a, and then five years later you get infected with virus be the second time you get infected, you get them, you’re more likely to get a severe disease, and that’s called antibody dependent enhancement or ADE. Now as it happens, there’s a cat Corona virus disease, and that we see the same thing in that disease. The second infection is more severe than the first, but that doesn’t seem to be true for common cold human coronaviruses or other coronaviruses in other animals necessarily, and we just don’t know enough yet about COVID. I would say the fact that we aren’t seeing more reinfections at least in the short term. suggests this is unlikely to happen, at least in the short term, it could well be that it might happen five or 10 years down the line. You just don’t know. Because obviously, that amount of time hasn’t elapsed. But in the short term, I would say immunity appears to be protected.

David Stokes 15:16
That is good news. And obviously the other good news coming out is around some of the preliminary data from some of the some of the vaccination tests which are coming out of Oxford, particularly, I think we probably was probably a little early to talk about the efficacy of the new vaccines coming out, as is still very early days. But in terms of how vaccines have been tested for the common cold has been a real difficulty in developing a vaccine that is effective at protecting people from cold. Cold viruses, particularly as we mentioned earlier, flu is something that changes rapidly and therefore you need a new one every year. But is there something inherent about viruses that could cause the common cold that make them more difficult to produce a vaccine effective against them?

Babak Javid 16:02
It’s a it’s a good question and the honest answer is we don’t know we’ve never had a human coronavirus vaccine. There are animal coronavirus, vaccines for which are variably effective, some are pretty effective, some are not so effective. But I think it’s partly because we just never tried very hard. Honestly, why would we spend billions of pounds developing a vaccine against the common cold, which doesn’t, you know, which hardly causes any problems for anybody. So there just hasn’t been that investment. And for the two serious coronavirus, diseases, SARS and MERS. SARS was contained and essentially eliminated before there was a need for a vaccine. So there was just no investment available, for MERS. In fact, the Oxford vaccine candidate was initially developed formers and that’s why they could rejig it for COVID so quickly because they had asked It already developed a vaccine for MERS, which they tested in animals and it worked. And therefore it was a quick question a bit of genetic engineering to really make it make it for COVID instead. So although we haven’t had a human coronavirus vaccine before, because of MERS, there have been a number of companies and academic groups that had been interested in MERS vaccines over the last decade. And it was that knowledge and know how that enabled very rapid redeployment of the technology to prove it. So I think that’s good news. I’m very optimistic we’ll have a vaccine that works, at least to an extent very quickly, because the incredible amount of resources that have been put to this important question, unprecedented amounts, you know, whether it’ll be 100% effective, I’m less confident about whether it’ll work in the people who need it most which is the vulnerable and elderly Again, I think you’ll at least be partly effective in that group. And they’re the people who need it the most, because COVID is par excellence, a disease of the elderly and vulnerable when for very serious outcomes.

David Stokes 18:14
So just to clarify the MERS virus is another Corona virus, which causes a very severe disease for the respiratory tract. And I think it came out of the Middle East, but people might not have heard of that in the same way that they did about SARS. Just Just one more thing that I came across recently, which I thought was interesting, but I don’t know whether there was any significant thought behind it and that is the Association of BCG vaccination versus severity of covid infection. Now, BCG is obviously a vaccine used for prevention of tuberculosis. So that’s a bacterial infection rather than viral but but it is one that is within the cell. Is there something that you’ve read about this The Do you know anything specific about this that you think is worth further follow up

Babak Javid 19:04
on? So I mean, this is obviously something I’ve thought about it a great deal because it’s sort of in my in my backyard interests of being, you know, a TB issue. So as you said, BCG is a live vaccine for tuberculosis. It was developed over 100 years ago in France. And it’s essentially a weakened form of cow tuberculosis. And the important thing is that it’s a living bacterium. It’s not a dead vaccine. It’s a living bacterium, it causes an actual small infection when we give it to people. It’s the most widely used vaccine in the world. Now, because of that, there’s been an awful lot of studies done on BCG actually, BCG is a terrible vaccine for preventing the epidemic form of TB. It’s very good at preventing life threatening TB in young children, certain the majority of countries in the world except the UK it’s given at birth. Many Studies have shown that infants that have been given BCG, not only were they less likely to die of TB over the first five years of life, but they were less likely to die of other infectious diseases that were not TB, such as pneumonia or diarrheal disease. And this is what’s called heterologous immunity, that means immunity to another organism.

And the reason for that is thought to be because BCG can train that innate immune system that we talked about right at the beginning of the interview. So the immune system that we normally that is our first responder, you know, our paramedic immune system. When I went to medical school, I was told that that immune system, you know, works the same no matter what, and it doesn’t adapt as it were. But in fact, in the last decade, it’s become clear that the innate immune system can also be trained to be more effective and more One of the best trainers have that immune system has turned out to be the BCG vaccine. But trained immunity only lasts for months or one or two years at most from what we can understand, and the studies that show a correlation between BCG and reduce the mortality from COVID, or what are called ecological studies that are really unable to answer this question effectively, because, for example, you know, once I saw published a couple of weeks ago said that, you know, Chinese is BCG China’s had a very low death rate, you know, under 5000 deaths from COVID. Therefore, you know, BCG protects, but the reality is that China controlled the outbreak, the actual death rate, the case fatality rate in China was very high. In the people who got it there was no less than countries that didn’t use BCG, such as Italy. So, I think the Say that BCG, given 50 years ago protects you from COVID is very unlikely to be true.

Having said that, I think a recent BCG vaccine may or may not be partly effective in preventing COVID or at least immediate rating the effects. And there are studies that are being done in a randomised controlled trial manner. So a very robust way where some people get to BCG, some people don’t. And then we see what happens over a period of time in the Netherlands and in Australia in particular, the studies have been performed. And we will then find out hopefully in the next six months, whether BCG is effective, at least decreasing the likelihood of a bad outcome from COVID. Now, the problem is that it’s never going to be as good as a specific vaccine. And secondly, the studies are probably being done in young doctors and nurses. They’re the people that often we experiment on and you know, Despite the headlines, actually, the risks of death are quite low in that group compared with, you know, all the people in Canada and so on. So whether we’ll actually get high quality data coming out in the end I’m not sure.

David Stokes 23:14
So is another one of these watch this space topics.

Babak Javid 23:17
It’s one of these watch this space but don’t over read into the headlines,

David Stokes 23:23
Indeed. So I think that’s that’s all of that I had on my list of topics that I was hoping to cover with you. Was there anything else that you’ve come across recently that I shouldn’t miss?

Babak Javid 23:35
Well, I think there’s a couple of things I wanted to mention is that actually, you might know that I was a very early advocate of wearing face coverings on masks.

David Stokes 23:44
Indeed, I saw your opinion piece in the Guardian,

Babak Javid 23:47
you know, a month before that we submitted a paper to the British Medical Journal. You know, the reality is that Britain is lagging behind on this issue, because we are diffident and we care.

I was in the UK five months before coming to Canada. fornia and staying with my 81 year old diabetic hypertensive mother, and therefore we were very careful, very cautious about, you know, COVID and all the rest of it. But you know what I suggested to my mother back in late January, early February that she should wear a face mask. She said, but what will people think of me if I’m wearing a face mask? And this is the typical British response? And I’d say we need to just get over this. And you know, if we want to actually Britain’s doing fantastically well, right now, you know, we’re over the hump. But if we want to stay with low numbers of cases, if we want to be able to recover our economy, and work and you know, that’s not just for economic purposes, we know that health outcomes are associated with economic outcomes, then actually wearing masks for face coverings is one way to mitigate against that. It’s not a panacea, it’s not a cure all. But it’s it’s certainly one way that we can reduce the risk of transmitting the virus other people and protecting ourselves to reasonably send in San Francisco here. It’s the law to wear face coverings in outdoors at all times. And I would say 95% of people do so even when walking the dog is become a habit. And you know, people think nothing of it. And there’s all sorts of fashion masks that help, you know, make it more socially acceptable, whatever. So that’s number one. The second thing I would say is that COVID is undoubtedly been, you know, the most severe pandemic in the last century. But it’s not an existential threat. Society is and civilization is not going to collapse as a result of COVID. So it is serious. It has caused an unfortunate trend and tragic loss of life, and more lives will be lost sadly, not just in the UK but all over the world. But society is not at risk. So, again, we need to put it in context. We’ve had we’ve had much worse, much, much worse, you know, the 1918 pandemic was 10 to 100 times worse than COVID. And, you know, we managed to, you know, recover from that, despite a tragic and appallingly tragic loss of life. So I think, again, you know, the headlines and the constant news cycle makes us think maybe this is the end of the world. It’s not, it is terribly serious. We need to do our best to protect ourselves and our loved ones and those in society that are most vulnerable. But we will get over this.

David Stokes 26:37
That’s great news. So I guess one question that occurs to me with regard to masks is this interesting question regarding First of all, infectious dose IE does a mask prevent you taking in enough virus particles to get a viral infection in the first place, and this other very interesting one, which is is the dose one receives it in fact, correlated to the severity of your infection as well. So for example, if you get a large number of virus particles when you’re infected, coming into the mouth, nose or eyes or however it goes into your body, is that in any way related to how severe the disease you develop,

Babak Javid 27:16
and I think this is really interesting, and there’s no strong evidence, but there’s some animal data and some corrupt correlative evidence of the salt that I prepared a minute ago with the BCG story. So I’ll do the correlative evidence first. And that is that, for example, San Francisco has seen a spike in cases over the last month, and has has has had one death despite over, you know, more than 1000 new cases in the last month. That’s an astonishing low mortality rate. You know, one and a fact less than 1000 actually. And it may well be that because people are wearing masks. It doesn’t 100% protect you. It doesn’t hundred percent Prevent you passing it on to someone else, but those who might be infected with maybe lower and therefore will lead to less severe disease and better outcomes. That’s number one. I think that’s strong, indirect evidence, but it’s not in a cast style. But actually people have done the experiment in hamsters. So hamsters can Syrian hamster specifically can get COVID. They essentially they mimic wearing masks of giving lower doses and you know, and so on. And those hamsters that glow, this is where I first of all less likely to get infected in the first place. So the dose needed to establish infection, as you said, but if they did get infected, they got less severe disease. So I think that there is there are data both ways and I think that’s again, another very good reason to wear a mask. Because if you’re going to get infected in the first place, you might as well get infected with less severe disease. So I think that that, you know, is a second reasonable data or less compelling, it’s a second reason to wear a mask. Absolutely. It’ll become more compelling over time.

David Stokes 29:06
And there’s certainly a very clear reason very clear message, whether a pass absolutely doesn’t matter what you don’t like wear a mask is just the sensible thing.

Babak Javid 29:13
If you care about what you look like wear a fashionable mask. That’s

David Stokes 29:18
excellent. Bob back. Thank you so much. I really appreciate your time tonight. I’d also like to thank you for joining us. I hope you’ve enjoyed some of the information we’ve heard tonight and learned a bit I certainly have. If you’ve enjoyed this, please share it with your friends. Subscribe and rate us in your podcast software, or on pod chaser. please do check out our websites and our Facebook pages and get involved by asking questions for us there. Until next time, thanks very much for joining us,