Coronapod: How to define rare COVID vaccine side effects

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 from Arkansas is Ariana Remmel, a journalist with Nature.

Ariana Remmel

Hey, Noah.

Noah Baker

Before we get going, people won’t have heard your voice before so tell us a little bit about what your beat is. What do you cover?

Ariana Remmel

Yeah, so with Nature I am covering a number of different topics primarily around chemistry and materials, but I’ve also been really involved in looking at how we monitor the safety of the current COVID-19 vaccines and what kinds of adverse events or unintended side effects that happen and how we actually go about linking them to the vaccine itself.

Noah Baker

Yeah, exactly, and that’s what we’re going to talk about today. This is a big and broad and complicated topic but it’s also really important, people often worry about this a lot, and I think I’m kind of really interested in getting the lowdown. So, to start with, what do we mean by an unintended consequence when we’re talking about vaccines?

Ariana Remmel

Yeah, so, unintended consequences can range from a really sore arm to flu-like symptoms and in some cases more severe reactions. I think some really good classic examples are an early form of the oral polio vaccine actually did cause polio in some patients. I do want to reiterate though that everyone that I’ve spoken to about these vaccines does say that they are safe and they are effective, and what needs to be done now is to really understand what is causing some of these adverse events and if we can really say that they were caused by the vaccines themselves.

Noah Baker

Yeah, absolutely, and when we talk about even that polio adverse event, we really are talking about very rare events here.

Ariana Remmel

Yes, absolutely.

Noah Baker

Can I actually also ask you, given that we’re Nature and we’re into detail, what is the difference between an adverse event and a side effect because people use them colloquially the same but they’re not necessarily the same.

Ariana Remmel

Yeah, so, ‘side effect’ implies that it is a side effect of the vaccine, and when researchers are looking at these events that happen after an immunisation, it’s really important to be agnostic, to come in open minded as to whether there’s an actual causal link more than just a temporal link. It’s not enough to say, ‘Oh, I got this vaccine and then 30 minutes, an hour, a day, a month later, this reaction happened,’ right? And so, for the sake of being very clear on the scientific side of things, it’s important to use the term ‘adverse event’ because we don’t actually know that it’s directly caused by the vaccine until designated studies have been done.

Noah Baker

Indeed, so an adverse event is any event that happens after immunisation but that does not necessarily mean that that was caused by the vaccine or that that was even related to having the vaccine. That could have just been something that would happen anyway.

Ariana Remmel

Absolutely, and that’s one of the things that’s really important for studying these adverse events is you have to be able to understand what the background rate of these events are in the general population. We need to know how often these kinds of adverse events happen by chance, not just in relation to the vaccine itself.

Noah Baker

And I think this is something that we’re going to go on to talk about in a little bit more detail, but I think before that can I just ask more broadly why it’s difficult to tie these adverse events to a vaccine? In many ways, you think you’ve got a lot of people that are receiving the same treatment in a relatively standardised way and then being monitored afterwards. This seems like kind of a good study. Why is it difficult to actually make that association clearly?

Ariana Remmel

Yeah, so what scientists actually need to know in order to analyse the causality aspect is we need either a mechanism – something that we can point to in a patient that says this biomarker, as they’re often called, directly links the vaccine to the medical condition that we’re seeing. And again, going back to the polio vaccine, you could actually see the virus strain from the vaccine in the spinal fluids of patients who developed the disease, so that’s like a pretty good lab test that you could do to link those cases. We don’t have those biomarkers available, especially not for the new vaccines because some of this technology is really still very innovative for us. That means that we’ve got to go by the statistics in some cases, and that’s one of the things that’s been looked at by a lot of public health agencies is these comparisons between the background rates of what we could expect in the general population for some of these adverse events happening just by chance compared to the number that’s showing up in vaccinated populations.

Noah Baker

And I think it’s probably worth pointing out here that this is not unusual for vaccine development. Always, these very rare adverse events are things that are going to be found after a vaccine has been approved because clinical trials are never going to be on a large enough scale to be able to pick up these extremely rare events. They’re certainly not designed to do that.

Ariana Remmel

Yeah, that’s absolutely true. The monitoring systems that we have in place are there because this is not our first time responding to a pandemic with a vaccine. I mean, one of the cases that I’ve been very interested in was after the H1N1 influenza pandemic that happened in 2009 there were a number of vaccines that were rolled out to try to protect people from the very serious illness that was caused by that virus, but in some countries, primarily in Sweden and Finland, there were increased reports of narcolepsy. And again, narcolepsy is not something that happens very commonly in the general population but the rates that were being reported in these Scandinavian countries were higher than might be expected. Those surveillance systems worked, right. Those surveillance systems were able to see an increased number of reports which led to a great number of studies that looked at the safety of that vaccine. One of the thing that public health officials and vaccinologists told me over and over again was that they’re not trying to unduly dismiss these reports of severe reaction because if something is happening we need to know, especially given that these vaccines, at least some of the platforms that we’re using, are likely to come up again if not for booster shots with the COVID-19 pandemic but in future pandemics. So, there’s a fine line that public health officials are trying to walk right now where they’re trying to be very cognisant of the fact that there could be real adverse side effects that are happening while also reassuring the public that for the most part these vaccines are safe. These are very, very rare events that are happening and millions of people worldwide have already died because of COVID-19.

Noah Baker

And additionally, rare adverse events are the norm in almost every pharmaceutical medical healthcare approach in the world. Even the aspirin that we take has rare side effects so this is not new. This is not something that is specific to this set of vaccines.

Ariana Remmel

That’s very true, and I think that it’s also worth noting that just because a rare adverse event happens in one person and you can in one person link the vaccine to that event, that doesn’t actually extrapolate out to the broader population. So, one of the goals of these clinical trials that are being done with regard to allergic reaction to the mRNA vaccines in the United States – and I imagine that this will be true for the other studies that follow with other COVID-19 vaccines – the goal is to assess whether there is a risk at all, really dig into that signal and see if they can find it. But then to be able to define that risk so that physicians can better advise their patients and maybe say, ‘If you’ve got this particular medical history, let’s not take this vaccine, maybe let’s direct you towards a different platform that uses a different ingredient or acts by a different mechanism.’

Noah Baker

Okay, so I think it would be really useful to use one worked example here and something that we talked about last week on Coronapod was about the ‘rollercoaster’ is the word I think I’m going to use to describe what the Oxford–AstraZeneca vaccine has been going through over the past month or so. Now, that’s linked to clinical trials and the way that information was communicated in press releases and so on, but a big part of that rollercoaster has been linked to rare adverse events that were detected in Europe. Now, this is something we mentioned last week but can you just catch us up about what those events were and then what that kind of triggered, what the response to that was.

Ariana Remmel

Yeah, so the European Medicines Agency has a surveillance system that they use to report adverse events that happen after immunisation, and what was seen was that in a group of about 20 million people who had been vaccinated with the AstraZeneca vaccine, that there were 25 cases of people who had some sort of severe blood clot often associated with a lower platelet count, so there seemed to be some sort of coagulation disorder that was happening. And so, what the European Medicines Agency did is they paused the administration of those vaccines so people weren’t getting them while experts came together and tried to understand what is the actual risk. And one of the things that they did was they compared the rate of these reactions that were happening in vaccinated groups with people who had not been vaccinated to see how often this kind of clot happens just by chance. And what they actually found was that in the vaccinated group, that rate was lower. If you were looking at chance alone, you were less likely of developing one of these clots if you had been vaccinated than if you hadn’t. But what they weren’t able to do was rule out a link. So, there was an overall assessment that the benefit of protection from these vaccines still outweighed the possible disease caused by COVID-19 than any risk of a rare side effect, but they weren’t to say definitively that the vaccine and the blood clots were or were not linked. Now, since then, more of these reports have been coming in, particularly in Germany where in a group of about 2.7 million people they’ve got 31 reports of some of these clotting events, and that’s a higher rate. So, in that case, all of the people who had that reaction were women and they were between the ages of 20 and 63, so Germany and a number of other countries at this point have decided that they are only going to vaccinate people in older age groups with the AstraZeneca vaccine. But again, we still don’t have a link and these countries are working to try to figure out if they can define that risk for this vaccine.

Noah Baker

Yeah, I think it’s really important to say that just looking at the raw numbers you may say the rate isn’t necessarily higher in people that have been vaccinated than in the background, but once you start getting into the details, the age of the people and you start looking for other trends, that’s when you might see a different thing. Because across a whole population you might expect people that are older maybe to have these blood clotting disorders more regularly but in younger cohorts it starts to look more surprising, and that’s the kind of detail that these regulators are getting into when they really dig into this data.

Ariana Remmel

And I think that it’s also important to note that COVID-19, the SARS-CoV-2 virus, has actually kind of messed up our background a little bit. I mean, this virus causes all kinds of adverse events all on its own, including blood-clotting disorders. So, one of the concerns is that the rate of these clotting reactions and the rate of a number of different adverse events may be different now than they were in the before times when there wasn’t a pandemic going on in which this virus was widely circulating in the population, especially in cases where people have had asymptomatic cases of COVID-19.

Noah Baker

It strikes me that in some ways – this is not a comparison that really makes sense but it does make sense in my head – some of the common adverse events that we see, things like pain in your arm, things like a headache, they’re actually indicators that the vaccine is working. They’re showing that the immune system is being stimulated and in a way the fact that we’re finding these more rare adverse events is also an indicator that the surveillance systems that we have in place are working. I think these are all things that we could actually be encouraged by even though on the face of it they’re not fun or nice to hear about.

Ariana Remmel

Yeah, I think that that is definitely true, and what we are learning now is new and better ways to communicate this information to audiences who are not as familiar with how these systems work and I think if anything being able to get folks to better understand how they can go about reporting these adverse events to their healthcare providers or directly to the systems themselves and these agencies are really trying to assess the safety of these vaccines. Everything is working the way that it’s supposed to. It’s just going to take more time.

Noah Baker

Ariana, thank you so much. These investigations will be ongoing but in the meantime I hope that everyone can get hold of that vaccine as soon as they can. I’m certainly looking forward to getting mine. And I hope you join us again in the future on Coronapod.

Ariana Remmel

Yeah, thank you so much, Noah.