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. Ben Thompson isn’t here this week but joining me from elsewhere in the country is Ewen Callaway. Hi, Ewen, how are you doing?
Ewen Callaway
Hey there. I’m well. How are you?
Noah Baker
Yeah, not bad, thanks. So, we’re going to talk this week about a bit of rollercoaster for the Oxford-AstraZeneca vaccine. So, just a little bit of background, it’s been approved for use in more than 100 countries. There’s tens of millions of doses that have been administered. Notably, it hasn’t yet been approved in the USA but we’ll come to that in a bit. But last week, many European countries paused their rollouts amidst concerns over rare cases of blood clots. There have been several updates on that that we can discuss. There have also been trials ongoing in the states which also have been fraught with controversy. We’ll talk more about that. There are also questions surrounding timing, doses. I mean, you name it, someone is questioning it. Ewen, there are a lot of threads to pull here and we’ll get to them one by one as we talk through this, but I think before we start, it’s worth mentioning that as far as we are aware and as far as the data says, this is still a safe and effective vaccine, right?
Ewen Callaway
Yeah, I mean, buckle up indeed. Yes, the clinical trials and ongoing rollouts emphasise again and again that this vaccine is very safe and highly effective, bottom line.
Noah Baker
And I think that’s really key to mention up front because what we’re going to go on to talk about now is the various ways in which people are questioning that or certainly the ways in which the method of communication of these studies could lead people to question that. And so, I think maybe let’s just start with the pause in EU countries over these blood clots. What was the story there and where are we now?
Ewen Callaway
Last week, some countries in Europe noticed that some tiny number of people developed blood clots after receiving the vaccine and some of these people sadly died. That’s unfortunately not unusual. Blood clots occur at a very low rate in a population and overall, people weren’t seeing higher rates in death due to blood clots in people who received the vaccine compared to other people. In fact, I think rates were lower in the vaccine population. But in some countries, they observed some unusual symptoms accompanying these clots which are occurring in younger people than you would expect and with some features that you wouldn’t already expect, which led to pauses in some of these countries such as Norway and Denmark. And then other countries in Europe just kind of followed suit like dominos, particularly after Germany announced that it was pausing the rollout. And the European Medicines Agency (EMA) launched an expedited investigation and initially found that it couldn’t confirm the links but it couldn’t rule them out, but given the huge benefits to this vaccine and the extreme rarity of these potential side effects that countries should continue administering the vaccine. A number of European countries have resumed their rollouts, some haven’t, and so I think that’s where it stands. Taking a step back, this has affected public confidence, I think, in this vaccine, somewhat.
Noah Baker
And I think that’s going to become a theme as we continue to talk here. Questions have been raised, studies have been done, results have been published and so far the results don’t seem to be necessarily concerning but there is a concern over what this might do for confidence in this vaccine.
Ewen Callaway
I mean, just because a potential side effect is extremely rare and the benefits seem to outweigh the risks or overwhelmingly outweigh the risks in people’s calculations, that does not mean that we should ignore these safety signals. They need to be investigated and that will continue, so there are no easy answers, I’m afraid.
Noah Baker
Indeed, and the EMA did say that although they couldn’t find any evidence to support the link between these two particular very rare, serious clotting conditions and the vaccine, they did say that because they couldn’t rule it out, they recommended that they were added to the list of possible side effects that you should be aware of so that people can have informed consent when they’re receiving the vaccine. And so, gradually, countries in the EU do appear to be starting their rollouts again, but one country that I mentioned at the beginning that has still not yet approved the Oxford-AstraZeneca vaccine is the USA. Can you tell us a little bit about the journey that’s going on there?
Ewen Callaway
Yeah, the FDA (US Food and Drug Administration) is one of the world’s leading regulators, and a lot of other regulators kind of look to FDA approval as a gold stamp. And other trials have gone on with this Oxford-AstraZeneca vaccine but generally, and particularly with these COVID vaccines, FDA has wanted to have kind of US-based trials to look at before giving any approval or authorisation to the vaccine. So, this is a trial that began recruiting months and months ago, but this is one of the first stumbles of this vaccine. There was, in a UK-based trial, an individual who potentially developed some neurological symptoms after receiving the vaccine. And in the UK that was investigated and not attributed to the vaccine but in the US the pause on the trial lasted a lot longer than in the UK. It really slowed down this trial. AstraZeneca would have hoped to be reporting results from this trial in late 2020 when other developers – Moderna and Pfizer – where reporting their results, but because of that long pause we’re only getting the results from this trial now, which also includes individuals from some others countries in Chile and elsewhere. This is a kind of a long ride to get to these results, but here they are. We’ve seen our first cut of them and they look good but confusing.
Noah Baker
Yeah, so I think that’s something that we should really dig into because there have been two releases from this trial in recent days, I suppose. Can you tell us a little bit more about how those data have been released and what that has meant, I suppose, because the method of communication of that really seems to be something that’s confusing scientists right now.
Ewen Callaway
Yeah, so, on Monday morning we awoke to news on the radio that AstraZeneca had announced the results from this long-awaited trial and their vaccine was 79% effective, which was a really good number indeed, with the caveat that this was a preliminary analysis. So, the way that these trials work is that they have these kind of independent data monitoring boards that are the only people who can see who’s been randomised vaccine or placebo, and this is mostly to protect the safety of participants because if a vaccine is not working and it’s clear it’s not working early on, you want to stop giving people that vaccine, or if a vaccine is working abundantly well, you want to stop randomising people to placebo. So, this data monitoring board kind of meets periodically to look at the data, and this first analysis was based on one of these early looks. And then, the rollercoaster is going up a hill and now we’re just about to go down, maybe around a twister. Three quarters of a day later, the US National Institutes of Health, which is kind of overseeing this trial through the US Operation Warp Speed Project, it issued a press release saying it had heard from members of this oversight committee, this data monitoring committee, that they weren’t happy with how AstraZeneca had communicated the efficacy, that 79% figure, and that it might be outdated and potentially misleading. I think those are the words they used. And so, everyone’s just like, ‘What is going on?’
Noah Baker
And what’s even more confusing is that the finalised results from that trial have now been released today, just a few days later, by AstraZeneca in another press release, and they’re not all that different from the previous results. They’re sitting at 76% efficacy. What’s your take on that?
Ewen Callaway
Yeah, I mean it’s just a real head-scratcher. I’ll explain. So, after this kerfuffle erupted between the data monitoring committee and AstraZeneca, AstraZeneca issued another press release saying, ‘That was our preliminary analysis based on looking at the data in mid-February, but we’ve got the final analysis already done and we’re going to present that to you in the next 48 hours. Just hold my beer while I do this. And trust me, it’s in line with what we reported.’ So, that left people just being like, ‘So, you had the final results of this study yet you chose to report a preliminary result that your data safety monitoring committee disagreed with.’ What the hell is going on? Then as you mentioned, today, here we are in – what day is it – it’s Thursday, maybe it was late Wednesday. I don’t know, this stuff happens when you’re asleep or you’re taking care of your children. AstraZeneca issued another press release saying the final results from this trial, they said the efficacy is 76%, right, so three points lower than this number they were told that was misleading and outdated, and it’s just a real, real head-scratcher. I mean, these are still like really encouraging results. I don’t think they’ll be the final say because they haven’t published a paper, they haven’t released a lot of details and I think a lot of people are going to wait until that comes out or the US Food and Drug Administration, which is going to decide whether to authorise this vaccine, until they look at the data. But it’s just a real head-scratcher. What’s going on?
Noah Baker
This inconsistency around press released data and what it means and when it’s being released is something that has been plaguing AstraZeneca for this entire pandemic. It strikes me that this seems like something that AstraZeneca’s comms team should be on top of by now.
Ewen Callaway
I know, I mean, I don’t know. Yeah, the comms just seem really bass-ackwards, as they would say in America. Roxanne Khamsi, who’s a former Nature Medicine editor, now a wonderful freelancer, said that it’s like some dude on a dating app who’s really 5”9 saying he’s 5”11 or something like that. You’re going to get caught at some point. But to your point, I don’t think AstraZeneca is – I know we’re talking about them – but I don’t think they’re the only people who are trying to manipulate press releases. Pfizer and BioNTech were notoriously detail-free in their first press release about their vaccine. It was just like 95%, hey, and no other detail. So, I don’t know, it’s a different culture is how I rationalised it. Maybe they’re not allowed to publish full analyses because of insider trading rules and so these companies try and control everything so you get these drip, drip, drip press releases that have some details but not all of them, and I think it’s really frustrating to scientists.
Noah Baker
You mentioned details. What is it that scientists want? What are the details that they’re missing right now?
Ewen Callaway
I mean, what people particularly want, I’ve been mentioning this before, is, okay, you say you’ve got a 180-some total cases that leads to an efficacy of 76%, and they gave confidence intervals so I think I’m going to call some statisticians up as soon as we get off the phone who will probably work backwards from those numbers to try and infer how many cases there were in the placebo arm and in the vaccine arm. That’s the kind of detail people want to know. They have this really potentially striking beneficial result that there are eight severe cases amongst all of these and all of them were in the placebo arm, so we’re looking at a vaccine that might be 100% effective against severe disease which is what we really need. But I think there’s some more details around that that people want to see. There’s some extra cases that have accrued that haven’t been adjudicated, they say. They haven’t been factored into that figure so that could turn a 100% effective vaccine against severe disease into an 85% effective or lower. Things could happen. So, I think people just want more detail and answers will come. I’m pretty sure – my sources have told me – this vaccine will get authorisation in the US. It probably won’t be used in the US but it will get authorisation in the US, which people are telling me could be a real boost for this vaccine. It could help it get back on track because the world needs this vaccine.
Noah Baker
Yeah, I think that really is the key here because the thing that stands AstraZeneca out when compared to the other vaccines that are on offer, from Pfizer, from Johnson & Johnson, from Moderna and so on, is that it is really cheap and it doesn’t require this hyper-cold storage, and that really means that the WHO have certainly been placing the AstraZeneca vaccine as the vaccine which will help vaccinate the global south and the developing world. And confidence in that vaccine could be really, really vital to what happens with that rollout, which is kind of vital for the whole world as well as people in those countries.
Ewen Callaway
Yeah, without a doubt. I think a lot of this is credit to the University of Oxford which I think forced these terms on any company that it was working with. It said, ‘We need to be able to license this vaccine widely,’ so you’ve got lots and lots of plants producing this vaccine. The Serum Institute of India is probably the most famous one, but they’ve got production in South America and kind of just all over the world to increase production, and this effort to deliver vaccines to low-income countries at low or no costs. I think often no costs – it’s called COVAX – is very reliant on AstraZeneca’s vaccine. So, yeah, these shenanigans have consequences.
Noah Baker
The other question that is certainly on a lot of people’s minds right now that wasn’t on people’s minds as much earlier on in the pandemic is how this vaccine might fare against variants, and there are ongoing trials with the Oxford-AstraZeneca vaccine looking at that and there are even plans to start trying to reformulate the vaccine to fight variants. How does that challenge fit into this picture more broadly?
Ewen Callaway
Well, that’s another head-scratcher. So, I guess the thing we know is that AstraZeneca, one of its early trials was in South Africa, and the trial was ongoing as this B.1.351 variant identified in South Africa was kind of rising to the fore. And we know that this variant escapes a portion of some people’s immune response so it’s more likely to cause reinfections, and we know from other vaccines that it lowers but doesn’t eliminate efficacy. So, we’re seeing figures more in like the 50s or something like that, 50s and 60s percent, instead of 80s and 90s, so it takes a hit but it wasn’t eliminated. And then there was an analysis of this really quite small trial of the AstraZeneca vaccine in South Africa and it had barely any efficacy against this variant. It was like 10% or something like that. I don’t think you can conclude that this vaccine is not effective against variants like the one identified in South Africa. The trial was really small and it was only powered to show that it had more than 60% efficacy, but we need answers to that question and I’m not sure how we’ll get them. I think South Africa has paused rollout of this vaccine while it scrutinises those data. And we’ve got other variants, such as one identified in Brazil, that have similar mutations and might behave similarly, and so, yeah, people will be very interested. But it’s hard to measure this without randomised controlled trials like the ones that was done in South Africa, so I think we’re just going to have more question marks over how this vaccine fares against variants.
Noah Baker
And then one other thing that has caused a lot of confusion is over the interval between doses. Can you give us a sort of catch up on that?
Ewen Callaway
Yeah, I mean, this is a long rollercoaster ride we’re on. This requires a bit of history, which I hope you’ll allow me. When AstraZeneca reported their first results from a UK trial as well as, I think, a trial that was going on in Brazil – this was back in November 2020 or something like that – they had this mystery result that participants who received two full doses four weeks apart had an efficacy in the 60s or something like that. But for these people who received half a dose and then received a full dose, efficacy was 90%. And so people were like half a dose, what’s going on with this half dose thing? And then researchers looked at it more closely, the people running the trial looked at it more closely, and found some evidence that the association was more likely to be down to the interval between the doses. So, the people who got the half dose, which I think was due to a manufacturing error in formulation of vaccines, I think they realised that and I think they paused some people’s second dose, and so you had these people receiving second doses at different intervals, up to 10-12 weeks later or something like that. And based on the biology of how vaccines like the Oxford-AstraZeneca vaccine work, it does make perfect sense that having a longer interval between doses could lead to a better, stronger immune response. But this US trial that we’ve been talking about, it was designed ages ago, back in the summer, even before that when we thought a four-week interval between doses, so a non-ideal interview between doses. So, this 79% figure could easily become – if Oxford and AstraZeneca are right – 90%, but we don’t know that and we might never know that to our satisfaction because I don’t think anyone’s going to run another randomised placebo-controlled trial of this vaccine to test a 12-week interval versus a 4-week interval. I think we’re just going to have to see what happens with rollouts in the messy, real world.
Noah Baker
But you can, I’m assuming, get some kind of epidemiological data on the efficacy of vaccines when they’re being rolled out. It’s not a controlled trial but it does provide you with some information about the efficacy of the vaccines.
Ewen Callaway
Yeah, yeah, 100%, for sure. And in the UK where there’s a really good joined up healthcare system and lots of good studies, I think we’re getting a lot of really, really encouraging data about this vaccine. The UK rollout offered clear evidence that this vaccine seems to be highly effective in older people. It’s offering up evidence that this vaccine seems to cut transmission and yes, it will give us more data. But the sorts of studies you do during a rollout are fundamentally different and many statisticians would say inferior from an evidence perspective to a randomised placebo-controlled trial. So, we’re going to learn more about this vaccine but there’s always going to be some mysteries. But that’s true for any medicine, any vaccine. Things are changing and we just have to do the best we can with the data we have.
Noah Baker
Ewen, thank you so much. There’s going to be a lot more to watch on this and I’m sure we’ll be talking about it again in the not-too-distant future. But for now, I hope you have a very good week and thanks for joining us on Coronapod.
Ewen Callaway
Yeah, no problem. See you later.