UCL Minds


Transcript: Episode 48

With the recent news that under-40s are going to be offered an alternative to the Oxford-AstraZeneca vaccine, we speak to two UCL experts to explore the risks and benefits of coronavirus vaccines. How safe are vaccines? Do they cause blood clots? And how does this risk compare with other day-to-day activities? Listen to find out.

Are COVID-19 vaccines safe?

Get the facts about COVID-19 vaccines.

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Vivienne Parry  0:04  
Hello, you're listening to Coronavirus the whole story the podcast that brings you UCL's latest research and analysis on the pandemic. I'm Vivienne Parry, a writer broadcaster proud UCL alumna and the person lucky enough to be the host of this award winning podcast. This week's episode is all about the Oxford AstraZeneca vaccine. It's been raising lots of questions recently. Is it causing blood clots? Is it safe? Who should it be given to? It should be no surprise to any of our regular listeners that the experts who can give us the answers to all these questions that we found at UCL, so let me introduce you to them. First up Bryony Franklin, who's professor of medication safety in the UCL School of Pharmacy. Bryony has over two decades of experience researching medication safety, and has quite literally written a textbook on it, how researchers cover prescription dispensation and admin errors, and how to study and reduce them. And I'm also joined by Professor Marie Scully, a professor of hemostasis and thrombosis. I want to be a professor of hemostasis and thrombosis. And he's also consultant haematologist that uclh. It was thanks to Marie's background and expertise in blood clots that we were first alerted to them being a rare side effect of the Oxford AstraZeneca vaccine. So let me turn to Bryony, firstly, let's have a bit of an understanding of the nature of side effects. How do we know that they're there that they are caused by whatever it is we're taking? And how common do they have to be to be considered a problem?

Bryony Dean Franklin  1:39  
Oh, well, lots of big questions there. I mean, everything we do in life has side effects. There are risks and benefits of everything. So whether we're crossing the road, taking a painkiller, taking a car journey, having a drink all of these things that we do have risks and benefits, and most of them will have consequences or side effects. So of course, it's exactly the same for medicines. So in terms of how we find out what side effects of medicine has, they'll often first come to light in clinical trials once medicines are being tested well initially in healthy volunteers, and then in patients. But clinical trials will usually involve numbers in the 1000s of people. And for many rare side effects, they won't come to light until after a medicine or vaccine is being used in much, much greater numbers. Because if something is very rare, then a clinical trial in a few 1000 people or even 10s of 1000s is unlikely to pick it up.

Vivienne Parry  2:39  
Now what do we mean by rare?

Bryony Dean Franklin  2:41  
Well, the these words are often used, aren't they? So you might see if you take the package insert for a medicine, some things described as very common or common or rare or very rare. And until fairly recently, they were words that were just used, which of course raises all sorts of issues, because some people will interpret these words in very different ways. But there are a fairly standard set of numbers that go with those words. So if something is a rare side effect, it happens somewhere between one in 1001 in 10,000 people, if something is very rare, then it's less often than one in 10,000. For example, if something is very common, then it affects more than one in 10 people.

Vivienne Parry  3:26  
And some of the side effects that we've already seen with AstraZeneca are the kind of ones that we expect with vaccines, you know, there's a sore arms. And these adenovirus mediated vaccines seem to be particularly what's called reactive genic. In other words, you have no like yellow fever or something you have a particularly sore arm afterwards.

Bryony Dean Franklin  3:45  
Yeah, that's right. In fact, with the other vaccines to the mRNA vaccines as well, it's actually either common or very common to have a sore arm to feel a bit feverish afterwards to you know, really just feel a bit fluey for perhaps 2448 hours afterwards. These things are fairly common, as you say, with all vaccines, and in some ways, it's it's the nature of how it works. It's going to affect your immune system, and often results in some side effects of those types.

Vivienne Parry  4:12  
So let me turn now to blood clots. So Marie, tell me about the patient you met in March, who had a blood clot because of the vaccine, what alarm bells were set ringing for you and why did you think this is vaccine caused?

Marie Scully  4:26  
So initially, I tried to ignore the fact that she'd had a vaccine within the last two weeks it was her first AstraZeneca one she presented with blood clots in the head, and a low platelet count and blood clots in the head. So cerebral venous sinus thrombosis in the main one confined an underlying cause for it. So in about 85% of cases, there's usually a reason for it and the low platelet count where we deal with immune mediated thrombocytopenia. So it Pay, not uncommonly and have quite a large practice. And it looked as if it was that so we initiated treatment for the ITP. But also wanted to cover the blood clot in the head and in the interim did some standard and also some very rare investigations to try and elucidate the underlying cause at the same time, and it was just by chance, we did an ultrasound of her abdomen, primarily looking to the size of her spleen, which would be in relation to her query ITP and found she had a clot in her liver. That's even more uncommon than the clot in the head. And that's when the alarm bells started to ring a bit more towards shimmery 30.

Vivienne Parry  5:46  
So very young. Yes,

Marie Scully  5:49  
very young. There were had been reports up till that point, in the background of my mind that there were similar cases in Europe. But nobody had elucidated The reason for it, although they were very convinced it was related to the A Zed vaccine. ITP, let's say on its own is not an uncommon condition, we're using that word again, uncommon, it's not uncommon. And indeed, we can see after vaccines or a viral infection, so it wouldn't necessarily be abnormal. And the count wasn't so terribly low that we would be necessarily concerned and indeed, she probably spent longer in hospital than we would normally keep someone in for, again, reasons unknown. And then she deteriorated One week later and became very sick and needed to be moved to intensive care. And this was really becoming very abnormal for the clots and the low platelet count and the fact that we have not identified a unifying reason. And then thinking back to the European situation, they similarly described these clots in the head and a low platelet count. And there is a limited differential to that. There was no reason then to look for anti p or for antibodies other than it looked similar to a situation called heparin induced thrombocytopenia, even though the patient had not received heparin pre admission and had no medical history. And the antibodies, very surprisingly, were very positive. And that was confirmed on a second and then third patient within 24 hours,

Vivienne Parry  7:26  
because you said that this condition can also be caused by viral infection. Is it possible that COVID in and of itself, because, for instance, she might have had COVID, when she had the vaccine? Could that also be a cause? Yeah, I

Marie Scully  7:41  
mean, that's a very important question. Firstly, she was PCR negative for COVID-19 when she came into hospitals, that everybody is automatically tested these days in all hospitals. So that was verified at the referring hospital and that uclh Secondly, we subsequently did some more extensive testing to look at her antibodies COVID-19 antibody, so whether she had previous infection, or whether they were in keeping with her recent vaccination, and she had no evidence of a previous infection, and did have antibodies developed to COVID-19 following vaccination. So it was clear that she had not had preceding COVID-19. And that is important because of course, there's been a lot of discussion during the primary and secondary pandemic phases in different countries about the risk of blood clots. But these are not the type of blood clots that one would see in acute severe covid 19 infection, they're quite different.

Vivienne Parry  8:43  
So these are not your regular blood clots, which are really quite common. They're not your clots that you would see with COVID-19 infection. But there's something really quite different. And that also particularly affecting younger people, and younger women, as I understand it.

Marie Scully  9:04  
So in Europe, yes, in Europe, they had a higher incidence in young women, many of whom are taking oral contraceptive, but their rollout the vaccine rollout was completely opposite to the UK. So we vaccinated our elderly population first with the A Zed. And obviously it's decreasing down the age groups now per decade. Whereas in, for example, Norway and Denmark and Germany, a lot of their health care workers received AstraZeneca. That's a first battle vaccine. So it's a different population. In the UK, we've obviously been collecting and reviewing all the cases clinically, and the split pretty 5050.

Vivienne Parry  9:47  
So that's fascinating and come to you Briony because when you see these things coming up, of course, you start to look for them more and then does it become more difficult to To decide how they've been caused,

Bryony Dean Franklin  10:02  
I think it becomes different because a lot of the data that we use for understanding how often and what side effects occur once a drug is being used in the general population, it's based on something called the yellow card reporting system reporting, a yellow card relies on somebody and it could be the person who's received a vaccine, or it could be one of the healthcare professionals who is involved with their care, and involves somebody completing a yellow card, which is usually done. It's not a piece of paper anymore. It's done on that on the computer. But obviously, that person has to think to do a yellow card to decide that something meets the criteria for doing a yellow card and has to actually report one. And I think, you know, we all have our own psychologies about in what situations you might decide to complete a yellow card, and in general, once you're sensitised to something. So once you're thinking, Oh, this might be important, you're probably more likely to do it. But that's probably a good thing, because it's more likely that we'll learn and collect more data. And yellowcard reporting will obviously have some under reporting where somebody either doesn't think to complete one or doesn't realise they should or means to and then forgets, you know, all of the things that happens to us as humans, but it also might mean some over reporting if things actually weren't linked to the vaccine, but in general, the analysis that's done will take into account some of those things. So it's really important that these cards are completed so that we can learn about the patterns of what is actually happening.

Vivienne Parry  11:35  
And presumably, Marie haematologists, UK wide, and are actively looking for this

Marie Scully  11:41  
is so they are reporting all the cases correct, we review all the cases. So there are some that we have felt as a large group, do not fulfil the diagnosis of vet vaccine induced immune thrombocytopenia and thrombosis. But there is obviously the yellow card reporting system and the HRA have to do their own analysis of the cases to see if they are indeed VITT or other. So we don't actively go looking for them in as much as the patients actually are very sick when they present. And that's the difference with regards to side effects that we are all used to with medications, particularly rare ones. This affects young people, it has a significant mortality, and we cannot predict who it's going to affect. So it was thought maybe it affected patients that had a higher risk of forming blood clots, that does not appear to be the case. If that was the situation, then you could put a plan in place to give that group of patients another type of vaccine to reduce the incidence of this condition. And that's what makes it quite hard is to predict who it's going to affect.

Vivienne Parry  12:58  
So $64,000 question, Marie, how does the vaccine cause the blood clot?

Marie Scully  13:05  
We don't know. All we can do is summarise what we know to date, there's two parts of the vaccine in simplistic terms, one is despite protein for which we generate antibodies to COVID-19. And the second is the delivery system, the platform

Vivienne Parry  13:19  
like it's an adenovirus mediated, correct.

Marie Scully  13:23  
So it doesn't appear even though the spike protein is very immunogenic, to be the cause at the moment. And we say that and feel that because all the vaccines have this spike protein, there may be some differences between them, but they all have this by protein. And we do not see the side effect in all the vaccines. A Zed is an ad a no viral vector, we thought it was primarily because it was a different type. So it's from chimpanzee maybe that was it until there was evidence that exactly the same situation with fit, came to light with the Johnson type of vaccine, which is also ad no viral, but not chimpanzee,

Vivienne Parry  14:08  
and presumably with the Sputnik one as well, are but

Marie Scully  14:11  
it that's from Russia, and there's very little detail about that.

Vivienne Parry  14:14  
So it's likely but we haven't been told about it.

Marie Scully  14:18  
Nobody knows they did put out a statement last week saying it was not associated with their vaccine. So we can't really comment now, whether it is the adeno virus or a constituent of the vaccine in the making of the vaccine that is unclear. And that's where all the efforts are currently being directed to elucidate the exact cause for this very rare syndrome.

Vivienne Parry  14:43  
So briny. This is exactly the kind of side effect that not only wouldn't have been apparent in your big clinical trials where we're talking about 10,000 people, maybe even 30,000, but it wouldn't have been apparent either in any testing. You know, this is not something that would have come up during the development of vaccine.

Bryony Dean Franklin  15:03  
No, that's right. It's that sometimes you can predict what side effects might be likely from a given medicine or vaccine due to how it works. So for example, something that's got, you know, opioid type structures in it, you would anticipate that it might make you drowsy, for example, but something like this, I would see as being completely unpredictable. And as we've just discussed, extremely rare, so actually very, very difficult to predict, to anticipate and to pick up really, which is why it's, I think, being so so challenging, really, to understand exactly what's going on.

Vivienne Parry  15:37  
We've seen Maria lots of different numbers attached to the risk for this. And there's obviously a different risk depending on age, but I wanted to do a bit of compare and contrast with other medicines that are responsible for thrombotic events, like the pill. And, and also, and I would remember when there was a huge scare about the pill, and everybody came off the pill thinking you know that they were at terrible risk of thrombosis, and then immediately became pregnant, which of course, carries a huge risk of thrombosis in itself. So how do we do this compare and contrast.

Marie Scully  16:20  
So firstly, we need to, we do need to be mindful that vaccination is the way forward. So we have to keep that in the back of our mind, whatever happens, we have to ensure that the planet is vaccinated against this virus with regards to the pills a brilliant analogy. And if you go back to the outcomes of all that work, essentially the oestrogen dose was too high. And even at that time, I don't think it was well, it definitely wasn't appreciated the inherent risk of thrombosis from pregnancy. And furthermore, thrombophilia abnormalities were beginning to be identified, in particular, factor five Leiden, so it all began to fall into place and those three things therapy was adapted, so that the risk of thrombosis is minimised as much as possible. So that's what happened with the pill. We must remember what this was seven weeks into a new syndrome. Critically, I think we need to understand what is it it has to be something within the vaccine, it's very difficult to see that it's patient specific related unless there's some sort of genetic polymorphism. That's common to everyone, which would not be highly likely but it is being investigated. think critically, we need to understand what is it about the vaccine delivery method and its constituents that could be aggravating and propagating a thrombotic risk, the HRA weekly put out a report which is very helpful. And last week's report in particular, was very useful. So it looked at a number of parameters, and one that struck particularly were the number of reports of headaches following A Zed vaccination way up and above greater than the other vaccines, accepting that Moderna has only just started to be rolled out in the UK. So there was over 61,000 yellow cards re headache. Well, we don't have for example is the detail of when these headaches occurred. And as you've already heard from Bryony within the first 4872 hours, some symptoms are not uncommon. But if patients are getting headaches, after this time, it could be the kind of primary hit this is just an hypothesis, just thinking clinically and translationally, that you're getting aggravation. And then there may be some other second hit that ends up with patients developing bit. We don't have all the preceding symptoms for all the patients who have fit. So there's an awful lot of work to do. So it may be hypothesis only based on low fat in patients who have extensive headaches in the first few days after vaccination. Maybe we should be looking more closely at them.

Vivienne Parry  19:16  
And actually, a banging headache is a feature of Coronavirus itself. So let's now do this compare and contrast. I hate the word safe because every vaccine has side effects. I was regular listeners to this podcast will know on the jcvi the Joint Committee on vaccination myself and there is no vaccine that does have no side effects always has to be a compare and contrast. You know how safe would I be if I got Coronavirus? Well actually, all that save how safe Will I be with the vaccine will actually compare to your risks of having the vaccine much much much safer. So let's do a compare and contrast Marie. First of all With Pil compare and contrast the risks of thrombotic events with the vaccine with the thrombotic events as a pill. What are the numbers,

Marie Scully  20:09  
Although there have been a number of reports, so we haven't got that data specifically, we've not been, you know, closely looking at that, although the initial investigations by MHRA and EMA a couple of months ago suggest it's no higher than the background rate. So thrombosis may not be uncommon. Or we're talking about a specific type of thrombosis, which is completely different. Trombosis from the pill can be very high, but it depends on the dose of oestrogen that you're using, and that's where the problems were. But if you have something like fact like flying, you go on the pill on a long journey, you know, your risk of developing a blood clot in your leg is increasing significantly.

Vivienne Parry  20:54  
So how does this vaccine compare to the other vaccines in terms of risk? I mean, is the Johnson and Johnson absolutely comparable? Or should we think about each vaccine separately?

Marie Scully  21:10  
So I think we can think about the groups of vaccines with regards to mRNA AAV so the J&J VITT cases are absolutely comparable to the Astra Zeneca ones. And that was not something that anyone had considered would happen. But they have and that's during I think it's around the time of their clinical trials. Although it's been suspended, it's now been restarted. Of course, the benefit with J&J is it's just one dose the risk of developing VITT it's not common. But it has a fatality that we can't ignore, and the morbidity attached to it, we haven't even started to address. It is significant, which is why it's become more important to consider. So you've heard already about side of side effects or side effects and in the main people get over them. Or we can treat them or we can identify them. And this is different, it's completely different. We can't distinguish who's going to get it. It has a circa 30 to 50% mortality in a young patient. And when we do risk and benefit, of course, we need to look at the risk of mortality and morbidity from COVID-19 infection versus that from a therapy to prevent COVID-19. And in younger age groups. And I don't know the numbers for the risk of VITT in younger age groups, because we don't have the denominator of the number of patients who've received it in the UK in the different ages. But the risk of dying between 20 and 30 is low from primary COVID-19 infection. And we have to be mindful of that.

Vivienne Parry  22:52  
So it's where the graph crosses that we're between the risk of dying of COVID and the risk of dying from this particular side effect. Yeah, so Bryony, you have a thought,

Bryony Dean Franklin  23:04  
yeah. And I think that's one of the things that makes this quite complicated is assessing these risks and benefits because exactly as you've just been saying the younger population or those who are less at risk of COVID. So that shifts the risk benefit ratio, particularly at times when COVID levels in the community are low. So that's the other factor that's quite complicated in weighing up the risks and benefits. If the population incidence of COVID is very high, then obviously everybody is at higher risk, including those in the 20 to 30 type of age group. So that's where the recommendation has come from, which is currently in place in the UK that people who would be eligible for COVID vaccination, who are under 30 years of age, if possible, should have one of the other vaccines at present, such as the Pfizer vaccine, because it's all about weighing up, as you say where these lines cross, and it's complex. And I think the other factor that complicates things is that you're thinking about the individual risks and benefits. So what are the risks to me? If I get COVID? What are the risks to me if I have a vaccine, but we've also got the risks to those around us? So what are the risks to the people I live with if I get COVID? And what are the risks to society, which makes this actually quite a nuanced risk benefit assessment for everybody, really.

Vivienne Parry  24:22  
And we're really never very good at understanding what risk means. I mean, David Spiegelhalter, who is the guru on risk, has said that for older people, there is greater risk going to the vaccine centre than the risk.

Bryony Dean Franklin  24:38  
Yes, absolutely. Probably drive. If you drive there in a car, you're probably at greater risk from that. So absolutely. And we have to put these things in perspective. In terms of the risks of getting one of these blood clots. It's probably comparable to driving in a car for sort of a million miles or something. It's still extremely rare but as Marie has been saying, the fact that it is such a serious side effect, it means that we do, of course need to take it very, very seriously as something that we need to avoid, but put into overall context, you know, the risks of COVID, to most of us are far, far greater than the risks of the vaccine.

Vivienne Parry  25:13  
Was it difficult at the beginning of this, Marie, in that you don't, you don't want to frighten people. But you do want to raise this as an issue. And there are people who are very interested in not undermining confidence in vaccines. And yet, you need to make sure that this is genuinely caused by the vaccine? Of course,

Marie Scully  25:39  
you're absolutely right. Clinically, we can only present what we observe. And what we have observed is a significant number of cases in the UK with a very, very similar pattern of which the mortality is significant in primarily a younger age group. They all fit the same pattern, but being responsible and understanding the criticality of vaccination has been, you know, my mantra and first statement with any discussion about this. So it was very sensitive when we found out about it, but similarly, we had to put measures in place because the treatment pathway is different. That's what the difference was. And that's why it had to be announced as such, but it was announced to the correct people, it was announced to the regulators, and the CMO and CSOs.

Vivienne Parry  26:35  
So there's no particular diagnostic test for this yet is there?

Marie Scully  26:39  
There is we do NTP for antibodies.

Vivienne Parry  26:41  
But what I mean is even do a diagnostic test. But you can't do a test which identifies which people might be at risk.

Marie Scully  26:48  
No. And we found no associating factors. And we have looked primarily people who are completely fit and well with no past medical history are coming in with this condition.

Vivienne Parry  26:59  
So do you think that it has put people off getting vaccinated? Or do you think that isn't the case?

Marie Scully  27:07  
I think people just need to be reassured. And so a lot of the questions we're getting now is, oh, I've heard about this, Shall I get my second dose? Yes, because we've only had it so far in association with the first dose, or I've had this medical condition or that medical condition, will I be at risk? No, because we have no association with other medical conditions. So we can advise people in the worried Well, if they hear, we've never had it with the second dose, have your second dose,

Vivienne Parry  27:39  
I want to finish this conversation between us by asking each of you what you would say, to a 30 year old asking you about the AstraZeneca vaccine and whether they should have it.

Marie Scully  27:55  
So I think that a 30 year old will have an option to have A Zed or another type of vaccine. And that's been very clearly communicated by the regulators with that option in place, I would go for the other vaccine. If we only had A Zed, I would advise to have AstraZeneca. It's very difficult because we don't have an incidence on the risk in that age group, we do not clinically have that information. Because comparatively, having seen a year's worth of very sick, very sick patients with COVID-19. We've also seen some very sick patients with VITT who are young, and whose life is going to it has been seriously affected or they have died. So I would go with another vaccine until we're clear on the cause. But if we only had one option, which we don't we have a number of options. The important thing is to get vaccinated. Sorry, that was a very long answer.

Vivienne Parry  29:05  
But it's a it's it's a nuanced thing. It's not a it's not a black and white thing, which we often think that these decisions about vaccines are black and white, but they never are. They are always Shades of Grey. Bryony, what would you say?

Bryony Dean Franklin  29:21  
I mean, very similar. Rarely. I mean, I think I'd be wanting to make sure somebody made an informed decision about you know, what the risks are. And of course, there's a lot of unknowns there. But trying to get your head round the figures and how rare VITT is in the context of COVID. But yes, exactly as Maria has said that if somebody is eligible to have an alternative, what why would you not, but if that meant either waiting a very long time or not being able to be vaccinated, then I would certainly go with the AstraZeneca because the primary thing is got to be to try and be vaccinated if at all possible.

Vivienne Parry  29:55  
Thank you both very much indeed. It's a fascinating story and still wants to be a professor of thrombosis and hemostasis

Marie Scully  30:05  
you say that now.

Vivienne Parry  30:09  
You've been listening to Coronavirus the whole story This episode was presented by myself Vivienne Parry produced by UCL with support from the UCL health of the public and UCL grand challenges and edited by the splendid Cerys Bradley. I was joined today by professors Byony Franklin and Marie Scully. If you'd like to hear more of these podcasts from UCL Minds, of course, you would! Subscribe wherever you download your podcasts or visit ucl.ac.uk forward slash Coronavirus. And don't forget to check out the new disruptive voices from UCL Grand Challenge while you're there. This podcast is brought to you by UCL Minds bringing together UCL knowledge, insights and expertise through events, digital content, and activities open to everyone. Hope to be with you again soon. Bye for now.