COVID vaccines: success mixing and matching

New results from the Com-Cov trial mixing doses of COVID vaccines are promising
05 July 2021

Interview with 

Matthew Snape, University of Oxford


A needle and bottle of the COVID-19 vaccine.


An important and eagerly awaited study into Covid vaccines published its initial findings this week. The ComCoV trial, run by the University of Oxford, has been looking at the effectiveness of mixing and matching between different Covid jabs to see what works best; for instance, is a first dose with AstraZeneca’s vaccine followed by an RNA vaccine like the Pfizer jab, at least as good, or better, than two doses of AstraZeneca? To find out, Matthew Snape recruited just shy of 900 over 50s, who included people with pre-existing health conditions and members of ethnic minority groups, as he told Chris Smith...

Matthew - This study was commissioned back in December last year, before we even knew which vaccines we were going to be using, but it was already anticipated. What if we had two vaccines? And what if there was a problem with supply of one of them, could we then swap over and complete immunisation courses with the other vaccine? So it was all about looking to see how flexible we could make the immunisation rollout and make it more robust and able to cope with any unexpected events.

Chris - But when you did the study, what did you measure?

Matthew - We measured the antibodies and also the T-cells, so the white blood cells that are an important part of the immune system. And the participants didn't know which vaccines they'd received, so that was called a blinded study from their point of view. So that was really kind of a good way of getting accurate data on what reactions they were experiencing and any safety concerns they have

Chris - And critically, how long did you leave between the doses? Because that's the other issue, isn't it? We've seen this go from one month when we first started rolling out vaccines, to 12 weeks in order to maximise uptake quickly, and then to be shrunk back to 8 weeks for certain groups in the community again now, what did you look at?

Matthew - Yeah, that's right. We've been kind of affected by that as it's gone along. When we planned the study it was with a 4 week interval, and then as we're about to get going that guidance changed to make that up to an 8 to 12 week interval. So for about half of the participants, they're getting the vaccines in a 4 week interval and half are receiving it at a 12 week interval. So we get across the whole broad range there and get an idea to see if changing the interval makes any difference in the actual interactions between the vaccines

Chris - When you mix and match between vaccine products. What story emerges there?

Matthew - Yeah, really interesting story. So if you, for example, take the AstraZeneca vaccine, and then you get a second dose of the Pfizer vaccine, you actually get a higher antibody level with that mixed schedule than if you receive the standard schedule. So AstraZeneca followed by Pfizer, actually the antibodies were about 9 times higher than AstraZeneca AstraZeneca. And similarly, we saw an increase in the T-cell responses as well. However, if you looked at it in the reverse, if you received the Pfizer vaccine first and then actually had a dose of the AstraZeneca vaccine as your secondary, your antibody levels weren't as good then. Your antibody levels were only about half that as if you'd received two doses of the Pfizer Pfizer. It's a little bit more complicated than that though, because even though that vaccine schedule didn't do as well as the Pfizer Pfizer schedule, the antibody levels were still higher than the AstraZeneca AstraZeneca schedule, which we know works. So to summarise that, what we found is that probably any of the combinations we looked at would be expected to protect against COVID disease.

Chris - And why do you think you get a good and powerful response when you mix in this way?

Matthew - With the AstraZeneca vaccines there may be a limitation there, in that the second dose of the AstraZeneca vaccine doesn't seem to boost your immune system as much as coming in with an RNA vaccine. And that may be because of the nature of the vaccines. The AstraZeneca vaccine is called an adenoviral vector vaccine. What that means in English is that they take a benign virus called an adenovirus, and then they insert the genes for the coronavirus spike protein into that benign virus so that the benign virus acts a vector or a Trojan horse that actually allows the spike proteins to be generated in the body safely. But at the time of the second dose, what may be going on here is that more antibodies and more of the immune response has been directed against that benign virus, the adenovirus, then against the spike protein. We know that this is an issue with these viral vector vaccines. And in fact, especially with the T-cell response, you really didn't see much increase at all with the second dose. Now, that said, we know a two dose schedule of the AstraZeneca is very effective against coronavirus disease and against the Delta variant that we're seeing at the moment, but you need both doses. So even though what we're measuring and I'm saying, oh well the response to the second dose wasn't necessarily as fantastic, it is actually still good enough, and it does provide good protection against the Delta variant. However, yes, when we do an RNA vaccine as the second dose, you do see an even better antibody and T cell response than two doses of the AstraZeneca.

Chris - This week the JCVI, the joint committee on vaccination and immunisation, have published some initial suggestions that come the autumn in the UK, people over the age of 50 should receive boosting. So if people have already had two doses of Pfizer's vaccine, should they just have a third dose of Pfizer's vaccine? Whereas if they've had two doses of AstraZeneca's vaccine, would the Pfizer vaccine be best for them?

Matthew - Yes, I think if you've had two doses of the AstraZeneca vaccine, I think you would get a better immune response to your third dose if it was a Pfizer vaccine. If you've had two doses of the Pfizer vaccine, I think actually probably you're still best off getting a booster dose of the Pfizer vaccine again, because overall, if you had Pfizer then AZ, then actually your antibodies weren't as good. What will be an important qualifier for that is to just look at the temporary side effects to make sure that that doesn't become an issue. The second dose of the Pfizer vaccine generates higher side effects in terms of fever, feeling chills, those kinds of things than the first dose. I think it's going to be really important to look at what a third dose of the Pfizer vaccine looks like.

Chris - Obviously we don't know yet, because we have no time machine to race forward in time and see how people's immune response changes with time, but what's your instinct telling you about the likely long-term protection that we're all going to derive from these vaccines?

Matthew - It's important to consider carefully what that question means. Are we talking about protection against infection, or are we protecting against severe disease and hospitalisation? And we know that even people who have had two doses actually can get coronavirus disease, and yet that is expected to become more common as increasing time goes on - 6 months, 1 year, whatever. The main objective is to protect against severe disease, hospitalisation, and death. And I think that's going to be much better preserved, even if somebody does have a breakthrough infection.


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