Titans of Science: Andrew Pollard
Today's Titan is former chair of the UK's Joint Committee on Vaccination and Immunisation, and a key figure in the Oxford-AstraZeneca vaccine which rolled out during the Covid pandemic. Andrew Pollard tells Chris Smith how vaccines work, how public health bodies decide what to protect us against, and how current technology will shape the future of immunisation...
In this episode
00:52 - Andrew Pollard: How do vaccines work?
Andrew Pollard: How do vaccines work?
Andrew Pollard has played a pivotal role in the development of numerous vaccines across his career, including those for typhoid, meningitis, influenza and Ebola. Here he gives us a rundown of how they work...
Chris – That’s quite a CV. Why did you end up going down the infectious diseases route and the vaccine route in the first place?
Andrew – Well, I actually got into the vaccine route later. I started off really interested in the immune system, and particularly the immune system of children. If you go back 250, 300 years, half of all children died during childhood before the age of 15. One in two children died. Most of those died from infectious diseases. So there’s no world in which having lots of bad things happen to you and surviving them is the right thing to do.
You really need to have an environment around children that protects them from these life-threatening illnesses. We’ve achieved that through public health since really the mid-1800s, when acts around clean water and air pollution started to appear, which then started a trend of plummeting under-five mortality in this country. That really was completed by the advent of vaccines, on a large scale, in the 20th century.
Chris – Do we have any insights, then, into roughly what the scale of morbidity and mortality is that are being prevented by vaccines? How game-changing have they really been worldwide?
Andrew – Well, if we think about the annual lives saved in childhood from the global vaccine programmes, which are not as comprehensive as ours here, we're talking about somewhere between three and five million lives saved every single year. So yes, a huge impact. And if you look at it in the context of individual diseases, we have smallpox, which was a terrible pandemic that went on for centuries and wiped out millions and millions of people.
And that is a virus that's been completely eradicated from the planet. If we think about measles – which, when I started in paediatrics, was killing a million children every year – the global rollout of vaccines over that 35-year period, which is still not reaching everyone, has reduced measles mortality globally by about 90%. The impact is just mind-blowing.
When I started out in paediatrics in the early 1990s, there were diseases I saw regularly then that my trainees here in Oxford today just do not see at all. I find that incredibly invigorating and exciting – to have been involved in vaccination over that period of time, which has essentially erased the experience of junior doctors encountering those diseases.
Chris – How do vaccines actually work, though? What’s the simple kind of mechanism by which what Edward Jenner did a few hundred years ago translates into protection from an infectious disease?
Andrew – Well, essentially, whether you're Edward Jenner or using the latest generation of RNA vaccines developed during the pandemic, they’re all doing the same thing – training our immune system to recognise things which are foreign on the surface of bacteria and viruses, but doing so in a safe way. So you give either part of a virus or you train the cells in our body to make parts of a virus or a bacterium, so that our immune system can be educated. Then, when we actually meet the real bug in the wild, the immune system already knows what to do and gets rid of it, rather than meeting it for the first time, allowing the infection to take hold in our bodies, cause disease, and kill children before the immune system has had time to be educated.
Chris – They fall into different categories, though, vaccines, don’t they? In some cases, we actually give live vaccines. In other cases, we give killed vaccines. In other cases, we give bits of the infectious entity that’s been busted apart, chemically brutalised. In other cases, we give toxins that they make. So what determines what we use and how it works?
Andrew – Some of it is because we knew the mechanisms of the disease were related to particular components. You mentioned the toxins. One great example is tetanus toxoid, which is one of the vaccines we give routinely in five doses throughout childhood.
Tetanus is a bug found in soil that releases a toxin after it gets into wounds in the skin, which can cause paralysis. It’s just by making an immune response against the toxin that we’re able to stop the disease. We’re not fighting the bug.
For other viruses, we know that you can just take one part of the surface of the virus and use that. So the shingles vaccine, which we now use in the UK in the elderly, just has a protein that sits on the surface of the shingles virus, which is the same as the chickenpox virus. And that boosts our immune response so that we’re able to keep shingles at bay.
For other vaccines, people have taken traditional approaches, such as asking, “What if we weaken a virus like measles? Could that then, without causing any significant disease, protect people from measles?” And by trial and error, many vaccines were tested many decades ago to show that this worked.
So in many ways, we choose the type of vaccine partly based on history and partly because of scientific knowledge about which is the right bit of the organism – the bacterium or the virus – to target.
08:00 - Andrew Pollard: Deciding what to vaccinate against
Andrew Pollard: Deciding what to vaccinate against
As former chair of UK's Joint Committee on Vaccination and Immunisation, the JCVI, Andrew Pollard knows all about the difficult trade-offs facing decision makers for immunisation programmes. Science, safety, and cost-effectiveness are the key criteria...
Chris – We saw this manifest during the pandemic – that with certain vaccinations, it’s a one-stop shop. You either get the disease or, ideally, you get vaccinated, and with one or two doses, you never get that thing for the rest of your life. On the other hand, we were updating Covid vaccines almost monthly, it felt, during the pandemic. So why is there that distinction? Some things, it’s a one-off – others, not?
Andrew – If we take something like coronavirus or influenza, we need to have regular vaccines if we want to completely prevent infection with them, because the viruses are changing all the time and we can never quite keep up with them. If, through mutation, the virus changes, the vaccines we had last year are no longer as effective. That doesn’t mean they’re not effective at all, but they’re less effective, because the virus, as it replicates, makes mistakes in creating new copies of itself.
Some of those new copies completely evade the immune responses we’ve already made. So that means you can get reinfected with coronavirus repeatedly, even if you’ve been vaccinated. The important thing, with Covid-19, is that the vaccines – even those from 2021 – still prevent death, but they’re no longer very good at preventing infection. Those infections can still be quite miserable. But now, if you encounter coronavirus, you don’t get the overwhelming disease that we saw filling intensive care units, because the vaccines still offer good protection against that severe endpoint.
With other viruses, they don’t change much at all, and survive by infecting unvaccinated people. Measles is a good example of that. The measles vaccine still works brilliantly today, just as it did when first used in 1960, because the measles virus has hardly changed in all that time. But if you allow a pool of unvaccinated people in a community – as happens in countries with poor vaccine coverage – then the virus can still spread and cause explosive outbreaks.
But once you’ve been vaccinated, you’re protected for life because the virus doesn’t really change.
Chris – Presumably, if you have enough people in a population who are vaccinated, that’s where this concept of herd immunity comes in – because there are so few people left who can catch the infection that the chances of an infected person running into a non-immune person are so slight, you just can’t get a chain of transmission.
Andrew – That’s correct. You don’t get a chain of transmission. But for that unimmunised individual, if they did encounter someone with measles, they could easily get infected – and it’s so infectious, it’s highly likely they would. The reason for maintaining very high levels of immunity in the population is to stop those chains of transmission, both because measles can be fatal for children and adults, and because there are people in our community who cannot be vaccinated – for example, those with compromised immune systems or undergoing cancer treatment. Those people really need everyone around them to build that shield of immunity and keep the virus out.
Chris – How do you decide what we’re going to vaccinate against? There must be umpteen things we could theoretically protect everyone from, but we choose a certain suite of diseases for routine paediatric vaccination, and let people catch others. How is that decision made?
Andrew – The starting point, historically, for deciding what vaccines to develop has been to focus on the most severe diseases – those that cause death. And most of the childhood diseases that are relevant in the UK and occur at any scale, we now have vaccines for. It doesn’t mean we can prevent every infectious death, but we’ve made incredible progress, especially in the last 60 years – and really since the early 20th century, when the first vaccines were used more widely.
That was the initial focus. But today, now that we've addressed the major killers like diphtheria and measles, the emphasis has shifted towards ensuring that any new intervention we add to the NHS is good value for taxpayers.
That’s determined by a cost-effectiveness metric set by the government’s Treasury. What that means is that we assess new vaccines on the same basis as any other NHS treatment – so we don’t end up funding vaccines for minor illnesses at the expense of, say, a new cancer drug that could offer much more benefit.
If we just take the health service perspective, you can do very detailed calculations across all the medicines and vaccines potentially available to the NHS, and prioritise only those that meet the threshold for being good value.
Chris – And is that the role of the JCVI in the UK, the Joint Committee on Vaccination and Immunisation, which you chair? Is it the committee's job to weigh those things up and make recommendations?
Andrew – It is, absolutely. The starting point is whether there’s a burden of disease. We have excellent data in the UK from the NHS, collated by the UK Health Security Agency, on a wide range of diseases affecting the population.
Next, is there a vaccine? Academic and commercial developers work on products that they hope to offer to the market. We then look at the data and assess whether the vaccine works, whether it’s safe, what impact it could have in the population, and – crucially – whether it meets the Treasury’s rules on cost-effectiveness.
15:04 - Andrew Pollard: The Oxford-AstraZeneca vaccine
Andrew Pollard: The Oxford-AstraZeneca vaccine
Andrew Pollard provides fascinating insight into the Oxford-AstraZeneca vaccine during the Covid pandemic given his central role in its clinical development, explaining how experience with past coronaviruses left his team well placed...
Chris – All this must have been like a massive dose of steroids once Covid came, because the committee must have been used to making decisions at a much slower pace. It’s not often that new vaccines come along and have to be evaluated, and so all of a sudden you were confronted with making decisions about a whole new disease, whole new groups of the population who might need to be protected, with a whole new slew of different vaccines all coming along all at once.
Andrew – Well, the first thing to say is that the committee does review new vaccines every year – it's the bread and butter. We're often re-evaluating the current schedule and perhaps reducing the number of doses because new evidence emerges that protection is sufficient. Sometimes we find that you need extra doses, and the wonderful surveillance system we have in the UK allows us to do that. When it came to the pandemic, I was working on the Oxford-AstraZeneca vaccine and the clinical development of it, so I actually stepped back from chairing the Covid committee for the JCVI during the pandemic. My colleague Wei-Shen Lim took over that role in order to make those decisions, and they really did work very hard, with meetings often several times a week, to review that huge deluge of data and new information being provided.
Chris – But we got the impression – I mean I'm talking in terms of the general public seeing this – we got the impression that the government were asking committees like the JCVI to make really important decisions about things like, well, do we give Covid jabs to kids? And almost justifying what the political position was going to be based on what the JCVI was saying. But you were operating with very, very limited data.
Andrew – Well, as I said, I wasn't involved myself directly in that decision-making, but I think one really important thing in policy decisions during such a situation is that you have to make decisions. The data are almost always incomplete, but if you do nothing, it results in people dying. So the decision-making has to be based on the best evidence available at the time. And always with programmes like this in an emergency, you're constantly reviewing and revising your decision-making depending on new information as it comes.
Chris – Did we learn a huge amount about how to conduct trials at scale, do it very quickly and make decisions very quickly, or did we go too fast, do you think? Because it really surprised everyone when all this started and we were told, well, normally it takes years to get a new drug even out of a test tube and into a person's arm, and then to do all the trials and get the approvals and so on. A decade's work was effectively condensed into – you know – ten years became ten months, almost, didn’t it? So what have been the learning points from the pandemic that have now improved and streamlined how we do this sort of thing?
Andrew – I would look at it slightly differently. I would say that we already knew a lot about coronaviruses, and because there had been small outbreaks over the 20 years prior to the COVID-19 pandemic, we already knew how to make the vaccine. There was an outbreak of the original SARS virus – severe acute respiratory syndrome virus – in 2001, and then the Middle East respiratory syndrome virus in around 2012, and those were pretty awful infections.
The first one killed about 10% of those infected, and the second epidemic about 30%. So that really focused efforts on understanding how to make a vaccine for coronaviruses. So when 2020 came, we didn’t need decades of research – we already knew exactly what to do to make a vaccine. All we had to do was that last sprint to the finishing line over that nine to eleven-month period in order to have a vaccine ready for licensure. The only bit we were doing was the clinical development – to show that in a large number of people, in our case about 25,000, the vaccine was safe and efficacious.
The reason why that bit could be done quickly was simply that you didn’t have to wait for someone to pay for each of the next steps. Normally, that process takes years just because you complete one stage, and then spend a year or two trying to find funding for the next bit. But during the pandemic, we had the money – or at least, we had to beg for it, but we got it – to run the trials and get the data to submit to regulators.
Chris – The vaccine that you helped to develop – the Oxford vaccine that then became more widely known as the Oxford-AstraZeneca vaccine – that actually is the sort of backbone technology that has been redeployed in various directions, hasn’t it? Because you've used it in a range of different disease contexts. Ebola benefited from that backbone, didn’t it, as well?
Am I right in saying that?
Andrew – Yes. The viral vector – this is adenoviruses. One of the Ebola vaccines uses a different adenovirus, an adenovirus type 26, which is the product produced by Janssen or Johnson & Johnson, who are now the parent company. We used a slightly different adenovirus from chimpanzees, called ChAdOx, for our vaccine backbone.
Chris – But basically, to make a long story short, it’s a virus that acts as a Trojan horse. It takes into the body a bit of the coronavirus that you want to persuade the immune system to recognise.
Andrew – Well, it actually takes the gene from a bit of the coronavirus, and then our cells make that bit of the coronavirus. So we’re using our own cells as a factory to generate the vaccine, which we then develop an immune response against.
Chris – How did AstraZeneca get involved? Because you had that technology, you were already working on it. So how did it end up being the AstraZeneca-Oxford tie-up?
Andrew – Well, what we know how to do in Oxford is design vaccines and conduct clinical development. But we're not a global pharmaceutical company – we're a university. What we really needed was a partner with expertise in manufacturing and distribution on a massive scale. AstraZeneca brought incredible expertise in that global space. They took on over 20 manufacturing sites to protect manufacturing across different world regions from nationalism. And they distributed those doses to the countries and geographies where the vaccine was needed.
Chris – It was done at cost though, wasn’t it? That was another attraction. Or was that the insistence of your team in Oxford – that they do this at a scale that wouldn't end up breaking the bank for countries that otherwise might not be able to afford vaccines?
Andrew – AstraZeneca was chosen as the partner because they were prepared to distribute the vaccine not for profit. For the university, this was very important – in a pandemic, there should be no perverse incentive to sell only to rich countries. Because there’s no profit involved, it doesn’t really matter whether you're going to low-income settings, middle-income countries or high-income countries. The point is to get it to those most at risk – which, of course, are the elderly in any population.
Chris – What about the risk to the company though? Because this is AstraZeneca in 2020. Were they, in their view, taking a big risk in taking on the technology in an untried, untested way, apart from the initial trials that had been done?
Were they worried about their reputation? Were there conversations around what could happen, and what safeguards were needed to protect the reputations of you at Oxford, AstraZeneca, and the public?
Andrew – I think the discussions about taking this on were, firstly, grounded in a strong view from AstraZeneca's leadership that there was a moral obligation. They had capabilities we didn’t have, and this was an opportunity to use those skills for the public good during a pandemic. There’s also a commercial argument: if you're able to contribute to ending a pandemic earlier, that benefits the entire business environment.
So, there’s good logic in using the resources and expertise of the company to help get the world back on its feet faster – which in turn allows them to return to their core business sooner.
24:33 - Andrew Pollard: Vaccine rollout, and mRNA promise
Andrew Pollard: Vaccine rollout, and mRNA promise
Andrew Pollard rounds of his extended interview with us by reflecting on his achievements during the pandemic, and looks to the future with mRNA vaccines...
Chris – What was it like, though, to watch something that you'd developed going out in millions of doses around the world? Effectively, it changed the course of the pandemic. You saved millions of lives, didn't you? What did that feel like? Was it both scary and exhilarating at the same time?
Andrew – That’s a really interesting question. Eventually, over 3 billion doses were produced, and some analyses suggest that over 6 million lives were saved in 2021 alone from the Oxford vaccine. It’s very difficult to connect with what that actually means. One of the problems with vaccination is that people who don’t get a disease and don’t die often don’t realise they've benefited.
To some extent, the work we did during the pandemic – in the lab and in clinical trials – didn’t feel so different from usual. What was different, without any doubt, was the public scrutiny. It’s hard to connect the daily work we did, guided by our usual ethos, to the actual impact it had.
I didn’t personally feel a sense of some amazing achievement. But there were moments – like giving interviews and having people come up and say, “Thank you, you saved my life.” That was very moving. But I certainly didn’t sit around every evening thinking how clever I was – that’s not the approach we take. It’s much more a technical and logistical challenge day-to-day.
Chris – There were some people who suffered severe side effects though, weren’t there? People who developed brain blood clots. Did we get to the bottom of why that happened and why it happened to the people it did?
Andrew – That’s right. It was, fortunately, a very rare event with the first dose of this type of vaccine. And it wasn’t just the Oxford vaccine – another adenovirus vaccine developed by Johnson & Johnson had exactly the same side effect. It’s a rare disorder where individuals can develop clots in certain parts of the body, but unusually this is associated with very low levels of platelets – the blood components involved in clotting.
So it’s almost the opposite of clotting, and that combination sadly led, in some cases, to deaths. The condition appears to vary by region – more common in Scandinavia, less so in the UK, and rare in Southern Europe. We don’t know why that is. There's a general view that there is some unknown reason for these population differences. There are lots of theories, but none are proven.
And they’re hard to test – ideally you’d want an animal model where animals reliably develop the same condition, so you could trial vaccine changes. But we don’t have that. So the cause of this rare condition remains uncertain.
Chris – You must’ve been very excited though when we ushered in the mRNA vaccines, because of the enormous impact they had – not just on the pandemic, but on their potential for other areas of medicine.
Andrew – I think there are two very exciting things about RNA vaccines. The first is just how quickly you can make them at scale. If there were another coronavirus pandemic today, and the supply chains were ready, you could manufacture millions of doses of a new vaccine within six weeks.
By contrast, traditional approaches can take months or years to scale up to that level. RNA vaccine manufacturing is now mature enough that millions of doses can be produced rapidly – a sea change in pandemic response potential.
The second is how easy it is to iterate. You can quickly make many different RNA vaccines in the lab, test them, and find out which works best before moving into human trials – or even give multiple versions to see which is most effective. In one of my areas of work – plague vaccines – we’ve made large numbers of RNA-based candidates over the past couple of years. That would be nearly impossible with other vaccine platforms.
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