Digesting the Ox/AZ vaccine developments

We digest the recent news about the Oxford University/Astra Zeneca Covid-19 vaccine candidate...
01 December 2020

Interview with 

Gillies O'Bryan Tear, Faculty of Pharmaceutical Medicine




Let’s turn our attention to some very relevant fast-moving science. Around the world, scientists are tirelessly working towards various Covid vaccines. We’ve heard about various candidates recently, including the Moderna vaccine, the Pfizer/BioNTech vaccine, and now news is out about the Oxford University/Astra Zeneca vaccine, whose “Phase 3 interim analysis including 131 Covid-19 cases indicates that the vaccine is 70.4% effective when combining data from two dosing regimens”. Gillies O’Bryan Tear from the Faculty of Pharmaceutical Medicine joins us to digest the recent announcements and what this actually means...

Gillies - The vaccine works by introducing DNA, which sends a message into the cells to make the spike protein from the coronavirus. Now in order to get into the cells, Oxford Virus sends the vaccine in using a vector, a carrying... if you like, a Trojan horse, which is in fact an inactivated virus which cannot replicate in the human body. It's sort of a weakened version of a common cold virus called adenovirus. Once the virus carries the DNA into the host cell, the human cells, the cells - our own body cells - start making, on the instruction of that DNA, the spike protein of the coronavirus. And the body then mounts an immune response to that spike protein, and the reason that disables the virus or prevents the virus from infecting the person who received the vaccine, is because the spike protein is what the virus uses to get into our bodies.

Katie - Who have they tested this vaccine on? Does it protect people who are actually most at risk?

Gillies - So far they've announced results of three phases of trials: the phase I trial; the phase II trial, which was published last week in the Lancet, a peer reviewed journal, in great detail - 560 participants in that trial, half of whom received the vaccine; and more recently they announced the interim results from the larger phase III trial, which has enrolled 24,000 people, half of whom received the vaccine and half of whom received a control vaccine, for meningitis as it happens. So in total they've enrolled tens of thousands of people, and they plan to enroll up to 60,000 people all over the world. And you ask whether they've enrolled people who are at high risk: the phase II results, in that study they enrolled people who were older, over 70, as well as younger people; and in a phase III trial they also enrolled people who are older. And because they've done the study all over the world, they've also enrolled a lot of people from different racial and ethnic backgrounds. As we know, the black and minority ethnic population are at higher risk from coronavirus, and elderly people are more at risk; that's well known. So they've made sure they've included in the trial those groups of patients, and encouragingly, from the phase II results we saw that the immune responses which the recipients of the vaccine mounted against the coronavirus were just as strong in the elderly people who were in the trial, over seventies, as in the younger ones. And that's significant because it's well known that older people have a weaker immune system than younger people.

Katie - Is this about preventing infection, or mitigating the consequences of getting COVID?

Gillies - The interim phase III results have shown both. It's been shown that it prevents COVID symptomatic illness in up to 90% of patients, depending on the doses used; but also it prevents severe illness, because no cases of severe illness were seen in the patients who received the COVID vaccine.

Katie - How safe is it?

Gillies - The phase II results have got very detailed safety data, and show the vaccine produces the normal side effects that most immunisations or vaccinations cause: a sore arm, sometimes a fever for a day or two, and a headache, which can all be treated with paracetamol. So it seems to be safe. There've be no serious adverse events reported on this trial.

Katie - So how well does this work? What's going on with these different response rates and different dosing regimens?

Gillies - Well, they enrolled patients at two different doses: a half dose followed by a full dose, and then another group received two full doses. Slightly counter-intuitively, they saw 90% efficacy in the first group who received a half dose followed by full dose, and a lower efficacy of 62% in the patients who received two full doses. Now vaccines are not like regular medicines, where the higher the dose, generally the higher the effect. And there may be one or two scientific reasons why this happened, but they are looking into that currently. But the important point is that even at the high dose-high dose regimen, they achieved very, very good efficacy; because if you remember, flu vaccination only vaccinates against 50% of cases. So it cleared the hurdle for an effective vaccine, and at the lower dose regime it was 90%; as effective as any other vaccines that have so far announced results.

Katie - What are the theories on why this half dose followed by a full dose seems to be better than full dose followed by full dose?

Gillies - One theory is that the body can mount an immune response to the vector. And if that's the case then it can reduce the efficacy of the vaccine, because its carrier is attacked by the body. Now it's possible that the low dose regime provoked a less brisk immune response to the vector than the high dose-high dose regimen. And that's one possible explanation, but they're still looking into this. There could be other explanations. AstraZeneca have said that the study was not initially designed to look at the lower dose, and that there was possibly some mishap that gave the patients a lower dose and they intended to; but first of all, a very large subgroup of patients did receive this lower dose, so it's a robust sample; and secondly, it probably doesn't matter in terms of the approval and the efficacy of this agent, because they've shown that it works very effectively and the regulators may choose to approve that lower dose because it has been shown to be more effective. We really await more results from the full publication and from AstraZeneca about what happened, exactly what happened.

Katie - Is it a fair question to ask you how this stacks up compared to other COVID vaccines in the making, or is it a bit too soon to be talking about that?

Gillies - It is too soon in the sense that all of these, the three announcements we've had, from three different programs, are all based on interim data, which is not the full data set, so that the numbers may change. However, I'd like to talk about the difference between efficacy on a clinical trial, in a very controlled setting, and effectiveness in stopping the pandemic, they're two different things, the Oxford AstraZeneca vaccine costs $3. It's very easy to transport and it's got very good efficacy. Even the blended efficacy rate is 70%. That is an extremely good efficacy rate. So even if it's got a slightly lower efficacy rate in clinical trials, doesn't mean that it's going to be less effective in containing the pandemic, because it's easier to get around the world. We need to stop this pandemic in all parts of the world, not just the Western world. So the fact that it's cheaper and easier to transport might mean that in the real world, it's the more effective vaccine. If you can understand that slight paradox.

Katie - What questions remain then? Because so far we haven't had a vaccine that's actually been approved by the regulators.

Gillies - Well, we anticipate regulatory approval before Christmas for at least two of these. I would imagine, at least an emergency use authorisation in the US for one or more of the messenger RNA vaccines. And the UK authorities are going to rapidly review the UK Oxford vaccine. And they'll be also reviewing the messenger RNA vaccines from Pfizer and Moderna. I think it's a very low probability they will not get approved. They will go through the proper review process though, looking at all the data. And secondly, of course, as I mentioned earlier, we've got unanswered questions about efficacy and safety. We need to see the full dataset. For example, how effective is the Oxford vaccine in the elderly? We know from the phase two results that the elderly have brisk immune responses, but does that translate into effectiveness, efficacy, in the big phase three trial? So there are a few unanswered questions still while we wait for the full results.

Do you know, nine months ago, we didn't even know if we could vaccinate against coronaviruses. Because we tried with MERS and SARS-1 and failed. And here we are nine months later, not only do we know we can vaccinate effectively, but in nine months we've got phase three trials of multi-tens of thousands of patients enrolled and we're nearing regulatory approval. It's an unprecedented achievement.


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