NATURE PODCAST

Coronapod: Is mixing COVID vaccines a good idea?

The science behind how and when to give vaccines doses.

Benjamin Thompson, Noah Baker and Heidi Ledford discuss the latest COVID-19 news.

As vaccines are rolled out, massive logistical challenges are leading scientists and policymakers to consider alternative dosing strategies.

But what does the science say? In this week’s episode of Coronapod, we discuss mixing and matching vaccines and lengthening the time between doses. Approaches like these could ease logistical concerns, but we ask what's known about their impact on vaccine efficacy – what is the science behind the decisions, and could they actually boost immune responses?

News: Could mixing COVID vaccines boost immune response?

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Transcript

Benjamin Thompson, Noah Baker and Heidi Ledford discuss the latest COVID-19 news.

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.

Benjamin Thomspon

Hi, listeners. Welcome to another edition of Coronapod. I’m Benjamin Thompson, firmly ensconced once more in the South London basement, and joining me this week are Noah Baker and, returning to the show, Heidi Ledford, a senior reporter here at Nature. Hello to you both.

Heidi Ledford

Hello.

Noah Baker

Hello, Ben. Hi, Heidi.

Benjamin Thomspon

This week, we’re talking as we often have recently about vaccines, and we know that vaccines of different sorts are being rolled out across the globe. Maybe some of our listeners have had their first shot already. But this rollout is of course a huge challenge, in some part because these vaccines or most of them at least require two doses, two shots. Now, researchers are trying to maybe alleviate that problem by looking at a mix and match approach, I guess, and we’ll talk about that in a minute but before we do, Heidi, why are the vaccines that are being used now, why do they require two shots?

Heidi Ledford

Yeah, that’s a great question. So, it’s really just to give you a stronger immune response. You’ve got the first shot, which is often called a prime, and that sort of introduces your immune system to the coronavirus protein that’s in the vaccine. And so, you get an initial response from that, and that’s good, but they find that often if you give a second shot, which is called a boost, it does exactly that, it’ll boost your immune response, you’ll get a stronger, for example, antibody response, and it might last longer.

Noah Baker

And we’ve talked about the fact that we might need two shots for various of these vaccines, but what we haven’t really discussed much on Coronapod is exactly how and when those shots are administered. So, the kind of dosing regimen of those shots varies from vaccine to vaccine, and there is a kind of a bit of a discussion among the scientific community of exactly how that could impact the efficacy. For the Pfizer vaccine, for example, the kind of manufacturer advice is that there should be a three-week gap between those shots and yet, in the UK right now, there’s sometimes up to a 12-week gap between those shots because of the way that the vaccines are being rolled out. And there’s a lot of kind of confusion and questions about whether or not this is going to make the vaccine ineffective or if it could change things. Heidi, do you have any way of clearing this up?

Heidi Ledford

Not really, no. I mean, I sort of laughed a little bit when you talked about the discussion because I thought, yeah, it’s a very big discussion in the UK. The UK did make this decision to allow for a delayed second, and I absolutely sympathise because it’s a very tough situation, right. At that time and still, hospitals are under enormous pressure. At that time we didn’t know when that pressure was ever going to be alleviated. We really needed to get vaccines out quickly. I absolutely understand the pressures they were under to try to do something to speed up the number of people who at least get one shot and some protection, but we really didn’t know what the effect of extending that interval between the two shots was going to be. There was a good guess that does seem to be sort of panning out for the vaccine that’s made by Oxford and AstraZeneca, that that one would be okay to go out to 12 weeks, and there were various reasons for thinking that. There was a little bit of evidence and also some good sort of theory behind it. But particularly when it came to the RNA vaccines, we really didn’t know what the effect of extending that interval between the two shots was going to be. We had inferences we could make based on past experience with other vaccines and knowledge of immunology, but there was, I would say, quite a bit of difference in the scientific community about whether or not that was enough to justify going forward, and there were people saying, ‘We need to do this. It’s a good bet that this is going to work out. These are desperate times.’ And then there were other people who were saying, ‘These are desperate times therefore we need to do something that we know will work and not take a gamble.’ But I think, by and large, these intervals that were tested, particularly for the RNA vaccines for example, there’s a little bit of trial and error to it. There is reason to think that if you wait longer, you may actually get a better response, and it may have to do with trying to get the trials out and done quickly and so on that maybe they wanted to have that interval short for the clinical trials. So, you could imagine a rationale for extending things. It was just a matter of do you want to see the data backing that up before you make a big decision. I was glad I was not in a position to ever have to make that kind of choice.

Noah Baker

And I think people that are receiving the vaccine are also very confused about what this means. I mean, I heard people on the radio being interviewed saying, ‘When I gave informed consent for my first vaccine, it was under the assumption that I would have my second vaccine in the appropriate amount of time, and maybe I wouldn’t have consented to the first vaccine if you then didn’t live up to the challenge of the second one.’ I mean, it’s a bit of a minefield about how to manage this.

Heidi Ledford

Yeah, that’s messy, isn’t it. And I have heard from people saying they felt really good about getting their first shot and then they found out that the second was going to be delayed and, particularly those who are a bit more familiar with the data were saying, ‘What’s this? Am I still going to be as protected as I thought in all this?’ They don’t want to gamble with their own health necessarily. Hopefully, it does seem like it’s likely to be fine, but it was quite a controversy. It’s sort of interesting because as some data has come out about the duration of immunity after the first shot we’ve got a little bit more data, and I’ll often see statements saying that the UK decision was vindicated. But I don’t know if that’s quite the right word. I don’t know if it can ever really be vindicated. They may be proven to have chosen the right gamble, but I don’t know that they necessarily are vindicated in taking that chance. But anyway, it was quite a tense discussion and I do realise it’s very difficult circumstances.

Noah Baker

So, from an immunology perspective, why would scientists think that lengthening that gap between vaccines may or may not impact someone’s overall immunity?

Heidi Ledford

Well, I think if you infer from what we already know about immunology, you’re not so worried about losing efficacy. I think the theory is that you potentially could gain some efficacy by waiting longer, and part of the reason for that is that you want that booster shot. The second shot that you get is most powerful if it’s really activating your memory cells in your immune system, so your memory B cells, your memory T cells, and they will then launch this immune response. If you still have the initial reaction to the first dose really raging in like high levels of antibodies and so on, you may not get as much activation of those memory cells and so it may not actually be as effective. So, there is, in theory, a good reason for thinking that maybe it would be better to even wait a little bit longer. And then again, there’s a wrinkle depending on which of the vaccines you’re talking about because also for vaccines like the Oxford-AstraZeneca one, which rely on a harmless virus called an adenovirus in this case to carry DNA for a coronavirus gene into cells, that vaccine, if you give it twice which is what the current dosing is for Oxford-AstraZeneca, you do have the possibility that you’re going to have immune responses not only against the coronavirus protein but also against the adenovirus vector that you used to shuttle that DNA into cells. You really want that to die down before you give the second shot or else you could end up reducing your chance of getting a good response to the spike protein from coronavirus. So, again, in theory, it makes absolute sense to wait a bit longer, and I think the debate really is just that we don’t have the hard evidence to show that it’s still going to be as effective, so that’s what’s worrying a lot of people.

Benjamin Thompson

Well, alongside that debate, part of the reason that these circumstances exist was that there was no guarantee there’d be enough to go around, so we try and extend out the gap between them to make sure that everyone could have their first shot. But to try and alleviate any potential sort of bottlenecks with just not having enough, researchers are maybe trying to get creative with what they do have.

Heidi Ledford

Yeah, so we’re seeing a few clinical trials getting started to look at the effects of starting with one vaccine for a prime dose, for example, and then switching to another one for the boost and then to see the effects of that, and that could have two benefits if we get some data showing that it works out. One would be to ease up on the logistics, right, because we’ve all see now how incredibly difficult this is to try to roll these things out, to realise, ‘Okay, I have to save a dose for that second dose to arrive. Even if its 12 weeks later, we need to know that it’s going to be there of that same kind for that person.’ But the other thing too is that mixed and matched vaccines is an approach that has been used before and has been shown in some cases to boost the immune effect of the vaccine itself, so it could be a benefit that way. It sounds good in theory but lots of things sound good in theory and you have to show them in practice.

Noah Baker

The trials that are going on, where are they, and presumably there are going to have to be quite a lot of them, right, because we could have one trial which could be a proof of principle about mixing vaccines, but you still don’t want to roll anything out unless you’ve specifically trialled the two vaccines you’re talking about in the order you’re talking about with the interval you’re talking about. That’s a lot of trials you might need to do to be able to just sort of say, ‘Okay, cool, we can just mix and match all of these vaccines all over the place now.’

Heidi Ledford

Yeah, I mean, I would say it’s not really being tested on that scale yet. So, the trial that we wrote about that recently got started, that one is a UK effort and it’s got sponsorship from the UK government, in part because they want to be able to ease the logistics and get things out more quickly, and it’s being run through Oxford. The other trial that I know of is also with the Oxford-AstraZeneca vaccine but it’s being run by AstraZeneca, and that’s combining that vaccine with one of the components of the Sputnik V vaccine that was developed in Russia. And the Sputnik V vaccine is itself kind of a mix and matched vaccine because it’s got two difference adenoviral vectors being used in each dose, so it’s got the same coronavirus protein as a target but its importing that target into human cells using different viruses, and so it, in a way, is also a kind of test of a mix and match.

Noah Baker

I’m really interested in, from an immunological perspective, what is the theory as to why having a mix and match vaccine approach could actually be a benefit because I think this is not an uncommonly held belief among immunologists. This isn’t like a wacky theory, right?

Heidi Ledford

Right, I mean we have approved vaccines. There’s one that was recently approved for Ebola, for example, which is this kind of system where you have two different vaccines given, one for the prime and one for the boost. The potential advantages sort of depend somewhat on which vaccines you’re talking about mixing. For example, the trial that Oxford is going to run, that trial is going to look at the vaccine that Oxford researchers developed along with AstraZeneca in combination with the vaccine developed by Pfizer, and the two vaccines work differently. They have the same target. They both are designed to raise immune responses against a coronavirus protein called spike, right, but they do them in slightly different ways and they get slightly different immune profiles as a result. So, the RNA vaccine for example from Pfizer gets you amazing antibody levels, really, really good. It also stimulates T cells which are another important part of the immune response to viruses. It does it well, but the data for the RNA vaccines is a little bit more mixed on the T cells side. And then conversely you’ve got the Oxford-AstraZeneca vaccine. That one does really, really well with T cells but maybe slightly less good with antibodies. So, the idea is that if you mix the two together, maybe you get the best of both worlds and you get an even better response. So, that’s a possibility.

Noah Baker

I think it’s easy to forget that the immune system isn’t just one thing. It’s not like you have a vaccine which makes your immune system work. Vaccines work in a whole bunch of different ways and they do different things in your immune system, so we’re still having to really learn about how this all works.

Heidi Ledford

Yeah, and what works for one vaccine may not work for another vaccine, so it may be that combinations worked well in Ebola but maybe we don’t know for sure how well they’ll work for these coronavirus vaccines, which is why it’s important to test it. But it’s a good theory to test, and one thing I kind of like about this whole effort, I guess, to mix and match and to test these combinations is that we got really lucky with this first generation of vaccines because they work so well. I mean, I really didn’t expect them to work this well. But it’s exciting to see how we’re going to improve them going forward, and I think especially with the variants coming out that are worrying all of us now every single day, like we want to get as strong of an immune response as we can. We know that now. So, it’s good that there’s still ways to tinker and play and get maybe something slightly better.

Benjamin Thompson

So, In terms of the Oxford trial that you wrote about in Nature then, is that what’s being looked at, the immune response and not a percentage of people getting sick or anything like that?

Heidi Ledford

Yeah, I mean, compared to these massive phase III trials that we saw for these key vaccines that are out there now which had tens of thousands of people, this is a much smaller trial and shorter. So, they’re testing a couple of different intervals between the prime and the boost as we were just talking about, but for the shorter interval I think it’s four weeks, and they’re hoping to get results from that I think by May-June, somewhere in there. And then if that’s useful, that could then potentially inform the rollout as we go into the summer. So, it’s something the UK’s very interested in hearing the results of. But it’s true, they won’t be looking at infections and protection against infection directly. They’ll be looking at the immune response that’s been stimulated and gathering data on safety and any kind of side effects and things like that that may come up.

Noah Baker

Yeah, one question that I think I had is, when you have a vaccine, it gives you a degree of protection against the disease, or the virus in this case, that that vaccine is protecting against. Is there a concern that if you were to give a different vaccine as your second booster that the first vaccine could interfere with the second vaccine? For example, you’ve already got some kind of immunity and then you get something else that looks like a spike protein but in a different way. Can vaccines interfere with each other in that way or is that what the trial is to work out?

Heidi Ledford

I guess a case where I have heard some concern that there may be a bit of a dampened immune response when you mix and match, it’s not so much mixing and matching different vaccines against spike, which is what most of these vaccines are against currently, it’s more about when you update the vaccines to account for the variants. So, then you’re going to be immunising with a different version of spike, and at that point it’s possible that the fact that you already had this initial immune response against the original version of spike may mean that you won’t mount such a good immune response against the new version. It’s a phenomenon in immunology called original antigenic sin. It’s kind of a fun name. But I’ve heard that possibility, but that’s a bit different from mixing and matching these first generation vaccines. But it is something to test.

Noah Baker

I think as well, we have to, kind of as you alluded to earlier on, keep in mind that we were so spoilt briefly by these initial responses with 90% efficacy and actually, if we think about the flu vaccine which people use every year, people would dream of a flu vaccine being 90% effective. I mean, it is unusual for a vaccine to have those kinds of numbers, and it could be less effective, but that doesn’t mean that even though its less that 90% it’s not pretty on board with most vaccines.

Heidi Ledford

It’s true. I mean, we really have to recalibrate. Most of these, when we talk about a decrease from, I don’t know, maybe from 95% to 70%, that’s still well above the efficacy that we had as our threshold for being a useful vaccine. So, I think if anything we’re just doubly lucky that they worked so well to begin with because now we’ve had these variants come out which we knew were probably going to show up eventually, but I think some people would say have shown up a bit earlier than we had hoped, so we’re just so lucky that we had such robust vaccines that we can take a bit of a hit in the efficacy and still have a significant benefit from them.

Benjamin Thompson

Well, finally, Heidi, vaccine delivery plans, as we know, have been thrashed out by governments and health departments across the world. If it does pan out that this mix and match approach proves to be effective, can you see this quickly changing how things are done or maybe not so much?

Heidi Ledford

I might be naïve but I could see that happening quickly because it’s almost like releasing a pressure valve or something. It’s not that it would require more sophisticated logistics to make it happen. It would require potentially slightly less sophisticated logistics to make it happen, and so I could see it actually taking place. But there are always bumps and wrinkles to these things that I can’t anticipate. It’s just amazing, every time I talk to a healthcare provider, especially in the United States where everything is much less centralised and coordinated than it is here in the UK, it just blows my mind, the logistics they’re dealing with.

Benjamin Thompson

Well, clearly, lots going on in this sphere, and definitely something that we’ll talk about when the results come out and, Heidi, I hope you’ll join us to talk about them when they do. But let’s leave it there for this week. Heidi and Noah, thank you so much.

Heidi Ledford

Thank you. I love the excuse to talk to you guys. Now that we don’t see each other in the office it’s so nice.

Noah Baker

Thanks, Heidi. Thanks, Ben.

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