Benjamin Thompson
Welcome to Coronapod.
Noah Baker
In this show, we’re going to bring you Nature’s take on the latest COVID-19 developments.
Benjamin Thompson
And we’ll be speaking to experts around the world about research during the pandemic.
Amy Maxmen
We’re entering a new era now. We have new COVID strategies, there’s some new unknowns and we’ve got a vaccine.
Noah Baker
Hello and welcome to Coronapod. I’m Noah Baker and joining me this week is Nature reporter Heidi Ledford. Hi, Heidi.
Heidi Ledford
Hello.
Noah Baker
Now, we’re going to open this week with some great news for you which is that you are getting your first COVID jab today. I am very happy for you, he says through gritted teeth as he awaits his own.
Heidi Ledford
Laughs. I’ll tell you, I think they announced on Tuesday that it would be 45 and older were now eligible here in London and Wednesday was my birthday and I turned 45. Thursday, I got the text from the NHS saying, ‘You may now book your appointment,’ and this afternoon, I’m going to walk five minutes down the road and get my shot. I’m just so happy. Who knew turning 45 would be wonderful?
Noah Baker
And you’re getting the AstraZeneca shot as well. Did you have any reaction to getting this particular shot?
Heidi Ledford
So, it said in the text message, ‘You may now book your AstraZeneca shot,’ so it told me right away what I’m getting, and I think I paused for about half a second and then I said, ‘Okey dokey, book me in.’ I was very happy. And that half a second pause, because I have been reporting about this a bit over the past couple of weeks, I guess the half a second pause was for me to think, ‘Do we need to know more before I do this? Should I wait a week or two just to see because the numbers are changing all the time?’ But I thought, even if the numbers go up a bit, we already know this is a handful of additional cases in a background of 25 million or whoever have been vaccinated, and this is just such a, ‘No, I’m absolutely going for it.’ I’m very happy.
Noah Baker
It’s amazing, and I think this is a really interesting backdrop for the conversation we’re going to have today which is about rare blood clots. So, this is something that is just continuing to swirl around the news media. People are reading about it all the time, particularly with the AstraZeneca vaccine but now there’s also been news possible cases raised related to the Johnson & Johnson vaccine. So, we’ve talked a lot about the fact that these clots have happened and that it’s very hard to attribute them to the vaccine. There’s various reasons for that. I’ll put a link in the show notes to the episode where we discuss that. But one of the things that we said in that episode that you really need to work out to be able to kind of get a clear understanding of whether or not this is a side effect or just a random occurrence is the biological mechanism for how a vaccine like this could actually lead to a blood clot like this, and that’s kind of what you’ve been looking into over the last week or so.
Heidi Ledford
Yeah, I’ve got to say, the disappointing answer to that is that it’s a little bit still anybody’s guess. Conversation has evolved over the past few weeks. I think initially we talked a lot about just sort of clots in general, and now we’re looking at this very unusual constellation of symptoms where you’ve got blood clots showing up in unusual places. So, normally, you think of blood clots in the limbs and the legs in particular. These are showing up in the brain and in the abdomen. And at the same time you have these blood clots, you also have actually a deficiency in the cellular fragments called platelets that are involved in clotting. So, on the one hand you’ve got lots of blood clots. On the other hand, you’re low in this factor that encourages clotting. So, they had observed this particular constellation of symptoms in very few people who’ve received the AstraZeneca vaccine. That was when it was first initially flagged. They’ve now also got a handful of cases, I think just six, in the United State from people who have received the J&J vaccine.
Noah Baker
Yeah, so this unusual combination of symptoms is something that we’ve kind of hinted at as well when we’ve kind of spoken about this before. My understanding is that this isn’t completely new. This is an understood combination of symptoms. This syndrome has happened before but nothing to do with vaccines in the past.
Heidi Ledford
That’s right, yeah. So, they’ve seen it before. It’s a very rare side effect of being treated with a blood thinner called heparin. They’ve known about that for decades. There’s a mechanism that’s been worked out involving heparin that has to do with a negatively charged heparin interacting with a positively charged protein in the body called platelet factor 4. It forms this complex. There’s an immune reaction to that. The body develops antibodies against that. Those antibodies then basically muck around with the proper functioning of the platelets and you end up with this syndrome. So, that’s the sort of idea, but we don’t know how is the vaccine serving as heparin in this scenario, right? So, there’s so many things that you could imagine. You could imagine that the AstraZeneca vaccine, the J&J vaccine, they both rely on an adenovirus to shuttle in a bit of coronavirus DNA that is then expressed in cells. Maybe it’s the virus where they used two different kinds of adenoviruses, but maybe it’s something to do with that vector. Then again, maybe it’s something to do with the intensity or the duration of expression of that particular viral protein. Then again, maybe it has something to do with the dosage that’s being used. Then again, maybe it has something to do with some contaminant that comes along through the purification process. You can imagine all of these scenarios, and people really don’t have a good handle on it yet. They certainly are looking at it. There are research labs that are jumping on this now, but at the moment it’s really speculation.
Noah Baker
And I guess there’s several ways that you could try to get to the bottom of what’s happening here, one of which is to do very sort of mechanistic lab studies looking at the constituents of the vaccine and then maybe look for negatively charged elements there, for example, that might act in the way that heparin is acting. Another thing that you can do is you can look at the epidemiology and try to find places where the people that are being affected by these very, very rare events happen to share something in common, which might give you a clue as to what is happening here. But that second of way of doing it, that’s also not that simple. People are suggesting maybe it’s younger women that are affected more here but actually, if you look at the stats, that’s not as clear-cut as it might be. The EMA has come to that conclusion as well.
Heidi Ledford
That’s right. I mean, and it’s been difficult because the narrative has kind of evolved over the past few weeks and it’s quite hard to sort of get yourself unstuck from what you heard first. So, initially what we heard was younger women, blood clots, and now what we’re hearing is maybe younger women but we don’t know and a very specific kind of blood clot. The trouble with narrowing it down to younger women, well, that kind of thing does tend to happen more often in women in general. But the problem is that the vaccine hasn’t been rolled out equally. This isn’t a controlled clinical trial. It’s messy, real-world data. We’ve had rollout programmes that often prioritise healthcare workers. Healthcare workers are more often women. So, what we need are good data in terms of how many women have gotten the vaccine, how many men have gotten the vaccine, and that data is not always available from every member state of the EU, for example. So, they weren’t able to draw a conclusion. And even with age, you again run into a problem because you may see it more often among younger people but if you have an elderly person who shows up with a clot in the brain, you may not investigate that as thoroughly as you would a 32-year old woman who shows up with a clot in her brain, right? A 32-year old woman with a clot in her brain is an unusual event. It sort of triggers extra investigation and then you may uncover that also her platelets are low. So, it’s possible that there have been cases among the elderly that we haven’t seen because we didn’t associate necessarily what they were experiencing with a potential adverse event. As awareness grows, we could sort of hope to get better data over the coming weeks, but it’s hard because decisions have to be made now, right, and they’re very important, big decisions.
Noah Baker
Yeah, and as you mentioned, with messy real-world data, that awareness in the population can also potentially cause its own problems as well. If people are hyperaware of the fact that this may be a potential thing then they may be looking for symptoms and they may be more likely to report that they’ve had this kind of clot more than they would have done in the past and again, that skews the way that that data is represented because perhaps this kind of event was happening more regularly but people weren’t looking for it so they didn’t necessarily find it as much.
Heidi Ledford
No, that’s right, so that’s one reason why you might expect the numbers to keep changing for a little while. While this knowledge sort of filters out, people start to report potentially more frequently what they’ve seen. But we are likely to see that being reported more often among people who are vaccinated than among the general public, let’s say, so we don’t have a good baseline comparison necessarily because we’re going to have so many people who are vaccinated on high alert for this. People who haven’t been vaccinated, particularly with AstraZeneca or J&J not as much on alert, may be less likely to catch it, and so it’s going to be hard to figure out the risk ratios there.
Noah Baker
And the baseline itself is a tricky thing to narrow down because we do know there’s lots of good evidence that shows that COVID itself changes the risk of various blood clots from happening, and we don’t have a clear understanding of how and why, and so it may be that the fact there’s been this rapid dissemination of COVID throughout the population could also be increasing the background and so therefore again, the relative occurrence of events like this could be a bit skewed by that, and we as of yet just don’t understand how that works.
Heidi Ledford
Yeah, that’s right. I mean there are so many things we don’t understand. So, there was, like I said, I had that half a second where I paused and thought, ‘Wait, should we find out more?’ But I still feel very comfortable doing this given the risks of COVID itself. But individuals will make that decision and countries are going to be making that decision, right, and they are already are to some extent. We already see more hesitancy to using these vaccines in countries where COVID levels may be low or where other vaccines are available. They’re more likely to say, ‘You know what, we’re not going to deal with this. We don’t have to.’ But then you have other countries where they’re very heavily reliant, particularly upon AstraZeneca and J&J. These are two globally very significant vaccines because they are cheaper to make than the mRNA vaccines and they are easier to transport. They don’t require the same intensive cold chain. So, these two vaccines are really important, so it’s important to get this information out and I think different countries are going to have sort of different risk-benefit calculations that they’re going to factor in as they work through this.
Noah Baker
And that’s something that I think is really key here, this question of risk and trying to actually put the risks that we’re talking about into some perspective here because it is always scary to say there is a potential, even if it’s not been demonstrated clearly, yet very rare risk of this very serious side effect from this vaccine. People think, ‘Well, I do have the choice of whether I take the vaccine or not so I should consider that.’ But in the process of this sort of risk discussion there have been various other risks of other medications that get brought up that people take on a daily basis. One key example of that is the contraceptive pill, which does have risks of blood clots associated with it.
Heidi Ledford
So, in the early days when we talked about young women and we talked about blood clots more generally and there was some speculation, ‘Oh, well, maybe this is because they’re taking hormonal birth control and so this already raises you risk of clots. Maybe there’s something to do with that.’ Now, since then, we’ve moved away from the general blood-clotting hypotheses. This isn’t what you see in response to birth control. We don’t know for sure if it’s more of a risk among young women as well, so we’ve sort of moved away from that but people have told me that this is a good frame of reference in terms of risk. Women take birth control, many are encouraged to by their doctors for that matter depending on where you live, but it does carry this risk of blood clots. We do sort of accept a certain amount of risk. Every medication has a risk. You have to sort of weigh, I guess, the relative risks and benefits.
Noah Baker
I mean, so much of this when I think about this is about balancing the kind of narrative that’s going on with what the data is actually showing and trying to get that perspective often. So, as you say, every therapeutic or drug or pharmaceutical has some form of risk associated with it. I don’t think there’s a single one in the world that doesn’t have some form or risk associated with it. And the numbers we’re looking at here, even if eventually these rare adverse events are attributed to the vaccine directly, they still are such low occurrences at the moment that it does not make this in anyway riskier than what you might expect for a pharmaceutical. But people are really focused on it and that changes the way that people think about things.
Heidi Ledford
Yeah, I think part of what’s feeding into it as well, part of the concern is that there are people who have died from these clotting events, right, and I think of the six that were reported in the United States, I think all six are in the hospital and I think at least one fatality, and so I think that’s looking very large over this discussion as well, that it’s not just stomach bleeding from aspirin, that this is something that could be very serious. There’s some hope that now that there’s wider awareness, people will be able to detect it earlier and potentially intervene earlier, and there are guidelines for intervention. There are certain drugs that could be used and certain treatments. We don’t know yet how well those are going to work because again, this is such a rare condition. It’s not something that we have a lot of data about. So, I think, to some extent maybe, how that narrative evolves may in part depend on our ability to treat this condition. I think we had this situation with anaphylaxis, right, in response to some of the mRNA vaccines early on and there was some concern about that among the public initially, but I haven’t heard anything about it recently. I don’t know if you have. But it seems like that has died down but I think part of the reason that has died down is because we were able to reassure, ‘Well, anaphylaxis, we’re going to treat it this way and that way and monitor you for x period of time to make sure that it doesn’t happen, or we’re going to have people onsite who are able to treat you and it’s going to be fine.’ And we can’t do that yet with this one, so I think that adds to the narrative. So, hopefully, we can get some clarity in terms of how best to treat and how effective that’s going to be. If we can find a way to better target monitoring and interventions, if we know who’s more at risk, if we have a way of detecting it earlier maybe by looking for certain antibodies and so on, all of these things I think could help sort of bring down some of the heat in that narrative.
Noah Baker
And it is worth saying as well that the vaccines do tend to have a lower tolerance for risk than other pharmaceuticals because vaccines are things we give to healthy individuals, so it would be expected that we should be very, very stringent with these.
Heidi Ledford
Yes, I mean, I even feel a bit of an emotional – I don’t know if you do – like I feel a bit of an emotional difference in doing something that could harm me as opposed to not doing something and taking the risk of being harmed. Do you know what I mean? Like there’s sort of an emotional difference there that I have to be aware of and step down on, and I had the same thing when my daughter was a baby and she got one of those suites of vaccines and for the next day she was very sluggish. And I sort of went back and took a second look at the materials that they give you and the side effects and what all and I thought, ‘This doesn’t feel good.’ I mean, absolutely I’m not hesitant at all about vaccines. My kids are fully vaccinated. I will be fully vaccinated. I’m rushing out to get AstraZeneca this afternoon. But instinctively it didn’t’ feel good, and so you’ve got to kind of get your rational mind, or for me anyway, I’ve got to get my rational mind to kind of fight with that instinctive idea, ‘Well, maybe I could just hide out in my office/bedroom for a few more months and not get COVID and then I don’t have to take this risk with the vaccine,’ but I think in the end that’s not good for me or society.
Noah Baker
Yeah, indeed. And I think that it is our nature to try to rationalise everything that we see and it is difficult when there is very, very sparse data or very confusing data on this but there is a signal that people can see. People try to make associations very quickly and so, for example, there’s been quite a lot of focus on the AstraZeneca vaccine and blood clots for quite some time and then when J&J announced that they have some rare cases associated with it, people immediately go, ‘Oh, both viral vector vaccines,’ therefore this is just bolstering that argument. Even within our news team, I remember the first thing was people were like, ‘Okay, does this mean it’s more likely now that this is definitely a thing,’ and I’m kind of interested in what your reaction to jumping to that conclusion is because that’s not really how data works.
Heidi Ledford
That’s true. That’s right. It’s not really how data works. I think right away, from the moment last week when the EMA said, ‘We do think that there is a possible association,’ and they did also use the word ‘strong’ association between the vaccine and these rare side effects, right away the question was, ‘Well, what about J&J?’ Is it a class effect? Is it because of the adenovirus?’ Because we don’t seem to be seeing it with the mRNA vaccines. And I just started to feel devested for J&J. I mean, they put a pause on distribution in many countries, and I was talking to someone in South Africa yesterday and she said, ‘We have barely gotten vaccination underway. We are terrified that there may be a third surge on its way of COVID. The mortality rate here is over 3% from COVID. And now they’re telling us that they’re not going to give us this vaccine because 6 out of 7 million people or what have you have come down with this very rare clotting disorder and it’s just not computing.’
Noah Baker
Yeah, absolutely, and I think this kind of perception of relative risk is really a core part of this discussion, but none of that is to say that just because the risk is low, we should ignore this or dismiss this. Of course, it’s still really vital to investigate these things and that investigation is part of what can give people confidence to take the vaccine in the first place. That fact that we know that people will investigate this, that’s why you’re going out to have a vaccine today.
Heidi Ledford
Yeah, that’s right, and it is a serious potential side effect and it’s something that needs to be looked at, and it’s remarkable that we’ve been able to pick it up so quickly given how rare it is and how unusual these particular symptoms are. It takes some digging to put this together and they did that incredibly quickly, and that they were transparent about it immediately is also something that I think could give one faith in the system and how it’s working and the safety reporting and so on. But I am aware that negative information tends to be sticky and it will be hard to shed that, I think, and there’s almost like a tension, I think, between this need to be very transparent and to act quickly and proactively but also a need to sort of not put people off of the vaccine unnecessarily or every time we find a potential association with this or that. It’s very difficult. It’s a tightrope, right, that these regulators and these public health officials are walking right now.
Noah Baker
This is something that we’re going to have to talk about again, I’m sure. I doubt this is going away. There are more vaccines still to be rolled out. They will all be monitored. It’s a long road ahead of us to try to vaccinate the world, so I’m sure we’ll be back to talk about this again but for now, thank you so much for joining me and enjoy your jab this afternoon.
Heidi Ledford
I have never looked forward to a shot so much in my life. Part of me keeps thinking, ‘Oh, it’s going to hurt though, isn’t it?’ But fine.